Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OCCC(C)C)=O.CS[S:11][CH3:12].[Br:13][C:14]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=1N>>[Br:13][C:14]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=1[S:11][CH3:12]
Reactant: CSSC
Reactant: Nc1ccc(Br)cc1Br
Agent: CC(C)CCON=O
Product: CSc1ccc(Br)cc1Br
Temperature: 85 °C
Yield: 18.4 %

Procedure:
A solution of isoamyl nitrite (8.06 mL, 60 mmol) in dimethyl disulfide (36.02 mL, 400 mmol) at 25° C. was slowly treated with 2,4-dibromoaniline (4.8 g, 20 mmol). The reaction was exothermic with gas evolution. The resulting brown reaction mixture was heated to 80-90° C. for 2 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was cooled to 25° C. and then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (200 mL). The organic layer was washed successively with a 1N aqueous hydrochloric acid solution (1×200 mL) and a saturated aqueous sodium chloride solution (1×200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification using a plug of silica (Merck Silica gel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded 2,4-dibromothioanisole (1 1.04 g, 99%) as a brown oil: EI-HRMS m/e calcd for C7H6Br2S (M+) 279.8623, found 279.8619.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][C:12](O)=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:15][C:16]1[C:17](=[O:36])[N:18]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:19](=[O:27])[N:20]([CH2:23][CH2:24][CH2:25][CH3:26])[C:21]=1[NH2:22].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:23]([N:20]1[C:21]2[N:22]=[C:12]([CH2:11][C:8]3[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:10][CH:9]=3)[NH:15][C:16]=2[C:17](=[O:36])[N:18]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:19]1=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: CC(=O)Nc1ccc(CC(=O)O)cn1
Reactant: CCCCn1c(N)c(N)c(=O)n(Cc2ccccc2F)c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(C)=O)nc3)nc21

Procedure:
This compound was prepared by the method similar to that described in example 11 (method 1) except that the hydrochloride salt of (6-acetylamino-pyridin-3-yl)-acetic acid was used in place of N-acetyl-4-aminophenylacetic acid and the coupling to 5,6-diamino-1-butyl-3-(2-fluorobenzyl)-1H-pyrimidine-2,4-dione was performed with O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate and diisopropylethyl amine in N,N-dimethylformamide. MS, m/z(M+)=464.1971.
Reaction SMILES: Br[C:2]1[C:3]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:13][N:14]([CH3:19])[C:15](=[O:18])[CH:16]=[CH2:17].C(N(CC)CC)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([CH:17]=[CH:16][C:15]([N:14]([CH3:19])[CH3:13])=[O:18])=[C:3]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:4]=1
Reactant: C=CC(=O)N(C)C
Reactant: CC(C)(C)c1cc(N)ncc1Br
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C=Cc1cnc(N)cc1C(C)(C)C
Temperature: 25 °C
Yield: 81 %

Procedure:
De-gas a mixture of 5-bromo-4-tert-butyl-pyridin-2-ylamine (330 mg, 1.4 mol), N,N-dimethylacrylamide (0.22 mL, 2.1 mmol), triethylamine (0.4 mL, 2.1 mmol) in toluene (4 mL) while purging with nitrogen for 3 minutes. Add palladium(II)acetate (60 mg, 0.28 mmol) and tetrakis(triphenylphosphine)palladium(0) (690 mg, 0.6 mmol) under nitrogen. Heat the reaction overnight in sealed vessel at 120° C. Cool the mixture to room temperature, filter through Celite® and concentrate. Purification by silica gel column chromatography (100% DCM to 3% MeOH in DCM) to yield the title compound (81% yield). LCMS (ES), m/z 248 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.Cl.[CH:20]12[CH2:26][CH:23]([NH:24][CH2:25]1)[CH2:22][N:21]2[C:27](=[O:30])[CH2:28][OH:29].CCN(CC)CC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CN1CCCC1=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:24]2[CH2:25][C@@H:20]3[CH2:26][C@H:23]2[CH2:22][N:21]3[C:27](=[O:30])[CH2:28][OH:29])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Oc2nc3ccccc3s2)cc1
Reactant: O=C(CO)N1CC2CC1CN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CO)N1C[C@@H]2C[C@H]1CN2Cc1ccc(Oc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
A mixture of 4-(benzothiazol-2-yloxy)-benzaldehyde (67 g, 0.26 mol), 1-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-hydroxy-ethanone hydrochloride (40.61 g, 0.26 mol), Et3N (183 mL, 1.31 mol), and N-methylpyrrolidinone (150 mL) in dichloroethane (750 mL) was stirred at rt for 1 h. Sodium triacetoxyborohydride (66.63 g, 0.314 mol) was then added in four equal portions over a 4 h period. After stirring overnight, the mixture was quenched with 3 N HCl(aq) (250 mL) and then 6 N HCl(aq) (3×50 mL) to a final pH of 0.54. The layers were separated and the organic was extracted again with 3 N HCl(aq) (250 mL). The combined aqueous layers were basified with Na2CO3 (50 g) and then 50% NaOH(aq) (130 mL) to a final pH of 13.2. After stirring for 1 h, isopropyl acetate (200 mL) was added and the mixture was stirred for 20 min. After separation of layers, the aqueous was extracted with additional isopropyl acetate (2×200 mL) and the organic layers were combined with an interstitial oil and concentrated. The resulting brown oil was purified by flash chromatography (0-5% MeOH in CH2Cl2) to provide the product as a clear oil (93.84 g, 91%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[CH2:11][CH2:10][O:9][C:8]2[CH:12]=[C:13]([C:16]([NH:18][C@@H:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@@H:21]([C:32]4[N:36]([CH2:37][CH2:38][OH:39])[C:35]5[CH:40]=[CH:41][CH:42]=[CH:43][C:34]=5[N:33]=4)[CH2:20]3)=[O:17])[CH:14]=[CH:15][C:7]1=2.O.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[O:6]1[CH2:11][CH2:10][O:9][C:8]2[CH:12]=[C:13]([C:16]([NH:18][C@@H:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@@H:21]([C:32]4[N:36]([CH2:37][CH2:38][O:39][S:2]([CH3:1])(=[O:4])=[O:3])[C:35]5[CH:40]=[CH:41][CH:42]=[CH:43][C:34]=5[N:33]=4)[CH2:20]3)=[O:17])[CH:14]=[CH:15][C:7]1=2
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc3c(c2)OCCO3)C[C@@H]1c1nc2ccccc2n1CCO
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc3c(c2)OCCO3)C[C@@H]1c1nc2ccccc2n1CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.1 %

Procedure:
Methanesulfonyl chloride (51.3 mg, 0.448 mmol) was added to a solution of (2R,4R)-tert-butyl 4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-(1-(2-hydroxyethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (78 mg, 0.15 mmol) and DMAP (3.5 mg) in pyridine (1 mL) at 0° C. and the resulting mixture was stirred at room temperature for 5 hours. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated and dried over MgSO4 and concentrated to give a yellow solid, which was purified by Companion (ReadSep, 12 g, silica gel packed) with ethyl acetate/heptane from 30-70% to give title compound as a white solid 65 mg (73%). LC-MS: 601.1 (t=2.6 min).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29](=O)[CH2:30][CH2:31][P:32]([CH3:37])(=[O:36])[O:33]CC)=[CH:25][CH:24]=1)=[O:22])=[O:7])([CH3:4])[CH3:3].[BH4-].[Na+].[NH4+].[Cl-]>C1COCC1>[CH3:37][P:32]1(=[O:36])[CH2:31][CH2:30][CH:29]([C:26]2[CH:25]=[CH:24][C:23]([C:21]([NH:20][C:10]3[CH:11]=[C:12]([C:15]4[S:16][CH:17]=[CH:18][CH:19]=4)[CH:13]=[CH:14][C:9]=3[NH:8][C:6](=[O:7])[O:5][C:2]([CH3:4])([CH3:1])[CH3:3])=[O:22])=[CH:28][CH:27]=2)[O:33]1
Reactant: CCOP(C)(=O)CCC(=O)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(C2CCP(C)(=O)O2)cc1
Reaction time: 8 h

Procedure:
Ethyl {3-[4-({[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]-3-oxopropyl}methylphosphinate (0.7 g, 1.258 mmol) was taken up in THF (6 mL) and sodium borohydride (0.052 g, 1.383 mmol) was added before stirring overnight. Saturated NH4Cl was added and the products extracted into EtOAc (×2). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC followed by HPLC gave 1,1-dimethylethyl [2-({[4-(2-methyl-2-oxido-1,2-oxaphospholan-5-yl)phenyl]carbonyl}amino)-4-(2-thienyl)phenyl]carbamate as a white solid. The title compound was obtained as a ˜1:1 mixture of diastereosiomers.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[I-].[K+]>C(N(C(C)C)CC)(C)C.C(OCC)C>[F:1][C:2]([F:6])([F:5])[CH2:3][NH:4][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: NCC(F)(F)F
Reactant: CCOC(=O)CBr
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNCC(F)(F)F
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
2,2,2-trifluoroethylamine (2.0 g) was added to a suspension of ethyl bromoacetate (2.3 mL), potassium iodide (0.34 g) in diisopropylethylamine (3.3 mL) and the mixture was stirred at RT for 5.5 h. The mixture was diluted with diethyl ether (30 mL), stirred at RT for 30 mins. The suspension was filtered and concentrated under reduced pressure. The sub-title compound (2.6 g) was obtained as a yellow oil; 1H NMR (300 MHz, CDCl3); 4.19 (2H, q), 3.50 (2H, s), 3.22 (2H, q), 1.26 (3H, t).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>ClCCl>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)NC1CCN(Cc2ccccc2)CC1

Procedure:
To a solution of 5.0 g of 4-amino-1-benzylpiperidine in 100 ml of dichloromethane were added 4.1 ml of pyridine and 2.2 ml of methanesulfonyl chloride at 0° C. Then the mixture was reacted at the same temperature for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the crystals thus precipitated were taken up by filtration to thereby give 7.0 g of the title compound as colorless crystals.
Reaction SMILES: O.NN.[C:4]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16](=O)[CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][CH:20]=3)=[CH:13][C:12]=2[CH:29]=1)([CH3:7])([CH3:6])[CH3:5].[OH-].[K+].Cl>C(O)COCCO>[C:4]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][CH:24]=3)=[CH:13][C:12]=2[CH:29]=1)([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)c1ccc2oc(C(=O)COc3ccc(C(=O)O)cc3)cc2c1
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: O
Solvent: OCCOCCO
Product: CC(C)(C)c1ccc2oc(CCOc3ccc(C(=O)O)cc3)cc2c1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 89.6 %

Procedure:
Diethylene glycol (10 ml) and 285 mg of hydrazine monohydrate were added to 5-tert-butyl-2-(4-carboxyphenoxyacetyl)benzofuran (1 g) obtained in Example 14 and the mixture was stirred at 90° C. for 40 minutes. Potassium hydroxide (398 mg) was added to the mixture and then heated at 120° C. for 2 hours with stirring and further heated at 180°-190° C. for 3 hours. The reaction mixture was poured into aqueous solution of hydrochloric acid and the crystals separated out therefrom were filtered to give 0.86 g of crystals.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH2:11]([NH:18][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[N:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Fc1cccc(NCc2ccccc2)c1C=NCc1ccccc1
Temperature: 150 °C
Yield: 82.7 %

Procedure:
A resealable tube was charged with 2,6-difluorobenzaldehyde (7.11 g, 50 mmol), benzylamine (27.3 mL, 250 mmol), cesium carbonate (19.5 g, 60 mmol), and dry toluene (170 mL). The tube was sealed and heated at 150° C. for 4 hours with rapid stirring. The reaction mixture was cooled and partitioned between ethyl acetate and 10% aqueous HCl. The organic layer was removed and the aqueous layer was extracted (2×, ethyl acetate). The combined organic extracts were washed (2×, saturated sodium bicarbonate; 2×, brine), dried (Na2SO4), filtered and concentrated under vacuum to provide the title compound (13.17 g; 83%) which was used without purification. MS (DCI/NH3) m/e 318 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:23][CH:22]=[N:21][CH:20]=3)=[CH:15][CH:14]=2)=[S:11])[CH:4]=1)[CH3:2].[Br-].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.[OH-].[K+]>C(O)(=O)C.O>[CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:18]3[CH:17]=[C:16]([C:19]4[O:23][CH:22]=[N:21][CH:20]=4)[CH:15]=[CH:14][C:13]=3[N:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1ccnc(NC(=S)Nc2ccc(-c3cnco3)cc2)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCc1ccnc(Nc2nc3ccc(-c4cnco4)cc3s2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 0.2 %

Procedure:
1-(4-Ethylpyridin-2-yl)-3-(4-(oxazol-5-yl)phenyl)thiourea (0.27 g, 0.8 mmol) was dissolved in 5 mL of acetic acid. Benzyltrimethylammonium tribromide (320 mg, 0.821 mmol) was then added directly. The mixture was stirred at 50° C. for 1 hour. The mixture was cooled to 0° C. and diluted with 15 mL of water. The resulting solution was then made basic through addition of solid KOH pellets. The resulting precipitate was collected by vacuum filtration, washed with water and dried under vacuum to afford the crude product as a tan solid. A portion of the solid was purified by rp-HPLC affording 0.6 mg of N-(4-ethylpyridin-2-yl)-6-(oxazol-5-yl)benzo[d]thiazol-2-amine 501 as a yellow solid. MS calculated for C17H14N4OS: 323.0888; [M+H]+. found: 322.93. 1H-NMR (400 MHz, MeOD) 8.25-8.23 (m, 2H), 8.17 (s, 1H), 7.75 (d, J=8.4, 1H), 7.66 (d, J=8.4, 1H) 7.50 (s, 1H), 6.97 (s, 1H), 6.88 (d, J=8.4, 1H), 2.68 (q, J=7.7, 2H), 1.28 (t, J=7.7, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([NH2:11])[CH3:10].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([NH:11][C:41]([C:37]1[CH:36]=[C:35]2[C:40](=[CH:39][CH:38]=1)[N:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]3[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:30][CH:29]=1)[C:33]([CH3:45])=[C:34]2[CH3:44])=[O:42])[CH3:10]
Reactant: C[C@H](N)c1ccc(F)cc1F
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(F)cc3F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(2,4-difluorophenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 539 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([C@H:20]([NH:26][C:27]([C:29]1[N:30]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])=[O:19].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:70](O)(=[O:79])[CH:71]=[CH:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1.C(N1CCOCC1)C>C(OCC)(=O)C.O.CN(C)C=O>[CH3:11][O:10][C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([C@H:20]([NH:26][C:27]([C:29]1[N:30]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:70](=[O:79])[CH:71]=[CH:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)=[O:19]
Reactant: O=C(O)C=Cc1ccccc1
Reactant: COC(=O)Cn1c(C(=O)N[C@H](CCCCN)C(=O)NCCCCCc2c(OC)cc(C)cc2OC)cc2ccccc21
Agent: CCN1CCOCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cn1c(C(=O)N[C@H](CCCCNC(=O)C=Cc2ccccc2)C(=O)NCCCCCc2c(OC)cc(C)cc2OC)cc2ccccc21
Temperature: -5 °C
Reaction time: 18 h

Procedure:
0.87 g of methyl (R)-{2-[N-{1-[(2,6-dimethoxy-4-methylphenyl)pentylcarbamoyl]-5-aminopentyl}carbamoyl]indol-1-yl}acetate, 0.645 g of BOP and 0.23 g of cinnamic acid are successively added to 30 ml of dimethylformamide. After cooling to -5° C., 0.26 g of N-ethylmorpholine is added under an inert atmosphere and the reaction mixture is maintained at 0° C. for 2 hours and is then left at room temperature for 18 hours. The reaction mixture is poured into a large volume of water and extraction is carried out with ethyl acetate. The organic extracts are dried over anhydrous sodium sulphate and evaporated to dryness. The residual oil is purified by flash chromatography on silica gel, eluent: CH2Cl2 /CH3OH 97/3 (v/v) in order to obtain methyl (R)-{2-[N-{1-[(2,6-dimethoxy-4-methylphenyl)pentylcarbamoyl]-5-(cinnamoylamino)pentyl}carbamoyl]indol-1-yl}acetate in the form of an oil.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[CH3:7][O:8][CH2:9][CH2:10]OCC(O)=O>CN(C=O)C.C(Cl)Cl>[CH3:7][O:8][CH2:9][CH2:10][O:3][CH2:2][C:1]([Cl:6])=[O:5]
Reactant: COCCOCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCOCC(=O)Cl
Reaction time: 17 h

Procedure:
Under a nitrogen atmosphere, 2.56 ml (29.8 mmol) of oxalyl chloride and 2 drops of DMF are added to 1.69 ml (14.9 mmol) of 2-(2-methoxyethoxy)-acetic acid (Fluka; Buchs/Switzerland) in 75 ml of methylene chloride. After 17 h at RT, the reaction mixture is carefully concentrated by evaporation in a RE with the exclusion of moisture. A 1H-NMR spectrum of the residue exhibits the signals of the title compound in addition to signals of ≈40% solvent (especially methylene chloride): 1H-NMR (200 MHz, CDCl3): 3.37 (s, MeO), 3.58 and 3.77 (2d, J=5 Hz, CH2 --CH2), 4.48 (s, CH2). That mixture is used above.
Reaction SMILES: CI.[F:3][C:4]([F:28])([F:27])[C:5]([N:7]1[CH2:14][CH2:13][C@:12]2([CH3:18])[C:15]([CH3:17])([CH3:16])[C@H:8]1[CH2:9][C:10]1[C:22]([OH:23])=[C:21]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:19][C:11]=12)=[O:6].[C:29](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[F:28][C:4]([F:3])([F:27])[C:5]([N:7]1[CH2:14][CH2:13][C@:12]2([CH3:18])[C:15]([CH3:17])([CH3:16])[C@H:8]1[CH2:9][C:10]1[C:22]([O:23][CH3:29])=[C:21]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:19][C:11]=12)=[O:6]
Reactant: CC1(C)[C@H]2Cc3c(ccc([N+](=O)[O-])c3O)[C@]1(C)CCN2C(=O)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c([N+](=O)[O-])ccc2c1C[C@H]1N(C(=O)C(F)(F)F)CC[C@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Methyl iodide (80 μL) is added to a mixture of 2,2,2-trifluoro-1-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-9-nitro-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone (0.40 g) and potassium carbonate (0.17 g) in N,N-dimethylformamide (5 mL). The mixture is stirred at room temperature overnight, before another portion of methyl iodide (80 μL) and potassium carbonate (0.16 g) are added. The mixture is stirred for another 6 h at room temperature. Then, water and ethyl acetate are added, the organic phase is separated, and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine and dried (Na2SO4). The solvent is evaporated to give the crude product that is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH2:30])=[NH:29])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:29]=[C:28]([NH:27][C:24]4[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=4)[N:30]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: COc1ccc(NC(=N)N)cc1
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)cc1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and 1-(4-methoxyphenyl)guanidine were converted to I-14 (39%): HRMS Calcd. for C19H15ClN4O2: 367.0960, Found 367.0975.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([N:12]3[C:16]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)=[CH:15][C:14]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[N:13]3)[CH2:9]2)C=CC=CC=1>CCOC(C)=O.CO.[Pd]>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:16]2[N:12]([CH:10]3[CH2:9][NH:8][CH2:11]3)[N:13]=[C:14]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:15]=2)=[CH:19][CH:20]=1
Reactant: Fc1ccc(Cc2cc(-c3ccncc3)nn2C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Fc1ccc(Cc2cc(-c3ccncc3)nn2C2CNC2)cc1
Temperature: 57 °C

Procedure:
To a flask charged with NH4CO2H (6.2 g, 98.4 mmol) was added MeOH (50 mL) and stirred to a solution, followed by addition of a solution of 4-[1-[1-(diphenylmethyl)azetidin-3-yl]-5-(4-fluorobenzyl)-1H-pyrazol-3-yl]pyridine (2.3 g, 4.85 mmol) in EtOAc (50 mL), and the mixture stirred to a homogenous solution. This was added to a second flask containing 10% Pd/C (0.84 g) in MeOH (100 mL) under N2, and the reaction mixture was heated to 57° C. under N2 for 5 hours. The mixture was cooled to room temperature and the solids removed by filtration through a GF/F filter set. The filtrate was concentrated and diluted with water (50 mL) and then saturated with NaOH. The emulsion was then extracted with CH2Cl2 (3×100 mL) followed by Et2O (4×100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (90:10:1 CH2Cl2/MeOH/NH4OH) to yield the title compound as a white solid, 0.892 g, 60%. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 8.61 (d, 2 H), 7.69 (d, 2 H), 7.06-7.14 (m, 2 H), 6.95-7.05 (m, 2 H), 6.42 (s, 1 H), 4.91-5.08 (m, 1 H), 4.29 (t, 2 H), 3.98 (s, 2 H), 3.61 (t, 2 H); m/z (APCI+) for C18H17N4F 309.2 (M+H)+.