Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[NH:6][C:7](=[O:15])[C:8]3[CH2:14][S:13][CH2:12][C:9]=3[N:10]([CH3:11])[C:4]=2[CH:3]=1.N1C=CC=CC=1.ClN1C(=O)CCC1=O>O>[Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[NH:6][C:7](=[O:15])[C:8]3[C:9](=[CH:12][S:13][CH:14]=3)[N:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CN1C2=C(CSC2)C(=O)Nc2cc(Cl)c(Cl)cc21
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: c1ccncc1
Product: CN1c2cc(Cl)c(Cl)cc2NC(=O)c2cscc21

Procedure:
To a suspension of 0.40 g. of 6,7-dichloro-1,3,4,9-tetrahydro-4-methyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one in 2.7 ml. of dry pyridine is added, in portions, a total of 0.18 g. of N-chlorosuccinimide. The resulting solution is heated on a steam bath for 15 minutes, cooled and diluted with water. The solid which separates is collected and recrystallized from methanol-water to give off-white crystals, m.p. 270°-272°C. (dec.).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[O:9][CH2:8]2.C=O.[C:17]([BH3-])#N.[Na+]>CC(O)=O.C(#N)C>[Cl:1][CH2:2][CH2:3][N:4]([CH3:17])[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[O:9][CH2:8]2
Reactant: [BH3-]C#N
Reactant: O=C1OCc2cc(NCCCl)ccc21
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(CCCl)c1ccc2c(c1)COC2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A mixture of 5-(2-chloro-ethylamino)-3H-isobenzofuran-1-one (3.0 g, 14.2 mmol), 37% formaldehyde aqueous solution (10 ml, 134 mmol) and sodium cyanoborohydride (3.6 g, 56.8 mmol) in a mixture of 10% AcOH aqueous solution (40 ml) and acetonitrile (40 ml) was stirred at 0° C. for 30 minutes. The mixture was allowed to warm to room temperature and was continuously stirred for 2 hours. The mixture was concentrated under reduced pressure, basified with 1M NaOH aqueous solution, and extracted with EtOAc (3×100 ml). The combined organic layers were washed with 1M NaOH aqueous solution (100 ml) and then water (2×100 ml), dried over anhydrous Na2SO4. Removal of the solvent led to a light yellow oil, which was crystallized with diethyl ether to produce 5-[(2-chloro-ethyl)-methyl-amino]-3H-isobenzofuran-1-one as a yellow solid (2.5 g, 78%).
Reaction SMILES: [C:1]1([CH2:11][N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:25])[C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][C:17]=3[C:26](=[O:28])[NH2:27])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C=O)C.C(OCC)(=O)C>[C:1]1([CH2:11][N:12]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([O:25][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][C:17]=3[C:26](=[O:28])[NH2:27])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc2ccccc12
Reactant: COC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc2ccccc12
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
40% Methanolic Triton B (0.2 mL, 0.26 mM) was added to a solution of the 9-[(1-naphthyl)methyl]-4-hydroxy-5-carbamoyl carbazole (80 mg, 0.22 mM) in 7 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (40 mg, 0.3 mM) was added and the resultant mixture stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate, washed twice with H2O, and once with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 81 mg (85%) of the {9-[(1-naphthyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (CDCl3) δ8.2 (d, 1H, J=8 Hz), 8.05 (d, 1H, J=8 Hz), 7.85-7.0 (m, 11H), 6.65 (d, 1H, J=8 Hz), 6.3 (d, 1H, J=8 Hz), 6.2 (s, 2H), 4.95 (s, 2H), and 3.8 (s, 3H). IR (KBr, cm−1) 3364, 1739, 1630, 1582, 1500, 1455, 1285, 1232, 1153, and 774. MS (FD) m/e 438.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.Cl.[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH2:19])[CH3:15].C1N=CN(C(N2C=NC=C2)=O)C=1>CCN(CC)CC>[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH:19][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH3:15]
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)CCc1ccc(O)cc1

Procedure:
3-(4-Hydroxyphenyl)propionic acid (2.49 g, 15 mmol) was reacted with glycine ethyl ester hydrochloride in the presence of CDI and Et3N as described in Example 56 Part A. After removal of the solvent the residue was dissolved in CHCl3 and washed with 1N HCl, saturated NaHCO3 solution and saturated NaCl solution. After drying (MgSO4) and removal of the solvent in vacuo crude title ester remained (2.44 g) as a viscous oil. NMR indicated this contained a major impurity but it was used without further purification.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[C:33]([O:37][C:38]([CH:40]1[CH:46]([CH:47]=O)[CH2:45][CH2:44][CH2:43][CH2:42][N:41]1[S:49]([C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=1)(=[O:51])=[O:50])=[O:39])([CH3:36])([CH3:35])[CH3:34]>C1COCC1.CCCCC>[C:33]([O:37][C:38]([CH:40]1[CH:46]([CH:47]=[CH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:45][CH2:44][CH2:43][CH2:42][N:41]1[S:49]([C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=1)(=[O:51])=[O:50])=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(C=O)C2C(=O)OC(C)(C)C)cc1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc(S(=O)(=O)N2CCCCC(C=Cc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Benzyl triphenylphosphonium bromide (229 mg, 0.528 mmoL) in 2 mL of THF at 0° C. was added 2.0M butyl lithium solution (0.272 mL) in pentane. After five minutes the solution was warmed to ambient temperature, and kept at that temperature for 30 minutes before adding in the 3-Formyl-1-(4-methoxy-benzene sulfonyl)-azepane-2-carboxylic acid tert-butyl ester (200 mg, 0.503 mmoL) dissolved in 1.52 mL of THF. After 20 hours the reaction was quenched by adding water dropwise, the reaction was diluted with ethyl acetate and washed twice with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The residue was purified by column chromatography (silica: 20% to 25% ethyl acetate in hexanes) to yield 1-(4-Methoxy-benzenesulfonyl)-3-styryl-azepane-2-carboxylic acid tert-butyl ester; MS: (M+H)+ =472, (M+NH4)+ =489.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:23]([NH:25][C@H:26]([C:31]([NH:33][C@H:34]([C:36]([NH:38][C@H:39]([C:45]([OH:47])=[O:46])[CH2:40][CH2:41][C:42](=[O:44])[NH2:43])=[O:37])[CH3:35])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[C@H:11]([CH2:13][CH3:14])[CH3:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(O)(=O)C>CO.[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:23]([NH:25][C@H:26]([C:31]([NH:33][C@H:34]([C:36]([NH:38][C@H:39]([C:45]([OH:47])=[O:46])[CH2:40][CH2:41][C:42](=[O:44])[NH2:43])=[O:37])[CH3:35])=[O:32])[CH2:27][CH:28]([CH3:29])[CH3:30])=[O:24])[CH2:19][CH:20]([CH3:21])[CH3:22])=[O:16])[C@H:11]([CH2:13][CH3:14])[CH3:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O

Procedure:
0.50 Gram of Z-Leu-Ile-Leu-Leu-Ala-Gln-OH was dissolved in 50 ml of methanol and 10 ml of 10%-acetic acid, and the mixture was catalytically reduced by using palladium as a catalyst to obtain H-Leu-Ile-Leu-Leu-Ala-Gln-OH. Hereinafter, this product is referred to as [Peptide A].
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.O[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[N:15]1([CH2:14][CH2:13][O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH2:1])[S:3][C:4]=3[CH:10]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: OCCN1CCOCC1
Reactant: Nc1nc2ccc(O)cc2s1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1nc2ccc(OCCN3CCOCC3)cc2s1
Reaction time: 3.5 h
Yield: 95.7 %

Procedure:
To a solution of benzothiazole 225 (3.62 g, 21.8 mmol) in THF at room temperature under nitrogen, were successively added 4-(2-hydroxyethyl)morpholine (3.17 mL, 26.1 mmol), triphenylphosphine (7.43 g, 28.3 mmol) followed by a dropwise addition of diethyl azodicarboxylate (4.46 mL, 28.3 mmol). The solution was stirred for 3.5 h and THF was partially removed in vacuo. The mixture was partitioned between ethyl acetate and H2O. The combined organic layers were extracted with 1N HCl. The combined acidic extracts were neutralized using a saturated aqueous solution of NaHCO3 and the precipitate was dissolved with ethyl acetate. These combined organic layers were washed with brine, dried over MgSO4, and concentrated. The filtrate was concentrated to afford the title compound 226 (5.83 g, 96% yield) as a light yellow oil. 1H NMR: (Acetone-d6) δ (ppm): 7.37 (d, J=8.8 Hz, 1H), 7.34 (d, J=2.6 Hz, 1H), 6.94 (dd, J=8.8, 2.6 Hz, 1H), 6.60 (bs, 2H), 4.19 (t, J=6.2 Hz, 2H), 3.70-3.67 (m, 4H), 2.90 (s, 2H), 2.81 (t, J=6.2 Hz, 2H), 2.62-2.58 (m, 4H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11]([O:19][CH:20]([CH3:22])[CH3:21])[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=2[O:7][C:6]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:37][C:38](=[O:40])[CH3:39]>CC(=O)CC>[CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11]([O:19][CH:20]([CH3:22])[CH3:21])[C:12]([N:14]([S:15]([CH3:18])(=[O:16])=[O:17])[CH2:37][C:38](=[O:40])[CH3:39])=[CH:13][C:8]=2[O:7][C:6]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:4]
Reactant: CC(=O)CCl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(OC(C)C)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(CC(C)=O)S(C)(=O)=O)c(OC(C)C)cc12
Temperature: 25 °C
Yield: 94 %

Procedure:
2-(4-Fluoro-phenyl)-5-isopropoxy-6-methanesulfonylamino-benzofuran-3-carboxylic acid methylamide (0.093 g, 0.221 mmol, which can be prepared according to one of the procedures described in Example 21) was dissolved in 2-butanone (20 mL). Potassium carbonate (0.20 g, 1.45 mmol) and chloroacetone (0.10 mL, 1.25 mmol) were added at 20° C. The reaction mixture was refluxed for 2 hours, cooled to room temperature and concentrated. The crude product was dissolved in ethyl acetate and washed with 1M hydrochloric acid. The organic layer was concentrated, and the product was purified by flash chromatography (silica gel, ethyl acetate/hexanes gradient) to provide 99 mg (94%) of the title compound as a white solid
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:4]=2[C:5]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6][C:7]=1[C:8](OCC)=[O:9].[NH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>>[OH:1][C:2]1[C:3]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:4]=2[C:5]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6][C:7]=1[C:8]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:9]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#Cc2ccccc2)c2c(-c3ccccc3)noc2c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(C#Cc2ccccc2)c2c(-c3ccccc3)noc2c1O
Temperature: 25 °C
Yield: 82.1 %

Procedure:
Ethyl 7-hydroxy-3-phenyl-4-(phenylethynyl)isoxazolo[4,5-c]pyridine-6-carboxylate (195 mg, 0.51 mmol) and glycine (1.9 g, 25.3 mmol) were added to sodium methoxide solution (38 mL, 19.0 mmol, 0.5 M in MeOH) and the mixture was refluxed for 3 days. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in 100 mL of water and hydrochloric acid was added until pH was 3. The precipitate was isolated by filtration and dried under vacuum to give 173 mg of the title compound. MS: (+) m/z 414.32 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6](Br)=[CH:5][CH:4]=1.C([Li])CCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.C(O)(=O)C>C1COCC1.CCCCCC.O>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([B:16]([OH:21])[OH:17])=[CH:5][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)c(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COc1ccc(B(O)O)c(C)n1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 6-methoxy-3-bromo-2-methylpyridine (59.8 g, 296 mmol) in dry THF (429 mL) was cooled with stirring to ˜−78° C. under a nitrogen atmosphere. A solution of n-butyl lithium (2.5 M, 130.4 mL, 326 mmol) in hexane was added dropwise over 30 min. The reaction mixture was stirred for 3 h at ˜−78° C. A solution of tri-isopropyl borate (102.7 mL, 445 mmol) in dry THF (100 mL) was added dropwise over 30 min. The reaction mixture was warmed to ambient temperature with stirring over 16 h. Acetic acid (37.35 g, 622 mmol), then water (110 mL) were added to the reaction mixture with stirring. After 2 h, the layers were separated and the organic layer was concentrated in vacuo. The residue was taken up in 2-propanol (750 mL) and solvent was removed on a rotary evaporator (bath temperature ˜50° C.). The residue was triturated with ether. The product was collected by filtration and dried in vacuo (48.4 g): mp>200° C.; 1H-NMR(CD3OH, 300 MHz): δ 7.83 (d, 1H, J=8), 6.56 (d, 1H, J=8), 3.85 (s, 3H), 2.44 (s, 3H); GC-MS: 168 (M++H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[CH3:48][C:49]([CH3:54])([CH3:53])[C:50](Cl)=[O:51]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:50](=[O:51])[C:49]([CH3:54])([CH3:53])[CH3:48])[CH2:42][CH2:41]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CC(C)(C)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 31 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 2,2-dimethylpropanoyl chloride as starting materials in 31% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.50 (s, 1H), 9.33 (s, 1H), 9.30 (s, 1H), 8.13 (s, 1H), 7.98 (s, 1H), 7.77 (s, 1H), 7.21 (d, 1H), 7.04 (m, 2H), 6.87 (d, 1H), 6.79 (d, 1H), 4.27 (m, 2H), 2.81 (m, 6H), 2.25 (m, 2H), 2.01 (m, 1H), 1.76 (m, 2H), 1.19 (s, 9H), 1.04 (m, 2H). LCMS for C30H36ClN6O2 (M+H)+: m/z=547.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.[C:14]([CH2:16]C(O)=O)#[N:15].C(O)(=O)CCCCCC.C(N)C1C=CC=CC=1.NC1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]=[C:10]2[CH2:16][C:14]#[N:15])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: N#CCC(=O)O
Agent: CCCCCCC(=O)O
Solvent: NCc1ccccc1
Solvent: Cc1ccccc1
Solvent: Nc1ccccc1
Product: COc1ccc2c(c1)C(CC#N)=CCC2
Yield: 90 %

Procedure:
There are introduced into a 670 litre reactor 85.0 kg of 7-methoxy-1-tetralone, 60.3 kg of cyanoacetic acid and 15.6 kg of heptanoic acid in toluene in the presence of 12.7 kg of benzylamine (or 11.0 kg of aniline). The mixture is heated at reflux. When all the starting substrate has disappeared, the solution is cooled and filtered. The precipitate obtained is washed with toluene and then the filtrate obtained is washed with 2N sodium hydroxide solution and then with water until neutrality. After evaporating off the solvent, the solid obtained is recrystallised from an ethanol/water (80/20) mixture to yield the title product in a yield of 90% and with a chemical purity of more than 99%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([O:62][CH3:63])[CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([O:62][CH3:63])[CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: COc1cccc(CCNCc2ccc(C(C)(C)C)cc2)c1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(CCN(Cc2ccc(C(C)(C)C)cc2)C(=O)c2cccc3cc[nH]c23)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.3 %

Procedure:
To a solution of 80 mg of 1H-indole-7-carboxylic acid (0.5 mmol) and 159 mg of TBTU (0.5 mmol) in 10 ml DMF, were added 0.425 ml (2.48 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 174 mg (0.68 mmol) of (4-tert-butyl-benzyl)-[2-(3-methoxy-phenyl)-ethyl]-amine were added. After stirring for 3 h at rt, the reaction mixture was diluted with 50 ml water and extracted twice with EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; heptane/EtOAc 2:1) to give 168 mg (75%) of a white solid. MS (ISP) 441.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCOCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Yield: 102.6 %

Procedure:
A solution of 4-chloro-3-nitro-pyridine (2.0 mmol, 0.32 g), triethylamine (3.0 mmol, 0.42 mL) and piperazine-1-carboxylic acid tert-butyl ester (2.5 mmol, 0.47 g) in dioxane (2 mL) was irradiated using microwave for 8 minutes at a temperature of 150° C. The solution was then cooled to room temperature and concentrated in vacuo and the resulting residue was purified using flash column chromatography on silica gel (eluent: ethyl acetate) to provide 4-(3-nitro-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (633 mg, quantitative yield). 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.40 (d, J=5.6 Hz, 1H), 6.87 (d, J=6.0 Hz, 1H), 3.68-3.56 (m, 4H), 3.32-3.18 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([F:25])[CH:16]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[NH2:10][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[C:17]([F:25])[CH:16]=1)[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[OH:12]
Reactant: O=C1NC(Cc2ccc(C(F)(F)F)c(F)c2)C(c2ccc(F)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(Cc1ccc(C(F)(F)F)c(F)c1)C(O)c1ccc(F)cc1
Yield: 86.5 %

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-4-((3-fluoro-4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (4.0 g, 11.2 mmol) in ethanol (70 ml) was added 8N aqueous sodium hydroxide solution (7.0 ml, 56 mmol) and the mixture was heated under reflux for 6 hrs. The reaction solution was concentrated, diluted with water (300 ml) and extracted with ethyl acetate (300 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-fluoro-4-(trifluoromethyl)phenyl)-1-propanol (3.21 g, 87%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[O:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[F:16]C1C=C(C(F)(F)F)C=C(C=1)N>>[F:16][C:7]1[CH:6]=[C:5]([NH:8][C:9]([NH2:11])=[O:10])[CH:4]=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:2]=1
Reactant: Nc1cc(F)cc(C(F)(F)F)c1
Reactant: NC(=O)Nc1ccc(F)c(C(F)(F)F)c1
Product: NC(=O)Nc1cc(F)cc(C(F)(F)F)c1

Procedure:
The title compound is prepared in analogy to 1-(4-fluoro-3-(trifluoromethyl)phenyl)urea (intermediate 42), using 5-fluoro-3-(trifluoromethyl)aniline (1.00 g, 5.58 mmol) as starting material. Yield: 630 mg; ESI mass spectrum [M+H]+=223; Retention time HPLC: 0.91 min (Z018_S04).
Reaction SMILES: [CH3:1][C:2]([OH:13])([CH3:12])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1.[H-].[Na+].[CH3:16]I>CN(C)C=O>[CH3:16][O:13][C:2]([CH3:1])([CH3:12])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1
Reactant: CI
Reactant: CC(C)(O)Cn1ccc([N+](=O)[O-])n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)(C)Cn1ccc([N+](=O)[O-])n1
Reaction time: 0.25 h
Yield: 88.9 %

Procedure:
In a round neck flask was placed 2-methyl-1-(3-nitro-pyrazol-1-yl)-propan-2-ol (Example 74, 1.39 g, 7.51 mmol) dissolved in N,N-dimethylformamide (25 mL). To this solution was added sodium hydride (667 mg, 9.01 mmol, 60% dispersion in oil) and it was stirred for 15 min until gas evolution ceased. To this was then added methyl iodide (700 μL, 11.26 mmol) and it was stirred for 2 h at 25° C. The reaction was then quenched with water (250 mL). The reaction was transferred to a separatory funnel and extracted with ethyl acetate (250 mL). The organics were dried over sodium sulfate and then concentrated with silica gel (3 g) in vacuo and purified on Biotage Flash chromatography system (40M column, silica gel, 20% ethyl acetate/hexanes) to afford 1-(2-methoxy-2-methyl-propyl)-3-nitro-1H-pyrazole (1.33 g, 88%) as a colorless oil.
Reaction SMILES: I.[CH3:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][C:6](=[O:11])[CH2:5][C:4]1([CH3:13])[CH3:12].Cl.N[OH:16].[OH-].[Na+]>O>[CH3:2][N+:3]1([O-:16])[C:8]([CH3:9])([CH3:10])[CH2:7][C:6](=[O:11])[CH2:5][C:4]1([CH3:13])[CH3:12]
Reactant: NO
Reactant: CN1C(C)(C)CC(=O)CC1(C)C
Agent: Cl
Agent: I
Agent: [Na+]
Solvent: O
Product: CC1(C)CC(=O)CC(C)(C)[N+]1(C)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.1 %

Procedure:
A suspension of 1,2,2,6,6-pentamethyl-4-piperidone hydroiodide (3 g, 10.0 mmol) and hydroxylamine hydrochloride (980 mg, 14 mmol) in water (6 ml) was stirred at RT for 15 min. Solid NaOH was added until basic pH and thickening of the suspension. Water (3 ml) was added and stirring at RT was continued overnight. The suspension was filtered and the solid washed with water (few ml) and dried. The solid was then dissolved in Et2O, the solution was dried (MgSO4) and concentrated to give after drying pure title compound (1.55 g, 8.41 mmol, yield 83.3%) as white crystals.