Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1.C(Cl)Cl>[C:27]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10])[C:16]1[O:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:19][N:20]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccccc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(N[C@@H](c2nnc(-c3ccccc3)o2)[C@H](C)OC(=O)c2ccccc2)ccc(C#N)c1Cl
Reaction time: 60 h
Yield: 88.1 %

Procedure:
To a solution of 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile (200 mg, 0.54 mmol) in pyridine (1.0 mL) and CH2Cl2 (7.0 mL) was added benzoyl chloride (94 μL, 0.81 mmol). Upon complete addition the reaction mixture was stirred for 60 h, then quenched with 10% aqueous HCl (15 mL). The mixture was partitioned between H2O (35 mL) and CH2Cl2 (40 mL). The aqueous layer was extracted with CH2Cl2 (35 mL). The combined organic extracts were washed with NaHCO3 (35 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide an off white solid, which was purified by flash chromatography over silica gel (20-40% EtOAc in hexanes) to provide the title compound as a colourless solid (225 mg, 88%): 1H NMR (400 MHz, CDCl3, □ in ppm) 8.05 (dm, J=7.2 Hz, 2H), 7.91 (dm, J=7.2 Hz, 2H), 7.62 (tt, J=1.2, 7.4 Hz, 1H), 7.55-7.41 (m, 5H), 7.39 (d, J=8.6 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 5.81 (pentet, J=6.3 Hz, 1H), 5.38 (d, J=7.6 Hz, 1H), 5.21 (dd, J=5.9, 7.4 Hz, 1H), 2.31 (s, 3H), 1.50 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:19]([O:21][CH3:22])=[O:20])=[N:11][N:12]2[CH2:17][CH2:16][NH:15][C:14](=[O:18])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26]>>[CH2:1]([O:8][C:9]1[C:10]([C:19]([O:21][CH3:22])=[O:20])=[N:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:24][C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[C:14](=[O:18])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)NCC2
Reactant: O=C(CCl)N1CCOCC1
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(CC(=O)N1CCOCC1)CC2

Procedure:
The title compound was prepared from methyl 3-benzyloxy-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate using a procedure similar to Example 13, Step 1, except that 4-(2-chloroacetyl)morpholine was used in place of iodomethane. 1H NMR (400 MHz, CDCl3) δ 7.53-7.50 (d, 2H), 7.37-7.28 (m, 3H), 5.31-5.30 (m, 3H), 4.49-4.46 (t, 2H), 4.41 (s, 2H), 3.93 (s, 3H), 3.88-3.84 (t, 2H), 3.77-3.71 (m, 3H), 3.65-3.62 (t, 2H), 3.55-3.52 (t, 2H); ES MS (M+1)=429.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C:12]([C:13]3[CH2:14][CH2:15][CH:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C@H:18](O)[CH2:17]4)=[CH:11][CH2:10]1)[CH3:8])[CH3:3].C(N(S(F)(F)[F:35])CC)C.O>C(Cl)Cl>[F:35][C@@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[CH:16]([CH2:15][CH2:14][C:13]3[C:12]4[C@:26]([CH3:27])([CH2:25][CH2:24][C:23]=32)[C@@H:9]([C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:10][CH:11]=4)[CH2:17]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)CC1CC3
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@@H](F)CC1CC3
Temperature: -78 °C

Procedure:
Cholesta-8,14-diene-3β-ol (1.17 g, 3 mmol) was dissolved in 10 ml of methylenechloride and cooled to −78° C. Over 10 min a solution of diethylaminosulfur trifluoride (1.4 g, 8.7 mmol) in 10 ml of methylenechloride was added at −78° C. The mixture was stirred for 1½ hour at −78° C. and was then slowly heated to room temperature. To the reaction mixture was added 15 ml of water while stirring was continued. The organic phase was separated and washed with 30 ml of 5% NaHCO3 and then with water. The organic phase was dried with MgSO4 and evaporated to dryness. The residue was purified by column chromatography using heptane for a first fraction and heptane/acetone, 95:5 (w/w) for a second fraction containing 3α-fluorocholesta-8,14 diene, 0.14 g (12%). Melting point: 98.6° C. Elementary analysis: Cal C: 83.88; H: 11.21; F: 4.91. Found C: 83.92; H: 11.75. 19F-NMR: d 181.0 and 181.2 (JHCF 45.2 Hz, C3-aF).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:38][CH:37]4[N:22]([C:23](=[O:59])[N:24](CC5C=CC(OC)=CC=5)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40]([NH:42][S:43]([C:46]6([CH3:49])[CH2:48][CH2:47]6)(=[O:45])=[O:44])=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:62])[C:13]([O:60][CH3:61])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>ClCCl>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:38][CH:37]4[N:22]([C:23](=[O:59])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40]([NH:42][S:43]([C:46]6([CH3:49])[CH2:48][CH2:47]6)(=[O:45])=[O:44])=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:62])[C:13]([O:60][CH3:61])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:2])[CH3:3]
Reactant: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)NS(=O)(=O)C3(C)CC3)NC(=O)C3CC(Oc4cc(-c5nc(C(C)C)cs5)nc5c(C)c(OC)ccc45)CN3C2=O)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6(C)CC6)CC5C=CCCCCCNC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To compound 139 (106 mg, 0.120 mmol) dissolved in dichloromethane (18 mL) were added triethylsilane (38 μL, 0.240 mmol) and TFA (9 mL) and the reaction mixture was stirred at room temperature for 1 hour. The solvents were evaporated and co-evaporated trice with toluene. The residue was dissolved in dichloromethane and the organic phase was washed twice with saturated NaHCO3 solution. The organic phase was dried, filtered, and concentrated and the crude product was purified by flash column chromatography (toluene/ethyl acetate 1:1) to yield the title compound (73 mg, 80%) as a slightly yellow solid. LC-MS purity: >95%. (M+H)+ cald: 765.3; found: 765.7.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[O:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[OH-].[K+].N1C=CC=CC=1.[Mn]([O-])(=O)(=O)=[O:29].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:29])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[C:9]([CH:10]=1)[C:8]([OH:7])=[O:11]
Reactant: COc1ccccc1C1OC(=O)c2cc(Br)ccc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1ccccc1C(=O)c1ccc(Br)cc1C(=O)O
Temperature: 100 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
This compound was prepared according to Ukita et al J. Med. Chem. 2001, 44, 2204. To a stirred mixture of 6-bromo-3-(2-methoxyphenyl)isobenzofuran-1(3H)-one (5.15 g, 16.1 mmol) in KOH (25% aqueous) (64.5 mL, 16.1 mmol) and pyridine (32.3 mL, 16.1 mmol) in a pressure tube was added powder potassium permanganate (3.83 g, 24.2 mmol). The reaction was heated at 100° C. After 4 h, LCMS showed ˜95% conversion to product. The reaction was cooled to rt. The mixture was filtered, and the solid residue was washed with water. The filtrate was acidified with concentrated HCl until pH=2. A sticky white solid was filtered off with the aid of water and dried to afford 5-bromo-2-(2-methoxybenzoyl)benzoic acid (4.2 g, 78% yield). m/z (ESI) 335.0 (M+H)+, 337.0 (M+3H)+.
Reaction SMILES: BrCCBr.Cl[C:6]1([F:18])[C:11](Cl)([F:12])[O:10][C:9]([F:15])([F:14])[C:8]([F:17])([F:16])[O:7]1>CN(C=O)C.[Zn]>[F:15][C:9]1([F:14])[C:8]([F:16])([F:17])[O:7][C:6]([F:18])=[C:11]([F:12])[O:10]1
Reactant: FC1(F)OC(F)(Cl)C(F)(Cl)OC1(F)F
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: BrCCBr
Product: FC1=C(F)OC(F)(F)C(F)(F)O1
Yield: 45.1 %

Procedure:
A suspension of 39.2 g (0.60 mol) of zinc dust in 300 mL of dry DMF was stirred under N2 while 5 mL of 1,2-dibromoethane was added. Then a small portion of 74.0 g (0.28 mol) of dichloride 5 was added, and the mixture was stirred and heated. When an exothermic reaction started (about 75° C.), the rest of 5 was added dropwise at a rate sufficient to maintain 110°-120° C. in the pot while product was collected in a -80° C. trap. When the addition was completed, the mixture was heated to reflux to drive out the last of the product. Fractionation of the crude volatile product gave 24.5 g (45%) of pure perfluoro-2,3-dihydro-1,4-dioxin (7), bp 18°-19.5° C.
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32].Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:30])=[CH:24][C:23]=1[C:31]([F:32])([F:33])[F:34]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.44 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a tan solid (0.36 g, 44% yield), mp=117–119° C.; MS (+) ESI m/z=402 (M+H)+, [α]D25=+22.3° (c=1, EtOH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][S:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:9]2=[O:29])=[CH:4][CH:3]=1.Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:16][CH:17]=3)[CH:10]([CH2:19][CH2:20][S:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C:9]2=[O:29])=[CH:4][CH:3]=1
Reactant: O=C1C(CCSc2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)COc1ccc(C2C(CCSc3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 1-(4-fluorophenyl)-3-[2-(4-fluorophenylthio)ethyl]-4-(4-hydroxyphenyl)azetidin-2-one (Method 13; 0.800 g, 1.944 mmol), t-butyl bromoacetate (0.32 ml, 2.17 mmol) and caesium carbonate (0.700 g, 2.15 mmol) in MeCN (15 ml) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between water (20 ml) and DCM (20 ml). The water layer was extracted once more with DCM (10 ml) and the combined organic layers were washed with brine, dried over magnesium sulphate and concentrated. The residue was purified by flash chromatography using heptane:EtOAc (4:1) as eluent The title compound was obtained as a colourless oil (0.884 g; 87%). NMR (400 MHz) 1.45 (s, 9H), 2.00-2.30 (m, 2H), 2.90-3.10 (m, 2H), 3.15-3.25 (m, 1H), 4.50 (s, 2H), 4.60 (d, 1H), 6.85-7.00 (m, 6H), 7.15-7.35 (m, 6H); m/z: 526.2.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[NH2:15][C:16]1[NH:20][N:19]=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)[C:17]=1[C:34]([NH2:36])=[O:35]>>[NH2:12][C:10]1[CH:11]=[C:2]2[C:3]([C:4](=[O:6])[NH:15][C:16]3[N:20]2[N:19]=[C:18]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:25][CH:26]=2)[C:17]=3[C:34]([NH2:36])=[O:35])=[CH:8][CH:9]=1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Cl
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1[nH]c(=O)c1ccc(N)cc12

Procedure:
The desired product was prepared from methyl 2-chloro-4-nitrobenzoate and 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide using the procedures similar to those for compound 76 and 77. 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.44-7.36 (m, 2H), 7.19-7.02 (m, 6H), 6.64 (d, J=8.4 Hz, 1H), 6.55 (br s, 2H). MS (ESI, m/e) [M+1]+ 412.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([F:18])=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[CH:26]1([N:32]=[C:33]=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CCN(CC)CC>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:9]2[N:10]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([F:18])=[CH:13]3)[C:33]([NH:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:34])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NC1CCCCC1
Reactant: Fc1ccc2c(Nc3cccc(Cl)c3)n(-c3ccc(Cl)cc3)nc2c1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)N(c1cccc(Cl)c1)c1c2ccc(F)cc2nn1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 1.2, (3-chloro-phenyl)-[2-(4-chloro-phenyl)-6-fluoro-2H-indazol-3-yl]-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 4 days under reflux conditions to give the title compound as yellow foam. MS: m/e=497.1 [M+H+].
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][N:6]([CH2:9][C@@H:10]([C:12]2[CH:21]=[CH:20][C:15]3[C:16](=[O:19])[O:17][CH2:18][C:14]=3[C:13]=2[CH3:22])[OH:11])[CH2:5]1.Cl[C:30]1[C:31]2[N:32]([CH:36]=[N:37][N:38]=2)[CH:33]=[CH:34][N:35]=1>>[N:38]1[N:37]=[CH:36][N:32]2[CH:33]=[CH:34][N:35]=[C:30]([NH:2][CH2:3][C:4]3([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:8][CH2:7][N:6]([CH2:9][C@@H:10]([C:12]4[C:13]([CH3:22])=[C:14]5[C:15](=[CH:20][CH:21]=4)[C:16](=[O:19])[O:17][CH2:18]5)[OH:11])[CH2:5]3)[C:31]=12
Reactant: Cc1c([C@@H](O)CN2CCC(CN)(c3ccccc3)C2)ccc2c1COC2=O
Reactant: Clc1nccn2cnnc12
Agent: Cl
Product: Cc1c([C@@H](O)CN2CCC(CNc3nccn4cnnc34)(c3ccccc3)C2)ccc2c1COC2=O

Procedure:
5-((1R)-2-(3-(([1,2,4]Triazolo[4,3-a]pyrazin-8-ylamino)methyl)-3-phenylpyrrolidin-1-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 18 starting from 5-[(R)-2-[3-(Aminomethyl)-3-phenylpyrrolidin-1-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one hydrochloride [INTERMEDIATE 15] and 8-chloro-[1,2,4]triazolo[4,3-a]pyrazine.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].Cl.[F:25][CH2:26][C@H:27]([NH2:29])[CH3:28]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:29][C@H:27]([CH3:28])[CH2:26][F:25])=[O:2])([CH2:11][CH2:10]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: C[C@@H](N)CF
Agent: Cl
Product: C[C@H](CF)NC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Yield: 38.9 %

Procedure:
In a similar manner to Example 146, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (100 mg) and (2R)-1-fluoro-2-propylamine hydrochloride (32.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-(4-[N-[(2R)-1-fluoro-2-propyl]amino]carbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (41.9 mg).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[CH3:15][O:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[H-].[Na+]>CN1C(=O)CCC1>[CH3:15][O:16][CH:17]1[CH2:22][CH2:21][N:20]([C:2]2[O:3][C:4]3[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=3)[N:6]=2)[CH2:19][CH2:18]1
Reactant: COC1CCNCC1
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1cccc2oc(N3CCC(OC)CC3)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.8 %

Procedure:
To a solution of methyl 2-chlorobenzoxazole-4-carboxylate (210 mg, 0.99 mmol) in NMP (5 mL) was added 4-methoxypiperidine (230 mg, 1.98 mmol) in NMP (5 mL) at room temperature. NaH was added to the mixture in two portions in 5 min. The mixture was stirred at room temperature for 18 h. The reaction was quenched by adding 10 mL of CH3OH followed by concentration to dryness. The crude material was purified by column chromatography (silica gel, 50% EtOAc in hexane) to afford methyl 2-(4-methoxypiperidin-1-yl)benzoxazole-4-carboxylate (146 mg, 50%) as a yellow solid. MS consistent.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[N:9]/[S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[C:4]([F:16])[CH:3]=1.[CH3:17][Mg]Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:9][S@:10]([C:12]([CH3:13])([CH3:15])[CH3:14])=[O:11])[CH3:17])=[C:4]([F:16])[CH:3]=1
Reactant: C[Mg]Cl
Reactant: CC(C)(C)[S@](=O)/N=C/c1ccc(Br)cc1F
Solvent: ClCCl
Product: C[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(Br)cc1F
Temperature: -48 °C
Reaction time: 6 h
Yield: 82.1 %

Procedure:
To a solution of (S)-2-methyl-propane-2-sulfinic acid 1-(4-bromo-2-fluoro-phenyl)-meth-(E)-ylideneamide (4.5 g, 14.7 mmol) in DCM (80 ml) was added methylmagnesium chloride (7.35 ml, 22.0 mmol, 3M solution in ether) dropwise at −48° C. After 1 h additional methylmagnesium chloride (2.45 ml, 7.35 mmol, 3M solution in ether) was added dropwise and the reaction mixture was stirred at −48° C. for 6 h. The reaction was then quenched by addition of sat. NH4Cl solution and the mixture was extracted three times with DCM. The combined organic layers were dried with Na2SO4 and evaporated. The remaining white solid was purified by chromatography (silica gel; heptane/EtOAc 2:1-1:1) to obtain the title compound as white solid (3.89 g, 82%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl.CN(C)CCCN=C=NCC.[C:24](O)([CH3:27])([CH3:26])[CH3:25]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[C:24]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=1[CH3:11])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)O
Reactant: Cc1ccc(I)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(I)cc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of 5-iodo-2-methylbenzoic acid (760 mg, 2.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (670 mg, 3.5 mmol), 4-dimethylaminopyridine (425 mg, 3.5 mmol), and t-butanol (1.07 g, 14.5 mmol) in dichloromethane (10 ml) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (25 ml) and washed with 5% NaHCO3, 1M HCl, water and, brine. The organic phase was dried and evaporated to give a pale yellow solid 600 mg 65%.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.[Cl:15][C:16]1[CH:21]=[C:20]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH:19]=[C:18]([Cl:30])[C:17]=1[C:31]1[N:35]2[CH:36]=[C:37](F)[CH:38]=[CH:39][C:34]2=[N:33][N:32]=1>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[C:20]([CH2:22][N:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]2)[CH:19]=[C:18]([Cl:30])[C:17]=1[C:31]1[N:35]2[CH:36]=[C:37]([O:14][C@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:38]=[CH:39][C:34]2=[N:33][N:32]=1
Reactant: CN1CCN(Cc2cc(Cl)c(-c3nnc4ccc(F)cn34)c(Cl)c2)CC1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(Cc2cc(Cl)c(-c3nnc4ccc(O[C@@H]5CC[C@H](N)c6ccccc65)cn34)c(Cl)c2)CC1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 18.6 %

Procedure:
A suspension of sodium hydride (60% dispersion in oil, 56 mg, 1.39 mmol) in dry DMF (2.0 mL) under nitrogen was treated with Intermediate 1 (46 mg, 0.28 mmol) and the mixture was stirred for 20 min. Intermediate 13d (110 mg, 0.28 mmol) was added and the mixture was heated to 60° C. for 1.75 h then quenched with MeOH. The mixture was further diluted with MeOH and applied to a pre-conditioned (MeOH) SCX-2 cartridge (10g). The cartridge was eluted with MeOH then 2M NH3 in MeOH. The relevant fractions were combined and concentrated in vacuo. The residue was dissolved in DCM containing a few drops of MeOH and purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (28 mg, 19%). LCMS (Method 3): Rt 2.08 min, m/z 537, 539 [MH+].
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29]([C:31]1[O:32][CH:33]=[CH:34][C:35]=1[CH3:36])=[O:30])#[CH:21]>>[CH3:36][C:35]1[CH:34]=[CH:33][O:32][C:31]=1[C:29]([NH:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]#[C:21][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:30]
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1ccccc1NC(=O)c1occc1C
Product: Cc1ccoc1C(=O)Nc1ccccc1C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Yield: 43.3 %

Procedure:
In a manner similar to that described for Example 460 (step 2), (S)-5-bromo-N-[methyl(oxido)phenyl--sulfanylidene]nicotinamide (0.050 g, 0.148 mmol) and 3-methyl-furan-2-carboxylic acid (2-ethynyl-phenyl)-amide (0.050 g, 0.222 mmol) were reacted to give the title compound (0.031 g, 43%).
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:38]=[CH:39][CH:40]=1)[CH2:15][C@H:16]1[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[O:22])[CH2:17]1>>[N:2]1([CH2:7][C:8]([N:19]2[CH2:20][C@H:16]([CH2:15][C:14]3[CH:38]=[CH:39][CH:40]=[C:12]([Cl:11])[CH:13]=3)[CH2:17][C@H:18]2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:22])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccc(Cl)c2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccc(Cl)c2)CN1C(=O)Cn1cncn1
Yield: 60 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(3-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 61, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(3-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (65 mg, 60%). 1H-NMR (400 MHz, CDCl3): δ 9.00 (s, 1H), 8.20 (s, 1H), 8.00 (s, 1H), 7.40-7.20 (m, 6H), 6.90-6.80 (m, 6H), 5.00 (dd, 2H), 4.90 (d, 1H), 3.80 (m, 1H), 3.20 (m, 1H), 3.00-2.80 (m, 5H). MS (EI) for C28H25ClFN5O3 found 534 (MH+).