Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5](=[C:16](SC)SC)[C:4]=2[CH:3]=1.[CH2:21]([Mg]Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5](=[C:16]([CH2:13][CH2:14][CH2:2][CH2:3][CH2:4][CH2:12][CH2:11][CH3:10])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]=2[CH:3]=1
Reactant: CSC(SC)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: CCCCCCCC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCC(CCCCCCCC)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a solution of 2,7-dibromo-9-(bis-methylsulfanyl-methylene)fluorene (5.1 g, 12 mmol) in dry THF (100 ml) at 0° C. under nitrogen, was added a solution of lithium tetrachlorocuprate (5 ml of a 0.1 M solution in THF, 5 mol %). A solution of octylmagnesium bromide (13 ml of a 2.0M solution in diethyl ether, 0.026 mol) was added dropwise over 30 min. The reaction was stirred for 2 h at 5° C. The reaction was cooled to 0° C. and further lithium tetrachlorocuprate (1 ml of a 0.1M solution in THF, 1 mol %) was added. The reaction was then stirred for 24 h at 15° C., before quenching and workup as above. Yield (60%). Purity (HPLC>99%). 1H and 13C NMR spectra as expected. M+=560 (t).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3([C:24]#N)[CH2:23][CH2:22]3)=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C([OH:29])(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3([CH:24]=[O:29])[CH2:23][CH2:22]3)=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)O
Reactant: N#CC1(c2ccc3ncccc3c2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=CC1(c2ccc3ncccc3c2)CC1
Temperature: -2.5 °C
Reaction time: 3 h

Procedure:
Diisobutylaluminum hydride (1M in THF, 96 mL, 96 mmol) was added to a solution of 1-quinolin-6-ylcyclopropanecarbonitrile (12.4 g, 63.9 mmol) in toluene (120 mL) at −78° C. under an atmosphere of nitrogen. The reaction mixture was allowed to warm to −5 to 0° C., and stirred at that temperature for 3 h. The reaction mixture was cooled to −60° C. Isopropyl alcohol (10 mL) was carefully added dropwise. After stirring for 30 min, the reaction mixture was warmed to −5 to 0° C. The reaction mixture was diluted with ethyl acetate, quenched with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered through a pad of silica gel eluting with 40% ethyl acetate in hexanes. The filtrate was concentrated to yield the desired product. (12 g, 95.1%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([OH:21])=O)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:51]1([C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[CH:58][CH:57]=2)[CH:55]=[N:54][N:53]=[N:52]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19](=[O:21])[NH:62][C:59]3[CH:60]=[CH:61][C:56]([N:51]4[CH:55]=[N:54][N:53]=[N:52]4)=[CH:57][CH:58]=3)[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Reactant: Nc1ccc(-n2cnnn2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)Nc3ccc(-n4cnnn4)cc3)cs2)CC1
Reaction time: 8 h

Procedure:
4-(4-Carboxy-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.28 mmol) was dissolved in anhydrous DMF (20 mL). To the solution was added triethylamine (4 eq.) and O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (1.5 eq.). The reaction was allowed to stir at room temperature for 5 minutes before 4-tetrazol-1-yl-phenylamine (1.2 eq.) was added. The reaction was stirred overnight, quenched with water, extracted with ethylacetate, washed with brine, dried over sodium sulfate and filtered. The organic filtrate was concentrated in vacuo and the residual oil was purified by column chromatography (EtOAC/Hex) furnishing the expected product. 1H NMR (CDCl3): δ 9.37 (1H, s), 9.02 (1H, s), 8.14 (1H, s), 7.96 (2H, d), 7.72 (2H, d), 4.23 (2H, m), 3.20 (1H, m), 2.91 (2H, m), 2.14 (2H, m), 1.79 (2H, m), 1.45 (9H, s).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH3:22][C:23]1([CH3:45])[C:27]([C:28]2[CH:33]=[C:32]([CH2:34]O)[CH:31]=[CH:30][C:29]=2[C:36]2[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=2[F:44])=[CH:26][CH2:25][CH2:24]1.N1C=CC=CC=1>C(Cl)Cl>[Br:20][CH2:34][C:32]1[CH:31]=[CH:30][C:29]([C:36]2[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=2[F:44])=[C:28]([C:27]2[C:23]([CH3:45])([CH3:22])[CH2:24][CH2:25][CH:26]=2)[CH:33]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2=CCCC2(C)C)c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CBr)cc2C2=CCCC2(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of triphenylphosphine (0.13 g, 0.51 mmol) in DCM (1.0 mL), was slowly added bromine (0.081 g, 0.51 mmol, 0.25 mL, 2M in CCl4) at 0° C. The resulting mixture was stirred at 0° C. for 15 minutes and then a mixture of compound T1.7 (0.15 g, 0.46 mmol) and anhydrous pyridine (0.041 mL, 0.51 mmol) in DCM (3.0 mL) was added to the mixture. The reaction mixture was stirred at room temperature for 2 hours. DCM (80 mL) was added, and the mixture was washed with water (20×2 mL), and dried over Na2SO4. The solvent was removed under reduced pressure to provide product T1.8. 1H NMR (400 MHz, CDCl3) δ ppm. 7.16-7.29 (m, 3H), 6.88 (t, 1H), 6.72 (m, 2H), 5.45 (s, 1H), 4.46 (s, 2H), 3.68 (s, 3H), 2.16-2.19 (m, 2H), 1.59 (t, 2H), 0.78 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:12]1([CH2:18][CH2:19][CH2:20][NH2:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)CC>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:21][CH2:20][CH2:19][CH2:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: NCCCc1ccccc1
Solvent: CCCO
Product: Brc1cnc2ccc(NCCCc3ccccc3)nn12
Temperature: 150 °C

Procedure:
A mixture of 3-bromo-6-chloro-imidazo[1,2-b]pyridazine (232 mg, 1 mmol) and phenylpropyl amine (1 ml, 7 mmol) in n-PrOH (1 mL) was heated in a microwave at 150° C. for 20 min. Additional phenylpropyl amine (0.5 ml) was added and reaction mixture heated for additional 20 min. then 30 min. in a microwave. The reaction mixture was concentrated and the residue was subjected to ISCO (40 g column, DCM 3 min. then 0-10% MeOH in DCM over 30 min.) to gave the product (380 mg ˜90% pure and was used directly for next step).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1.[CH2:26]([NH2:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:32][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:3]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][C:14]=3[N:15]=2)[CH:4]=1)([O-:10])=[O:9]
Reactant: CCCCCCN
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Product: CCCCCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.60 mmol), and hexylamine (2 ml) the subtitle compound was obtained (298 mg, 100%). MS 416 m/z (M+H)+.
Reaction SMILES: C[O:2][C:3]1[C:4](=O)[CH:5]([C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][C:7]([CH3:10])([CH3:9])[CH:8]=1.[CH3:19][NH:20][NH2:21]>C(O)(=O)C.O>[CH3:19][N:20]1[C:4]2[C:3](=[O:2])[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5]=2[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:21]1
Reactant: CCOC(=O)C(=O)C1CC(C)(C)C=C(OC)C1=O
Reactant: CNN
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(C)c2c1CC(C)(C)CC2=O
Reaction time: 24 h
Yield: 67.5 %

Procedure:
A solution of ethyl (3-methoxy-5,5-dimethyl-2-oxocyclohex-3-en-1-yl)(oxo)acetate (15.50 g, 0.061 mol) in acetic acid (100 mL) was treated dropwise with a solution of methyl hydrazine (3.49 mL, 0.066 mol) dissolved in acetic acid (50 mL). After 24 hours at room temperature, the reaction mixture was diluted with water (2 L) under vigorous stirring. The resulting precipitate was filtered and washed with water to obtain the title compound (10.30 g, 67.6% yield) as a yellow solid.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][C:5]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:25]([CH3:28])=[N:26][CH:27]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>CN(C=O)C>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:21][C:22]3[CH:23]=[C:24]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:25]([CH3:28])=[N:26][CH:27]=3)=[N:3][CH:4]=[C:5]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH:6]=2)[N:9]=1
Reactant: COCCOc1cnc(F)c(-c2nc(C)nc(N)n2)c1
Reactant: Cc1ncc(N)cc1NS(C)(=O)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCOc1cnc(Nc2cnc(C)c(NS(C)(=O)=O)c2)c(-c2nc(C)nc(N)n2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 30.3 %

Procedure:
To a 15 mL round-bottom flask was added 4-(2-fluoro-5-(2-methoxyethoxy)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (Example 335 Step 3) (0.050 g, 0.179 mmol), N-(5-amino-2-methylpyridin-3-yl)methanesulfonamide (0.043 g, 0.215 mmol), and DMF (2.0 mL). The mixture was cooled to 0° C. under N2. Sodium bis(trimethylsilyl)amide, 1.0 m in THF (Aldrich) (0.145 mL, 0.716 mmol) was then added to the solution in one portion. The now dark burgundy color mixture was stirred at 0° C. for 10 min then warmed up to rt and stirred for 1 h. The reaction mixture was partitioned between sat. NH4Cl and CHCl3. The aqueous layer was extracted with more CHCl3 (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (16 g, 5% to 10% MeOH in DCM) to afford the desired product as a yellow solid (25 mg). MS (ESI pos. ion) m/z: 461.0. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.45 (d, J=2.63 Hz, 6H) 2.52 (s, 3H) 3.06 (s, 3H) 3.61-3.73 (m, 2H) 4.09-4.23 (m, 2H) 7.77 (br. s., 1H) 7.89 (br. s., 1H) 8.17 (d, J=2.92 Hz, 1H) 8.33 (d, J=1.75 Hz, 1H) 8.42 (d, J=3.07 Hz, 1H) 8.65 (s, 1H) 9.29 (br. s., 1H) 11.76 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.[C:13]([C:15]1[CH:16]=[C:17]([S:22](Cl)(=[O:24])=[O:23])[CH:18]=[CH:19][C:20]=1[F:21])#[N:14].Cl>ClCCl>[C:13]([C:15]1[CH:16]=[C:17]([S:22]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:24])=[O:23])[CH:18]=[CH:19][C:20]=1[F:21])#[N:14]
Reactant: Nc1nccs1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1F
Yield: 66.6 %

Procedure:
To 2-aminothiazole (12.55 g, 125.3 mmol) was added pyridine (46 ml) and dichloromethane (75 mL) and the mixture stirred to give a solution. A solution of 3-cyano-4-fluorobenzenesulfonyl chloride (25 g, 114 mmol) in dichloromethane (50 ml) was added over approx 20 minutes at room temperature. The reaction was stirred at this temperature for 2 days before decanting the supernatant and concentrating in vacuo to furnish a dark oil. 2M HCl (200 ml) was added and the mixture triturated until solidification occurred. A brick red solid was filtered off, washed with water and dried to furnish 21.5 g of the title product. 1HNMR (d6-DMSO): δ 6.9 (d, 1H), 7.3 (m, 1H), 7.6 (m, 1H), 8.15 (m, 1H), 8.3 (d, 1H), 12.9 (br s 1H). LCMS Rt=2.34 min MS m/z 284 [MH]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-])=O)[CH:3]=1>C(O)(=O)C.C(O)C.[Fe]>[NH2:10][C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc(Br)ccc1C=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
To a 0.2M solution of 4-bromo-2-nitrobenzaldehyde in acetic acid and ethanol (v/v 1:1) solvent system was added iron powder. The reaction mixture was stirred at ambient temperature under Argon for 1.5 h and LCMS showed the reaction was complete. Insoluble solid was filtered off and the filtrate was concentrated in vacuum. Residue was diluted with ethyl acetate and was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. Crude product was purified by Biotage using 15% ethyl acetate in hexane to give desired product in 38% yield. ES/MS m/z 200/202 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.O.O.Cl.Cl.[NH2:20][CH:21]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=[CH:35][CH:34]=2)=[CH:28][CH:27]=1)[C:22]([OH:24])=[O:23].C([O-])([O-])=O.[K+].[K+].Cl>CS(C)=O.O>[C:22]([CH:21]([NH:20][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=[CH:35][CH:34]=2)=[CH:28][CH:27]=1)([OH:24])=[O:23]
Reactant: NC(Cc1ccc(Nc2ccnc3ccccc23)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccc(Nc2ccnc3ccccc23)cc1)C(=O)O
Temperature: 110 °C
Reaction time: 24 h
Yield: 83.6 %

Procedure:
A mixture of 2,6-dichloro-quinoline-3-carboxylic acid (0.17 g, 0.7 mmol), 2-amino-3-[4-(quinolin-4-ylamino)-phenyl]propionic acid dihydrochloride dihydrate (0.291 g, 0.7 mmol) and K2CO3 (0.507 g, 3.7 mmol) in DMSO (1.5 mL) is stirred at 110° C. temperature for 24 h in a Pierce reaction vial. After cooling the reaction mixture is diluted with water (10 mL) and acidified with 2N aqueous HCl till pH ˜3. The precipitated solid is collected on filter and washed with water to give the title compound (0.3 g, 84%) as yellow solid.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([C:21]([NH2:23])=O)[C@@H:17]2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.B.CSC>C1COCC1>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([CH2:21][NH2:23])[C@@H:17]2[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:32])([F:1])[F:31])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CC[C@@H](C(N)=O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: C[C@@H](O[C@H]1CC[C@@H](CN)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.6 %

Procedure:
To a solution of 0.70 gm of the amide from Step B in 10 mL of THF was added 2.25 mL of 2M borane-dimethylsulfide in THF. The reaction was stirred at room temperature for 16 hours and then warmed at 50° C. for another 6 hours. The excess borane was quenched with dropwise addition of methanol and then 20 mL of methanol and 5 mL of 2N hydrochloric acid were added and the reaction was stirred at room temperature for 24 hours. The mixture was concentrated in vacuo, diluted with water, made basic with 2N sodium hydroxide and extracted twice with methylene chloride. The organic layers were washed with brine, dried over sodium sulfate, combined and evaporated. The residue was purified by FC (methylene chloride, the 5 -10% methanol in methylene chloride) to give 350 mg of title compound. NMR (CDCl3) δ1.33 (d, 3H, J=6.5 Hz), 1.53 (br s, NH2+H2O), 1.5-1.65 (m, 1H), 1.7-1.85 (m, 1H), 1.85-2.0 (m, 2H), 2.0-2.15 (m, 1H), 2.59 (dd, 1H, J=8 and 10 Hz 2.52 and 2.67 (dABq, 2H, J=4.6 and 12.6 Hz), 3.67 (q, 1H, J=6 Hz), 4.45 (q, 1H, J=6.5 Hz), 6.85-6.95 (m, 2H), 6.95-7.05 (m, 2H), 7.38 (s, 2H), 7.64 (s, 1H). Mass spec (ESI): 450(M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[OH:24][C@@H:25]1[CH2:29][CH2:28][C@H:27]([C:30](O)=[O:31])[CH2:26]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:30]([C@H:27]3[CH2:28][CH2:29][C@@H:25]([OH:24])[CH2:26]3)=[O:31])=[C:16]2[N:15]=1
Reactant: O=C(O)[C@H]1CC[C@@H](O)C1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12)[C@H]1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
A DMA (1 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 50 mg, 0.16 mmol), (1S,3R)-3-hydroxycyclopentanecarboxylic acid (23 mg, 0.17 mmol) [purchased from AFID Therapeutics Inc.] and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) (56 mg, 0.17 mmol) was first cooled in an ice-water bath, then DIEA (0.083 mL, 0.48 mmol) was added to reaction drop-wise. Ice bath was then removed and the reaction was stirred at ambient temperature for 1 hour to reach completion. The reaction mixture was diluted with water (10 mL) and vacuum-filtered, yielding the crude product as a beige solid. The crude was purified by reverse phase column chromatography, eluting with 5 to 57% acetonitrile/water to yield the final product as a solid (20 mg, 30% yield). MS (apci) m/z=428.2 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH2:18][C:19](=[O:35])[NH:20][C:21]4[CH:27]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=5)[CH:25]=[CH:24][C:22]=4[N:23]=3)[CH:12]=2)[S:9][CH:10]=1)=O)C.COCCO[AlH2-]OCCOC.[Na+].C1(C)C=CC=CC=1>C1COCC1>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:26]2[CH:25]=[CH:24][C:22]3[N:23]=[C:17]([C:13]4[CH:14]=[CH:15][CH:16]=[C:11]([C:8]5[S:9][CH:10]=[C:6]([CH2:4][OH:3])[N:7]=5)[CH:12]=4)[CH2:18][C:19](=[O:35])[NH:20][C:21]=3[CH:27]=2)=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1csc(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)n1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1CC(c2cccc(-c3nc(CO)cs3)c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
To a solution of 2-{3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-phenyl}-thiazole-4-carboxylic acid ethyl ester (Example 153) (110 mg, 0.23 mmol) in THF (7 mL) was added a 3.5 M solution of sodium dihydrido-bis(2-methoxyethoxy)aluminate in toluene(0.66 mL, 2.3 mmol). The raction mixture was stirred at 23° C. for 15 min. and then poured into ice-cold 10% aq. acetic acid. The mixture was extracted with ethyl acetate and the organic layer was washed successively with H2O, sat. Na2CO3-sol. and brine, dried over Na2SO4 and evaporated in vacuum. The residue was triturated with ethyl acetate to give the title compound as light yellow solid (48 mg).
Reaction SMILES: [CH2:1]([N:8]1[N:12]=[N:11][C:10]([CH2:13][N:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C@@H:24]3[C@@H:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:27][N:26]([C@@H:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]4[CH2:41][C:42]([O:44]CC4C=CC(OC)=CC=4)=[O:43])[CH2:25]3)[CH2:19][CH2:18]2)[CH2:15][CH3:16])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:1]([N:8]1[N:12]=[N:11][C:10]([CH2:13][N:14]([CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][C@@H:24]3[C@@H:28]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:27][N:26]([C@@H:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]4[CH2:41][C:42]([OH:44])=[O:43])[CH2:25]3)[CH2:21][CH2:22]2)[CH2:15][CH3:16])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(Cc1nnn(Cc2ccccc2)n1)C1CCN(C[C@H]2CN([C@@H]3CCCCC3CC(=O)OCc3ccc(OC)cc3)C[C@@H]2c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCN(Cc1nnn(Cc2ccccc2)n1)C1CCN(C[C@H]2CN([C@@H]3CCCCC3CC(=O)O)C[C@@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.7 %

Procedure:
To 54 mg of 2-(R)-(3-(S)-((4-(N-(2-Benzyl-2H-tetrazol-5-yl)methyl-N-ethylamino)-piperidine-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-Methoxybenzyl ester (from Step E) were added 150 mg of anisole and 3 ml of triflouroacetic acid. The reaction was stirred at room temperature for 1 hour. The trifluoroacetic acid was evaporated under reduced pressure. The residue was purified by flash chromatography with 20% MeOH in EtOAc followed by 20% MeOH+2% NH4OH in EtOAc to give 48 mg of the title compound. ESI−MS 601 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[F:21])=[C:9]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=O)[CH:8]=1)=[O:4].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)S2)=CC=1.O.[CH:53]([NH:55][NH2:56])=O>C1(C)C=CC=CC=1>[CH3:29][C:2]([CH3:1])([CH3:28])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[F:21])=[C:9]([C:22]2[N:24]([CH:25]([CH3:26])[CH3:27])[CH:53]=[N:55][N:56]=2)[CH:8]=1)=[O:4]
Reactant: NNC=O
Reactant: COc1ccc(F)c(-c2ccc(COC(=O)C(C)(C)C)cc2C(=O)NC(C)C)c1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(F)c(-c2ccc(COC(=O)C(C)(C)C)cc2-c2nncn2C(C)C)c1
Temperature: 120 °C
Yield: 52.2 %

Procedure:
To a room temperature solution of 29.3 (244 mg, 608 μmol) in toluene was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (369 mg, 912 μmol, Acros Organics). The mixture was heated at 120° C. for 1.0 hour, cooled to room temperature, treated with water, and then extracted with EtOAc. After removal of organic solvent under reduced pressure, the residue was dissolved in dioxane (4 mL). To the solution was added formohydrazide (208 mg, 3461 μmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) and mercuric acetate (202 μL, 2076 μmol, Acros Organics). The resulting mixture was heated at 130° C. for 1.5 hours, cooled to room temperature, treated with water, and extracted with 30% IPA. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel with 0-60% EtOAc/hexanes for elution gave 29.4 as a colorless oil (135 mg, 52%).
Reaction SMILES: C([Li])CCC.[CH2:6]([C:9]12[CH2:16][S:15][CH:12]([S:13][CH2:14]1)[S:11][CH2:10]2)[CH2:7][CH3:8].Cl[CH2:18][O:19][CH2:20][CH2:21][C:22]#[CH:23].O>O1CCCC1>[CH2:20]([O:19][CH2:18][C:12]12[S:11][CH2:10][C:9]([CH2:6][CH2:7][CH3:8])([CH2:16][S:15]1)[CH2:14][S:13]2)[CH2:21][C:22]#[CH:23]
Reactant: CCCC12CSC(SC1)SC2
Reactant: C#CCCOCCl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C#CCCOCC12SCC(CCC)(CS1)CS2
Reaction time: 0.5 h

Procedure:
n-Butyllithium (0.3 ml,1.6M solution in hexane) was added to a solution of 4-n-propyl-2,6,7-trithiabicyclo[2.2.2]octane (0.1 g) in dry tetrahydrofuran (5 ml) at -70°, under nitrogen. The solution was stirred for 30 minutes and but-3-ynyl chloromethyl ether (0.058 g) in dry tetrahydrofuran (2.0 ml) was added and the reaction mixture was allowed to warm to 20°. Water (10 ml) was added and the mixture was extracted with diethyl ether. The ethereal extracts were dried over anhydrous magnesium sulphate and the solvent was removed in vacuo. The residue was purified by chromatography on alumina, eluting with 1:10 dichloromethane:hexane saturated with ammonia. 1-(But-3-ynyloxy-methyl)-4-n-propyl-2,6,7-trithiabicyclo[2.2.2]octane was obtained as a waxy solid (0.032 g).