Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.C([NH:25][C:26]1[S:27][CH:28]=[C:29](/[C:31](=[N:35]/[O:36]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:32]([O-:34])=O)[N:30]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Na+].[NH2:57][C@@H:58]1[C:77](=[O:78])[N:60]2[C:61]([C:70]([O:72]C(C)(C)C)=[O:71])=[C:62]([C@H:65]3[CH2:69][CH2:68][CH2:67][O:66]3)[CH2:63][S:64][C@H:59]12.N1C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C>[NH2:25][C:26]1[S:27][CH:28]=[C:29](/[C:31](=[N:35]/[OH:36])/[C:32]([NH:57][C@@H:58]2[C:77](=[O:78])[N:60]3[C:61]([C:70]([OH:72])=[O:71])=[C:62]([CH:65]4[CH2:69][CH2:68][CH2:67][O:66]4)[CH2:63][S:64][C@H:59]23)=[O:34])[N:30]=1
Reactant: CC(C)(C)OC(=O)C1=C([C@H]2CCCO2)CS[C@@H]2[C@H](N)C(=O)N12
Reactant: O=C([O-])/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(C4CCCO4)CS[C@H]23)cs1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 151.3 %

Procedure:
Methanesulphonyl chloride (96 μl, 1.25 mmol) was added to sodium 2-(2-tritylaminothiazol-4-yl)-2-(Z)-trityloxyiminoacetate (852 mg, 1.2 mmol) in DMF (2 ml) at <-40° C. The mixture was stirred 0.5 h at -30±10° C. then t-butyl (6R,7R)-7-amino-3-[(R)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (326 mg, 1 mmol) in DMF (2 ml), followed by pyridine (101 μl, 1.25 mmol), were added. The reaction was stirred for 1 h without further cooling then diluted with ethyl acetate, washed twice with water and with brine, dried, concentrated in vacuo and flash chromatographed eluting with 25, 30% ethyl acetate in hexane to give the title compound as a colourless foam (665 mg, 68%); νmax (CH2Cl2) 3395, 1787, 1722, 1687, 1527, 1449, 1156 and 1051 cm-1 ; δH (CDCl3 /CD3OH) 1.55 (9H, s), 1.65-2.25 (4H, m), 3.32 and 3.40 (2H, ABq, J 17.6 Hz), 3.8-4.0 (2H, m), 5.08 (1H, d, J 4.8 Hz), 5.13 (1H, dd, J 7.0, 8.1 Hz), 5.91 (1H, d, J 4.5 Hz), 6.56 (1H, s), 7.2-7.5 (30H, m). [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (1002)].
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].F[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH3:34])[CH:26]=3)[C:22]([CH3:35])=[CH:21][N:20]=2)=[C:11]([O:36][CH3:37])[CH:10]=1>CC(N(C)C)=O>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH3:6])[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH3:34])[CH:26]=3)[C:22]([CH3:35])=[CH:21][N:20]=2)=[C:11]([O:36][CH3:37])[CH:10]=1
Reactant: CNCCN(C)C
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Solvent: CC(=O)N(C)C
Product: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Temperature: 140 °C
Yield: 42.1 %

Procedure:
N1,N1,N2-Trimethylethane-1,2-diamine (221 mg, 2.16 mmol) was added to a suspension of N-(4-Fluoro-2-methoxy-5-nitrophenyl)-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 79, 400 mg, 0.98 mmol) in DMA (4 mL). The mixture was heated in a microwave at 140° C. for 0.5 h. The mixture was then concentrated in vacuo and the residue was dissolved in EtOAc (100 mL). This solution was washed with water (2×100 mL) and sat. brine (100 mL), dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-8% methanolic ammonia in CH2Cl2 gave the title compound (202 mg, 42%) as an orange dry film; m/z: ES+ MH+ 444.55.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5]2.C([N:21]1[CH2:25][CH2:24][NH:23][C:22]1=O)(=O)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:5]2[C:22]1[NH:23][CH2:24][CH2:25][N:21]=1
Reactant: CC(=O)N1CCNC1=O
Reactant: Clc1ccc2[nH]c(Sc3ccccc3)cc2c1
Product: Clc1ccc2[nH]c(Sc3ccccc3)c(C3=NCCN3)c2c1

Procedure:
Treatment of 5-chloro-2-(phenylthio)-1H-indole (3.8 mmol, 1 g) with N-acetyl-4,5-dihydro-1H-imidazol-2-one as described in Example 89, Step 3 gave 5-chloro-2-phenylthio-3-(4,5-dihydro-1H-imidazol-2-yl)-1H-indole (0.19 g): MS:327M−; m.p.178° C.; yield (13,4%).
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([OH:12])[C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl>ClCCl>[OH:12][C@@H:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:11]
Reactant: C1COCCN1
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: O=C([C@@H](O)Cc1ccccc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
A sample of (S)-3-phenyllactic acid (1, 21 g, 126 mmol) is dissolved in dichloromethane (300 mL) and treated with morpholine (55 g, 631 mmol). The reaction is cooled in an ice/water bath and a solution of PyBOP (72 g, 139 mmol) in dichloromethane (200 mL) is added dropwise through a pressure equalizing funnel. The reaction mixture is stirred overnight and allowed to warm to room temperature. After addition of 110 mL of 4 M HCl, the reaction mixture is filtered and the organics are separated. The aqueous layer is extracted twice with dichloromethane and discarded. The combined organics are dried over MgSO4 and the solvent is removed. The resulting material is chromatographed on silica gel and eluted with ethyl acetate to afford 20.65 g (68% yield) of (S)-2-hydroxy-1-morpholin-4-yl-3-phenyl-propan-1-one (2) as an oil; HPLC-MS calculated for C13H17NO3 (M+H+) 236.1, found 236.4.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[C:16]=1Br.Cl>[Cu]Br.O1CCOCC1>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[C:16]=1[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: Clc1cc(Cl)c(Br)c(Cl)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cu]Br
Agent: Cl
Agent: [H-]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1c(Cl)cc(Cl)cc1Cl
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
Diethyl malonate (6.21 mol) is added to a mixture of sodium hydride (5.13 mol) and 1,4-dioxane (1400 ml) at 55 to 60° C. within 3 hours. The mixture is stirred for 10 minutes at 55° C. and copper(I) bromide (0.5 mol) is added. A mixture of 2,4,6-trichlorobromobenzene (2.50 mol) and 1,4-dioxane (600 ml) is added. The reaction mixture is heated at 100° C. for 14 hours and cooled to 15° C. Hydrochloric acid (12N, 350 ml) is added slowly at 15 to 20° C. The organic phase is separated off and the aqueous phase is extracted with ethyl acetate (250 ml) and toluene (200 ml). The combined organic phases are concentrated in vacuo. The residue is filtered over silica gel, washed with petroleum ether/ethyl acetate (15:1) and the solvent is distilled off. The residue is distilled in vacuo to yield 540 g of the product as a white solid, 144-150° C. at 0.4 mbar.
Reaction SMILES: [BH4-].[Li+].[C:3]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[CH:28]=[CH:27][N:26]=[C:25]3[C:20]=2[C:21]2[CH:33]=[CH:32][C:31]([C:34](OC)=[O:35])=[CH:30][C:22]=2[C:23](=[O:29])[NH:24]3)=[CH:14][CH:13]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1>[OH:35][CH2:34][C:31]1[CH:32]=[CH:33][C:21]2[C:20]3[C:25](=[N:26][CH:27]=[CH:28][C:19]=3[NH:18][C:15]3[CH:14]=[CH:13][C:12]([NH:11][C:3](=[O:10])[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:17][CH:16]=3)[NH:24][C:23](=[O:29])[C:22]=2[CH:30]=1
Reactant: COC(=O)c1ccc2c(c1)c(=O)[nH]c1nccc(Nc3ccc(NC(=O)c4ccccc4)cc3)c12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4cc(CO)ccc4c23)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 30.2 %

Procedure:
Lithium borohydride (33 mg, 1.51 mmol) was added to a stirred solution of 267 (100 mg, 0.22 mmol) in THF (10 mL) at 0° C., and stirred for 20 min. at room temperature, then overnight at 45° C. The reaction solution was quenched with MeOH and H2O, acidified with HCl (1 mL, conc.), and stirred for 20 min. The crude product was purified via HP-LC to provide 273 (29 mg, 31% yield) as a solid. LC-MS (M+H=437, obsd.=437).
Reaction SMILES: [NH2:1][C:2]1[C:5](=[O:6])[C:4](=[O:7])[C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[O:20])[CH:14]=1.N1CCCCC1.Cl.O>C(O)C.[Pd]>[NH2:1][C:2]1[C:5](=[O:6])[C:4](=[O:7])[C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=1
Reactant: Nc1c(NCCCOc2cccc(C=O)c2)c(=O)c1=O
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: C1CCNCC1
Product: Nc1c(NCCCOc2cccc(CO)c2)c(=O)c1=O
Reaction time: 4 h
Yield: 71.3 %

Procedure:
A suspension of 1-amino-2-[3-(3-formylphenoxy)propylamino]-1-cyclobutene-3,4-dione (2.09 g, 7.29 mmoles), piperidine (0.8 mL, 690 mg, 8.1 mmoles) and 200 mg of 10% Pd/C in 300 mL of 95% ethanol was shaken on a Parr hydrogenator at 50 psi for 4 hours. To the resultant mixture with stirring was added 8.3 mL of aqueous 1.0N HCl and 25 mL of water. The reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated under reduced pressure. The solid residue was treated with acetone and allowed to stand at 0° C. for 18 hours. The mixture was filtered and the solid dried to give 1.437 g of product containing a small amount of starting aldehyde; mp=207°-212° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](I)[CH:7]=1)=[O:4].[CH2:15]=[C:16]1[CH2:20][CH2:19][O:18][C:17]1=[O:21].CC([O-])=O.[K+]>CN1C(=O)CCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](/[CH:15]=[C:16]2\[C:17](=[O:21])[O:18][CH2:19][CH2:20]\2)[CH:7]=1)=[O:4]
Reactant: C=C1CCOC1=O
Reactant: O=C(Nc1cccc(I)c1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C1OCC/C1=C/c1cccc(NC(=O)C(F)(F)F)c1
Temperature: 110 °C
Yield: 80.9 %

Procedure:
The reaction mixture of 2,2,2-trifluoro-N-(3-iodophenyl)acetamide (160 mg, 0.52 mmol), 3-methylenedihydrofuran-2(3H)-one (62 mg, 0.63 mmol), Pd(OAc)2 (33 mg, 0.015 mmol) and KOAc (200 mg, 2.04 mmol) in NMP (2 mL) was degassed and heated to 110° C. for 12 hrs. The mixture was extracted with EtOAc and washed with H2O, brine, dried over MgSO4, filtered, concentrated in reduced pressure to dryness, and recrystallized in MeOH to give desired intermediate (Z)-2,2,2-trifluoro-N-(3-((2-oxodihydrofuran-3(2H)-ylidene)methyl)phenyl)acetamide (120 mg). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.4 (s, 1H), 7.96 (s, 1H), 7.74 (dt, J=7.6, 1.6 Hz, 1H), 7.51 (7, J=7.6 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.47 (dt, J=7.6, 1.6 Hz, 1H), 7.38 (t, J=2.8 Hz, 1H), 4.43 (t, J=7.2 Hz, 2H), 3.24 (dt, J=2.8, 7.2 Hz, 2H). MS (ESI) m/z=284 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccccc1Sc1ccc(Cl)cc1
Yield: 94.1 %

Procedure:
This compound was synthesized by the model procedure from the following compounds: 4-Chlorothiophenol (15.0 g, 0.10 mol), Na2CO3 (15.50 g, 0.15 mol), and 2-chloro-nitrobenzene (16.3 g, 0.10 mol). The crude product, mp 91°-93° C., was recrystallized from alcohol to afford 25.0 g (91%) of yellow crystals, mp 94°-95° C. (lit. mp 94° C.). IR(KBr) 3050 (C--H), 1512 and 1336 cm-1 (NO2); 1H NMR (CDCl3) δ 8.2 (m, 1 H) and 7.45 (m, 7 H).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:6]([F:22])[C:5]=1Cl)(=[O:3])[CH3:2].[N-:24]=[N+]=[N-].[Na+]>CC(C)=O.O>[F:22][C:6]1[C:5]2[C:4](=[C:1]([CH3:2])[O:3][N:24]=2)[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1nc(C(C)=O)c(Cl)c(F)c1Nc1ccccc1F
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1nc2c(C)onc2c(F)c1Nc1ccccc1F
Temperature: 65 °C

Procedure:
To a solution of methyl 6-acetyl-5-chloro-4-fluoro-3-(2-fluorophenylamino)picolinate (WO 2005/051906) (2 g, 5 mmole) in a mixture of acetone (36 ml) and H2O (12 ml) is added NaN3 (487 mg, 7.5 mmol). The reaction is heated at 65° C. for 16 h and cooled to room temperature. Acetone is concentrated and the resulting mixture is extracted with EtOAc (2×50 ml). The combined organic solution is washed with brine (50 ml), dried over MgSO4 and concentrated to give a yellow solid. To the solid is added H2O (24 ml) and the reaction is heated at reflux for 3 h. The reaction is cooled to room temperature, filtered, and washed with H2O. The resulting solid is dried under high vacuum with P2O5 at 65° C. for 24 h to give the title compound.
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH:19]=O)[N:15]3[CH3:18])=[C:11]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:10]=2)[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)([CH3:3])[CH3:2].[NH:31]1[CH2:34][CH:33]([N:35]2[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]2)[CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:1]([C:4]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH2:19][N:31]4[CH2:34][CH:33]([N:35]5[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]5)[CH2:32]4)[N:15]3[CH3:18])=[C:11]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[N:10]=2)[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)([CH3:2])[CH3:3]
Reactant: OC1CCN(C2CNC2)CC1
Reactant: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCC(O)CC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
A mixture of 2-(2-isopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.150 g, 0.37 mmol), 1-azetidin-3-ylpiperidin-4-ol (0.069 g, 0.44 mmol) and 4 Å molecular sieves (0.37 g) in DCE (3 mL) was stirred for 2 h at room temperature. Sodium triacetoxyborohydride (0.157 g, 0.74 mmol) was added and the reaction mixture was stirred for 4 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 20:80) to give 550 as a white solid (0.137 g, 68%). LCMS (Method I): RT=2.41 min, [M+H]+ 546.3. 1H NMR (400 MHz, DMSO-d6): δ 7.90-7.85 (m, 1 H); 7.66-7.61 (m, 1 H); 7.25-7.21 (m, 2 H); 4.53 (d, J=4.1 Hz, 1 H); 4.28-4.23 (m, 4 H); 3.96-3.86 (m, 1 H); 3.86 (s, 2 H); 3.85-3.68 (m, 7 H); 3.48-3.43 (m, 1 H); 3.42 (t, J=6.5 Hz, 2 H); 2.95 (t, J=6.5 Hz, 2 H); 2.90-2.82 (m, 1 H); 2.45-2.55 (m, 2 H); 1.85 (t, J=10.6 Hz, 2 H); 1.71-1.68 (m, 2 H); 1.40-1.34 (m, 2 H); 1.35 (d, J=6.80 Hz, 6 H)
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][C:22]([NH2:24])=[O:23])=[CH:13]1.C([O:27][C:28](=O)[C:29]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[N:38]([CH3:40])[CH:37]=[CH:36]2)=O)C.Cl>CN(C=O)C.CCOC(C)=O>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[C:22](=[O:23])[NH:24][C:28](=[O:27])[C:29]=2[C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:39]=2[N:38]([CH3:40])[CH:37]=[CH:36]3)=[CH:13]1
Reactant: CCOC(=O)C(=O)c1cccc2ccn(C)c12
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c21
Temperature: 60 °C
Reaction time: 7 h

Procedure:
A 1.0 M solution of KOtBu in THF (6 mL, 6 mmol) was added to a solution of 2-(1H-indol-3-yl)-acetamide (296 mg, 1.70 mmol) and (1-methyl-1H-indol-7-yl)-oxo-acetic acid ethyl ester (381 mg, 1.65 mmol) in DMF (20 mL). The deep red-orange solution was stirred 7 h at 60° C., allowed to cool overnight and 1N HCl added. The orange mixture was poured into EtOAc, and the EtOAc layer was separated and washed with 1N HCl, water (3×), saturated aq NaHCO3 (2×) and brine, dried (MgSO4), filtered and concentrated onto SiO2. Flash chromatography (1:1 EtOAc:hexanes) afforded the title compound as a 1:1 solvate with EtOAc (514 mg, 72%) as a bright orange-red solid. Heating under vacuum at 70° C. afforded material which was used without further purification. 1H NMR (400 MHz, DMSO-d6) 11.85 (br s, 1H), 11.13 (s, 1H), 7.93 (d, J=3 Hz, 1H), 7.61 (dd, J=8, 1.5 Hz, 1H), 7.33 (d, J=8 Hz, 1H), 7.26 (d, J=3 Hz, 1H), 6.93–7.0 (m, 2H), 6.88 (d, J=7 Hz, 1H), 6.46–6.52 (d, J=7 Hz, 1H), 6.35 (d, J=7 Hz, 1H), 3.68 (s, 3H). MS (electrospray, m/z) 342.1 (M++1), 340.2 (M−−1). HRMS 342.1249 (M++1, calcd for C21H16N3O2 342.1242).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([OH:13])=O)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]([OH:29])=[O:28])[CH2:23][CH2:22]2)=[N:19][CH:20]=1>>[C:10]([O:28][C:27]([N:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:11]([C:8]3[S:7][C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=4[CH:9]=3)=[O:13])=[CH:20][N:19]=2)[CH2:22][CH2:23]1)=[O:29])([CH3:2])([CH3:9])[CH3:6]
Reactant: Nc1ccc(N2CCN(C(=O)O)CC2)nc1
Reactant: O=C(O)c1cc2c(Cl)cccc2s1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3cc4c(Cl)cccc4s3)cn2)CC1

Procedure:
This compound was prepared from 4-chloro-benzo[b]thiophene-2-carboxylic acid and 4-(5-amino-pyridin-2-yl)-piperazine-1-carboxylic acid tort-butyl ester as described in the preparation of the intermediate section. LCMS for C23H25ClN4O3S calcd. (m/e) 472, observed 471 (M−H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[C:25]([Cu])#[N:26]>CN(C=O)C>[C:25]([C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])#[N:26]
Reactant: N#C[Cu]
Reactant: CC1(C)CCN(c2ccc(CNC(=O)OC(C)(C)C)cc2Br)CC1
Solvent: CN(C)C=O
Product: CC1(C)CCN(c2ccc(CNC(=O)OC(C)(C)C)cc2C#N)CC1
Temperature: 140 °C
Yield: 44.8 %

Procedure:
In a screw cap pressure tube were tert-butyl 3-bromo-4-(4,4-dimethylpiperidin-1-yl)benzylcarbamate (105 mg, 0.26 mmol) and CuCN (47.3 mg, 0.53 mmol) suspended in DMF (1.0 ml). N2 was bubbled through the suspension for 5 min. The tube was sealed and the mixture heated to 140° C. overnight. The mixture was allowed to cool and then it was poured over ice-water. FeCl3 (94.3 mg, 0.58 mmol) was added and the product extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography (Pet. Ether/EtOAc 4:1) affording 40 mg (45%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]([C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1>CCO.[Pd]>[C:4]1([CH:8]([C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cccc(C(=Cc2ccccc2)c2c[nH]cn2)c1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(CC(c2ccccc2)c2c[nH]cn2)cc1

Procedure:
A mixture of 4-(1-(3-chlorophenyl)-2-phenylvinyl)-1H-imidazole (AGN-216677) (35 mg) in EtOH (10 mL) was reduced by the action of 10% Pd/C (20 mg) under H2 atmosphere for l6 h at rt. The mixture was filtered through Celite and freed of solvent under reduced pressure. The residue was purified by chromatography on silica gel with 5% NH3-MeOH: CH2Cl2 to give 4-(1,2-diphenylethyl)-1H imidazole as a solid, (31 mg), AGN217242. 1H NMR (300 MHz, CD3OD): δ 7.38 (s, 1H), 7.10-7.26 (m, 8H), 7.08 (s, 1H), 4.41 (t, J=9 Hz, 3H), 3.43 (dd; J=9 Hz, 15 Hz, 1H), 3.27 (dd, J=6 Hz, 9 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:11]2[N:12]=[CH:13][N:14]=[CH:15][C:10]=2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:12]1[C:11]2[CH2:16][CH2:17][NH:8][CH2:9][C:10]=2[CH:15]=[N:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ncncc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ncc2c(n1)CCNC2
Temperature: 25 °C

Procedure:
A solution of the product from Step B above (730 mg) in 10 mL of dichloromethane was cooled to 0° C. and treated dropwise with 5 mL of trifluoroacetic acid. The solution was warmed to room temperature and, after 1 h, concentrated under reduced pressure. The residue was dissolved in methanol and applied to an ion-exchange column (Varian Bond-Elut SCX, 5 g; preconditioned with methanol). The column was washed several times with methanol, and the amine product was eluted with 1.0M ammonia-methanol. The fractions containing product were concentrated under reduced pressure to afford the title compound as an orange oil. LC/MS 136.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=O)=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1.CCOCC>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:20])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 81 %

Procedure:
32 g (0.1 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline were dissolved in 300 ml of dry tetrahydrofuran and the solution was cooled to -10° C. 12.7 ml (0.1 mol) of N-ethylmorpholine and 13.1 ml (0.1 mol) of isobutyl chloroformate were added and the solution was stirred for 20 minutes while maintaining the temperature at -10° C. 9.3 ml of aniline were then added and the mixture was stirred at 0° C. for 1 hour. The mixture was found to be slightly acidic and a further 1 g of N-ethylmorpholine was added. The solution was then left to stand at room temperature for 16 hours. The solution was evaporated, there being obtained a white crystalline solid which was treated with 500 ml of ether, filtered, washed and dried to give 31.8 g of N-benzyloxycarbonyl-L-alanyl-L-proline anilide of melting point 139.5°-140.5° C.; [α]D20 =-125.5° (c=1.195% in methanol). A second crop (1.4 g; melting point 138°-139° C.) was obtained by evaporating the mother liquor to a small volume, when crystallisation took place. The total yield was 81%.