Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[C:24](O)=[O:25])/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[NH2:28][CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH:33]([NH:36][C:37](=[O:39])[CH3:38])[CH2:32]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C1COCC1.CN(C=O)C>[C:37]([NH:36][CH:33]1[CH2:34][CH2:35][N:31]([CH2:30][CH2:29][NH:28][C:24]([C:23]2[CH:22]=[C:21]([CH3:27])[NH:20][C:19]=2/[CH:18]=[C:10]2\[C:11](=[O:17])[NH:12][C:13]3[C:9]\2=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:16]=[CH:15][CH:14]=3)=[O:25])[CH2:32]1)(=[O:39])[CH3:38]
Reactant: CC(=O)NC1CCN(CCN)C1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(=O)NC1CCN(CCNC(=O)c2cc(C)[nH]c2/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)C1
Yield: 75.3 %

Procedure:
2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (90.5 mg) was coupled with N-[1-(2-amino-ethyl)-pyrrolidin-3-yl]-acetamide (58.5 mg, 1.5 eq.), HOBt (1 eq.), EDC (1.5 eq.) and TEA (3 drops) in THF (2 mL), DMF (0.3 mL) at rt for overnight to give 97 mg (78%) of the titled compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6](OC)=[O:7].O.[NH2:17][NH2:18]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6]([NH:17][NH2:18])=[O:7]
Reactant: NN
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)NN)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 70.6 %

Procedure:
To methyl 3-methoxy-4-nitrobenzoate (5.16 g, 24.5 mmol) in EtOH (250 mL) was added hydrazine monohydrate (5.95 mL, 122 mmol) in one portion. The reaction was heated at 80° C. overnight and concentrated upon completion by TLC. The residue was taken up in EtOAc, heated and hot filtered. The filtrate was concentrated and the residue was triturated with diethyl ether to provide the title compound (3.65 g, 17.3 mmol, 71%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.96 (s, 3H), 4.60 (br. s., 2H), 7.50 (dd, J=8.4, 1.5 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.93 (d, J=8.1 Hz, 1H), 10.05 (br. s., 1H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:18]=[CH:19][CH:20]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH3:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:38][CH2:39][CH3:40])=[C:32]([NH:34][C:35]([NH2:37])=[S:36])[CH:33]=1.[C:41]([O-])(=[O:43])C.[Na+]>>[CH3:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:38][CH2:39][CH3:40])=[C:32]([NH:34][C:35]([NH:37][C:41]([NH:24][CH2:23][CH2:22][CH2:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=4)[N:11]=3)[CH:16]=2)=[O:43])=[S:36])[CH:33]=1
Reactant: CC(=O)[O-]
Reactant: CCCc1ccc(C)cc1NC(N)=S
Reactant: NCCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Agent: [Na+]
Product: CCCc1ccc(C)cc1NC(=S)NC(=O)NCCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 63 using 3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (CA18) and 1-(5-methyl-2-propylphenyl)thiourea (CA38). Sodium acetate was used in place of sodium bicarbonate. The title compound was isolated as a white solid (0.134 g, 40%): 1H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 10.04 (s, 1H), 9.40 (s, 1H), 8.14-8.04 (m, 2H), 8.03-7.92 (m, 2H), 7.68-7.57 (m, 2H), 7.45 (t, J=7.6 Hz, 1H), 7.42-7.32 (m, 2H), 7.11 (t, J=7.1 Hz, 2H), 7.01 (ddd, J=7.9, 1.7, 0.8 Hz, 1H), 3.18 (q, J=6.5 Hz, 2H), 2.73 (dd, J=8.7, 6.6 Hz, 2H), 2.45 (dd, J=8.6, 6.6 Hz, 2H), 2.26 (s, 3H), 1.91-1.75 (m, 2H), 1.55-1.41 (m, 2H), 0.84 (t, J=7.3 Hz, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.98; ESIMS m/z 597 ([M+H]+), 595 ([M−H]−).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13].[S:24](Cl)([CH3:27])(=[O:26])=[O:25].CCCCCC.C(OCC)(=O)C>C(OCC)(=O)C>[CH3:27][S:24]([O:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])(=[O:26])=[O:25]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 10 °C

Procedure:
Triethylamine (20 mL, 144.6 mmol) was added to a solution of compound 54 (29.5 g, 119.9 mmol) in ethyl acetate (300 mL). The mixture was cooled to 10° C. in an ice bath. Then, a solution of mesyl chloride (10.2 mL, 131.8 mmol) in ethyl acetate (50 mL) was added dropwise at a temperature ≦20° C. The resulting solution was stirred at room temperature for 3 h (TLC monitoring, eluent: hexane-ethyl acetate, 4:1). The reaction mixture was filtered to remove the precipitate-triethylamine hydrochloride. The filtrate was washed with aqueous NaHCO3, water, and evaporated. Yield of 55: 32.2 g (83%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([C@@H:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[CH2:12][CH2:13]O)[C:8](=[O:22])[C:7]2([CH3:24])[CH3:23].C1(C)C(S(Cl)(=O)=O)=CC=CC=1.[N:36]1C=CC=C[CH:37]=1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([C@@H:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[CH2:12][CH2:13][NH:36][CH3:37])[C:8](=[O:22])[C:7]2([CH3:24])[CH3:23]
Reactant: c1ccncc1
Reactant: CC1(C)C(=O)N([C@H](CCO)c2cccc(F)c2)c2c(F)cccc21
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: CNCC[C@H](c1cccc(F)c1)N1C(=O)C(C)(C)c2cccc(F)c21
Reaction time: 6 h

Procedure:
7-fluoro-1-[(1R)-1-(3-fluorophenyl)-3-hydroxypropyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (0.24 g, 0.73 mmol) was dissolved in pyridine (5 mL) and toluenesufonyl chloride (0.18 g, 0.94 mmol) was added. Stirred for 6 hours then the reaction mixture was diluted with ethyl acetate and washed with water, 2N hydrochloric acid, saturated copper sulfate, 2N hydrochloric acid, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was immediately dissolved in methylamine (8M in ethanol, 25 mL) and stirred for 16 hours. The mixture was concentrated in vacuo and purified via chromatography (silica, 3% methanol saturated with ammonia in chloroform) to give 7-fluoro-1-[(1R)-1-(3-fluorophenyl)-3-(methylamino)propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one as a colorless oil (0.22 g). The freebase was dissolved in ether (5 mL) and treated with 1N hydrochloric acid in ether (0.64 mL, 1.0 equivalent). The white precipitate was collected and dried under vacuum to give 120 mg (43% over three steps) 7-fluoro-1-[(1R)-1-(3-fluorophenyl)-3-(methylamino)propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]2=[O:22])[CH:7]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]2=[O:22])[CH:7]=1
Reactant: CCCCCN1C(=O)C(O)(c2cc(F)ccc2O)c2ccccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCN1C(=O)C(c2cc(F)ccc2O)c2ccccc21
Temperature: 40 °C
Reaction time: 15 h
Yield: 91.2 %

Procedure:
To a solution of 3-(5-fluoro-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one (2.42 g, 7.35 mmol) in dichloromethane (10.0 mL) were added trifluoroacetic acid (1.00 mL) and triethylsilane (1.00 mL) at ambient temperature. The reaction mixture was stirred at 40° C. for 15 hrs and concentrated in vacuo to dryness. The residue was triturated with ether to give the title compound (2.10 g, 91%) as a solid: MS (ES+) m/z 314 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[N+:15]([O-])=O.[Cl-].[NH4+].O1CCCC1.C(O)C>[Fe].O>[NH2:15][C:6]1[CH:7]=[C:8]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][C:3]1[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:2]=1[F:1]
Reactant: NS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1cc(S(N)(=O)=O)ccc1Oc1ccc(F)cc1F
Temperature: 95 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
The product from Example 51A (3.24 g, 9.81 mmol), iron (2.74 g, 49.1 mmol), and ammonium chloride (0.787 g, 14.72 mmol) were combined in the solvent mixture of tetrahydrofuran (21.0 mL), ethanol (21.0 mL) and water (7.0 mL) and heated at 95° C. with vigorous stirring for 3 hours. The mixture was cooled and filtered through a plug of Celite to remove solids. The plug was rinsed repeatedly with methanol and tetrahydrofuran. The filtrate was concentrated and the residue partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated to afford the title compound (2.81 g, 95%).
Reaction SMILES: [C@H:1]([NH:5][C:6]1[C:7]([C:17]([NH2:19])=[O:18])=[CH:8][C:9]([CH3:16])=[C:10]([CH:15]=1)[C:11]([O:13]C)=[O:12])([CH2:3][CH3:4])[CH3:2].[OH-].[Na+]>CO.ClCCl>[C@H:1]([NH:5][C:6]1[C:7]([C:17]([NH2:19])=[O:18])=[CH:8][C:9]([CH3:16])=[C:10]([CH:15]=1)[C:11]([OH:13])=[O:12])([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@@H](C)Nc1cc(C(=O)OC)c(C)cc1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC[C@@H](C)Nc1cc(C(=O)O)c(C)cc1C(N)=O
Temperature: 45 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a solution of (R)-methyl 5-(sec-butylamino)-4-(aminocarbonyl)-2-methylbenzoate (300 mg, 1.13 mmol) in methanol (2.0 mL) and dichloromethane (1.0 mL) was added 2.0M aqueous sodium hydroxide solution (2.0 mL, 4.0 mmol). The reaction mixture was heated to 45° C. and stirred for 2 h, at which time it was cooled to room temperature and all volatiles were removed by rotary evaporation. To the residual solution was slowly added 1.0M aqueous hydrochloric acid until pH<2. The yellow precipitate was collected by filtration and washed with water to afford (R)-5-(sec-butylamino)-4-(aminocarbonyl)-2-methylbenzoic acid (210 mg, 65%). MS (EI) for C13H18N2O3: 251 (MH+).
Reaction SMILES: [NH2:1][C@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:5]2[CH:17]=[C:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([CH3:21])=[CH:20][C:4]=2[CH2:3]1.[C:30](=O)(O)[O-:31].[Na+].C(Cl)(Cl)=O.C1(C)C=CC=CC=1.C(O)(=O)C.[O:50]=[C:51]1[N:60]([CH:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH2:59][C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[NH:52]1>ClCCl>[CH2:10]([N:7]1[C:8](=[O:9])[C@H:2]([NH:1][C:30]([N:64]2[CH2:65][CH2:66][CH:61]([N:60]3[CH2:59][C:58]4[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=4)[NH:52][C:51]3=[O:50])[CH2:62][CH2:63]2)=[O:31])[CH2:3][C:4]2[CH:20]=[C:19]([CH3:21])[C:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:17][C:5]=2[CH2:6]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: O=C([O-])O
Reactant: Cc1cc2c(cc1NC(=O)OC(C)(C)C)CN(Cc1ccccc1)C(=O)[C@H](N)C2
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1NC(=O)OC(C)(C)C)CN(Cc1ccccc1)C(=O)[C@H](NC(=O)N1CCC(N3Cc4ccccc4NC3=O)CC1)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
(R)-tert-Butyl 4-amino-2-benzyl-7-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylcarbamate (155 mg, 0.39 mmol) was dissolved in dichloromethane (10 mL). Aqueous sodium bicarbonate (10 mL) was added to the mixture. A solution of 20% phosgene in toluene (230 μL, 0.43 mmol) was added to the mixture with vigorous stirring. Reaction stirred at room temperature for 20 minutes. 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine acetate (140 mg, 0.48 mmol) was added to the mixture. Reaction stirred at room temperature for 1 hour. Reaction layers were partitioned. Organic layer was washed successively with 1N hydrochloric acid and brine. Organic was dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as off-white solid in 94% yield. MS m/e (M+H)+=653.
Reaction SMILES: Cl[C:2]1[CH:35]=[CH:34]C=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16][CH2:17]C(C)(C)C(O)=O)=[CH:14][N:15]=1.Br.BrCC1C=[N:41]C=CC=1.C([O:47][C:48](=[O:57])CSC1SC(N)=NC=1)C>>[CH3:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:8]([CH2:7][CH2:6][O:5][CH2:4][C:3]2[CH:32]=[N:41][CH:34]=[CH:35][CH:2]=2)[C:9](=[O:24])[NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:48]([OH:57])=[O:47])=[CH:14][N:15]=2)[CH2:26][CH2:27]1
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: BrCc1cccnc1
Agent: Br
Product: C[C@H]1CC[C@H](N(CCOCc2cccnc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using 3-bromomethylpyridine hydrobromide and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [Mg].[CH2:2](Cl)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH2:15]([Mg]Cl)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[CH2:29]([Sn:33](Cl)(Cl)Cl)[CH2:30][CH2:31][CH3:32]>C1(C)C(C)=CC=CC=1.O1CCCC1>[CH2:29]([Sn:33]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCCl
Reactant: CCCC[Sn](Cl)(Cl)Cl
Reactant: CCCCCCCCCCCC[Mg]Cl
Agent: [Mg]
Solvent: Cc1ccccc1C
Solvent: C1CCOC1
Product: CCCCCCCCCCCC[Sn](CCCC)(CCCCCCCCCCCC)CCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The same reactor as used in Preparation Example 1 was charged with 12.1 g (0.5 mole) of magnesium, 102.4 g (0.5 mole) of n-dodecyl chloride and 200 g of tetrahydrofuran, and they were reacted in a stream of nitrogen. To the resulting n-dodecyl magnesium chloride solution was added dropwise a solution of 42.3 g (0.15 mole) of mono-n-butyltin trichloride in 200 ml of xylene with stirring at room temperature over the course of 30 minutes. Then, the reaction mixture was reacted for 3 hours at the refluxing temperature, and then subjected to a hydrolysis treatment to obtain 99.8 g of n-butyl tri-n-dodecyltin having a purity of 98.7% as an oily substance.
Reaction SMILES: [CH:1]([CH:4]1[NH:8][C:7](=[O:9])[NH:6][C:5]1=[O:10])([CH3:3])[CH3:2].[Cl-].[Li+].[CH2:13]1[O:16][CH:14]1[CH3:15]>OS(O)(=O)=O.CN(C)C=O>[OH:16][CH:14]([CH3:13])[CH2:15][N:8]1[CH:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:10])[N:6]([CH2:13][CH:14]([OH:16])[CH3:15])[C:7]1=[O:9]
Reactant: CC(C)C1NC(=O)NC1=O
Reactant: CC1CO1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(O)CN1C(=O)C(C(C)C)N(CC(C)O)C1=O
Temperature: 50 °C

Procedure:
A mixture of 995.0 g of 5-isopropylhydantoin (7 mols), 2000 ml of dimethylformamide and 14.8 g of lithium chloride is stirred at 50° C. 1220 g of propene oxide (21 mols) are slowly added dropwise over the course of 6 hours. Thereafter the temperature is gradually raised to 70° C. and after a total of 15 hours the reaction mixture is allowed to cool. It is adjusted to pH=7 with a few drops of 2 N H2SO4 and the pale yellow solution is filtered. The solution is completely concentrated at 90° C. bath temperature on a rotational evaporator under a waterpump vacuum and is subsequently treated at 90° C./0.1 mm Hg until constant weight is reached. 1654.5 g of a pale yellow highly viscous product (91.7% of theory) are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:18])[C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH2:23])=[O:22]>>[C:21]([C@@H:20]([NH:19][C:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[OH:18])[N:14]=1)=[O:17])[CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:22])[NH2:23]
Reactant: O=C(O)c1cccc(C(O)c2ccc(F)cc2)n1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)c1cccc(C(O)c2ccc(F)cc2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-((4-fluorophenyl)(hydroxy)methyl)picolinic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials. MS (EI): m/e=360.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]1([CH3:20])[CH2:19][O:18]1.N1C=[CH:24][N:23]=[N:22]1.[OH-].[Na+].[CH3:28][N:29]1C(=O)CCC1>CC(OC)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([OH:18])([CH3:20])[CH2:19][N:23]1[CH:24]=[N:29][CH:28]=[N:22]1
Reactant: CC1(c2ccc(Oc3ccc(F)cc3F)cc2Cl)CO1
Reactant: CN1CCCC1=O
Reactant: c1c[nH]nn1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: CC(O)(Cn1cncn1)c1ccc(Oc2ccc(F)cc2F)cc1Cl
Temperature: 120 °C
Reaction time: 15 h

Procedure:
2-[2-chloro-4-(2,4-difluorophenoxy)phenyl]-2-methyl-oxirane (5.0 g), triazole (5.24 g) and NaOH (1.52 g) were dissolved in NMP (50 mL) and the reaction mixture heated to 120° C. and stirred for 15 h. The reaction mixture was diluted with MTBE (200 mL) and extracted three times with 100 mL H2O. The organic phase was washed with sat. aq. NaCl-sol and dried over Na2SO4. After evaporation and column chromatography (CH2Cl2/MeOH, O-20% MeOH), 2-[2-chloro-4-(2,4-difluorophenoxy)phenyl]-1-(1,2,4-triazol-1-yl)propan-2-ol (2.7 g) was obtained as an orange oil.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][C@@H:5]1[CH2:11][OH:12].[N+](C1C=CC([O:22][C:23]([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)=O)=CC=1)([O-])=O>C1COCC1>[F:37][C:34]1[CH:33]=[CH:32][C:31]([N:28]2[CH2:27][CH2:26][N:25]([C:23]([O:12][CH2:11][C@H:5]3[CH2:6][N:7]([CH3:10])[CH2:8][CH2:9][N:4]3[CH3:3])=[O:22])[CH2:30][CH2:29]2)=[CH:36][CH:35]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2)CC1
Reactant: CN1CCN(C)[C@@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(C)[C@@H](COC(=O)N2CCN(c3ccc(F)cc3)CC2)C1
Temperature: 0 °C
Yield: 34.5 %

Procedure:
NaH (60% dispersion in mineral oil; 0.45 g, 11.3 mmol) was suspended in anhydrous THF (20 mL) under nitrogen and the reaction mixture was cooled to 0° C. with stirring. A solution of 1,4-dimethyl-(R)-2-hydroxymethyl piperazine (Intermediate 4; 0.50 g, 3.47 mmol) in THF (20 mL) was added dropwise. The reaction mixture was stirred for 10 minutes at 0° C. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 1.50 g, 4.34 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with sat. aq. NaHCO3 (40 mL) and the THF was removed in vacuo. The aqueous phase was extracted with EtOAc (100 mL). The organic layer was washed with sat. aq. NaHCO3 (5×100 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 μm, 460×26 mm (100 g), 30 mL/min, gradient 0% to 30% (over 75 min) to 100% (over 13 min) MeOH in water with 1% formic acid). The residue was de-salted using K2CO3 in DCM to give [(2R)-1,4-dimethylpiperazin-2-yl]methyl 4-(4-fluorophenyl)piperazine-1-carboxylate (0.42 g, 35%) as a colourless gum.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH:12]([F:14])[F:13].[C:15]([Cu])#[N:16].[Li+].[Br-]>O1CCCC1.C1(C)C=CC=CC=1>[F:13][CH:12]([F:14])[O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[C:15]#[N:16]
Reactant: O=[N+]([O-])c1cccc(OC(F)F)c1Br
Reactant: N#C[Cu]
Agent: [Br-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1c(OC(F)F)cccc1[N+](=O)[O-]
Temperature: 200 °C
Yield: 84.6 %

Procedure:
A mixture of 2-bromo-1-difluoromethoxy-3-nitro-benzene (1 g, 3.7 mmol), CuCN (0.40 g, 4.5 mmol) and LiBr (0.32 g, 3.7 mmol) in tetrahydrofuran (10 ml) are heated in a microwave oven at 200° C. for 40 minutes. The reaction mixture is cooled to ambient temperature, diluted with toluene and washed with aqueous sodium bromide (1M) and aqueous sodium hydrogen sulfite (saturated). The organic phase is dried over sodium sulfate and concentrated. The residue is purified by HPLC to give 2-difluoromethoxy-6-nitrobenzonitrile (0.67 g, 84% yield). 1H-NMR (CDCl3, 400 MHz): 8.20 (d, 1H), 7.85 (t, 1H), 7.75 (d, 1H), 6.75 (t, 1H) ppm.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[CH3:23][S:24][CH2:25][CH2:26]/[CH:27]=[CH:28]/[C:29]#[N:30].C1CCN2C(=NCCC2)CC1.C(#N)C>>[CH3:23][S:24][CH2:25][CH2:26][CH:27]([N:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1)[CH2:28][C:29]#[N:30]
Reactant: CSCC/C=C/C#N
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CSCCC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 120 h
Yield: 83.2 %

Procedure:
A mixture of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (0.30 g, 0.00095 mol), (2E)-5-(methylthio)pent-2-enenitrile (0.28 g, 0.0016 mol) and DBU (45 μL, 0.00030 mol) in ACN (3 mL, 0.06 mol) was stirred at rt for 5 days. The solvent was removed by rotary evaporation to give an orange oil. The crude oil was chromatographed with 30-70 ethyl acetate/hex, to give 0.35 g of a colorless oil (83% yield).
Reaction SMILES: [C:1]1([CH2:7][C@H:8]2[N:14]([S:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)(=[O:17])=[O:16])[CH2:13][C:12]3[CH:23]=[C:24]([C:27]#[N:28])[CH:25]=[CH:26][C:11]=3[NH:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:29]1[CH:33]=[C:32]([CH:34]=O)[N:31]=[CH:30]1.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1>[NH:29]1[CH:33]=[C:32]([CH2:34][N:10]2[C:11]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:12]=3[CH2:13][N:14]([S:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)(=[O:17])=[O:16])[C@H:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:9]2)[N:31]=[CH:30]1
Reactant: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2
Reactant: O=Cc1c[nH]cn1
Agent: CC[SiH](CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2Cc1c[nH]cn1
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
(R)-2,3,4,5-tetrahydro-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H- 1,4-benzodiazepine-7-carbonitrile (10 g) and imidazole-4-carboxaldehyde (2.6 g) were mixed in toluene (20 mL) at 20 to 25° C. To this stirred slurry, first trifluoroacetic acid (9.4 mL) and then trifluoroacetic acid anhydride (5.2 mL) were added sequentially while maintaining the temperature below 30° C. The biphasic mixture was vigorously stirred at 20 to 25° C. for 2 hours. Triethylsilane was then added and the reaction mixture was stirred at 20 to 25° C. until the reaction was determined to be complete according to HPLC assay. The reaction mixture was polish-filtered, e.g., through filter paper or a celite bed. The solvent was removed by evaporation, and a viscous yellow oil containing approximately 100% yield of the crude title product was collected.