Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[O:23][CH3:24])[C:12](=O)[CH2:13][N:7]3[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:32])=O.N1C=CC=CC=1>>[Cl:32][C:12]1[N:11]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=2[O:23][CH3:24])[C:8]2[N:7]([CH:13]=1)[C:6]1[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=1[N:9]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CC(=O)N3c1c(C)cc(Cl)cc1OC
Solvent: c1ccncc1
Product: CCC(CC)c1ccc(Cl)c2nc3n(-c4c(C)cc(Cl)cc4OC)c(Cl)cn3c12
Temperature: 150 °C
Reaction time: 120 h

Procedure:
The mixture of 8-chloro-1-(4-chloro-2-methoxy-6-methylphenyl)-5-(1-ethylpropyl)-1H-imidazo[1,2-a]benzimidazol-2(3H)-one (31.8 mg, 0.0736 mmol) and phosphorus oxychloride (0.76 mL) and pyridine (11.9 μL, 0.147 mmol) was stirred at 150° C. for 5 days. After cooling, the mixture was concentrated in vacuo. The residue was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-15% ethyl acetate/n-hexane gradient mixture to give the title compound as an amorphous (8.7 mg, 0.0193 mmol, 26%).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:9][CH:8]2[CH2:24][C:25]([OH:27])=O)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:48]([CH3:50])[CH3:49])C2C=CC=CC=2N=N1.CNC>C1COCC1.ClCCl>[CH3:49][N:48]([CH3:50])[C:25](=[O:27])[CH2:24][CH:8]1[CH2:9][N:10]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:11][C:12](=[O:13])[N:7]1[CH2:6][C:5]1[CH:28]=[CH:29][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C(O)CC1CN(C(=O)OCc2ccccc2)CC(=O)N1Cc1ccc(F)cc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)CC1CN(C(=O)OCc2ccccc2)CC(=O)N1Cc1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a solution of [1-(4-fluorobenzyl)-4-(benzyloxycarbonyl)-6-oxo-piperazin-2-yl]acetic acid (0.8 g, 2.0 mmol) in THF (30 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.07 g, 4.68 mmol) and dimethylamine (2.0 M in THF, 2.34 mL, 4.68 mmol). The reaction was stirred overnight. The reaction mixture was then diluted with dichloromethane, washed with aqueous hydrochloric acid, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography with silica gel using hexanes and ethyl acetate as eluents to give the title compound. 1H NMR (400 MHz, CDCl3) δ 7.23-7.38 (m, 7H), 7.01 (t, J=8.6 Hz, 2H), 5.0-5.24 (m, 3H), 4.45-4.60 (m, 1H), 3.88-4.26 (m, 4H), 3.02-3.20 (m, 1H), 2.62-2.95 (m, 6H), 2.42-2.62 (m, 1H), 2.24 (d, J=15.8 Hz, 1H).
Reaction SMILES: ClCCl.[Cl:4][C:5]1[C:6]([CH:13]([S:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])=[CH:7][C:8]([CH2:11]O)=[N:9][CH:10]=1.C(Br)(Br)(Br)[Br:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCCCCC>[Br:31][CH2:11][C:8]1[CH:7]=[C:6]([CH:13]([S:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[C:5]([Cl:4])=[CH:10][N:9]=1
Reactant: OCc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(CBr)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.3 %

Procedure:
To a dichloromethane (15 ml) solution of the [5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridin-2-yl]methanol (582 mg, 1.41 mmol) obtained in Example 256 were sequentially added carbon tetrabromide (936 mg, 2.82 mmol) and triphenylphosphine (407 mg, 1.55 mmol) at 0° C. The resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=20:1 eluate was concentrated under reduced pressure to give the title compound (518 mg, 1.09 mmol, 77%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[NH:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([N:17]3[C@@H:18]4[C@@H:23]([C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[CH2:20][CH2:19]4)[CH2:14][CH2:15][CH2:16]3)=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2ccc(C(=O)O)cc2s1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1nc2ccc(C(=O)N3CCC[C@@H]4c5ccccc5CC[C@@H]43)cc2s1
Yield: 24 %

Procedure:
The title compound is prepared from 2-amino-benzothiazole-6-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 24% of theory; LC (method 4): tR=1.80 min; Mass spectrum (ESI+): m/z=364 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:14]([OH:16])=O)=[CH:11][NH:12][CH:13]=1.C([N:19](CC)CC)C.S(Cl)(Cl)=O.CN(C)C=O.N>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:14]([NH2:19])=[O:16])=[CH:11][NH:12][CH:13]=1
Reactant: O=C(O)c1c[nH]cc1-c1cccc(Cl)c1Cl
Reactant: CCN(CC)CC
Agent: N
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)c1c[nH]cc1-c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
A mixture of 4-(2,3-dichlorophenyl)pyrrole-3-carboxylic acid (2.43 g, 9.5 mmol) and triethylamine (7 mL, 50 mmol) in tetrahydrofuran is stirred for 15 minutes at room temperature and concentrated in vacuo to obtain a residue. A mixture of the residue, thionyl chloride (2.77 mL, 38 mmol) and N,N-dimethylformamide (0.73 mL, 9.5 mmol) is stirred overnight at room temperature and concentrated in vacuo to obtain a yellow oil. The oil is added to a concentrated ammonia solution and stirred for 1 hour. This mixture is filtered to give a solid. The solid is washed with water, dried and chromatographed using silica gel and a 4:1 hexanes/ethyl acetate mixture to obtain the title product as a white solid (1.6 g, mp 185°-190° C.).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:21][C:22]1[CH:41]=[CH:40][C:25]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38]C)=[O:37])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.[OH-].[Na+].Cl>CN(C)C=O.CO.O>[CH:1]([C:4]1[N:5]=[C:6]([N:9]([CH2:21][C:22]2[CH:41]=[CH:40][C:25]([CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Reactant: CC(C)c1csc(NCCc2ccccn2)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1csc(N(CCc2ccccn2)Cc2ccc(COc3ccc(CCC(=O)O)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
To a solution of 4-isopropyl-N-(2-pyridin-2-ylethyl)-1,3-thiazole-2-amine (127 mg) in N,N-dimethylformamide (2 mL) was added sodium hydride (20 mg), and the mixture was stirred at room temperature for 1 hr. Methyl 3-{4-([4-(chloromethyl)benzyl]oxy}phenyl)propanoate (159 mg) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19-1:1 in volume ratio) to give a yellow oil. The oil was dissolved in methanol (5 mL), 2N aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was dried using a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.) and concentrated to give the title compound (105 mg, yield 41%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=2)=[N:11][N:10]=[C:9]1/[CH:23]=[CH:24]/[C:25]([NH:27][NH:28][C:29]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]([O:37][CH3:38])[CH:32]=1)=[O:30])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:9](/[CH:23]=[CH:24]/[C:25]2[O:30][C:29]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([O:37][CH3:38])[CH:32]=3)=[N:28][N:27]=2)=[N:10][N:11]=[C:12]1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][N:14]=1
Reactant: COc1cc(C(=O)NNC(=O)/C=C/c2nnc(-c3ccc(S(C)(=O)=O)cn3)n2-c2ccccc2Cl)ccn1
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(-c2nnc(/C=C/c3nnc(-c4ccc(S(C)(=O)=O)cn4)n3-c3ccccc3Cl)o2)ccn1
Reaction time: 2 h

Procedure:
N′-[(E)-3-[4-(2-chlorophenyl)-5-(5-methylsulfonyl-2-pyridyl)-1,2,4-triazol-3-yl]prop-2-enoyl]-2-methoxy-pyridine-4-carbohydrazide 10 was dissolved into dichloromethane (10 mL), and triphenyl phosphine (0.27 g, 1.0 mmol), carbon tetrabromide (0.34 g, 1.04 mmol) and triethylamine (0.18 mL, 1.30 mmol) were added. The reaction mixture was kept at ambient temperature for 2 h. The final compound was purified by column chromatography (eluting with hexane and ethyl acetate 1:3) to give 2-(4-(2-chlorophenyl)-5-((E)-2-(5-(2-methoxypyridin-4-yl)-1,3,4-oxadiazol-2-yl)vinyl)-4H-1,2,4-triazol-3-yl)-5-(methylsulfonyl)pyridine as a yellow solid. Yield: 0.031 g, 11%.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH3:11])[N:10]=[C:6]2[C:5]([C:12]([O:14]C)=[O:13])=[CH:4][C:3]=1[Cl:16].[OH-].[Li+].[CH3:19]O>>[CH3:19][C:8]1[N:7]2[C:2]([NH2:1])=[C:3]([Cl:16])[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[C:6]2=[N:10][C:9]=1[CH3:11]
Reactant: CO
Reactant: COC(=O)c1cc(Cl)c(N)n2cc(C)nc12
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc2c(C(=O)O)cc(Cl)c(N)n2c1C
Yield: 96 %

Procedure:
A mixture of methyl 5-amino-6-chloro-2-methylimidazo[1,2-a]pyridine-8-carboxylate (EXAMPLE 1, Step 4, 10.5 g, 43.9 mmol,) and 1 N lithium hydroxide (87.7 mL, 87.7 mmol) in methanol (100 mL) was stirred under reflux for 1 h. After removal of the solvent in vacuo, the residue was suspended with water and treated with 2 N hydrochloric acid to adjust to pH 4. The resulting solid was filtered, washed with water and diethyl ether and dried in vacuo with heating to give 9.5 g (42.2 mmol, 96%) of the title compound as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[C:23]([C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C@@H:33]2[CH2:35][O:34]2)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([CH2:35][C@H:33]([OH:34])[CH2:32][O:31][C:30]5[CH:36]=[CH:37][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCNCC1)O2
Product: CC(C)(C)c1ccc(OC[C@@H](O)CN2CCC3(CC2)CSC2=C(O3)c3cc(Br)ccc3C(=O)C2=O)cc1

Procedure:
Compound 189 was synthesized using 9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=150-152° C.; 400 MHz 1H NMR (CDCl3) δ: 7.92-7.89 (m, 1H), 7.87-7.85 (m, 1H), 7.65-7.62 (m, 1H), 7.33-7.29 (m, 2H), 6.89-6.85 (m, 2H), 4.20-4.10 (m, 1H), 4.03-3.98 (m, 2H), 2.96 (s, 2H), 2.83-2.73 (m, 2H), 2.73-2.62 (m, 2H), 2.62-2.50 (m, 1H), 2.20-2.12 (m, 2H), 2.00-1.85 (m, 2H), 1.29 (s, 9H); LCMS: 586 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=2[N+:15]([O-:17])=[O:16])=[C:4]([N+]([O-])=O)[CH:3]=1.[CH3:21][O-:22].[Na+].CO>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=2[N+:15]([O-:17])=[O:16])=[C:4]([O:22][CH3:21])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1-c1ccc(Br)cc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(Br)ccc1-c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the solution of 4,4′-dibromo-2,2′-dinitro-biphenyl (6.58 g, 16.5 mmol) in DMF (50 ml) at 0° C. was added a solution of sodium methoxide in Methanol (4.4 M, 4.5 ml, 19.8 mmol). The mixture was stirred at 25° C. for 12 hours and was poured into ice-water (140 ml). The mixture was extracted with EtOAc (2×). The combined organic phase was washed with water and brine and dried with Na2SO4. Concentration under reduced pressure gave pale solid. The re-crystallization from CH3CN/MeOH gave 4,4′-dibromo-2-methoxy-2′-nitro-biphenyl as a white solid (3.76 g).
Reaction SMILES: O/[N:2]=[CH:3]/[C:4]1[S:8][CH:7]=[C:6]([CH:9]([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:10][C:11]#[N:12])[CH:5]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>O>[C:11]([CH2:10][CH:9]([C:6]1[CH:5]=[C:4]([C:3]#[N:2])[S:8][CH:7]=1)[N:13]1[CH:17]=[C:16]([C:18]2[C:19]3[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH:15]=[N:14]1)#[N:12]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4csc(/C=N/O)c4)c3)ncnc21
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4csc(C#N)c4)c3)ncnc21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-(5-[(E)-(hydroxyimino)methyl]-3-thienyl)-3-[4-(7-[2-(trimethylsilyl)-ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (70 mg, 0.0001 mol) in pyridine (1 mL, 0.01 mol), methanesulfonyl chloride (100 μL, 0.001 mol) was added. The mixture was stirred at 60° C. for 2 hours. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with 0.1 N HCl, brine, dried over magnesium sulfate, filtered and concentrated to give 4-(2-cyano-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl)thiophene-2-carbonitrile as a crude product (30 mg, 44%). MS (ES): 476 (M+1).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([C:12]([O:14]C)=O)[CH:6]=1)=[O:4].[NH2:16][CH:17]([CH2:20][OH:21])[CH2:18][OH:19]>CO>[NH2:11][C:9]1[CH:10]=[C:5]([C:3]([NH:16][CH:17]([CH2:20][OH:21])[CH2:18][OH:19])=[O:4])[CH:6]=[C:7]([C:12]([NH:16][CH:17]([CH2:20][OH:21])[CH2:18][OH:19])=[O:14])[CH:8]=1
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: NC(CO)CO
Solvent: CO
Product: Nc1cc(C(=O)NC(CO)CO)cc(C(=O)NC(CO)CO)c1
Temperature: 105 °C
Yield: 90 %

Procedure:
5-Amino-1,3-benzenedicarboxylic acid dimethyl ester (40.0 g, 191 mmol) and 2-amino-1,3-dihydroxypropane (104.5 g, 1.147 mol) are loaded into a 1 L vessel equipped with a mechanical stirrer, a thermometer and a refluxing refrigerator. The suspension is heated up to 105° C., and is maintained at this temperature for 150 minutes to yield a solution. After cooling to 50° C., methanol (0.7 L) is added and the obtained suspension is maintained for 4 hours at room temperature. The solid that separates is filtered, washed with methanol (0.3 L), and dried in the oven at 45° C. for 4 hours yielding the compound of the title (56.3 g, 0.172 mol, yield: 90%).
Reaction SMILES: C[O:2][C:3](=O)[NH:4][CH2:5][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)([CH3:8])[CH3:7].N>>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:3](=[O:2])[NH:4][CH2:5][C:6]2([CH3:8])[CH3:7]
Reactant: COC(=O)NCC(C)(C)c1cccc(Cl)c1
Agent: N
Product: CC1(C)CNC(=O)c2ccc(Cl)cc21
Temperature: 120 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
Under N2 protection, a mixture of [2-(3-chloro-phenyl)-2-methyl-propyl]-carbamic acid methyl ester (1.84 g, 7.63 mmol) and PPA (polyphosphoric acid) (8 g) in a 100 mL round bottom flask was stirred at 120° C. for 2 hours. After cooling to room temperature, the mixture was treated with ice-water and aq. ammonia solution to adjust the pH to 8. After extraction with ethyl acetate, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo. The crude product formed was further washed with ether to give the title compound (0.32 g, 20%) as a white solid. MS: 210.1 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.[CH3:34][Si:35]([CH3:51])([CH3:50])[CH2:36][CH2:37][O:38][CH2:39][O:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][CH:42]=1.Cl.C(N=C=NCCCN(C)C)C>>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][O:22][CH:10]1[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][O:1][C:45](=[O:46])[C:44]3[CH:48]=[CH:49][C:41]([O:40][CH2:39][O:38][CH2:37][CH2:36][Si:35]([CH3:50])([CH3:34])[CH3:51])=[CH:42][CH:43]=3)=[CH:4][CH:5]=2)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: C[Si](C)(C)CCOCOc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COC(=O)c3ccc(OCOCC[Si](C)(C)C)cc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described under (g) by condensing tert-butyl (3RS,4RS)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate and 4-(2-trimethylsilanyl-ethox-ymethoxy)-benzoic acid using N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) as the condensation agent there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-{4-[4-(2-trimethylsilanyl-ethoxy-methoxy)-benzoyloxymethyl]-phenyl}-piperidine-1-carboxylate; MS: 715 (M+NH4)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]1=2.CC1SC2C=CC(O)=CC=2N=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32](=[O:39])[C:31]2=[O:40])=[CH:26][CH:25]=1.N1C2C(=CC=CC=2)C(=O)C1=O>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([OH:39])([C:9]3[C:8]([OH:11])=[CH:7][C:3]4[O:4][CH2:5][CH2:6][O:1][C:2]=4[CH:10]=3)[C:31]2=[O:40])=[CH:28][CH:29]=1
Reactant: Oc1ccc2c(c1)OCCO2
Reactant: O=C1C(=O)N(c2ccc(F)cc2)c2ccccc21
Agent: Cc1nc2cc(O)ccc2s1
Agent: O=C1Nc2ccccc2C1=O
Product: O=C1N(c2ccc(F)cc2)c2ccccc2C1(O)c1cc2c(cc1O)OCCO2

Procedure:
Following the procedure as described in PREPARATION 1A and making non-critical variations using 2,3-dihydrobenzo[b][1,4]dioxin-6-ol to replace 2-methylbenzo[d]thiazol-5-ol, and 1-(4-fluorophenyl)indoline-2,3-dione (Coppola, G. M Journal of Heterocyclic Chemistry 1987, (24):1249) to replace isatin, 1-(4-fluorophenyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one was obtained (23%) as a beige solid: mp 195-200° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.12 (s, 1H), 7.47-7.41 (m, 4H), 7.26 (s, 1H), 7.21-7.16 (m, 1H), 7.01-6.93 (m, 2H), 6.68 (d, J=7.8 Hz, 1H), 6.63 (s, 1H), 6.14 (s, 1H), 4.23-4.14 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.3, 160.9 (d, 1JC-F=245 Hz), 147.1, 143.9, 142.6, 135.6, 132.0, 131.2 (d, 4JC-F=2.9 Hz), 128.6 (d, 3JC-F=8 Hz), 124.0, 122.4, 121.2, 116.4 (d, 2JC-F=22.8 Hz), 115.1, 108.2, 103.4, 74.4, 64.3, 63.7, 57.2; MS (ES+) m/z 390.0 (M+1).
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH:16]([CH3:32])[C@@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1>>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([N:16]([CH3:32])[C@@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:5]
Reactant: CN[C@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Product: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)N(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 69 %

Procedure:
Condensation of BocProOH (4.63 g.) and MeDTrpOMe (5.00 g.) by the mixed anhydride method using diphenylphosphinyl chloride gave BocPro-MeDTrpOMe in 69% yield. Demethylation of BocPro-MeDTrpOMe (6.33 g.) using aqueous sodium hydroxide gave BocPro-MeDTrpOH in 77% yield. Condensation of BocPro-MeDTrpOH (3.60 g.) and HPheOBz (3.70 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-MeDTrp-PheOBz in 83% yield. Debenzylation of BocPro-MeDTrp-PheOBz (4.60 g.) by hydrogenation with palladium catalyst gave BocPro-MeDTrp-PheOH in 100% yield.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.C(O)(=O)C(O)=O.[C:54]1([C:60]2[O:64][C:63]([CH2:65][NH2:66])=[N:62][N:61]=2)[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:66][CH2:65][C:63]4[O:64][C:60]([C:54]5[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=5)=[N:61][N:62]=4)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1nnc(-c2ccccc2)o1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Agent: O=C(O)C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1nnc(-c2ccccc2)o1
Yield: 67 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (5-phenyl-1,3,4-oxadiazol-2-yl)methanamine oxalate, the title compound was obtained as a colorless solid in 67% yield: 1H NMR (300 MHz, CDCl3) δ 8.06-8.01 (m, 2H), 7.55-7.45 (m, 3H), 7.30-7.24 (m, 2H), 7.07-6.98 (m, 2H), 6.45 (t, J=5.4 Hz, 1H), 6.11 (s, 1H), 4.90 (d, J=5.4 Hz, 2H), 4.43 (s, 2H), 3.84-3.76 (m, 2H), 3.48-3.40 (m, 2H), 2.50 (s, 3H); MS (ES+) m/z 514.1 (M+23).