Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7](C)[CH:6](NC=O)[N:5]=2)[CH2:3][CH2:2]1.[CH2:13]([N:15](CC)[CH2:16]C)C.O=P(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([CH2:16][N+:15]#[C-:13])[N:5]=2)[CH2:2][CH2:3]1
Reactant: CCN(CC)CC
Reactant: CN1OC(C2CC2)=NC1NC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: [C-]#[N+]Cc1noc(C2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 5-cyclopropyl-3-formylamino-methyl-1,2,4-oxadiazole (60 mmol) and triethylamine (176 mmol) in CH2Cl2 (100 ml) was charged dropwise with POCl3 (60 mmol) at 0° C. The mixture was then left for 30 min. with stirring at 0° C., whereafter a solution of Na2CO3 (60 mmol) in H2O (50 ml) was added. The mixture was heated to room temperature, whereafter the organic phase was separated, dried and evaporated in vacuo. The residue was treated with ether, decanted and the solution was evaporated to give the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1I.BrC1C=CC=C(F)C=1N>>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: Fc1cccc(Br)c1I
Reactant: COc1ccc(S)cc1
Agent: Nc1c(F)cccc1Br
Product: COc1ccc(Sc2c(F)cccc2Br)cc1

Procedure:
Prepared from 4-methoxy-benzenethiol and 1-bromo-3-fluoro-2-iodo-benzene (prepared from 2-bromo-6-fluoro-phenylamine by diazotization according to the general procedure by Tunney and Stille J. Org. Chem. 1987, 52, 748-753).
Reaction SMILES: [H-].[Na+].[CH3:3]CCCC.[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]([CH:27]=[CH2:28])[CH2:17][NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=[CH:13][C:14]=1[Cl:15].CCCCCC.CCOC(C)=O>CCCCCC.C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]([CH:27]=[CH2:28])[CH2:17][N:18]([CH3:3])[C:19](=[O:26])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: CCCCC
Reactant: C=CC(CNC(=O)c1ccccc1)c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC(CN(C)C(=O)c1ccccc1)c1ccc(Cl)c(Cl)c1
Temperature: 23 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
Wash a suspension of NaH (312 mg of 60% in mineral oil, 7.81 mmol, 1.25 eq) in hexane with dry pentane (2×100 mL), suspend in dry THF (30 mL) and treat with the product of step 7 (2.0 g, 6.25 mmol) at 23° C. Stir the resulting yellow suspension for 20 min at 23° C., then add CH3 l (777 μL, 12.5 mmol, 2.0 eq). After 1 h, pour the mixture onto a pad of silica gel packed with hexane:EtOAc (1:1) (500 mL) and concentrate the filtrate to give 2.1 g (6.25 mmol, >99%) of N-[2-(3,4-dichlorophenyl)-3-butenyl]-N-methyl benzamide as a light yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([CH:21](O)[C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[C:19]([CH:33]([CH3:35])[CH3:34])[CH:18]=[C:17]3[C:9]=2[C:10](=[O:36])[CH2:11][C:12]2([O:16]3)[CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:43])CC)C.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:20]([CH:21]([F:43])[C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:27]=3)=[C:19]([CH:33]([CH3:34])[CH3:35])[CH:18]=[C:17]3[C:9]=2[C:10](=[O:36])[CH2:11][C:12]2([O:16]3)[CH2:13][CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(C(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under argon, 180 mg (0.32 mmol) of 5-(4-fluorophenyl)-6-{hydroxy[4-(trifluoromethyl)phenyl]-methyl}-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 52A) are dissolved in 3.2 ml of toluene, 52 μl (0.39 mmol) of diethylaminosulfur trifluoride are slowly added at −78° C. and the mixture is stirred at −78° C. for 1 h. The temperature is then slowly increased to −60° C. After 2 h, water is added and the mixture is extracted twice with ethyl acetate. The combined organic phases are washed once with saturated sodium bicarbonate solution and once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate 12:1). This gives 107 mg (66% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20](OC)[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28][C:29](=O)[CH3:30].[Br:32]C1C=C2C(=CC=1)NC=C2CC(O)=O.Cl[C:47]1C=C(CN)C=C[C:52]=1[N:53]1[CH2:58]CN(C)CC1>>[Br:32][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:13][C:12]([NH:11][C:10]([NH:9][CH2:8][C:6]1[CH:7]=[CH:2][C:3]([N:28]2[CH2:47][CH2:52][N:53]([CH3:58])[CH2:30][CH2:29]2)=[C:4]([Cl:27])[CH:5]=1)=[NH:26])=[O:25]
Reactant: O=C(O)Cc1c[nH]c2ccc(Br)cc12
Reactant: CN1CCN(c2ccc(CN)cc2Cl)CC1
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Product: CN1CCN(c2ccc(CNC(=N)NC(=O)Cc3c[nH]c4ccc(Br)cc34)cc2Cl)CC1

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using 2-(5-bromo-1H-indol-3-yl)acetic acid in step 19 (A) and (3-chloro-4-(4-methylpiperazin-1-yl)phenyl)methanamine (preparation F) in step 19 (B), the title compound was prepared. MS (ESI) (M+H)+=517.02/518.98 1H-NMR (500 MHz, CD3OD) δ 7.73 (s, 1 H), 7.45 (s, 1 H), 7.27-7.38 (m, 3 H), 7.17-7.26 (m, 2 H), 4.49 (s, 2 H), 3.93 (s, 2 H), 3.57-3.68 (m, 2 H), 3.47-3.58 (m, 2 H), 3.28-3.40 (m, 2 H), 3.06-3.18 (m, 2 H), 2.96-3.01 (s, 3 H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17](I)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17]([C:27]3[CH:28]=[CH:29][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:25][CH:26]=3)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: O=C1CNc2ncc(I)cc2N1Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)cc1
Yield: 43 %

Procedure:
1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (46 mg) was reacted with 4-(methanesulfonyl)phenyl boronic acid as in General Procedure 4B to give the title compound as a yellow solid (43% yield). LCMS: m/z=394.22 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.08 (3H, s), 4.54 (2H, s), 5.28 (2H, s), 7.30 (3H, m), 7.39 (3H, m), 7.45 (2H, d, J=8.3 Hz), 7.78 (1H, d, J=1.5 Hz), 7.94 (2H, d, J=8.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:16]([OH:18])=O)=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[C:60]([Si:64]([CH3:75])([CH3:74])[O:65][C:66]1[CH:67]=[C:68]([CH:71]=[CH:72][CH:73]=1)[CH2:69][NH2:70])([CH3:63])([CH3:62])[CH3:61]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:16](=[O:18])[NH:70][CH2:69][C:68]2[CH:71]=[CH:72][CH:73]=[C:66]([O:65][Si:64]([C:60]([CH3:63])([CH3:62])[CH3:61])([CH3:74])[CH3:75])[CH:67]=2)=[CH:8][C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:4]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CN)c1
Reactant: COC(=O)c1sc(C(=O)O)cc1-c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To a solution of 3-Phenyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (500 mg, 1.91 mmol) in anhydrous DMF (10 mL) was added triethylamine (0.53 mL, 3.82 mmol), HBTU (1.45 g, 3.82 mmol), HOBT (390 mg, 3.82 mmol), and 3-(tert-Butyl-dimethyl-silanyloxy)-benzylamine (540 mg, 2.29 mmol). The mixture was stirred at room temperature 1 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-30% EtOAc in hexane to afford the desired product (0.36 g, 39% yield).
Reaction SMILES: CC([O-])(C)C.[K+].CS(C)=O.[CH2:11]([O:18][CH2:19][C@@H:20]1[CH2:23][C@H:22](C2C=C(C)C=CC=2S([O-])(=O)=O)[CH2:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CCOCC>[CH2:11]([O:18][CH2:19][CH:20]1[CH2:23][CH:22]=[CH:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])c([C@H]2C[C@@H](COCc3ccccc3)C2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: C1=CC(COCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 250 mL flask with t-BuOK (11.95 g, 0.11 mol) inside, dry DMSO 50 mL was added under argon to give a colorless solution. Then at room temperature, cis-3-(benzyloxymethyl)cyclobutyl-tosylate (12.3 g, 35.5 mmol) was added very slowly to the previous flask. The reaction mixture was left stirring at room temperature for 4 hr, after which time quench the reaction by adding H2O 200 mL slowly, followed by the addition of 100 mL Et2O. The separated water phase was re-extracted with Et2O three times and the combined organic phase was washed with H2O four times. The organic phase was dried over MgSO4 and concentrated to dryness to give a light yellow oil which was purified by silica gel flash chromatography (Hexane:EtOAc=9:1) to give 4.45 g (71.9%, Rf=0.59 ((Hexane: EtOAc=9:1)) the desired product. 1H NMR (CDCl3, 600 MHz): δ 2.19-2.21 (d, J=12, 1H), 2.66-2.69 (dd, J=13.2, 4.2, 1H), 3.11-3.14 (m, 1H), 3.50-3.56 (m, 2H), 4.54 (s, 2H), 6.09-6.11 (m, 2H), 7.27-7.35 (m, 5H). 13C NMR (CDCl3, 150 MHz): δ 34.40, 43.72, 73.32, 74.07, 127.75, 127.89, 128.59, 137.16, 138.59. IR (neat) νmax 3257, 2917, 2849, 1739, 1462, 1376, 1241, 967, 746.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[CH2:11][CH:12]=C.C[N+]1([O-])CC[O:19]CC1>CC(C)=O.O.C(OCC)(=O)C.O=[Os](=O)(=O)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[CH2:11][CH:12]=[O:19]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCc1cc(C)ccc1C(=O)OC
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(C)cc1CC=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.3 %

Procedure:
To a solution of 2-allyl-4-methyl-benzoic acid methyl ester (0.980 g, 5.15 mmol) in acetone (20 mL) and water (2.0 mL) are added N-methyl morpholine oxide (0.89 g, 7.57 mmol) and OsO4 (1 mg). The resulting reaction mixture is stirred at room temperature for three hours. The reaction mixture is diluted with ethyl acetate (50 mL) and is washed with Na2S2O3 (1.0 M, 20 mL). The organic layer are concentrated and the residue is dissolved in THF (25 mL) and water (15 mL). To the solution, NaIO4 (3.24 g, 15.2 mmol) is added and the mixture is stirred at room temperature for two hours. The mixture is filtered and the filtrate is concentrated, diluted with ethyl acetate (60 mL), and washed with Na2S2O3 (1.0 M, 20 mL). The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue is purified via flash chromatography eluting with 30-40% ethyl acetate in hexane to give the title compound (0.260 g, 26%). 1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 7.94-7.92 (d, 1H), 7.15-7.13 (d, 1H), 7.00 (s, 1H), 3.99 (s, 2H), 3.81 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: C[N:2]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][N+:12]([O-:14])=[O:13])[CH2:7][CH2:6]1)[CH:3]=[O:4].CN[C@H]1CC[C@H](O[N+]([O-])=O)CC1>>[CH:3]([NH:2][C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][N+:12]([O-:14])=[O:13])[CH2:7][CH2:6]1)=[O:4]
Reactant: CN(C=O)[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Agent: CN[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Product: O=CN[C@H]1CC[C@H](O[N+](=O)[O-])CC1

Procedure:
trans-N-methyl-N-formyl-4-nitroxycyclohexylamine from trans-N-methyl-4-nitroxycyclohexylamine melting point: 52°-54° C. (ether/isohexane), yield: 60% of theory.
Reaction SMILES: [C:1]1([C@H:11]([NH:13][CH2:14]/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(O)=O>C(O)C.C1(C)C=CC=CC=1.Cl[Pd]Cl>[CH3:12][C@@H:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=12
Reactant: C[C@@H](NC/C=C/c1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Agent: Cl[Pd]Cl
Solvent: O=CO
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[C@@H](NCCCc1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Yield: 66.3 %

Procedure:
A mixture of compound (VI) (3.0 g), PdCl2 (0.01 g) in ethanol (10 mL) was heated up to reflux temperature and added in 5 hrs with formic acid (0.3 g). The mixture was then cooled down, diluted with toluene and washed with 30% w/w aqueous sodium hydroxide until neutrality. The organic layer was dried and concentrated to give Cinacalcet free base, compound (I) (2.0 g).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[C:8](=[O:16])[NH:7][C:6]2[CH:17]=[CH:18][CH:19]=[N:20][C:5]1=2)=[O:3].[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:33][CH2:34][NH2:35])[CH2:24][CH3:25])[CH3:22]>C(#N)C>[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:33][CH2:34][NH:35][C:2]([N:4]1[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[C:8](=[O:16])[NH:7][C:6]2[CH:17]=[CH:18][CH:19]=[N:20][C:5]1=2)=[O:3])[CH2:24][CH3:25])[CH3:22]
Reactant: Cc1ccc2c(c1)N(C(=O)Cl)c1ncccc1NC2=O
Reactant: CCN(CC)CC1CCCCN1CCN
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CCNC(=O)N1c2cc(C)ccc2C(=O)Nc2cccnc21
Yield: 40 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-9-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[(diethylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 40% of theory. Colourless crystals, m.p. 183°-185° C. (acetonitrile).
Reaction SMILES: CN1C[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl[CH2:9][CH2:10][O:11][C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13].ClC(OCC(C)C)=O.[C:30]([C:32]1[CH:42]=[CH:41][C:35]([O:36][CH2:37][CH:38]([NH2:40])[CH3:39])=[CH:34][CH:33]=1)#[N:31]>C(Cl)Cl.O>[C:30]([C:32]1[CH:42]=[CH:41][C:35]([O:36][CH2:37][CH:38]([NH:40][C:19](=[O:21])[C@H:15]([CH:16]([CH3:17])[CH3:18])[NH:14][C:12]([O:11][C:10]2[CH:9]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:13])[CH3:39])=[CH:34][CH:33]=1)#[N:31]
Reactant: CN1CCCCC1
Reactant: CC(C)[C@H](NC(=O)OCCCl)C(=O)O
Reactant: CC(N)COc1ccc(C#N)cc1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](NC(=O)Oc1ccccc1)C(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
0.5 g of N-methylpiperidine was added to a solution containing 1.1 g of N-(2-chloroethoxycarbonyl)-L-valine dissolved in 40 ml of methylene chloride, at -20° C. After the mixture was stirred for 15 minutes at the same temperature, 0.7 g of isobutyl chloroformate was added to the mixture at -40° C., and subsequently the whole mixture was stirred for 1 hour at -20° C. 0.9 g of 2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred. The whole mixture was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue, which was an oily substance, was purified by column chromatography on silica gel, thus yielding 1.0 g of the desired product in the form of colorless grains (yield: 52%).
Reaction SMILES: Cl.[C:2]([O:6][C:7]([C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][C:15]([OH:17])=O)=[O:8])([CH3:5])([CH3:4])[CH3:3].[NH2:18][C@@H:19]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)=[O:21]>>[CH2:39]([O:38][CH2:37][C@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:10]1[CH2:11][CH2:12][CH2:13][C@H:9]1[C:7]([O:6][C:2]([CH3:3])([CH3:4])[CH3:5])=[O:8])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)=[O:21])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1CC(=O)O
Agent: Cl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1CC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 42.3 %

Procedure:
Proceeding as in Example 1, but substituting (S)-2-(2-(tert-butoxycarbonyl)pyrrolidin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 103, (S)-tert-butyl 1-(2-((S)-3-(benzyloxy)-1-(4-(4-fluorophenoxy)phenylamino)-1-oxopropan-2-ylamino)-2-oxoethyl)pyrrolidine-2-carboxylate (3 mg, 42.3%). MS (EI) for C33H38FN3O6. found 592.7 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)cc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-Amino-pyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 10.7 mmol) in methanol (20 mL) was added 4-Chloro-benzaldehyde (1.5 g, 10.7 mmol). The resultant solution was heated at 60° C. overnight. The reaction mixture was cooled to 0° C. and to it was added NaBH4 (629 mg, 10 mmol). After 1 h, the reaction solution was quenched with saturated NaHCO3 solution and extracted with ethyl acetate. The organic extract was dried over MgSO4, filtered and concentrated to provide the crude product as an oil. The crude product was used in the subsequent reaction without further purification. LCMS (retention time=1.27, ES+311).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[C:17](=O)[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:46])([F:45])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([C:39](=[O:44])/[CH:40]=[C:41](\[NH2:43])/[CH3:42])[CH2:35][CH2:34]1>C(O)(C)C>[F:46][C:24]([F:23])([F:45])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]([C:40]2[CH:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]([N+:20]([O-:22])=[O:21])=[C:17]([CH3:18])[NH:43][C:41]=2[CH3:42])=[O:44])[CH2:37][CH2:38]1
Reactant: CC(=O)C(=Cc1ccccc1OCc1ccccc1)[N+](=O)[O-]
Reactant: C/C(N)=C/C(=O)N1CCN(CCc2ccccc2C(F)(F)F)CC1
Solvent: CC(C)O
Product: CC1=C(C(=O)N2CCN(CCc3ccccc3C(F)(F)F)CC2)C(c2ccccc2OCc2ccccc2)C([N+](=O)[O-])=C(C)N1

Procedure:
2.97 g (10 mmol) of 1-(-2-benzyloxyphenyl)-2-nitro-1-buten-3-one and 2.96 g (mmol) of 3-aminocrotonic acid 4-(2-trifluoromethylphenylethyl)piperazide are heated in 15 ml of isopropanol at 60° C. for 4 hours. After cooling, a crude product is obtained, and this is recrystallized from a littel ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.Cl.[N:13]1([CH2:18][CH2:19][NH2:20])[CH:17]=[N:16][CH:15]=[N:14]1.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][CH2:19][CH2:18][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: NCCn1cncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCn1cncn1)c1ccc(Br)cc1
Reaction time: 8 h

Procedure:
A mixture of about 2.2 g of 4-bromobenzoyl chloride, about 1.85 g of 1H-1,2,4-triazole-1-ethanamine dihydrochloride, about 30 ml of approximately 1N sodium hydroxide and about 75 ml of methylene chloride was stirred overnight, then about 5 ml of approximately 1N sodium hydroxide and about 75 ml of methylene chloride were added. The layers were separated and the organic layer was concentrated to remove the solvent. The crystalline residue was washed onto a filter with ether giving the desired product, mp 160°-162° C.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[Cl:16]Cl>C(O)(=O)C>[Cl:16][C:3]1[C:4]2[C:13](=[N:12][C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:14]=[CH:15][C:2]=1[OH:1]
Reactant: Oc1ccc2nc3ccccc3cc2c1
Reactant: ClCl
Solvent: CC(=O)O
Product: Oc1ccc2nc3ccccc3cc2c1Cl
Temperature: 15 °C
Reaction time: 8 h

Procedure:
2-Hydroxyacridine (3.17 grams; 0.015 mole) and acetic acid (100 ml) are charged into a glass reaction vessel equipped with a stirrer and thermometer. The mixture is cooled to 15° C. and a solution of chlorine (0.015 mole) in acetic acid (25 ml) is added dropwise with stirring. After the addition is completed stirring is continued at room temperature overnight. After this time the reaction mixture is filtered to recover product. The product is then washed, dried and dissolved in tetrahydrofuran (50 ml). The solution is treated with triethylamine (2 ml). The treated solution is then filtered and the filtrate treated with activated charcoal. The filtrate is then stripped of solvent in a rotary evaporator to yield chloro-2-hydroxyacridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](CC#N)=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1.[OH-:20].[K+].[CH2:22]([OH:24])[CH3:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:23][C:22]([OH:20])=[O:24])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1
Reactant: CCO
Reactant: N#CCc1cc(C(F)(F)F)nn1-c1ccccc1Cl
Reactant: [OH-]
Agent: [K+]
Product: O=C(O)Cc1cc(C(F)(F)F)nn1-c1ccccc1Cl

Procedure:
Into a 250 mL round bottom flask was weighed 2.3 g of crude 2-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)acetonitrile (8.0 mmol). To this was added 40 mL of ethanol and 2.5 g of KOH (44 mmol). The resulting mixture was heated to reflux. After 17 hours at reflux the reaction was cooled and concentrated in vacuo to remove most of the ethanol. The resulting dark oil was taken up in H2O and EtOAc and acidified by the addition of 3N aqueous HCl. The acidic aqueous was extracted with EtOAc (3×), the combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the crude acid as a dark oil. The crude product was purified by silica gel flash chromatography on an 80 g column using gradient elution from 0% to 40% acetonitrile/CH2Cl2 and collected by monitoring the UV response at 240 nm. Appropriate fractions were combined and concentrated in vacuo to afford 2-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)acetic acid as a dark glass. The product was not completely pure and was taken up in 1N NaOH and Et2O. The ether layer was extracted with 1N NaOH (1×) and the combined basic aqueous layers were extracted with Et2O (1×). The basic layer was acidified by the addition of concentrated HCl and was extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 2-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)acetic acid as a yellow oil that partially solidified after standing under vacuum overnight: yield 1.5 g (61% yield); 1H NMR (400 MHz, CDCl3): δ 7.58-7.54 (m, 1H), 7.52-7.39 (m, 3H), 6.73 (s, 1H), 3.80-3.45 (broad hump, 2H); MS (ESI) m/z 305.0 [M+H]+.