Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:14]([CH2:16][NH2:17])[OH:15]>C(O)C>[OH:15][CH2:14][CH2:16][NH:17][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NCCO
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Solvent: CCO
Product: O=C(O)c1cccc([N+](=O)[O-])c1NCCO
Temperature: 100 °C

Procedure:
2-Chloro-3-nitrobenzoic acid (5.0 g, 24.8 mmol) was suspended in ethanol (90 mL) and ethanolamine (4.5 mL, 74.8 mmol) was added. The resulting clear solution was heated at 100° C. for two days. The volatiles were removed under reduced pressure. The residue was treated with water (40 mL) and the mixture was acidified with 1M hydrochloric acid to pH 2. A yellow precipitate formed was collected by filtration and washed with water to yield 2-(2-hydroxyethylamino)-3-nitrobenzoic acid, 5.14 g (92%). MS (ESI) m/z 225 [M−H]. 1H NMR (400 MHz, CD3OD) δ ppm 3.04 (t, J=5.31 Hz, 2H), 3.69 (t, J=5.31 Hz, 2H), 6.71 (t, J=7.96 Hz, 1H), 7.93 (dd, J=8.21, 1.64 Hz, 1H), 8.13 (dd, J=7.71, 1.64 Hz, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:15].[ClH:16].Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[C:30]3=[N:31][CH:32]=[CH:33][CH:34]=[C:29]3[N:28]=[C:27]2[NH:35][CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C=O>[ClH:1].[ClH:16].[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[C:30]3=[N:31][CH:32]=[CH:33][CH:34]=[C:29]3[N:28]=[C:27]2[NH:35][CH:36]2[CH2:37][CH2:38][N:39]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[CH:11]=[CH:12][CH:13]=[CH:14][C:7]4=[N:6][C:5]=3[CH3:15])[CH2:40][CH2:41]2)=[CH:21][CH:20]=1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3cccnc32)cc1
Reactant: Cc1nc2ccccn2c(=O)c1CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1nc2ccccn2c(=O)c1CCN1CCC(Nc2nc3cccnc3n2Cc2ccc(F)cc2)CC1
Temperature: 70 °C
Yield: 60 %

Procedure:
A mixture of 3.34 parts of 3-(2-chloroethyl)-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one, 6 parts of 3-(4-fluorophenylmethyl)-N-(4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amine dihydrochloride, 4.8 parts of sodium carbonate, 0.1 parts of potassium iodide and 135 parts of N,N-dimethylformamide was stirred and heated overnight at 70° C. The reaction mixture was poured onto water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 4 parts (60%) of 3-[2-[4-[[3-[(4-fluorophenyl)methyl]-3H-imidazo[4,5-b]-pyridin-2-yl]amino]-1-piperidinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one dihydrochloride; mp. 195.7° C. (compound 22).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:20](=[O:21])[N:19]([CH3:22])[C:10]3[N:11]=[C:12](S(C)(=O)=O)[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.CO>CN1CCCC1=O>[F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:20](=[O:21])[N:19]([CH3:22])[C:10]3[N:11]=[C:12]([NH:30][C:29]4[CH:31]=[CH:32][C:26]([F:25])=[CH:27][CH:28]=4)[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cn1c(=O)c(Oc2ccc(F)cc2)cc2cnc(S(C)(=O)=O)nc21
Solvent: CO
Solvent: CN1CCCC1=O
Product: Cn1c(=O)c(Oc2ccc(F)cc2)cc2cnc(Nc3ccc(F)cc3)nc21
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A mixture of 6-(4-fluorophenoxy)-8-methyl-2-(methylsulfonyl) pyrido[2,3-d]pyrimidin-7(8H)-one (see Example 8 replacing methyl 2-fluorophenoxyacetate with methyl 4-fluorophenoxyacetate—Step A–B, 0.35 g, 1 mmol) and 4-fluoroaniline (0.284 mL, 3 mmol) in 0.5 mL 1-methyl-2-pyrrolidinone was stirred at 110° C. for 12 hours and then cooled to room temperature. Methanol (2 mL) was added and the suspension was stirred for 30 minutes. Filtration and washing of the precipitate thoroughly with methanol followed by drying provided the crude product which was purified by column chromatography (SiO2, CH2Cl2/MeOH—95/5). The column fractions were combined and concentrated under reduced pressure to provide the free amine. This was suspended in ethyl acetate (1–2 mL) and hydrochloric acid in ether (1M, 1.2 eq) was added. Isolation of the solid via filtration and drying provided 0.101 g of the hydrochloride salt (Mass spec. M+1=381, MP=242.3–242.6° C.).
Reaction SMILES: C[C:2]([Si:5](Cl)([CH3:7])[CH3:6])(C)C.C1CCN2C(=NCCC2)CC1.[OH:20][CH:21]([C:27]1[S:28][CH:29]=[CH:30][N:31]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1COCC1>[CH3:2][Si:5]([CH3:7])([CH3:6])[O:20][CH:21]([C:27]1[S:28][CH:29]=[CH:30][N:31]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCC(O)c1nccs1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCCCC(O[Si](C)(C)C)c1nccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.3 %

Procedure:
TBDMSCl (1.37 g, 9.07 mmol) and DBU (1.4 mL, 9.07 mmol) were added to a solution of 2-(1-hydroxyhexyl)thiazole (0.7 g, 3.8 mmol) in dry THF (8 mL). The mixture was stirred at rt for 3 h, then quenched with water and the layers separated. The aqueous portion was extracted with EtOAc, the combined extracts dried (MgSO4) and concentrated. The material was purified by flash chromatography to give 1.03 g (91%) of 2-(1-trimethylsiloxyhexyl)thiazole as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([O:10][C:11]2[CH:20]=[CH:19][C:14]3[N:15]=[C:16]([NH2:18])[S:17][C:13]=3[CH:12]=2)[CH3:9])[CH:5]=[C:4]([Cl:21])[N:3]=1.NC1SC2C=C(O)C=CC=2N=1.BrCC1C=C(Cl)N=C(Cl)C=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([O:10][C:11]2[C:12]3[N:15]=[C:16]([NH2:18])[S:17][C:13]=3[CH:14]=[CH:19][CH:20]=2)[CH3:9])[CH:5]=[C:4]([Cl:21])[N:3]=1
Reactant: CC(Oc1ccc2nc(N)sc2c1)c1cc(Cl)nc(Cl)c1
Agent: Clc1cc(CBr)cc(Cl)n1
Agent: Nc1nc2ccc(O)cc2s1
Product: CC(Oc1cccc2sc(N)nc12)c1cc(Cl)nc(Cl)c1

Procedure:
6-[1-(2,6-Dichloropyridin-4-yl)ethoxy]-1,3-benzothiazol-2-amine can be prepared as in Example 8 but from 0.50 g of 2-amino-1,3-benzothiazol-6-ol and 0.723 g of 4-(bromomethyl)-2,6-dichloropyridine. After purification of the residue by silica-column flash chromatography [eluent: dichloromethane/methanol (95/5 by volume)], we obtain 306 mg of -[1-(2,6-dichloropyridin-4-yl)ethoxy]-1,3-benzothiazol-2-amine in the form of a beige solid, which has the following characteristics:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]([NH:5][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:8][CH:7]=1)=[O:4].[S:24]1[CH:28]=[C:27]([CH:29]=O)[N:26]=[CH:25]1.CN(C)C=O.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:18]1([CH2:17][C@H:2]([NH:1][CH2:29][C:27]2[N:26]=[CH:25][S:24][CH:28]=2)[C:3]([NH:5][C:6]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[N:8][CH:7]=2)=[O:4])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1cscn1
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1cnc(-c2ccncc2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1cnc(-c2ccncc2)s1)[C@H](Cc1ccccc1)NCc1cscn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.3 %

Procedure:
To a mixture of (S)-2-amino-3-phenyl-N-(2-(pyridin-4-yl)thiazol-5-yl)propanamide (0.075 g, 0.23 mmol), thiazole-4-carbaldehyde (0.026 g, 0.23 mmol) and N,N-dimethylformamide (0.500 ml, 0.23 mmol) in 1,2-dichloroethane (1.000 ml, 0.23 mmol) was added sodium triacetoxyborohydride (0.17 g, 0.81 mmol). The resulting mixture was allowed to stir at room temperature for 4 hours. Upon completion, the mixture was directly subjected to HPLC purification give 10 mg of (S)-3-phenyl-N-(2-(pyridin-4-yl)thiazol-5-yl)-2-(thiazol-4-ylmethylamino)-propanamide 5.3. 400 MHz 1H NMR (CD3OD) δ: 9.30 (d, 1H), 8.81 (d, 2H), 8.07 (d, 2H), 7.95 (d, 1H), 7.76 (s, 1H), 7.28-7.37 (m, 3H), 7.24 (dd, J=8.0, 4.0 Hz, 2H), 4.49 (d, J=16 Hz, 1H), 4.44 (d, J=16 Hz, 1H), 4.43 (dd, J=12, 8.0 Hz, 1H), 3.49 (dd, J=12, 4.0 Hz, 1H), 3.23 (dd, J=12, 8.0 Hz, 1H). LCMS (ES+) m/z 422.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([C:15](O)=[O:16])[NH:13][C:12](=[O:18])[C:11]3[S:19][C:20]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:21][C:10]2=3)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.C[N:30](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[OH-].[NH4+].O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([C:15]([NH2:30])=[O:16])[NH:13][C:12](=[O:18])[C:11]3[S:19][C:20]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:21][C:10]2=3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1N[C@@H](C(=O)O)[C@H](c2ccc(Cl)c(Cl)c2)c2cc(N3CCOCC3)sc21
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: NC(=O)[C@@H]1NC(=O)c2sc(N3CCOCC3)cc2[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of rel-(4R,5R)-4-(3,4-dichlorophenyl)-2-(morpholin-4-yl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-carboxylic acid (0.100 g, 0.234 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.090 g, 0.47 mmol), 1-hydroxybenzotriazole hydrate (0.072 g, 0.47 mmol) in methylene chloride (4 mL) was added a solution of 33% ammonium hydroxide in water (0.40 mL, 4.7 mmol). The mixture was stirred at rt overnight. The mixture was concentrated and the residue was purified by silica gel chromatography. Final purification by HPLC afforded the product as a white solid. LCMS: (AA), ES+: 426, 428, 1H NMR (400 MHz, DMSO) δ 7.58 (d, J=8.3 Hz, 1H), 7.53-7.47 (m, 2H), 7.37 (d, J=4.2 Hz, 1H), 7.20 (s, 1H), 7.10 (dd, J=8.5, 2.0 Hz, 1H), 6.00 (s, 1H), 4.52 (s, 1H), 3.96 (dd, J=4.3, 2.2 Hz, 1H), 3.73-3.63 (m, 4H), 3.12 (d, J=5.6 Hz, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:4][CH:3]=1.[CH3:20][C:21]([S:24]([NH2:26])=[O:25])([CH3:23])[CH3:22]>>[C:21]([S:24]([N:26]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[O:25])([CH3:23])([CH3:22])[CH3:20]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccc(F)cc1
Reactant: CC(C)(C)S(N)=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=NS(=O)C(C)(C)C)c1ccc(F)cc1

Procedure:
The intermediate in Reference Example 5, t-butyl N-[(1S)-2-(4-fluorophenyl)-1-methyl-2-oxoethyl]carbamate and 2-methyl-2-propanesulfinamide were condensed in the presence of a dehydrating agent to give t-butyl N-[(1S)-2-[(t-butylsulfinyl)imino]-2-(4-fluorophenyl)-1-methylethyl]carbamate. 1.0M trimethylaluminum-hexane solution (0.43 mL) was added to the solution of said sulfinylimine compound (80 mg) in toluene (2 mL) at −78° C., and the mixture was stirred for 5 minutes. The obtained solution was dropwise added slowly to 2-fluoro-4-pyridyllithium solution (prepared by the reaction of 4-fluoro-2-bromopyridine (114 mg) and 1.56M butyllithium-hexane solution (0.46 mL) in diethyl ether solvent (3 mL) at −78° C.) at −78° C. Thereafter tetrahydrofuran (3 mL) was added to the reaction mixture, and then the reaction mixture was stirred at −78° C. for 2.5 hours. Saturated sodium chloride aqueous solution was added to the reaction mixture, and temperature of the reaction mixture was raised to room temperature. The obtained reaction mixture was filtered through celite, and then the organic layer of filtrate was dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and then the organic solvent was evaporated in vacuo. The obtained residue was purified by silica gel column chromatography (C-300; hexane:ethyl acetate=2:1) to give the optical active t-butyl N-[(1S)-2-[(t-butylsulfinyl)amino]-2-(4-fluorophenyl)-2-(2-fluoro-4-pyridyl)-1-methylethyl]carbamate (49 mg). The product was treated with 4N hydrogen chloride-dioxane solution to give the optical active title diamine (31 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[C:13]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])([NH:21][C:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[O:23])[C:12]2=[O:36])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:37](Cl)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>N1C=CC=CC=1>[C:38]([C:37]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[C:13]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])([NH:21][C:22]([N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])=[O:23])[C:12]2=[O:36])(=[O:10])=[O:9])=[CH:4][CH:3]=1)=[O:42])([CH3:41])([CH3:40])[CH3:39]
Reactant: CCN(CC)C(=O)NC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc(N)cc2)c2ccc(Cl)cc21
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CCN(CC)C(=O)NC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc(NC(=O)C(C)(C)C)cc2)c2ccc(Cl)cc21
Reaction time: 18 h

Procedure:
A solution of 0.400 g of the compound obtained in EXAMPLE 13 in 3 ml of pyridine is cooled to 0° C. and 0.100 g of pivaloyl chloride is added. The mixture is stirred for 18 hours, the temperature being allowed to rise to RT, and then evaporated under vacuum. The residue is extracted with AcOEt, washed with a 5% solution of potassium hydrogensulfate, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (95/5; v/v) as the eluent to give the expected product after crystallization from a DCM/iso ether mixture. m=0.180 g. M.p.=228° C.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:10].Cl.[Cl:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][SH:27])[CH2:20][CH2:19]2)=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:12].[ClH:10].[C:1]1([NH:7][C:8](=[SH:27][CH2:26][CH2:25][CH2:24][N:21]2[CH2:22][CH2:23][N:18]([CH2:17][C:16]3[CH:15]=[CH:14][C:13]([Cl:12])=[CH:29][CH:28]=3)[CH2:19][CH2:20]2)[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OC(Nc1ccccc1)=[SH]CCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 107.1 %

Procedure:
The procedure described in Example 2 was followed, using 4.3 g of phenyl isocyanate, 12.7 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 7.3 g of triethylamine and 100 ml of methylene chloride, to give 9.1 g (53% of theory) of N-phenyl-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. >230° C. (dec.).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]([O:30][CH:31]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([O:39][Si](C(C)(C)C)(C)C)[CH:34]=4)[CH3:32])=[O:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Li+]>O>[OH:39][C:35]1[CH:34]=[C:33]([CH:31]([O:30][C:28]([NH:27][C:22]2[C:23]([CH3:26])=[N:24][O:25][C:21]=2[C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]4)=[CH:14][CH:13]=3)=[CH:16][CH:17]=2)=[O:29])[CH3:32])[CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OC(C)c4cccc(O[Si](C)(C)C(C)(C)C)c4)cc3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1NC(=O)OC(C)c1cccc(O)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1-[4′-(4-{1-[3-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-ethoxycarbonylamino}-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.400 g, 0.63 mmol) in 3:1 MeOH:H2O (10 mL) was treated with excess lithium hydroxide. The reaction was stirred overnight at 60° C., and then acidified and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[O:22]=[C:20]1[NH:19][C:18](=[O:23])[C:17](=[CH:16][C:13]2[CH:12]=[CH:11][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N:3]([CH2:1][CH3:2])[C:31]([NH:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:32])[CH:5]=3)=[CH:15][CH:14]=2)[S:21]1
Reactant: O=C=Nc1ccccc1
Reactant: CCNc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Product: CCN(C(=O)Nc1ccccc1)c1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Yield: 95.2 %

Procedure:
In a manner similar to that of Example 9(a), by reacting 500 mg (1.54 mmol) of 5-(3′-ethylamino-biphenyl-4-ylmethylene)thiazolidine-2,4-dione with 340 μl (3.1 mmol) of phenyl isocyanate, 650 mg (95%) of the expected product are obtained in the form of a yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[O:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][O:16]2)=[CH:11][C:10]=1[O:23][CH2:24][CH2:25][CH3:26])C1C=CC=CC=1>[Pd].O1CCCC1>[CH3:21][C:18]1([CH3:22])[CH2:17][O:16][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:23][CH2:24][CH2:25][CH3:26])[CH:11]=2)[O:20][CH2:19]1
Reactant: CCCOc1cc(C2OCC(C)(C)CO2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCOc1cc(C2OCC(C)(C)CO2)ccc1O
Yield: 98.9 %

Procedure:
A mixture of 1.07 g (3.00 mmol) of 2-(4-benzyloxy-3-propoxyphenyl)-5,5-dimethyl-1,3-dioxane, 15 ml of tetrahydrofuran and 107 g of 10% palladium/C hydrogenation catalyst was hydrogenated at room temperature. After the absorption of 62.4 ml of hydrogen, the reaction suspension was filtered through Dicalite and evaporated down. Chromatography of the residue over 25 g of silica gel using 19:1 toluene/ethyl acetate gave 790 mg of 4-(5,5-dimethyl-1,3-dioxan-2-yl)-2-propoxyphenol.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]2[C:8](=[C:9]([Br:22])[CH:10]=[CH:11][C:12]=2[O:18][CH:19]([CH3:21])[CH3:20])[CH:7]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.Cl>C1COCC1>[Br:22][C:9]1[C:8]2[C:13](=[C:14]([O:16][CH3:17])[CH:15]=[C:6]([CH2:4][OH:3])[CH:7]=2)[C:12]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1cc(OC)c2c(OC(C)C)ccc(Br)c2c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CO)cc2c(Br)ccc(OC(C)C)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
A solution of 4.80 g (13.1 mmol) ethyl-8-bromo-5-isopropoxy-4-methoxy-2-naphthoate in 100 mL dry THF was cooled to 0° C. under Ar. A suspension of 498 mg (13.1 mmol) LiAlH4 in 60 mL dry THF was cooled to 0° C. and added to the ester over a period of 45 min. After stirring for 30 min at 0° C., 10 mL water and 10 mL 2N HCl were added carefully. The THF was concentrated in vacuo and the residue was extracted with dichloromethane, dried (MgSO4) and concentrated in vacuo. Column chromatography (dichloromethane/acetone, 95:5) afforded 4.00 g (95%) 1-bromo-7-hydroxymethyl-4-isopropoxy-5-methoxy-naphthalene as colorless needles (m.p. 120°-121° C.).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:12]([CH3:18])[C:13](=O)[CH2:14][CH2:15]Cl.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1C=CC=CC=1>[CH3:18][N:12]1[C:3]2[CH:4]=[CH:5][C:6]3[C:11]([C:2]=2[N:1]=[C:13]1[CH2:14][CH2:15][N:28]1[CH2:29][CH2:30][N:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:26][CH2:27]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CN(C(=O)CCCl)c1ccc2ccccc2c1N
Solvent: c1ccccc1
Product: Cn1c(CCN2CCN(c3ccccc3)CC2)nc2c3ccccc3ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.4 %

Procedure:
A solution of 5.25 g (0.02 mole) of N-(1-amino-2-naphthyl)-3-chloro-N-methyl-propanamide in 150 cc of anhydrous benzene is gradually added to a solution of 9.73 g (0.06 mole) of 1-phenylpiperazine in 25 cc of anhydrous benzene under argon atmosphere over a period of time of twenty minutes. The reaction mixture is then refluxed for 21 hours. Further, 11.73 g (0.0724 mole) of 1-phenylpiperazine is added and reflux is continued for an additional 24 hours. After cooling to room temperature, the mixture is diluted with 350 cc of benzene, poured into a separatory funnel and washed with 100 cc of water containing 7.8 cc of acetic acid. The benzene phase is extracted four times with 40 cc portions of 8% HCl. The pH of the aqueous acid phase is brought to 9 by addition of concentrated NH4OH and this aqueous solution is extracted with methylene chloride. The organic extracts are combined, dried over Na2SO4, filtered and evaporated to dryness yielding 4.03 g of raw compound which is recrystallized from 25 cc of ethanol. M.p. 153°-155° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[CH:17]=1)=O.[C:22]([O:29][CH3:30])(=[O:28])[CH2:23][CH2:24][C:25]([CH3:27])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:30][O:29][C:22](=[O:28])[CH2:23][C:24]1[C:11]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=2)=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:25]=1[CH3:27]
Reactant: COC(=O)CCC(C)=O
Reactant: Nc1sc2c(c1C(=O)c1cc3ccccc3o1)CCCC2
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1cc2ccccc2o1)CCCC3
Yield: 85.6 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(benzofuran-2-yl)methanone (0.297 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol), chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-50%) in heptane furnished 0.335 g (85%) of the title compound as a yellow solid.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31])=[N:28][CH:29]=2)[CH:19]=[C:20]([CH:22]=O)[CH:21]=1.[F:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=2)=[CH:43][CH:42]=1.CC(O)=O>ClCCCl>[Cl:15][C:16]1[CH:17]=[C:18]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31])=[N:28][CH:29]=2)[CH:19]=[C:20]([CH2:22][NH:53][C:50]2[CH:49]=[CH:48][C:47]([C:44]3[CH:45]=[CH:46][C:41]([F:40])=[CH:42][CH:43]=3)=[CH:52][CH:51]=2)[CH:21]=1
Reactant: Nc1ccc(-c2ccc(F)cc2)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)cc(C=O)c2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)cc(CNc3ccc(-c4ccc(F)cc4)cc3)c2)cn1
Temperature: 50 °C

Procedure:
Solid NaBH(OAc)3 (106 mg, 0.50 mmol) was added to a DCE solution (10 mL) of ethyl 3-(5-(3-chloro-5-formylphenyl)picolinamido)propanoate (90 mg, 0.25 mmol), 4′-fluoro-[1,1′-biphenyl]-4-amine (47 g, 0.25 mmol), and AcOH (0.06 mL, 1.00 mmol) and the resulting mixture was heated to 50° C. After 16 h the mixture was concentrated and purified via column chromatography to yield the title compound.