Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2].[CH3:14][CH2:15][O:16][C:17](OCC)(OCC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OC(=O)C)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:17]([O:16][CH2:15][CH3:14])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2ccccc21
Reactant: CCOC(OCC)(OCC)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reaction time: 18 h

Procedure:
35.0 g (0.2 mol) of 1-acetyl-2-indolinone are dissolved in 300 ml of acetic anhydride and after the addition of 135 g (0.6 mol) of triethyl orthobenzoate the mixture is refluxed for 22 hours. The solvent is distilled off and the residue diluted with petroleum ether. After 18 hours' standing at ambient temperature, the crystalline precipitate is suction filtered, washed and dried.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[K].Cl[C:10]1[C:18]2[NH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[N:15][C:14]=2[C:13]([N+:23]([O-:25])=[O:24])=[CH:12][C:11]=1[N+:26]([O-:28])=[O:27].O>CN(C)P(=O)(N(C)C)N(C)C>[CH:1]1([O:7][C:10]2[C:18]3[NH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[N:15][C:14]=3[C:13]([N+:23]([O-:25])=[O:24])=[CH:12][C:11]=2[N+:26]([O-:28])=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c2c1Cl
Reactant: OC1CCCCC1
Agent: [K]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c2c1OC1CCCCC1
Reaction time: 8 h

Procedure:
Cyclohexanol (5.4 grams) and potassium (1.9 grams) were reacted in 50 milliliters of dry hexamethylphosphoric triamide. When reaction had ceased, the solution was stirred and 5 grams of 4-chloro-5,7-dinitro-2-trifluoromethylbenzimidazole were added. Stirring was continued overnight. The reaction mixture was then poured into water, acidified, and extracted with ethyl acetate. The ethyl acetate was then removed by evaporation, and the residue was chromatographed on 300 milliliters of silica gel using benzene as eluant. The benzene was removed by evaporation and the crude product was recrystallized from an aliphatic hydrocarbon fraction boiling at 60°-80° C., to which there had been added a trace of benzene. The resulting 4-cyclohexyloxy-5,7-dinitro-2-trifluoromethylbenzimidazole product melted at 151°-2° C. Its identity was confirmed by NMR and by elemental analysis.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]1([C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[OH:33])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH:20]1([C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[O:33][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: OCCN1CCOCC1
Reactant: Oc1ccc(Cl)cc1C1CCCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(OCCN2CCOCC2)c(C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.1 %

Procedure:
Triphenylphosphine (7.47 g, 19.58 mmol) was added to a solution of 2-cyclohexyl-4-chlorophenol (6 g, 28.48 mmol) and 2-hydroxyethylmorpholine (3.5 g, 28.48 mmol) in tetrahydrofuran (50 ml), followed by the dropwise addition of diethylazodicarboxylate (4.5 ml, 28.48 mmol). The mixture stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and triturated with dichloromethane/hexanes and then washed with more hexanes. Chromatography (silica, 10-20-30% ethyl acetate/hexanes) afforded 8.4 g (95%) of 3-cyclohexyl-4-morpholinoethoxy-chlorobenzene as a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[C:38]2[CH:39]=[C:40]([N+:43]([O-])=O)[CH:41]=[CH:42][C:37]=2[O:36][N:35]=1>CCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:43][C:40]2[CH:41]=[CH:42][C:37]3[O:36][N:35]=[C:34]([CH3:33])[C:38]=3[CH:39]=2)[C:9]2[C:10]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:16])[CH3:15])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(C)C)c1C(O)c1ccc(Cl)cc1
Reactant: Cc1noc2ccc([N+](=O)[O-])cc12
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(-c2cnc(OC)nc2OC)c(C(C)C)c1C(Nc1ccc2onc(C)c2c1)c1ccc(Cl)cc1

Procedure:
The title product was prepared in analogy to the procedure described in Step 46.12 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-isopropyl-1H-pyrazole-3-carboxylate (Step 46.11) and 3-methyl-5-nitrobenzo[d]isoxazole (Step 33.3). tR: 1.34 min (LC-MS 2); ESI-MS: 591 [M+H]+ (LC-MS 2); Rf=0.25 (hexane/EtOAc 1:1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.N1CCCC1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15](/[CH:16]=[C:3]2\[C:2](=[O:10])[NH:1][C:9]3[C:4]\2=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:14][CH:13]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: C1CCNC1
Product: O=C1Nc2ccccc2/C1=C/c1ccc(Cl)cc1
Yield: 93.9 %

Procedure:
Oxindole (0.13 g, 1 mmol), 4-chlorobenzaldehyde (0.17 g, 1.2 mmol) were mixed in alcohol; then pyrrolidine (0.17 ml, 2 mmol) was added. The mixture was refluxed for 3 hours. The formed precipitates was collected by filtration and washed with alcohol twice to give the title compound as yellow powder (0.24 g, 92%). LC/MS m/e calcd. for C15H10ClNO 255, observed (M+H)+: 256.1.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:11][C:12]([CH3:20])([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[CH3:13])C(=O)OC(C)(C)C>O1CCOCC1.CCOCC>[ClH:1].[CH3:2][NH:3][CH2:11][C:12]([CH3:20])([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)[CH3:13]
Reactant: CN(CC(C)(C)N1CCOCC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CNCC(C)(C)N1CCOCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4 M HCl in dioxane (0.890 mL, 3.5 mmol) was added dropwise to a solution of tert-butyl methyl(2-methyl-2-morpholinopropyl)carbamate (970 mg, max. 2.98 mmol) in dry dioxane (5 mL) under a N2 atmosphere. The mixture was stirred at room temperature for 6 h. The mixture was evaporated to dryness and the residue was stirred in Et2O overnight. The solids were filtered off, rinsed with Et2O and dried on air to yield a white solid. The solids were dissolved in dry dioxane (2 mL) and 4 M HCl in dioxane (0.890 mL, 3.5 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with Et2O and the solids were filtered off, which resulted in AMN-39 (453 mg, 73% over 2 steps).
Reaction SMILES: NC1(C#N)CCC(NS(C2C=CC(OCC)=C(C)C=2)(=O)=O)CC1.[C:24]([C:26]1([NH:46][C:47](=[O:49])C)[CH2:31][CH2:30][CH:29]([NH:32][S:33]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH3:44])=[C:38]([CH3:45])[CH:37]=2)(=[O:35])=[O:34])[CH2:28][CH2:27]1)#[N:25].C(Cl)=O>>[C:24]([C:26]1([NH:46][CH:47]=[O:49])[CH2:27][CH2:28][CH:29]([NH:32][S:33]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH3:44])=[C:38]([CH3:45])[CH:37]=2)(=[O:35])=[O:34])[CH2:30][CH2:31]1)#[N:25]
Reactant: CCOc1ccc(S(=O)(=O)NC2CCC(C#N)(NC(C)=O)CC2)cc1C
Agent: CCOc1ccc(S(=O)(=O)NC2CCC(N)(C#N)CC2)cc1C
Agent: O=CCl
Product: CCOc1ccc(S(=O)(=O)NC2CCC(C#N)(NC=O)CC2)cc1C

Procedure:
Intermediate 128 was prepared from Intermediate 124 by a method analogous to the method of preparing Intermediate 126 using formyl chloride instead of acetyl chloride as the starting material.
Reaction SMILES: [S:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][CH2:6][CH2:5][C:4]=2[N:3]=[C:2]1[C:15]([OH:17])=O.C(Cl)(=O)C(Cl)=O.[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[NH:27][CH3:28]>C(Cl)Cl.CN(C=O)C>[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[N:27]([CH3:28])[C:15]([C:2]1[S:1][C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][CH2:6][CH2:5][C:4]=2[N:3]=1)=[O:17]
Reactant: CNc1ccccc1Cl
Reactant: O=C(O)c1nc2c(s1)-c1ccccc1OCC2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C(=O)c1nc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 29.8 %

Procedure:
To a suspension of 4,5-dihydro-6-oxa-1-thia-3-aza-benzo[e]azulene-2-carboxylic acid (1 eq, 0.38 mmol, 101 mg) in anhydrous DCM (3 ml), 1 drop of DMF was added, followed by 2M oxalyl chloride in DCM (1.7 eq, 0.65 mmol, 330 ul) dropwise. Effervescence was seen and the reaction was stirred at room temperature for 40 mins before evaporating in vacuo. The crude material was dissolved in DCM (3 ml) and 2-chloro-N-methyl aniline (2 eq, 0.76 mmol, 94 ul) was added. The reaction was stirred at room temperature for 16 hr and extracted into DCM, washed with aq K2CO3, the organic layer dried over MgSO4, filtered, and purified on silica (ISCO, gradient 0% ethyl acetate/petrol to 25% ethyl acetate/petrol) to give 326 as a white solid (42 mg, yield 30%). 1H NMR DMSO, 2.89-2.92 (2H, m), 3.43 (3H, s), 4.23 (2H, br. m), 7.02 (1H, d, J=8.4), 7.08 (1H, t, J=7.6), 7.26 (1H, t, J=8), 7.38-7.41 (2H, m), 7.48-7.51 (2H, m), 7.58 (1H, d, J=8.4). MS: (ESI+): MH+ 371, purity >95%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH:7]2[CH2:10][CH:11]=[CH:12][CH2:13][CH:6]2[C:5]1=[O:14].[C:15]([O:30]CC(C)C)(=O)[CH:16]1[CH2:28][CH:27]=[CH:26][CH2:25][CH:17]1[C:18]([O:20][CH2:21][CH:22](C)C)=[O:19]>[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4].O>[C:18]([O:20][CH2:21][CH2:22][N:4]1[C:5](=[O:14])[CH:6]2[CH2:13][CH:12]=[CH:11][CH2:10][CH:7]2[C:8]1=[O:9])(=[O:19])[CH:17]1[CH2:25][CH:26]=[CH:27][CH2:28][CH:16]1[C:15]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH:7]2[CH2:10][CH:11]=[CH:12][CH2:13][CH:6]2[C:5]1=[O:14])=[O:30]
Reactant: O=C1C2CC=CCC2C(=O)N1CCO
Reactant: CC(C)COC(=O)C1CC=CCC1C(=O)OCC(C)C
Agent: [Ti+4]
Agent: CCCC[O-]
Solvent: O
Product: O=C(OCCN1C(=O)C2CC=CCC2C1=O)C1CC=CCC1C(=O)OCCN1C(=O)C2CC=CCC2C1=O
Temperature: 230 °C
Reaction time: 24 h
Yield: 101 %

Procedure:
N-(2-Hydroxyethyl)-1,2,3,6-tetrahydrophthalimide (195.2 g, 1 mol) was dissolved in diisobutyl 1,2,3,6-tetrahydrophthalate (141.2 g, 0.5 mol). The mixture was kept at 150° C. under vacuum to eliminate any traces of water. Titanium tetrabutoxide (1.7 g) was added under atmospheric pressure and the transesterification reaction was carried out distilling off the isobutyl alcohol formed. As the reaction proceeded the temperature was increased stepwise to 230° C. and the pressure was lowered to 20 Torr (26.7 mbar). After ca. 24 h, 265 g of brown crude bis[2-(1,2,3,6-tetrahydrophthalimido)ethyl] 1,2,3,6-tetrahydrophthalate were obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][C:10]([O:13][C:14]([NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:15])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+].C[Sn](C)(C)C1N=C(N2CCC(NC(=O)OC(C)(C)C)CC2)C=NC=1>CN(C=O)C>[Cl:8][C:4]1[N:3]=[C:2]([N:20]2[CH2:19][CH2:18][CH:17]([NH:16][C:14](=[O:15])[O:13][C:10]([CH3:11])([CH3:9])[CH3:12])[CH2:22][CH2:21]2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(C)(C)OC(=O)NC1CCN(c2cncc([Sn](C)(C)C)n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(c2cncc(Cl)n2)CC1
Temperature: 85 °C
Yield: 53.7 %

Procedure:
A suspension of 2,6-dichloropyrazine (223.5 g, 1.5 mol, 1.0 eq), 4-N-boc-aminopiperidine (300 g, 1.5 mol, 1.0 eq) and K2CO3 (228 g, 1.65 mol, 1.1 eq) in DMF (900 mL) was heated to 85° C. for 20 h. LC-MS analysis showed that tert-butyl 1-(6-(trimethylstannyl)pyrazin-2-yl)piperidin-4-ylcarbamate was formed as the major product. The reaction mixture was cooled to RT and poured into ice-water (3 L). The resulting precipitate was collected by filtration, washed with water (1 L×2) and hexane (1 L×2), and dried at 50° C. under vacuum affording tert-butyl 1-(6-chloropyrazin-2-yl)piperidin-4-ylcarbamate (252 g, >98% purity) in 54% yield. MS (ESI, pos. ion) m/z: 393.0 (M+1). A suspension of tert-butyl 1-(6-chloropyrazin-2-yl)piperidin-4-ylcarbamate (245 g, 0.75 mol, 1.0 eq), hexamethylditin (492 g, 1.5 mol, 2.0 eq) and Pd(PPh3)4 (87 g, 0.075 mol, 0.1 eq) in anhydrous toluene (2 L) was degassed with N2 for 30 min and heated to 110° C. for 24 h. LC-MS analysis showed around 50% conversion and no more further reaction. The reaction mixture was cooled to RT, quenched with water (2 L), and stirred well. After filtration through a celite pad and phase separation, the aqueous layer was extracted with EtOAc (1 L×2). The combined organics were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography eluting with DCM/EtOAc (20/1), affording title compound 1d (150 g, >96% purity) in 45% yield. MS (ESI, pos. ion) m/z: 443.2 (M+1)
Reaction SMILES: [Br-].[CH3:2]C(C)([O-])C.[K+].[C:8]([O:12][C:13]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].O>C1COCC1>[C:8]([O:12][C:13]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH2:2])=[CH:18][CH:17]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)Oc1ccc(C=O)cc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc(OC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
A suspension of 34.1 g of methylriphenylphosphonium bromide in 400 mL of dry THF was treated with 10.7 g of potassium t-butoxide under a nitrogen atmosphere. After stirring for 10 min at room temperature, the yellow solution was treated with a solution of 21.2 g of p-t-butoxycarbonyloxybenzaldehyde in 100 mL of dry THF. After stirring for one hour, the mixture was poured into cold water and extracted with ethyl acetate. The organic phase was washed, dried over magnesium sulfate and concentrated. The crude product was purified by preparative HPLC to yield 16.6 g (79%) of pure p-t-butoxycarbonyloxystyrene. Alternately, IIIc was purified by distillation under reduced pressure.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]2=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)[O:9][C:10](=O)[C:4]2=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1CCC(N=C=NC2CCCCC2)CC1>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:1][N:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]2[C:5](=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)[N:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:10]2=[O:9])[C:6]1=[O:7]
Reactant: CN1C(=O)C2=C(c3ccc(Br)cc3)OC(=O)C2=C1c1ccccc1
Reactant: Nc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C2=C(c3ccc(Br)cc3)N(c3ccccc3)C(=O)C2=C1c1ccccc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 47.9 %

Procedure:
A mixture of furopyrrole 7 (300 mg, 0.79 mmol), aniline (146 mg, 1.57 mmol), DCC (323 mg, 1.57 mmol), trifluoroacetic acid (2-3 drops) and DCM was stirred at room temperature for 144 hours. The solvent was removed, and washing with methanol gave the pyrrolopyrrole 8 as a red solid (173 mg, 55%), m.p. 255-256° C. δH (CDCl3) 7.88-7.83 (2H, m, Ar—H), 7.49-7.43 (5H, m, Ar—H), 7.40-7.26 (5H, m, Ar—H), 7.12-7.07 (2H, m, Ar—H) and 3.35 (3H, s, NCH3)
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:16][S:17][CH2:18][C:19]#[N:20].C(OCl)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:4](=[O:5])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:12][CH:13]=[CH:14][C:15]=1[CH:18]([S:17][CH3:16])[C:19]#[N:20]
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: CSCC#N
Agent: CC(C)(C)OCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC(C#N)c1cccc(C(=O)c2ccccc2)c1N
Temperature: -69 °C
Reaction time: 1 h
Yield: 106.7 %

Procedure:
To a slurry of 29.6 g (0.15 mole) of 2-aminobenzophenone and 13.1 g (0.15 mole) of (methylthio)acetonitrile in 400 ml of methylene dichloride at a temperature of -68° C. was added dropwise 16.8 g (0.155 mole) of t-butyloxychloride at a rate to ensure that the reaction temperature did not exceed -64° C. The resulting solution was stirred at -69° C. for one hour, treated with 15.7 g (0.155 mole) of triethylamine and allowed to warm to ambient temperature. The solution obtained was washed twice with water, dried over sodium sulphate, and concentrated to give 45.2 g of a dark oil as the residue. This residue was chromatographed on 1 kg of silica gel to yield 22.5 g (53%) of the title compound as tan crystals, m.p. 107°-108° C.
Reaction SMILES: Cl.N(OC(C)(C)C)=O.[NH:9]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:10]([C:17]([NH:19][C@H:20]([C:27]([NH:29]N)=[O:28])[CH2:21][O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:18])[CH2:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14].N[C@H:42]([C:47]([NH:49][C@H:50]([C:52]([O:54][CH3:55])=[O:53])[CH3:51])=[O:48])[CH2:43][C:44](=[O:46])[NH2:45].C(N1CCOCC1)C>C(OCC)(=O)C.CN(C)C=O>[NH:9]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:10]([C:17]([NH:19][C@H:20]([C:27]([NH:29][C@H:42]([C:47]([NH:49][C@H:50]([C:52]([O:54][CH3:55])=[O:53])[CH3:51])=[O:48])[CH2:43][C:44](=[O:46])[NH2:45])=[O:28])[CH2:21][O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:18])[CH2:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)[C@H](C)NC(=O)[C@@H](N)CC(N)=O
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](COC(C)(C)C)C(=O)NN
Agent: CC(C)(C)ON=O
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](COC(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 15 h

Procedure:
61.8 ml of 2.32 N-hydrochloric acid in ethyl acetate and 7.3 ml of tert.butyl nitrite are added to 25.95 g of Z-Ser(But)-Ser(But)-NH-NH2 in 200 ml of dimethylformamide at -10°. After 10 minutes a solution of 14.8 g of HCl.H-Asn-Ala-OMe and 36.16 ml of N-ethyl morpholine in 150 ml of dimethylformamide is added dropwise and the mixture is then kept for one hour at -10° and 15 hours at 0°. The solution is freed from the solvent by evaporation, the residue is taken up in chloroform and washed with sodium bicarbonate, dilute hydrochloric acid and with water. The Z-Ser(But)-Ser(But)-Asn-Ala-OCH3 obtained after evaporation of the solvent is reprecipitated from chloroform-petroleum ether. The Rf-value on silicagel in the system chloroform-methanol 9:1 is 0.35.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:12](=[O:14])[CH3:13])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[H-].[Na+].[CH2:18](I)[CH2:19][CH3:20].[Na+].[Cl-]>CS(C)=O.O>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:12](=[O:14])[CH3:13])([CH2:18][CH2:19][CH3:20])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: CCCI
Reactant: CCOC(=O)CC(C(C)=O)C(=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCC(CC(=O)OCC)(C(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-acetyl-succinic acid diethyl ester (30 g, 139 mmol) in DMSO (250 ml) is added NaH (5.8 g, 60% in mineral oil, 145 mmol) in 10 portions over a period of 1 hour. The resulting solution is stirred at room temperature for another 1.5 hours. PrI (17.1 ml, 174 mmol) is added slowly over the period of 45 minutes and the resulting solution is stirred at room temperature overnight. Water (500 ml) is added, the solution is saturated with NaCl and extracted with EtOAc (3×250 ml). The combined extracts are washed with brine (400 ml), dried over Na2SO4 and evaporated in vacuo. The resulting 2-acetyl-2-propyl-succinic acid diethyl ester is obtained as a yellow oil, which is used for the next step without further purification.
Reaction SMILES: [C:1]1([C@@:7]23[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C@@H:8]2[CH2:9][NH:10][CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>C(Cl)(Cl)Cl>[CH:27]1([C:30]([N:10]2[CH2:11][CH2:12][C@:7]3([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C@@H:8]3[CH2:9]2)=[O:31])[CH2:29][CH2:28]1
Reactant: O=C(Cl)C1CC1
Reactant: c1ccc([C@]23CCNC[C@H]2c2ccccc2O3)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(C1CC1)N1CC[C@]2(c3ccccc3)Oc3ccccc3[C@@H]2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.1 %

Procedure:
To a solution of 3.77 g of cis-1,2,3,4,4a,9b-hexahydro-4a-phenyl-benzofuro[3,2-c]pyridine in 100 ml of chloroform containing 1.67 g of triethylamine was added dropwise with stirring under nitrogen a solution of 1.65 g of cyclopropane carbonyl chloride in 25 ml of chloroform. The reaction mixture was stirred at room temperature for 4 hours, diluted with 100 ml of chloroform and washed with 100 ml of 2N HCl and 100 ml of 10% aqueous NaOH. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to afford 4.70 g (98.1%) of a glass.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5]2.Cl.[N:18]([O-])=[O:19].[Na+]>C(O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([N:18]=[O:19])[CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5]2
Reactant: O=N[O-]
Reactant: Cc1ccc2c(c1)CC(c1ccccc1)N2
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)CC(c1ccccc1)N2N=O
Reaction time: 0.08 h
Yield: 100.5 %

Procedure:
5-Methyl-2-phenylindoline (0.7 g, 0.00334 mol) was dissolved in ethanol (5 mL), and 1N hydrochloric acid solution (3.5 mL) was added at 0° C. The resulting reaction mixture was stirred for 5 min, and then a solution of sodium nitrite (0.462 g, 0.00668 mol) in water (8.5 mL) was added at 0° C. The mixture was stirred for 1 h at RT, and after completion of reaction (monitored by TLC), the solvent was removed under reduced pressure to obtain product as a brown colored oil (0.8 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16]([F:20])[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[N+:26]([O-])([O-:28])=[O:27].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:26]([O-:28])=[O:27])=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16]([F:20])[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1cn(-c2cc([N+](=O)[O-])c(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To 10 ml of conc. sulfuric acid was added 1.7 g of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. Potassium nitrate (1.5 g) was added in portions to the solution, which was heated at 60° C. and stirred overnight. The reaction solution was allowed to cool down, poured into ice water, and stirred overnight. The precipitated solid was collected by filtration and washed with water, ethanol and diethyl ether to give 1.7 g of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:38])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[C:33]([CH2:34][N:35]([CH3:37])[CH3:36])=[CH:32][N:31]=[N:30]2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([F:17])=[CH:10][C:9]2[NH:18][C:19](=[O:38])[CH2:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[C:33]([CH2:34][N:35]([CH3:37])[CH3:36])=[CH:32][N:31]=[N:30]4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)Cc1cnnn1-c1cccc(C(=O)CC(=O)Nc2cc(F)c(N(C)C)cc2NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)Cc1cnnn1-c1cccc(C2=Nc3cc(N(C)C)c(F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (5-dimethylamino-2-{3-[3-(5-dimethyl-aminomethyl-[1,2,3]triazol-1-yl)-phenyl]-3-oxo-propionylamino}-4-fluoro-phenyl)-carbamic acid tert.-butyl ester (Example M39) (170 mg, 0.32 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (34 mg).