Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14](N)=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:25])=O.CN(C)C=O>C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]([Cl:25])=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC(=O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Yield: 89 %

Procedure:
Heat 40 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxamide together with 290 ml of thionyl chloride and 1 ml of dimethylformamide for 16 hours at boiling point. Cool the resulting solution, draw off the formed precipitate and wash it with thionyl chloride and with carbon tetrachloride to obtain an 89% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid chloride [m.p. 208° to 210° C (from dioxane)].
Reaction SMILES: FC1C=C(C=CC=1)CNC1N2N=CC(C(O)=O)=C2N=CC=1C([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=O.[C:36](=O)([O-])O.[Na+].O1[CH2:46][CH2:45]OCC1.Cl>>[CH3:36][C:45]1[C:24]2([CH2:23][CH2:22][NH:21][CH2:26][CH2:25]2)[C:27]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:46]=1
Reactant: O=C([O-])O
Reactant: C1COCCO1
Reactant: O=C(O)c1cnn2c(NCc3cccc(F)c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Agent: Cl
Agent: [Na+]
Product: CC1=Cc2ccccc2C12CCNCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
tert-Butyl 2-methylspiro[inden-1,4′-piperidine]-1′-carboxylate (1.19 g, 3.98 mmol) obtained in step 2 was dissolved in 4 mol/L hydrogen chloride-1,4-dioxane (6 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the obtained residue, and the mixture was suction-filtered to give white crystals. Saturated aqueous sodium hydrogen carbonate solution was added to the white crystals, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.790 g, 72%).
Reaction SMILES: [CH2:1]([N:4]([CH2:10]Cl)[C:5](=[O:9])[CH:6]([Cl:8])[Cl:7])[CH:2]=[CH2:3].[CH3:12][O:13][CH2:14][CH2:15][OH:16].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:4]([CH2:10][O:16][CH2:15][CH2:14][O:13][CH3:12])[C:5](=[O:9])[CH:6]([Cl:8])[Cl:7])[CH:2]=[CH2:3]
Reactant: C=CCN(CCl)C(=O)C(Cl)Cl
Reactant: COCCO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCN(COCCOC)C(=O)C(Cl)Cl

Procedure:
A solution of N-allyl-N-chloromethyldichloroacetamide (21.7 g., 0.1 mole) and 2-methoxyethanol (8.4 g., 8.7 ml., 0.11 mole) in dry chloroform (50 ml.) is placed in a round-bottomed, four-necked flask of 250 ml., equipped with a calcium chloride tube, reflux condenser, mechanical stirrer, dropping funnel and thermometer. Triethylamine (10.1 g., 13.9 ml., 0.1 mole) is added under stirring and external cooling in such a rate that the temperature does not exceed 35° C. After the addition is complete, the mixture is stirred for an additional 2 hours at room temperature. The mixture is washed with water (2×70 ml) for removing the triethylamine hydrochloride formed, the chloroform solution is dried over anhydrous sodium sulfate and, after distillation of the chloroform, the product is dried under reduced pressure to give 23.6 g. (92%) of a pale yellow oil which is the named compound of 95% purity according to an analysis by gas chromatography; nD25 =1.4801. This product is directly useful for practical purposes.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12]C(OC(C)(C)C)=O)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]>FC(F)(F)C(O)=O>[NH2:12][C:3]1[C:2]([NH2:1])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(N)c1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc(N)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.8 %

Procedure:
Methyl 3-amino-2[(tert-butoxycarbonyl)amino]benzoate (61.8 g, 232 mmol) was added to trifluoroacetic acid (250 mL), and the mixture was stirred at room temperature for 3 hr. Trifluoroacetic acid was evaporated in vacuo, and the resulting solid was suspended in ethyl acetate (200 mL), collected by filtration and washed with ethyl acetate (50 mL). The solid was partitioned between ethyl acetate (300 mL) and saturated aqueous sodium hydrogen carbonate (400 mL), and the aqueous layer was seated and extracted with ethyl acetate (300 mL). The combined organic layer was washed with water (300 mL×2) and concentrated in vacuo to give the title compound (24.6 g, 148 mmol, 64%) as a brown solid. The filtrate described above was concentrated in vacuo, and the resulting solid was collected by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo, and the resulting solid was collected by filtration and washed with diethyl ether. The combined solid was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium hydrogen carbonate (100 mL), and the aqueous layer was seated and extracted with ethyl acetate). The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (8.29 g, 49.9 mmol, 22%) as a brown solid. Total amount: 32.9 g, 198 mmol, 85%.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].FC1C=CC(C2(C3C=CC(F)=CC=3)CCN(CC(O)=O)C2=O)=CC=1.[F:47][C:48]1[CH:58]=[CH:57][C:51](/[C:52](=[N:55]/[H])/[NH:53]O)=[CH:50][CH:49]=1.ON/C(=N\[H])/C1C=CC(C(F)(F)F)=CC=1>>[F:47][C:48]1[CH:58]=[CH:57][C:51]([C:52]2[N:55]=[C:20]([CH2:19][N:3]3[CH2:4][CH2:5][C:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:2]3=[O:1])[O:21][N:53]=2)=[CH:50][CH:49]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(\NO)c1ccc(F)cc1
Agent: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Product: O=C1N(Cc2nc(-c3ccc(F)cc3)no2)CCC1(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared using the procedure described in Example 190 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid and (Z)-4-fluoro-N-hydroxybenzimidamide for (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide. 1H NMR (300 MHz, CDCl3) δ ppm 8.02-7.96 (m, 2H), 7.45-7.27 (m, 10H), 7.18-7.11 (m, 2H), 4.88 (s, 2H), 3.57 (t, J=6.5, 2H), 2.88 (t, J=6.5, 2H); MS (DCI) m/z 414.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH2:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[C:26](O)=[O:27].C1(N=C=NC2CCCCC2)CCCCC1.O>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH:16][C:26]([C:25]3[CH:24]=[CH:23][N:22]=[CH:21][C:20]=3[CH3:19])=[O:27])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CCN)CCN(C)C1
Reactant: Cc1cnccc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCNC(=O)c2ccncc2C)CCN(C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 4.7 %

Procedure:
A mixture of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethanamine (0.1 g, 0.411 mmol), 3-methylpyridine-4-carboxylic acid (0.056 g, 0.411 mmol), N,N′-dicyclohexylcarbodiimide (0.093 g, 0.452 mmol) and 4-dimethylaminopyridine (0.055 g, 0.452 mmol) in dry dichloromethane (2.0 ml) were stirred at room temperature for 4 h. To the reaction mixture was added 10 ml of water and the product extracted with dichloromethane (10 ml×3). Combined dichloromethane layers were dried over sodium sulfate and concentrated under reduced pressure to obtain 7 mg of N-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)-3-methylpyridine-4-carboxamide as TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml). 1H NMR (DMSO) 10.05 (bs, 1H), 8.7 (t, 1H), 8.45-8.55 (m, 2H), 7.4 (d, 1H), 7.22 (s, 1H), 7.15 (d, 1H), 7.0 (d, 1H), 4.6 (d, 1H), 3.72-3.85 (m, 3H), 3.4-3.6 (m, 3H), 3.1-3.2 (m, 3H), 3.0 (s, 3H), 2.4 (s, 3H), 2.2 (s, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:21])[NH:9][C@@H:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@@H:13]([OH:20])[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].[Cl:22][C:23]1[CH:28]=[C:27]([N+]([O-])=O)[CH:26]=[CH:25][N:24]=1>CN(C=O)C.O>[C:3]([O:7][C:8](=[O:21])[NH:9][C@@H:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@@H:13]([O:20][C:27]2[CH:26]=[CH:25][N:24]=[C:23]([Cl:22])[CH:28]=2)[CH2:12][CH2:11]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)c2ccccc21
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccnc(Cl)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Sodium hydride (60% in mineral oil, 0.32 g, 8.00 mmol) was suspended in dry DMF (15 mL) under argon. To this was added Intermediate 10a (1.05 g, 4.00 mmol) followed by 2-chloro-4-nitropyridine (0.64 g, 4.02 mmol). The dark coloured mixture was stirred at RT under argon for 30 min. The reaction mixture was diluted with water and extracted with DCM (3×30 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, concentrated in vacuo. Purification by FCC, eluting with 0-70% ethyl acetate in cyclohexane, gave the title compound as a white foam (1.43 g, 95%). LCMS (Method 3): Rt 4.22 min, m/z 373.1 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]([CH3:11])[CH2:8][CH2:9]O)=[CH:4][CH:3]=1.O=S(Cl)[Cl:16]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]([CH3:11])[CH2:8][CH2:9][Cl:16])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CN(CCO)Cc1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: CN(CCCl)Cc1ccc(Br)cc1
Temperature: 60 °C
Yield: 92.8 %

Procedure:
To a solution of 72 (2.9 g, 11.9 mmol) in toluene (20 ml) at RT was added SOCl2 (2.83 g, 2 eq, 23.8 mmol) and the mixture was heated to 60° C. for 3 hrs. The solvent was removed and the crude was dissolved in EtOAc then partitioned between water and satd NaHCO3 soln. The organic phase was collected, dried over Na2SO4, filtered and concentrated. The crude was purified by column chromatography (20% EtOAc in hexane) to afford 73 as a brown oil (2.9 g, 93% yield). 1H NMR (DMSO-d6) δ (ppm): 7.45 (m, 2H), 7.21 (m, 2H), 3.57 (t, J=6.85 Hz, 2H), 3.52 (s, 2H), 2.74 (t, J=6.85 Hz, 2H), 2.26 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([C:18]1[C:19](=[O:38])[N:20]([CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)[CH:21]=[CH:22][C:23]=1O)[CH3:17].O>N1C=CC=CC=1>[CH2:16]([C:18]1[C:19](=[O:38])[N:20]([CH:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]2)[CH:21]=[CH:22][C:23]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH3:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCc1c(O)ccn(C2CCN(C(=O)OC(C)(C)C)CC2)c1=O
Solvent: c1ccncc1
Solvent: O
Product: CCc1c(OS(=O)(=O)C(F)(F)F)ccn(C2CCN(C(=O)OC(C)(C)C)CC2)c1=O
Reaction time: 0.5 h

Procedure:
Trifluoromethanesulfonic anhydride (1.76 mL) was added at 0 C to a mixture of tert-butyl 4-(3-ethyl-4-hydroxy-2-oxopyridin-1(2H)-yl)piperidine-1-carboxylate (1.12 g) in pyridine (17.4 mL), and the mixture was stirred at 0 C for 30 minutes in a nitrogen atmosphere. Water was added thereto, and then, the solvent was distilled off under reduced pressure. Water was added again to the residue, followed by extraction with ethyl acetate. The obtained organic layer was washed with 1 M hydrochloric acid and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.14 g).
Reaction SMILES: [OH:1][C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH:10]2[CH:6]([CH2:7][NH:8][CH2:9]2)[C:5](=[O:11])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][C:36](O)=[O:37].Cl.CN(C)CCCN=C=NCC>ClCCl.O.OC1C2N=NNC=2C=CC=1>[OH:1][C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH:10]2[CH:6]([CH2:7][N:8]([C:36](=[O:37])[CH2:35][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[O:28][CH3:27])[CH2:9]2)[C:5](=[O:11])[CH2:4][CH2:3]1
Reactant: COc1ccccc1CC(=O)O
Reactant: COc1ccccc1C1(O)CCC(=O)C2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=O)N1CC2C(=O)CCC(O)(c3ccccc3OC)C2C1
Temperature: 20 °C
Reaction time: 20 h
Yield: 81.2 %

Procedure:
To a solution of 2.8 g of (3aRS,7RS,7aSR)-7-hydroxy-7-(2-methoxyphenyl)-4-perhydroisoindolone and 1.3 cm3 of triethylamine in 60 cm3 of anhydrous dichloromethane are added 1.55 g of (2-methoxyphenyl)acetic acid, 0.03 g of hydroxybenzotriazole hydrate and 1.96 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. After stirring for 20 hours at 20° C., the reaction mixture is washed with 100 cm3 of water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is recrystallized in ethyl ether and the crystals are drained and then dried under reduced pressure (2.7 kPa). 3.1 g of (3aRS,7RS,7aSR)-7-hydroxy-7-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]-4-perhydroisoindolone are obtained, in the form of a white solid melting at 184° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]([CH2:19][NH:20][CH3:21])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1C2C(=CC=CC=2)C=C1CNC.[OH:35][CH2:36][C@@H:37]1[C:43](=[O:44])[N:42]([CH3:45])[CH2:41][C:40]2[CH:46]=[C:47]([C:50](O)=[O:51])[CH:48]=[CH:49][C:39]=2[NH:38]1.C(C[C@@H]1C(=O)N(C)CC2C=C(C(O)=O)C=CC=2N1)(OC)=O>>[CH3:21][N:20]([CH2:19][C:13]1[N:14]([CH3:18])[C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[CH:17][CH:16]=2)[C:50]([C:47]1[CH:48]=[CH:49][C:39]2[NH:38][C@H:37]([CH2:36][OH:35])[C:43](=[O:44])[N:42]([CH3:45])[CH2:41][C:40]=2[CH:46]=1)=[O:51]
Reactant: CNCc1cc2cc(OCc3ccccc3)ccc2n1C
Reactant: CN1Cc2cc(C(=O)O)ccc2N[C@H](CO)C1=O
Agent: CNCc1cc2ccccc2n1C
Agent: COC(=O)C[C@H]1Nc2ccc(C(=O)O)cc2CN(C)C1=O
Product: CN(Cc1cc2cc(OCc3ccccc3)ccc2n1C)C(=O)c1ccc2c(c1)CN(C)C(=O)[C@@H](CO)N2
Yield: 94 %

Procedure:
According to the procedure of Example 1 (a), except substituting 5-benzyloxy-1-methyl-2-(methylaminomethyl)indole (0.42 g, 1.50 mmole) for the 1-methyl-2-(methylaminomethyl)indole, and substituting (2R)-2-(hydroxymethyl)-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylic acid (0.34 g, 1.37 mmole) for the (2R)-2-[(carbomethoxy)methyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylic acid, the title compound (0.66 g, 94%) was prepared as an off-white solid: MS (ES) m/e 513 (M+H)+.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)[Cl:4].[NH2:13][C:14]1[CH:41]=[CH:40][C:17]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=3)[C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:22][CH2:21]2)=[O:19])=[C:16]([F:42])[C:15]=1[F:43].C(N(C(C)C)C(C)C)C.[CH:53]1([NH2:57])[CH2:56][CH2:55][CH2:54]1>ClCCl.O>[ClH:4].[C:33]([NH:32][C:30](=[O:31])[C:29]1[CH:37]=[CH:38][CH:39]=[C:27]([CH2:26][N:23]2[CH2:22][CH2:21][N:20]([C:18](=[O:19])[C:17]3[CH:40]=[CH:41][C:14]([NH:13][C:1]([NH:57][CH:53]4[CH2:56][CH2:55][CH2:54]4)=[O:12])=[C:15]([F:43])[C:16]=3[F:42])[CH2:25][CH2:24]2)[CH:28]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3F)CC2)c1
Reactant: NC1CCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)NC4CCC4)c(F)c3F)CC2)c1
Product: Cl
Reaction time: 0.5 h
Yield: 115.9 %

Procedure:
To a stirred solution of bis(trichloromethyl) carbonate (0.26 mmol, 76 mg) in dichloromethane (3 mL) was added a mixture of 3-((4-(4-amino-2,3-difluorobenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (0.6 mmol, 257 mg) and N-ethyl-N-isopropylpropan-2-amine (0.11 mL) in dichloromethane (2 mL) dropwise over 2 minutes. After 30 minutes stirring, a mixture of cyclobutylamine (1.192 mmol, 0.113 mL, 85 mg) and N-ethyl-N-isopropylpropan-2-amine (0.22 mL) was added. After 2 hours stirring, the reaction mixture was diluted with dichloromethane and water. The organic layer separated, dried with sodium sulfate and purified by basic reverse phase HPLC. The water/acetonitrile fractions were concentrated under vacuum. The residue was taken up in dichloromethane (1 mL) and 2M hydrochloric acid (2 mL) in ether was added. The volatiles were removed under reduced pressure. Drying in a vacuum oven over night at 50° C. gave the title compound (170 mg). MS (ESI) m/z 528.5[M+H]+
Reaction SMILES: [CH:1]1([CH2:4][Br:5])[CH2:3][CH2:2]1.[C:6]([O:9][C@@H:10]1[C@@H:27]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:26][C@@:25]2([CH3:34])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH2:17][C@H:18]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[C@@H:19]2[O:35][C:36](=[O:38])[CH3:37])[CH2:11]1)(=[O:8])[CH3:7]>C(#N)C>[Br-:5].[C:6]([O:9][C@@H:10]1[C@@H:27]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:26][C@@:25]2([CH3:34])[C@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH2:17][C@@H:18]([N+:39]3([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:40][CH2:41][CH2:42][CH2:43]3)[C@@H:19]2[O:35][C:36](=[O:38])[CH3:37])[CH2:11]1)(=[O:8])[CH3:7]
Reactant: BrCC1CC1
Reactant: CC(=O)O[C@H]1C[C@@H]2CC[C@@H]3[C@H](CC[C@@]4(C)[C@H]3C[C@H](N3CCCC3)[C@@H]4OC(C)=O)[C@@]2(C)C[C@@H]1N1CCOCC1
Solvent: CC#N
Product: CC(=O)O[C@H]1C[C@H]2CC[C@@H]3[C@H](CC[C@@]4(C)[C@H]3C[C@@H]([N+]3(CC5CC5)CCCC3)[C@@H]4OC(C)=O)[C@@]2(C)C[C@@H]1N1CCOCC1
Product: [Br-]

Procedure:
Cyclopropylmethyl bromide (1.0 ml) was added to a solution of (2β,3α,5α,16β,17β)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)-androstane-3,17-diol diacetate (2.0 g) in acetonitrile (20 ml) and the solution was heated under reflux for 14 d. Evaporation of the reaction mixture to dryness under reduced pressure gave a pale brown solid (2.30 g), which was crystallised from dichloro-methanediethyl ether to remove most of the unreacted starting material. Further purification, by chromatography on alumina as described above, gave material, which was dissolved in dichloro-methane and precipitated from the solution with diethyl ether to give 1-[(2β,3α,5α,16β,17β)-3,17-bis(acetyloxy)-2-(4-morpholinyl)-androstan-16-yl]-1-(cyclopropylmethyl) pyrrolidinium bromide, m.p. decomposes above 175° C.; [α]D20 =-11.6° (c 0.66 in CHCl3).
Reaction SMILES: C(N[C:6]([NH:8][S:9]([C:12]1[C:16]([CH3:17])=[CH:15][S:14][CH:13]=1)(=[O:11])=[O:10])=[O:7])CCC.C1(C2CCCCCCC2)CCCCCCC1.C(Cl)(Cl)=O>>[CH3:17][C:16]1[C:12]([S:9]([N:8]=[C:6]=[O:7])(=[O:10])=[O:11])=[CH:13][S:14][CH:15]=1
Reactant: CCCCNC(=O)NS(=O)(=O)c1cscc1C
Agent: C1CCCC(C2CCCCCCC2)CCC1
Agent: O=C(Cl)Cl
Product: Cc1cscc1S(=O)(=O)N=C=O

Procedure:
A mixture of 18.8 g of N-butylaminocarbonyl-4-methyl-3-thiophenesulfonamide, 0.3 g of 1,4-diaza[2.2.2.]bicyclooctane and 100 ml of dry xylenes was heated to reflux (136° C.) and 7.4 g of phosgene was then added at a rate to maintain the temperature at above 125°. The mixture was refluxed for three and one half hours after the addition was completed. It was then cooled, filtered and concentrated in vacuo to yield a dark oil, (15 g) which showed absorption in the infrared spectrum at 2250 cm-1. This intermediate was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=3)[N:9]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[Cu][C:31]#[N:32].[OH-].[NH4+].[CH3:35][N:36](C=O)C>O>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([N:9]2[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([C:35]#[N:36])=[CH:3][CH:4]=3)[CH2:12][CH2:11][CH:10]2[C:13]2[CH:18]=[CH:17][C:16]([C:31]#[N:32])=[CH:15][CH:14]=2)=[CH:21][CH:22]=1)([CH3:28])([CH3:29])[CH3:27]
Reactant: CC(C)(C)c1ccc(N2C(c3ccc(Br)cc3)CCC2c2ccc(Br)cc2)cc1
Reactant: N#C[Cu]
Reactant: CN(C)C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1ccc(N2C(c3ccc(C#N)cc3)CCC2c2ccc(C#N)cc2)cc1
Yield: 78 %

Procedure:
A solution of Example 42C (2.0 g, 3.9 mmol) and copper(I) cyanide (1.047 g, 11.69 mmol) in DMF (19 mL) was heated in a microwave for 7 hours at 160° C. Afterwards the mixture was poured in water (700 mL) and then concentrated ammonium hydroxide (40 mL) was added and the solution extracted with EtOAc. The organic extract was dried, filtered, concentrated and the residue purified by flash chromatography (silica gel, EtOAc/hexanes) to afford 1.23 g (78%) of the title compound. MS (ESI) m/z 406 (M+H)+.
Reaction SMILES: Br[CH:2]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=O.[CH:17]([NH2:19])=O.O.[OH-].[NH4+:22]>C(Cl)(Cl)Cl>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:2]2[N:22]=[CH:17][NH:19][C:3]=2[C:5]2[S:6][CH:7]=[CH:8][CH:9]=2)=[CH:11][CH:12]=1
Reactant: O=C(c1cccs1)C(Br)c1ccc(Cl)cc1
Reactant: [NH4+]
Reactant: NC=O
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Clc1ccc(-c2nc[nH]c2-c2cccs2)cc1

Procedure:
A mixture of 35 g of 2-bromo-2-(4-chlorophenyl)-1-(2-thienyl)ethanone and 200 ml of formamide was refluxed under an air condenser for two hours. It was cooled, poured into water and the pH adjusted to 8-9 by adding ammonium hydroxide. Chloroform was added to the solution, and solid separated and was filtered and washed with chloroform; yield 19.3 g. This was recrystallized from dimethylformamide, filtered and washed with acetonitrile; yield 14.7 g, m.p. 244°-245° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[O:41][CH3:42])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=3)[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[OH-].[Na+]>O1CCOCC1.C(O)C.O>[Cl:1][C:2]1[C:3]([C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[O:41][CH3:42])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(F)cc1-c1c(Cl)cnc2c1cc(C1=CCN(C(=O)OC(C)(C)C)CC1)n2S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(F)cc1-c1c(Cl)cnc2[nH]c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc12

Procedure:
A mixture of Example 229D (0.16 g, 0.261 mmol) and 3N sodium hydroxide (0.261 mL, 0.784 mmol) in 1,4-dioxane (1.743 mL), ethanol (1.743 mL) and water (0.7 mL) was heated at 75° C. for 2.5 hours. The mixture was concentrated and the residue was partitioned in ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel (AnaLogix IntelliFlash 280) eluting with a gradient of from 0-4% methanol in dichloromethane afforded the title compound. MS (ESI+) m/z 458.1 (M+H)+.