Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C@@H:5]([NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[CH3:6])[CH3:2].[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37]([NH:39][C@@H:40]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=3)[C:41](O)=[O:42])=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1>>[C:52]([O:51][C:48]1[CH:47]=[CH:46][C:45]([CH2:44][C@H:40]([NH:39][C:37](=[O:38])[O:36][CH2:35][CH:33]2[C:34]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:41]([N:7]([C@@H:5]([CH3:6])[CH:4]([O:3][CH2:1][CH3:2])[O:19][CH2:20][CH3:21])[CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)=[O:42])=[CH:50][CH:49]=1)([CH3:55])([CH3:53])[CH3:54]
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2ccccc12
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 79.1 %

Procedure:
According to the procedure described in the synthesis method of Compound III-5, (S)-1,1-diethoxy-N-(naphthalen-1-ylmethyl)propan-2-amine (Compound IX-6)(686 mg, 2.4 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid (1.15 g, 2.51 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: n-hexane:ethyl acetate=7:3) to obtain the title compound (1.384 g, 79%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:29]=[O:30])=[C:10]2[C:14]=1[N:13]=[C:12]1[N:15]([C:19]3[C:20]([CH3:28])=[N:21][C:22]([O:26][CH3:27])=[N:23][C:24]=3[CH3:25])[CH2:16][CH2:17][CH2:18][N:11]21>O1CCCC1>[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[C:20]([CH3:28])=[N:21][C:22]([O:26][CH3:27])=[N:23][C:24]=4[CH3:25])[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH:29]([OH:30])[CH2:1][CH3:2])=[CH:8][CH:7]=1
Reactant: COc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(C)n1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)nc(OC)nc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
Ethylmagnesium bromide (3.0 M solution in diethyl ether, 0.25 mL, 0.75 mmol) was added to a stirred solution of 9-chloro-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (256 mg, 0.689 mmol) in tetrahydrofuran (3.5 mL) at 0° C., and the mixture was stirred at 0° C. for 30 min. The reaction was quenched by water, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was washed with ethyl acetate/diisopropyl ether to give the title compound as a colorless powder (224 mg, 0.557 mmol, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[C:24](=[O:35])NC2CCN(C(C)C)CC2)=[O:10])=[N:6][CH:7]=1.NCC[OH:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[C:24]([OH:35])=[O:39])=[O:10])=[N:6][CH:7]=1
Reactant: CC(C)N1CCC(NC(=O)c2nc3ccc(C(=O)O)cc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Reactant: NCCO
Product: O=C(Cn1c(C(=O)O)nc2ccc(C(=O)O)cc21)Nc1ccc(Cl)cn1

Procedure:
5-[(2-hydroxy-ethyl)-amide]2-[(1-isopropyl-piperidin-4-yl)-amide]3-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-3H-benzoimidazole-2,5-dicarboxylic acid 5-[(2-hydroxy-ethyl)-amide]2-[(1-isopropyl-piperidin-4-yl)-amide] was prepared by a procedure according to example 22 starting from 50 mg (0.10 mmol) 3-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole-5-carboxylic acid and 6.7 mg (0.11 mmol) 2-amino-ethanol. The title compound was obtained as its formiate in form of a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.Br[CH2:24][CH:25]([CH3:27])[CH3:26]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[C:7]([CH3:11])[N:8]2[CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2cc(Cl)ccc2c1Sc1cccc(CC(=O)O)c1
Reactant: CC(C)CBr
Product: Cc1c(Sc2cccc(CC(=O)O)c2)c2ccc(Cl)cc2n1CC(C)C

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: [3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid and 1-bromo-2-methylpropane.
Reaction SMILES: [F:1][C:2]([F:56])([F:55])[C:3]1[CH:4]=[C:5]([CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([O:32][C:33]([F:36])([F:35])[F:34])[CH:29]=[CH:28][C:27]=1[C:37]1[CH:42]=[C:41]([CH:43]([CH3:45])[CH3:44])[CH:40]=[CH:39][C:38]=1[O:46][CH3:47])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:10][N:9]=1.Cl.O1CCOCC1.[OH-].[Na+]>C(Cl)(Cl)Cl>[F:56][C:2]([F:1])([F:55])[C:3]1[CH:4]=[C:5]([CH:48]=[C:49]([C:51]([F:52])([F:53])[F:54])[CH:50]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([O:32][C:33]([F:36])([F:35])[F:34])[CH:29]=[CH:28][C:27]=1[C:37]1[CH:42]=[C:41]([CH:43]([CH3:45])[CH3:44])[CH:40]=[CH:39][C:38]=1[O:46][CH3:47])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(OC(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OC(C)(C)C)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1ccc(C(C)C)cc1-c1ccc(OC(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
To tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (57 mg) is added 4N-hydrogen chloride/dioxane solution (2 ml) and the mixture is stirred at room temperature overnight. To the reaction solution are added an aqueous saturated sodium hydroxide solution and chloroform, and the mixture is separated, dried over magnesium sulphate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→23:2) to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butanoic acid (46.6 mg). MS (m/z): 746 [M+H]+
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[CH2:34]([CH2:36][NH2:37])[OH:35]>>[OH:35][CH2:34][CH2:36][NH:37][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5]
Reactant: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4cccc(OC)c4)c3)csc12
Reactant: NCCO
Product: COc1cccc(C(=O)Nc2cccc(OCc3csc4c(C(=O)NCCO)cncc34)c2)c1

Procedure:
3-[3-(3-Methoxy-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide was prepared from 3-[3-(3-methoxy-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 13 supra) and ethanolamine (Aldrich) following the procedure described in Example 16 as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:16].[H-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH3:16])[C@@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.2 %

Procedure:
To a 0° C. solution of (S)-2-(tert-butoxycarbonylamino)butanoic acid (1.00 g, 4.92 mmol) in THF (16.4 ml) was added iodomethane (2.45 ml, 39.4 mmol) followed by sodium hydride (60% w/w dispersion in mineral oil, 590 mg, 14.8 mmol), portionwise. The reaction was allowed to warm to rt and stirred for 18 h, then cooled to 0° C., quenched by the careful addition of H2O, and washed with Et20. The aqueous layer was acidified by the addition of 1 M aq. HCl and extracted with Et20. The combined organic layers were washed with sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated to provide (S)-2-(tert-butoxycarbonyl(methyl)amino)butanoic acid (1.05 g, 98%) as a white solid. MS m/z 240 (MNa)+.
Reaction SMILES: [F:1][CH:2]([C:5]1[CH:6]=[C:7]([CH:30]=[CH:31][CH:32]=1)[CH2:8][N:9]1[CH2:29][CH2:28][C:12]2([O:17][CH2:16][CH2:15][N:14]([C:18]([C:20]3[N:21]=[C:22]([CH:25]([CH3:27])[CH3:26])[S:23][CH:24]=3)=[O:19])[CH2:13]2)[CH2:11][CH2:10]1)[CH2:3][OH:4].FC(F)(F)C(O)=O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][CH:2]([C:5]1[CH:32]=[CH:31][CH:30]=[C:7]([CH2:8][N:9]2[CH2:29][CH2:28][C:12]3([O:17][CH2:16][CH2:15][N:14]([C:18]([C:20]4[N:21]=[C:22]([CH:25]([CH3:26])[CH3:27])[S:23][CH:24]=4)=[O:19])[CH2:13]3)[CH2:11][CH2:10]2)[CH:6]=1)[CH:3]=[O:4]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(C(F)CO)c4)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(C(F)C=O)c4)CC3)C2)cs1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of (9-(3-(1-fluoro-2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 39, step f) (0.213 g) in DCM (5 mL) was cooled in ice-water and treated with trifluoroacetic acid (0.053 mL) and stirred for 5 minutes. Dess-Martin periodinane (0.296 g) was added and the mixture was removed from the cooling bath and stirred at room temperature for 20 minutes. More Dess-Martin periodinane (0.295 g) was added and the mixture was stirred at room temperature for an additional 30 minutes. The reaction was then quenched by the addition of saturated sodium thiosulphate solution (5 mL), saturated sodium bicarbonate solution (5 mL) and ethyl acetate (5 mL), and the resulting two-phase mixture was stirred for 10 minutes. The mixture was then extracted twice with ethyl acetate, and the combined organic extracts washed with brine. Acetic acid (0.1 mL) was added, then the acidified extracts were dried over anhydrous magnesium sulphate and concentrated in vacuo to afford the crude subtitled product as an off-white foam. Yield 0.240 g.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)=[CH:7][C:6]=1[CH3:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[CH3:20][C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([CH3:19])[CH:16]=1)[O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]2[N:22]=[C:23]([NH2:25])[S:24][CH:2]=2)=[C:6]([CH3:21])[CH:7]=1
Reactant: NC(N)=S
Reactant: Cc1cc(C)cc(Oc2cc(C)c(C(=O)CBr)c(C)c2)c1
Solvent: CCO
Product: Cc1cc(C)cc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)c1
Yield: 59 %

Procedure:
A mixture of 2-bromo-1-(4-(3,5-dimethylphenoxy)-2,6-dimethylphenyl)ethanone (8.15 g, 23.5 mmol) and thiourea (1.79 g, 23.5 mmol) in 95% EtOH (33.5 mL) was heated at reflux for 120 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4-(3,5-dimethylphenoxy)-2,6-dimethylphenyl)thiazol-2-amine (4.50 g) as yellow solids in 59% yield: 1H NMR (500 MHz, CDCl3) δ 6.76 (s, 1 H), 6.68 (s, 2 H), 6.64 (s, 2 H), 6.26 (s, 1 H), 2.29 (s, 6 H), 2.16 (s, 6 H).
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=2)=[N:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[C:26](Cl)(Cl)=[S:27]>C(Cl)(Cl)Cl>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]([N:16]=[C:26]=[S:27])=[CH:17][CH:18]=2)=[N:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2ccc(N)cc2)nc1
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCc1ccc(-c2ccc(N=C=S)cc2)nc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 1.256 g of p-(5-pentyl-2-pyridyl)aniline in 29 ml of chloroform was treated at 5° C. under nitrogen with 1.46 ml of triethylamine. Then, at 1° C. within 20 minutes a solution of 0.49 ml of 95 percent thiophosgene in 14.5 ml of chloroform was added dropwise to the reaction mixture so that the temperature did not exceed 3° C. The reaction mixture was subsequently stirred at room temperature for 45 minutes and under reflux for a further 40 minutes, then cooled and washed with 40 ml of 3N ammonia and with water. The aqueous phases were back-extracted with methylene chloride. The organic phases were dried over sodium sulphate, filtered and freed from solvent. Purification of the resulting brownish paste (1.56 g) by chromatography on 60 g of silica gel with 700ml of methylene chloride/hexane (vol. 1:1) and subsequent crystallization from diethyl ether/hexane gave 1.17 g of p-(5-pentyl-2-pyridyl)phenylisothiocyanate as colourless crystals with m.p. (C--SA) 36.3° C. and cl.p. (SA --I) 97.2° C.
Reaction SMILES: C1COCC1.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:12]([O:14][C:15](=[O:16])[C:7]=12)=[O:13].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Mg]Br)=[CH:21][CH:20]=1.[NH4+].[Cl-]>Cl>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:15]([C:7]2[C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=[CH:11][N:6]=2)=[O:16])=[CH:21][CH:20]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: O=C1OC(=O)c2ncccc21
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ncccc2C(=O)O)cc1
Reaction time: 1 h
Yield: 27.8 %

Procedure:
To a THF (15 ml) solution of pyridine-2,3-dicarboxylic acid anhydride (1.0 g, 6.7 mmol) was added dropwise a THF solution of 4-methoxyphenylmagnesium bromide (0.89M, 8.0 ml, 7.1 mmol) at -78° C. The reaction mixture was stirred at the same temperature for 1 h and then a saturated aqueous solution of NH4Cl (20 ml) was added to quench the reaction. The reaction mixture was diluted with 1N HCl and extracted with AcOEt. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (E. Merck, Kieselgel 60/chloroform:methanol=10:1) to give 2-(4-methoxyphenylcarbonyl)-3-pyridine carboxylic acid (479 mg) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[CH2:14][N:15]([C@@H:23]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:43]([O:45][C:46]1[CH:55]=[CH:54][C:49]([C:50]([O:52]C)=[O:51])=[CH:48][CH:47]=1)=[O:44]>C1COCC1>[C:18]([O:17][C:16]([N:15]([CH2:14][CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:13][CH2:12][N:11]([C:43]([O:45][C:46]2[CH:55]=[CH:54][C:49]([C:50]([OH:52])=[O:51])=[CH:48][CH:47]=2)=[O:44])[CH2:10]1)[C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(C(=O)Oc2ccc(C(=O)O)cc2)CCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a solution of 300 mg of tert-butyl {[4-(3-fluorophenyl)piperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate in 2 mL of THF were added 0.136 mL of triethylamine and 167 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate (Fluka), followed by stirring at room temperature for 2 hours. It was washed with water, and extracted with ethyl acetate, and the organic layer was then washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and to the obtained residue were added 8 mL of THF, 8 mL of isopropanol, and 4 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 2 days. After neutralizing by addition of 4.1 mL of 1 M hydrochloric acid, the reaction mixture was concentrated under reduced pressure. The obtained residue was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 387 mg of 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(3-fluorophenyl)piperidin-1-yl]carbonyl}oxy)benzoic acid as a colorless foamy substance. ESI+: 627
Reaction SMILES: Cl.[NH2:2][CH2:3][P:4]([CH2:7][NH2:8])(=[O:6])[OH:5].[C:9]([O:13][C:14]([NH:16][C@H:17]([C:25]([OH:27])=O)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][C:14]([NH:16][C@H:17]([C:25]([CH:3]([P:4]([CH:7]([NH2:8])[C:25](=[O:27])[C@H:17]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH:16][C:14]([O:13][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:15])(=[O:5])[OH:6])[NH2:2])=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])([CH3:11])([CH3:12])[CH3:10]
Reactant: NCP(=O)(O)CN
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)C(N)P(=O)(O)C(N)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Synthesis in analogy to Example 1 from bis(aminomethyl)phosphinic acid hydrochloride and tert.-butoxycarbonyI-L-phenylalanine
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11].[CH3:12][C:13]1[S:14][C:15]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@H:24]([OH:32])[CH2:25][N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:18][C:16]=2[N:17]=1.CCN(C(C)C)C(C)C>CCO>[CH3:12][C:13]1[S:14][C:15]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@H:24]([OH:32])[CH2:25][N:26]3[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[CH3:11])[CH2:30][CH2:31]3)=[CH:18][C:16]=2[N:17]=1
Reactant: Cc1ccccc1OCCBr
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCOc4ccccc4C)CC3)ccc2s1

Procedure:
To a solution of 2-bromo-1-(2-methylphenoxy)ethane (1.09 g, 5.09 mmol, crude) in EtOH (15 mL) was added (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-piperazinylpropan-2-ol as prepared in Example 3A (250 mg, 0.81 mmol) and DIEA (1.5 mL, 8.6 mmol). The solution was stirred at reflux for 14 hours. Upon cooling, the solution was concentrated to an oil and then purified on an Isco™ (100% EtOAc hold 2 min, 8 min. gradient to 20% MeOH/EtOAc, hold 10 min) to afford (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-{4-[2-(2-methylphenoxy)ethyl]piperazinyl}prop an-2-ol.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](COCC[Si](C)(C)C)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:31]([NH2:35])[CH2:32][CH2:33][NH2:34]>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([NH:34][CH2:33][CH2:32][CH2:31][NH2:35])[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: NCCCN
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(F)n2)c2cc(-c3cccnc3)ncc21
Product: NCCCNc1cccc(-c2n[nH]c3cnc(-c4cccnc4)cc23)n1
Yield: 31 %

Procedure:
Following the procedures in Example 271, 3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and propane-1,3-diamine were reacted and the product was deprotected to give 280 as a yellow solid (20 mg, 31%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.30 (s, 1H), 9.22 (s, 1H), 9.03 (s, 1H), 8.60 (s, 1H) 8.43-8.44 (m, 1H), 7.53-7.57 (m, 2H), 7.38-7.40 (m, 1H), 7.03 (s, 1H), 6.53 (d, J=6.4 Hz, 1H), 4.01 (t, J=1.2 Hz, 2H), 2.92 (m, 2H), 2.50 (t, J=1.2 Hz, 2). ESI MS m/z=346 (M+1)
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[S:4]/[C:3]/1=[CH:12]\[C:13]([O:15][CH3:16])=[O:14].[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[S:4]/[C:3](=[CH:12]\[C:13]([O:15][CH3:16])=[O:14])/[C:2]1=[O:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)/C=C1\Sc2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C1\Sc2ccccc2N(Cc2ccccc2)C1=O
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Methyl (Z)-2-(3,4-dihydro-3-oxo-2H-1,4-benzothiazin-2-ylidene)acetate (940 mg) was dissolved in 8 ml of N,N-dimethylformamide, and the solution was added dropwise to a suspension of sodium hydride (60% in oil, 192 mg) in 2 ml of N,N-dimethylformamide. The mixture was stirred for 30 minutes. To the mixture was added dropwise a solution of 752 mg of benzyl bromide in 2 ml of N,N-dimethylformamide. The stirring was continued for an hour under ice-cooling, the reaction mixture was poured onto ice water, and extracted with ethyl acetate. Then, the ethyl acetate layer was washed with water. After the drying of the organic layer over anhydrous magnesium sulfate, the solvent was distilled off. The resulting oily matter was solidified in isopropyl etherhexane to give 1.04 g of methyl (Z)-2-(4-benzyl-3,4-dihydro-3-oxo-2H-1,4-benzothiazin-2-ylidene)acetate as yellow powder. The structural formula and physical data of this compound are shown in Table 14.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[F:29])[NH2:25]>CCOC(C)=O>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[CH:3]=[C:4]([NH:8][CH:9]3[CH2:13][CH2:12][NH:11][CH2:10]3)[N:5]=[CH:6][N:7]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ncn2)C1
Solvent: CCOC(C)=O
Product: Fc1ccc(Nc2cc(NC3CCNC3)ncn2)cc1Cl
Temperature: 140 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
A neat mixture of tert-butyl 3-(6-chloropyrimidin-4-ylamino)pyrrolidin-1-carboxylate (354 mg, 1.18 mmol) and 3-chloro-4-fluoroaniline (3.03 g, 20.8 mmol) was heated at 140° C. for 21 hours. Upon cooling to ambient temperature, the melt was diluted with EtOAc and the mixture was stirred for 1 hour. A beige, amorphous precipitate was collected, washed with water and dried in vacuo at 50-60° C. giving 292 mg (80%) of N4-(3-chloro-4-fluorophenyl)-N6-(pyrrolidin-3-yl)pyrimidine-4,6-diamine. MS (APCI): (M+1)=308, (M−1)=306.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[NH:17][C:16](=[O:18])[O:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6]>C1COCC1>[O:18]=[C:16]1[O:15][N:14]=[C:13]([CH:10]2[CH2:9][CH2:8][CH:7]([C:5]([OH:6])=[O:4])[CH2:12][CH2:11]2)[NH:17]1
Reactant: COC(=O)C1CCC(c2noc(=O)[nH]2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C1CCC(c2noc(=O)[nH]2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 19.1 %

Procedure:
A mixture of aqueous lithium hydroxide (215 mg, 5.13 mmol, 10 mL H2O), 4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-cyclohexanecarboxylic acid methyl ester (580 mg, 2.56 mmol) and THF (40 mL) were stirred at room temperature for 5 hr. The reaction was then concentrated, diluted with aqueous sodium hydroxide (0.1 M, 100 mL) washed with ethyl acetate (100 mL). The basic solution was acidified with concentrated HCl and extracted with ethyl acetate (125 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, concentrated, and dried from dichloromethane to give 4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-cyclohexanecarboxylic acid (104 mg, 20%) as a white solid. LCMS calcd for C9H12N2O4 (m/e) 212, obsd 213 (M+H) and 211 (M−H).