Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.[N:11]([O-])=[O:12].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[N:11]=[O:12]
Reactant: Cn1c(=O)cc(N)[nH]c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(=O)[nH]c(N)c(N=O)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-amino-3-methylpyrimidine-2,4(1H,3H)-dione (6 g, 42.6 mmol) in acetic acid (50 mL) was added a solution of sodium nitrite (6.8 g, 98.6 mmol) in water (20 mL) dropwise, then the mixture was stirred at room temperature for 1 h. The mixture was filtered, the filter cake was washed with water and ethanol and dried under vacuum to give 6-amino-3-methyl-5-nitrosopyrimidine-2,4(1H,3H)-dione as violet solid, which was used directly in the next step.
Reaction SMILES: [Na+].[I-:2].[F:3][CH2:4][C:5]([N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])([CH2:8][CH2:9][CH2:10]OCC1C=CC=CC=1)[C:6]#[N:7].C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC#N.O>[F:3][CH2:4][C:5]([N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])([CH2:8][CH2:9][CH2:10][I:2])[C:6]#[N:7]
Reactant: N#CC(CF)(CCCOCc1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: [I-]
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#CC(CF)(CCCI)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
Chlorotrimethylsilyl (22 g) is added dropwise over 20 minutes to a suspension of NaI (30 g) in CH3CN (300 ml) cooled to 0° C. Stirring is continued for 30 minutes at room temperature. 2-Fluoromethyl-2-phthalimido-5-benzyloxypentanenitrile (25 g) in CH3CN (50 ml) is added, and the mixture is stirred overnight at room temperature. This mixture is then poured into cold water containing sodium bicarbonate and sodium thiosulfate, and extracted with diethyl ether. The organic layer is dried over MgSO4 and concentrated in vacuo. The residue is taken up in THF (200 ml) and triethylamine (7 g) is added. After stirring for 1 hour, the mixture is poured into water and extracted with diethyl ether. The organic layer is washed with H2O, dried over MgSO4, and concentrated in vacuo. The residue, a mixture of 2-fluoromethyl-2-phthalimido-5-hydroxypentanenitrile and 2-fluoromethyl-2-phthalimido-5-iodopentanenitrile is taken up in CH3CN (50 ml) and added to a solution of iodotrimethylsilyl prepared as described above from TMS Cl (22 g) and NaI (30 g) in CH3CN (300 ml). The mixture is stirred overnight at room temperature. Then it is poured into cold water containing sodium bicarbonate and sodium thiosulfate, and extracted with diethyl ether. The residue obtained after concentration of the organic layer in vacuo is filtered on a florisil column (30 g). Elution with diethyl ether and removal of the solvent under reduced pressure gives 22 g of 2-fluoromethyl-2-phthalimido-5-iodopentanenitrile as an oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:6]=[C:5]1[CH3:25])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]1([NH2:57])[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[NH2:56].CN1CCOCC1>CN1C(=O)CCC1.O.C(#N)C>[NH2:56][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[NH:57][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:11]2[N:10]=[C:9]([C:8]3[N:4]([CH:1]([CH3:2])[CH3:3])[C:5]([CH3:25])=[N:6][CH:7]=3)[N:14]=[CH:13][N:12]=2)=[CH:24][CH:23]=1
Reactant: Cc1ncc(-c2ncnc(Nc3ccc(C(=O)O)cc3)n2)n1C(C)C
Reactant: Nc1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: Cc1ncc(-c2ncnc(Nc3ccc(C(=O)Nc4ccccc4N)cc3)n2)n1C(C)C
Reaction time: 16 h

Procedure:
To the above ester in EtOH/THF (10:3) (13 mL) was added 3N NaOH (4.5 mL) and stirred at room temperature. After 14 hours, the reaction mixture was concentrated, diluted with water and washed with ether (30 mL). The aqueous phase was then neutralized with 6N HCl (1.5 mL) and then extracted with ethyl acetate and dried (MgSO4). The mixture was then filtered, concentrated and diluted with water and acetonitrile and directly purified by preparative HPLC giving 4-[4-(3-isopropyl-2-methyl-3H-imidazol-4-yl)-[1,3,5]triazin-2-ylamino]-benzoic acid. MS found for C17H18N6O2 as (M+H)+ 339.06. To the above carboxylic acid (150 mg, 0.4 mmol) in NMP (3 mL), was added HATU (228 mg, 0.60 mmol), 1,2-phenylenediamine (95 mg, 0.90 mmol) and NMM (0.2 mL, 1.60 mmol) and stirred for 16 hours. The reaction mixture was diluted with water and acetonitrile and directly purified by preparative HPLC affording the title compound, after lyophilization. MS found for C23H24N8O as (M+H)+ 429.09. 1H NMR (400 MHz, dmso-d6): δ 9.85 (s, 1H); 9.21 (s, 1H); 8.85 (s, 1H); 8.30 (s, 1H); 7.99 (d, J=8.4 Hz, 2H); 7.79 (m, 2H); 7.21 (d, J=7.6 Hz, 1H); 7.08-6.84 (m, 3H); 5.89 (septet, J=6.8 Hz, 1H); 2.71 (s, 3H); 1.53 (d, J=6.8 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]([N:20]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][N:23]2[C:31]([C:34]([OH:36])=O)=[CH:32][CH:33]=[C:22]2[CH2:21]1)=[O:19].[NH2:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]([N:20]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][N:23]2[C:31]([C:34]([NH:37][CH2:38][C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)=[O:36])=[CH:32][CH:33]=[C:22]2[CH2:21]1)=[O:19]
Reactant: O=C(O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3cccc4ccccc34)cc1Cl)C2
Reactant: NCc1ccncc1
Product: O=C(NCc1ccncc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3cccc4ccccc34)cc1Cl)C2

Procedure:
The title compound was prepared by the coupling the 10-[2-chloro-4-(naphthalen-1-yl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step C, with 4-(aminomethyl)pyridine (1.25 equiv) in the manner of Example 1, Step G.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][C@H:23]([CH2:26][C:27]1[N:28]=[CH:29][NH:30][CH:31]=1)[CH2:24][OH:25]>>[OH:25][CH2:24][C@H:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[CH2:26][C:27]1[N:28]=[CH:29][NH:30][CH:31]=1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: N[C@@H](CO)Cc1c[nH]cn1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N[C@@H](CO)Cc3c[nH]cn3)cc2c1=O
Yield: 43 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with (R)-2-amino-3-(1H-imidazol-4-yl)-propan-1-ol according to the GPA affording 22.7 mg (43%) of a red powder. Rt=1.73 min.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:14]([S:15][CH3:16])=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8].O.Cl>CO>[CH3:3][O:4][C:5]1[C:14]([S:15][CH3:16])=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1ccc(C(F)(F)F)c(SC)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(C(=O)O)ccc(C(F)(F)F)c1SC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
16 ml of 20% strength aqueous sodium hydroxide solution were added to 16.0 g (57.1 mmol) of methyl 2-methoxy-3-methylthio-4-(trifluoromethyl)benzoate in 160 ml of methanol, and the mixture was stirred at RT for 4 h. For work-up, the mixture was freed from the solvent and the residue was taken up in a little water. The mixture was cooled in an ice bath and then acidified with dilute HCl. The mixture was stirred at RT for 5 min, and the contents were then filtered. This gave 15.3 g of 2-methoxy-3-methylthio-4-(trifluoromethyl)benzoic acid as residue.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[CH3:30]>>[F:9][C:5]1[CH:4]=[C:3]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[C:2]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[C:22]([CH3:30])[CH:23]=2)=[CH:7][C:6]=1[F:8]
Reactant: Cc1cc(B(O)O)ccc1F
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Product: Cc1cc(-c2cc(F)c(F)cc2-c2ccc(S(C)(=O)=O)cc2)ccc1F

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene (Example 18, Step 2) was reacted with 4-fluoro-3-methylphenylboronic acid (Step 1) to give 1,2-difluoro-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 167.2-167.5° C.; NMR (CDCl3) δ 2.19 (d, J=2 Hz, 3H), 3.04 (s, 3H), 6.71-6.78 (m, 1H), 6.84 (t, J=9 Hz, 1H), 6.92 (dd, J=2, 8 Hz, 1H), 7.18-7.32 (m, 4H), 7.81 (d, J=8 Hz, 2H); MS (FAB) m/z 383 (M+Li)+; HRMS calc'd for M+ 376.0745, found 376.0752. Anal. Calc'd for C20H15F3O2S: C, 63.82; H, 4.02; F, 15.14. Found: C, 64.00; H, 3.95; F, 14.96.
Reaction SMILES: C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1.[NH:24]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[C@@H:25]([C:36]([OH:38])=O)[CH2:26][CH2:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].[NH2:49][C@H:50]([C:54]([NH:56][C@H:57]([C:70]([O:72][CH3:73])=[O:71])[CH2:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[CH:61][CH:60]=1)=[O:55])[CH:51]([CH3:53])[CH3:52].Cl.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[NH:24]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[C@@H:25]([C:36]([NH:49][C@H:50]([C:54]([NH:56][C@H:57]([C:70]([O:72][CH3:73])=[O:71])[CH2:58][C:59]1[CH:60]=[CH:61][C:62]([O:65][C:66]([CH3:67])([CH3:68])[CH3:69])=[CH:63][CH:64]=1)=[O:55])[CH:51]([CH3:53])[CH3:52])=[O:38])[CH2:26][CH2:27][CH2:28][C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30]
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](N)C(C)C
Reactant: CC(C)(C)OC(=O)CCC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](NC(=O)[C@@H](CCCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.28 ml (10 mmoles) of N-ethylmorpholine and 2.1 g of dicyclohexylcarbodiimide are added at 0° C. to a solution in 20 ml of dimethylformamide of 3.54 g (10 mmoles) of Z-D-Aad(OBut)-OH, 3.86 g (10 mmoles) of H-Val-Tyr(But)-OMe.HCl and 1.35 g (10 mmoles) of 1-hydroxybenzotriazole. The mixture is stirred for 1 hour at 0° C. and then at room temperature. It is left to stand overnight and the precipitate is filtered off on the following day. The filtrate is concentrated in a high vacuum and the residue is partitioned between ethyl acetate and water. The ethyl acetate phase is extracted by shaking successively with saturated NaHCO3 solution, KHSO4 solution and water, is dried over Na2SO4 and is concentrated. The residue crystallizes from petroleum ether. Yield 5.96 g. The substance is purified further by hot recrystallization from 90 ml of isopropyl ether and 30 ml of isopropanol. Yield 2.48 g, melting point 104°-107°, [α]D23 =-11.5° (c=1, methanol).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=2)=[O:21])[CH2:11]1)=[O:7])(C)(C)C.[NH2:32][C:33]1[C:41]([Cl:42])=[CH:40][C:36](C(O)=O)=[C:35]([O:43][CH2:44][CH:45]2[CH2:47][CH2:46]2)[CH:34]=1>>[NH2:32][C:33]1[C:41]([Cl:42])=[CH:40][C:36]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH3:31])[CH:23]=3)=[O:21])[CH2:11]2)=[O:7])=[C:35]([O:43][CH2:44][CH:45]2[CH2:46][CH2:47]2)[CH:34]=1
Reactant: Cn1cc(C(=O)NCCCCN2CCC(CNC(=O)OC(C)(C)C)C2)c2ccccc21
Reactant: Nc1cc(OCC2CC2)c(C(=O)O)cc1Cl
Product: Cn1cc(C(=O)NCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OCC3CC3)C2)c2ccccc21

Procedure:
N-(4-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)butyl)-1-methyl-1 H-indole-3-carboxamide (1.00 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-cyclopropylmethyloxybenzoic acid (0.56 g) to give N-(4-(3-(4-amino-5-chloro-2-cyclopropylmethyloxybenzoylaminomethyl)-pyrrolidin-1-yl)butyl)-1-methyl-1 H-indole-3-carboxamide.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:8][CH:7]=1)=[O:4].CN1CCOCC1.ClC(OCC(C)C)=O.[C@@H:32]12[C:38](=[O:39])[NH:37][C@@H:36]1[CH2:35][CH2:34][NH:33]2>O1CCCC1.ClCCl.CN(C)C=O>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9](/[CH:12]=[CH:13]/[C:14](=[O:16])[N:33]2[CH2:34][CH2:35][C@@H:36]3[C@H:32]2[C:38](=[O:39])[NH:37]3)=[CH:10][CH:11]=1)=[O:4]
Reactant: O=C1N[C@@H]2CCN[C@H]12
Reactant: O=C(O)/C=C/c1ccc(NC(=O)CCl)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(CCl)Nc1ccc(/C=C/C(=O)N2CC[C@H]3NC(=O)[C@H]32)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
(E)-3-(4-Chloroacetylaminophenyl)acrylic acid (1.44 g, 6.0 mmol) was suspended in 50 ml of tetrahydrofuran, treated with 0.66 ml (6.0 mmol) of N-methylmorpholine and cooled to −10° C. Subsequently, 0.8 ml (6.0 mmol) of isobutyl chloroformate was added dropwise thereto, the mixture was stirred for 30 minutes while cooling and then, at room temperature overnight. The solvent was removed in a vacuum, the residue was taken up in ethyl acetate and extracted twice with water and once with saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulphate and concentrated. The thus-obtained mixed anhydride was diluted in 25 ml of dichloromethane and added dropwise to a solution of 500 mg (4.5 mmol) of (1S,5R)-2,6-diazabicyclo[3.2.0]heptan-7-one (Example 2) dissolved in 25 ml of dichloromethane and 4 ml of dimethylformamide. The mixture was left to react overnight and the product which separates was filtered off under suction. The latter was purified by chromatography (silica gel, 1. ethyl acetate, 2. ethyl acetate/ethanol=3:2). Yield: 1.0 g (50%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([N:24]=[C:25]=[S:26])[CH:20]=[CH:21][C:22]=1[Cl:23].C1(C)C=CC=CC=1>CCOCC>[CH2:9]([O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:19]2[CH:20]=[CH:21][C:22]([Cl:23])=[C:17]([Cl:16])[CH:18]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: S=C(Nc1ccc(Cl)c(Cl)c1)Nc1ncccc1OCc1ccccc1

Procedure:
A mixture of 2-amino-3-benzyloxypyridine (2.14 g, 0.011 mol), 3,4-dichlorophenyl isothiocyanate (2.62 g, 0.013 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with ether to induce crystallisation of the product. Yield 3.64 g (84%), m.p. 144°-146 ° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:31][C:32]([F:35])([F:34])[F:33])[CH:30]=1)[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[C:12]3=[CH:11][C:10]=2[CH:9]=1)#[N:2].C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:31][C:32]([F:35])([F:33])[F:34])[CH:30]=1)[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([OH:23])=[O:22])[C:12]3=[CH:11][C:10]=2[CH:9]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3cc(C#N)cc(OC(F)(F)F)c3)ccc12
Solvent: CSc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc(OC(F)(F)F)c1
Temperature: 23 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
To a solution of tert-butyl 2-(7-(3-cyano-5-(trifluoromethoxy)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (50 mg, 0.103 mmol) and thioanisole (0.121 mL, 1.028 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.305 mL, 4.11 mmol). The solution was stirred at 23° C. for 3 h. The reaction mixture was concentrated. The residue was triturated with hexanes and purified by HPLC to provide the title compound as a white solid (19 mg). LCMS m/z=431.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 2.27-2.36 (m, 1H), 2.68 (dd, J=16.6, 8.2 Hz, 1H), 2.87-2.96 (m, 2H), 3.76 (quintet, J=7.5 Hz, 1H), 3.99-4.05 (m, 1H), 4.11-4.17 (m, 1H), 5.11 (s, 2H), 6.13 (s, 1H), 6.86 (dd, J=8.7, 2.4 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 7.16 (d, J=8.7 Hz, 1H), 7.43 (s, 1H), 7.57 (s, 1H), 7.68 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:21])[CH:11]([NH:18][CH2:19][CH3:20])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.C=O.[C:26](=O)([O-])[O-].[K+].[K+]>CCCCCC.C(OCC)(=O)C>[CH2:19]([N:18]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:21])[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:23])[F:1])[CH:4]=2)[CH2:26]1)[CH3:20]
Reactant: CCNC(C(=O)Nc1cccc(C(F)(F)F)c1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCN1CN(c2cccc(C(F)(F)F)c2)C(=O)C1c1ccccc1
Yield: 203.4 %

Procedure:
An ethanolic (50 mL) solution of the above N-aryl-2-ethylamino-2-phenylacetamide prepared in Example II (6.8 grams, 0.02 mol) and paraformaldehyde (0.65 grams, 0.02 mol) and potassium carbonate (1.5 grams, 0.01 mol) was heated under reflux for 2 hours. The reaction was followed by thin layer chromatography (3:1 hexane-ethyl acetate). The mixture was concentrated in a rotary evaporator. The product was extracted into ethyl acetate and washed with water and isolated to give the desired 1-ethyl-5-phenyl-3-(3-trifluoromethylphenyl) imidazolidine-4-one (6.8 grams, 97% yield) whose structure was confirmed by nuclear magnetic resonance, infra-red spectroscopy, and mass spectroscopy analysis.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([CH3:42])=[C:18]([CH:28]2[CH2:31][N:30]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:29]2)[C:19]([O:25][CH2:26][CH3:27])=[C:20]([CH:22](O)[CH3:23])[CH:21]=1.O>ClCCl>[Cl:15][C:16]1[C:17]([CH3:42])=[C:18]([CH:28]2[CH2:31][N:30]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:29]2)[C:19]([O:25][CH2:26][CH3:27])=[C:20]([CH:22]([Cl:3])[CH3:23])[CH:21]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCOc1c(C(C)O)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1c(C(C)Cl)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Yield: 43 %

Procedure:
Cyanuric chloride (200 mg, 1.1 mmol) was added to N,N-dimethylformamide (0.083 mL, 1.1 mmol) at room temperature. After the formation of a white solid (ca. 10 minutes), methylene chloride (5 mL) was added, followed by benzyl 3-[3-chloro-6-ethoxy-5-(1-hydroxyethyl)-2-methylphenyl]azetidine-1-carboxylate (310 mg, 0.77 mmol). After addition, the resultant mixture was stirred at room temperature overnight. Water was added, and then diluted with dichloromethane. The organic phases were washed with sat. NaHCO3 solution, water and brine, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 40% EtOAc/hexanes) to give the desired product (140 mg, 43%). LCMS calculated for C22H26Cl2NO3 (M+H)+: m/z=422.1; Found: 422.0.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([N:11]2[CH:15]=[CH:14][N:13]=[N:12]2)[CH:8]=[CH:7][C:6]=1[CH2:16][C:17]([O:19]C)=[O:18].O.O[Li].O.Cl>C1COCC1>[F:22][C:2]([F:1])([F:21])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([N:11]2[CH:15]=[CH:14][N:13]=[N:12]2)[CH:8]=[CH:7][C:6]=1[CH2:16][C:17]([OH:19])=[O:18]
Reactant: COC(=O)Cc1ccc(-n2ccnn2)cc1OCC(F)(F)F
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(-n2ccnn2)cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of methyl 2-(2,2,2-trifluoroethoxy)-4-(1-triazolyl)phenylacetate (0.54 g, 1.7 mmol) from Step 2 above in THF (10 mL) and water (2.5 mL) was added LiOH.H2O (0.11 g, 2.6 mmol). The mixture was stirred at ambient temperature for 14 h. The solution was adjusted to pH 2 by the addition of 5 N aqueous HCl and the solvents were removed under reduced pressure to give 2-(2,2,2-trifluoroethoxy)-4-(1-triazolyl)phenylacetic acid was obtained as a gum (HPLC retention time=6.0 min (method A)).
Reaction SMILES: Br.[S:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][CH2:5][CH2:4][CH2:3]1.[Li][CH2:14]CCC.CI>C1COCC1>[CH3:14][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc2c(c1)NCCCS2
Reactant: [Li]CCCC
Agent: Br
Solvent: C1CCOC1
Solvent: CI
Product: CN1CCCSc2ccccc21
Reaction time: 1 h

Procedure:
8.30 g of 3,4-dihydro-2H-1,5-benzothiazepine hydrobromide were placed in 150 ml of THF and deprotonized with 48 ml of 1.55M nBuLi (hexane) under an Argon atmosphere at -10° C. After 1/4 hour, 4.64 ml of Methyl iodide (MeI) were added dropwise to the yellow solution of the Li amide and the mixture was stirred for 1 hour. It was then poured on to ice, extracted with ether, washed with water, dried and evaporated. Column chromatography on silica gel (petroleum ether/ethyl acetate 96/4) yielded 5.70 g of 3,4-dihydro-5-methyl-2H-1,5-benzothiazepine as a colorless oil which was formulated as follows:
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.O=[C:12]1[CH2:17][CH2:16][N:15]([C@H:18]([CH3:22])[CH2:19][C:20]#[N:21])[CH2:14][CH2:13]1.[C-]#N.[Na+]>O.CO>[NH2:21][CH2:20][CH2:19][C@H:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:6][C:5]2[CH:7]=[CH:8][C:9]3[O:10][CH2:1][O:2][C:3]=3[CH:4]=2)[CH2:13][CH2:14]1)[CH3:22]
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Reactant: Nc1ccc2c(c1)OCO2
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@H](CCN)N1CCC(Nc2ccc3c(c2)OCO3)CC1

Procedure:
Using general procedure A with 3,4-(methylenedioxy)aniline (250 mg, 1.8 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (329 mg, 2.0 mmol) followed by general procedure J gave a green oil, which was subsequently treated with a solution of NaCN (175 mg) in H2O (5 mL) and MeOH (5 mL) to afford [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-benzo[1,3]dioxol-5-yl-amine as a white solid (281 mg, 68% over 2 steps) after work-up and purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([S:17][C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Sc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: Nc1ccc(Sc2ccccc2)cc1

Procedure:
The titled compound was prepared from 4-fluoronitrobenzene and thiophenol using the procedures in Steps 1 and 2 of Example 8.