Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C-:19]#[N:20].[K+].C(OCC)(=O)C.CCCCCC>CN(C)C=O.C(OCC)(=O)C.O>[F:16][C:15]([F:18])([F:17])[C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][C:19]#[N:20])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: [C-]#N
Reactant: FC(F)(F)c1ccc(-c2ccc(CBr)cc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#CCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
A mixture of 4′-bromomethyl-4-trifluoromethyl-biphenyl (0.797 g, 2.53 mmol) and potassium cyanide (0.181 g, 2.78 mmol) in N,N-dimethyl-formamide (6 mL) is stirred for eighty-eight hours at room temperature. The mixture is diluted with ethyl acetate and water. Organic phase is washed with water twice then brine, dried over sodium sulfate, filtered and concentrated. Column chromatography on silica gel with 0-40% ethyl acetate/hexane gradient gives 0.295 g (1.13 mmol, 45%) of title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([O:22]C)[C:3]=1[I:24].B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([OH:22])[C:3]=1[I:24]
Reactant: COc1c(I)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(I)c2O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 3.0 grams (0.006 mole) of 3-(4-chloro-6-fluoro-3-iodo-2-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione in 75 mL of methylene chloride was cooled in a dry ice/acetone bath and 22.0 mL (0.022 mole) of 1M boron tribromide (in methylene chloride) was added dropwise during a 20 minute period. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature were it stirred for about one hour. At the conclusion of this period, the reaction mixture was poured into 200 mL of water and extracted with two 50 mL portions of methylene chloride. The combined extracts were washed with one 100 mL portion of an aqueous saturated sodium chloride solution, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding 2.6 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=1)(OC)[CH3:4].NC1N=C(C(=O)C)C=CN=1.[BrH:24]>C(O)=O.C(O)(=O)C.BrBr.C(OCC)(=O)C>[BrH:24].[NH2:13][C:9]1[N:8]=[C:7]([C:3](=[O:2])[CH2:4][Br:24])[CH:12]=[CH:11][N:10]=1
Reactant: COC(C)(OC)c1ccnc(N)n1
Agent: Br
Agent: BrBr
Agent: CC(=O)c1ccnc(N)n1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O=CO
Product: Nc1nccc(C(=O)CBr)n1
Yield: 65 %

Procedure:
A mixture of 3,3-dimethoxy-2-butanone (25 g, 189.2 mmol) and N,N-dimethylformamide dimethylacetal (22.5 g, 189.2 mmol) were stirred at 110° C. for 30 hours and then distilled (115° C., 1 mmHg) thus obtaining 1-(dimethylamino)-4,4-dimethoxypent-1-en-3-one, as a yellow solid (27.3 g, 146 mmol, 77%). Onto a solution of sodium (3.48 g, 151.6 mmol) in anhydrous ethanol (400 mL), solid guanidine hydrochloride (14.5 g, 151.6 mmol) was added at r.t., to give a white suspension into which a solution of 1-(dimethylamino)-4,4-dimethoxypent-1-en-3-one (28.4 g, 151.6 mmol) in anhydrous ethanol (50 mL) was added. The mixture was refluxed for 19 hours. After cooling, the precipitate was filtered and washed with ethanol and with plenty of water, thus obtaining a white solid (8.56 g). The ethanolic solutions were concentrated to dryness, taken up with boiling ethyl acetate (1 L), filtered while hot and then cooled to yield a second crop. Total amount of 4-(1,1-dimethoxyethyl)pyrimidin-2-amine: 17.66 g, 63.5%. A solution of the said amine (17.5 g, 95.5 mmol) in formic acid was stirred at r.t. for 6 hours and concentrated to dryness and the residue was stirred in ethanol (50 mL) and then filtered thus obtaining 1-(2-aminopyrimidin-4-yl)ethanone (9.2 g, 70%). To a solution of 1-(2-aminopyrimidin-4-yl)ethanone (412 mg, 3 mmol) in glacial acetic acid (1 mL) and 48% aq. HBr (0.3 mL), bromine (0.153 mL) in acetic acid (0.4 mL) was added and the resulting orange solution was stirred at room temperature for 15 hours. After diluting with ethyl acetate (15 mL), the precipitate was filtered and washed with ethyl acetate thus affording the title compound as a whitish solid (580 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:12]([O:15]C(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:15][CH2:11][C:3]1[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][N:4]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc[n+]([O-])c(C)c1Cl
Product: COc1ccnc(COC(C)=O)c1Cl
Temperature: 25 °C

Procedure:
The above 3-chloro-4-methoxy-2-methylpyridin-1-oxide (890 mg) was dissolved in acetic anhydride (12 mL), and the resulting solution was then heated under reflux for 30 minutes. After leaving to cool to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was then purified by silica gel chromatography (hexane-ethyl acetate), so as to obtain the title compound (576 mg) as an oily substance.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C(Cl)Cl.CCOC(C)=O>[CH:8]([C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:30]2[CH2:29][CH2:28][N:27]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:32][CH2:31]2)[N:4]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1nc(CCl)cs1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)c1nc(CN2CCN(C(=O)OC(C)(C)C)CC2)cs1
Temperature: 35 °C
Reaction time: 5 h
Yield: 64.7 %

Procedure:
4-(Chloromethyl)-2-isopropyl-thiazole (0.500 g, 2.85 mmol, 1 eq) was suspended in DCM (4.5 mL). DIPEA (1.24 mL, 7.1 mmol, 2.5 eq) was added dropwise, followed by N-Boc-piperazine (1.170 g, 6.3 mmol, 2.2. eq). The reaction mixture was stirred at 35° C. for 5 h, then diluted with EtOAc, and washed with H2O and brine. The organic layer was separated, dried (MgSO4) and the solvent removed in vacuo. The crude product was purified by column chromatography on a Biotage SP1 system (DCM/EtOAc; v/v 1:1) to give the title compound as a clear oil (0.600 g, 65%); 1H-NMR (500 MHz, CDCl3): δ 1.39 (d, J=7.0 Hz, 6H, iPr—CH3), 1.46 (s, 9H, C(CH3)3), 2.47 (br t, J=5.0 Hz, 4H, piperazine N(CH2)2), 3.34 (m, 1H, iPr—CH), 3.6 (br t, J=5.0 Hz, 4H, piperazine N(CH2)2), 3.66 (s, 2H, NCH2), 6.98 (s, 1H, thiazole 5-H); LC (Method B)-MS (ESI, m/z): Rt=2.80 min—326 [(M+H)+, 100%].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:23])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([F:21])[CH:15]=3)[N:13]=2)[CH:8]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>C1COCC1>[Cl:23][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:8][C:7]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([F:21])[CH:15]=2)[N:13]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(Cl)c(F)c3)c(=O)[nH]2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(Cl)c(F)c3)c(=O)[nH]2)c1

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chlorophenyl)-2-(4-chloro-3-fluorophenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-76, 0.250 g), pivaloyl chloride (1.0 mL), DIPEA (2.0 mL), dry THF (5 mL) to afford 0.110 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 1.24 (s, 9H), 4.30 (d, J=14.7 Hz, 2H), 7.40 (dd, J=4.5 Hz, 3.6 Hz, 1H), 7.43 (d, 1H), 7.60 (d, J=5.4 Hz, 1H), 7.74 (d, 1H), 7.98 (d, 1H), 8.18 (t, J=15.0 Hz, 11H), 12.70 (s, 1H); MS (m/z): 437.59 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[OH:6].[H-].[Na+].[F:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([O:25][CH3:26])[C:17]=1[CH2:18]Br.Cl>CN(C)C=O.O>[Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([O:6][CH2:18][C:17]2[C:20]([O:25][CH3:26])=[CH:21][CH:22]=[C:23]([F:24])[C:16]=2[F:15])=[C:4]([OH:12])[CH:3]=1
Reactant: COc1ccc(F)c(F)c1CBr
Reactant: O=[N+]([O-])c1cc(O)c(O)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)c(F)c1COc1cc([N+](=O)[O-])c(Cl)cc1O
Reaction time: 0.17 h
Yield: 97.5 %

Procedure:
To a solution of 4-chloro-5-nitrocatechol (10.4 g) in N,N-dimethylformamide (55 mL) was added sodium hydride (55%, 5.04 g) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added N,N-dimethylformamide (11 mL), followed by adding a solution of 2,3-difluoro-6-methoxy-benzyl bromide (14.3 g) in N,N-dimethylformamide (22 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes, and then stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water. The mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=7/3−1/1) to give the title compound (18.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH3:30][N:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1.CO.C(O)(=O)C.[BH3-]C#N.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)[CH2:13][CH2:12]3)[C:9]=2[CH:10]=1
Reactant: CN1CCC(=O)CC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCNCC2)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCN(C3CCN(C)CC3)CC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 24 %

Procedure:
To a stirred solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(piperidin-4-yl)-1H-indazole-4-carboxamide (1 equiv.) and 1-methylpiperidin-4-one (1.5 equiv.) in methanol (5 mL per 0.3 mmol), acetic acid (1 equiv.) was added and reaction stirred at room temperature for 5 h. Then NaBH3CN (1 equiv.) was added and the reaction stirred overnight. On completion, the solvent was removed under reduced pressure and the residue purified by column chromatography (24% yield). LCMS: 555.15 (M+1)+; HPLC: 92.59% (@ 254 nm) (Rt; 4.143); 1H NMR (DMSO-d6, 400 MHz) δ 11.52 (s, 1H), 8.60 (t, 1H, J=5.2 Hz), 8.35 (s, 1H), 8.24 (s, 1H), 7.68 (s, 1H), 5.88 (s, 1H), 4.63-4.68 (m, 1H), 4.32 (d, 2H, J=4.8 Hz), 2.97 (d, 2H, J=11.6 Hz), 2.79 (d, 2H, J=10.8 Hz), 2.22-2.40 (m, 3H), 2.19 (s, 3H), 2.13 (s, 3H), 2.11 (s, 3H), 1.99-2.08 (m, 2H), 1.81-1.88 (m, 4H), 1.69 (d, 2H, J=11.2 Hz), 1.43-1.48 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.C([O-])(O)=O.[Na+]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][NH2:7])=[CH:11][CH:12]=2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(F)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 100.3 %

Procedure:
Entire reaction was performed under argon atmosphere using syringe septa technique. ({2-[4-(4-fluoro-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (3.018 mmol, 1 eq) was dissolved in dichloromethane (10 ml) and stirred at 0° C. for 5 min. TFA (15.088 mmol, 5 eq) was added and stirring was continued for overnight. Reaction mixture was diluted with 50 ml NaHCO3 (sat.) and extraction with DCM (3×20 ml) followed. Organic layers were combined and evaporated in vacuo to give 2-[4-(4-fluoro-phenoxy)-phenyl]ethylamine (3.027 mmol, yield=94%, purity=94%). [M+H]+=265.25 1H NMR (300 MHz, CDCl3) δ/ppm 2.86 (s, 2H), 3.09 (s, 2H), 7.01 (d, J=8.7 Hz, 5H), 7.24 (s, 2H), 7.37 (s, 1H)
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].Br[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>O>[CH2:1]([O:5][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][C:3]#[CH:4]
Reactant: C#CCCO
Reactant: BrCCCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CCCOCCCCc1ccccc1
Reaction time: 72 h
Yield: 66.7 %

Procedure:
A mixture of 3-butyn-1-ol (5.0 g), (4-bromobutyl)benzene (15.0 g), aqueous sodium hydroxide (30 ml, 50% w/v), and TAB (0.6 g) was stirred vigorously for 3 days, treated with water (100 ml) and extracted with ER (2×200 ml). The dried extract was evaporated and the residue was purified by FCC eluting with CX-ER 19:1 to give the title compound as a colourless oil (9.5 g). T.l.c. (CX-ER 9:1) Rf 0.45.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:11][CH3:12])[NH:10][C:5]2=[C:4]([CH3:13])[CH:3]=1.[NH4+].[OH-].[BrH:16].CC(O)=O>>[Br:16][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:11][CH3:12])[NH:10][C:5]2=[C:4]([CH3:13])[CH:3]=1
Reactant: CCc1nc2nc(Cl)cc(C)c2[nH]1
Reactant: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCc1nc2nc(Br)cc(C)c2[nH]1
Temperature: 100 °C

Procedure:
A mixture of 22.2 g (0.113 mol) of the product of Step B in 30% HBr-HOAc was heated to 100° C. for 19 hours. The mixture was poured onto ice, neutralized with NH4OH, extracted (5×EtOAc), and the organic layers were concentrated to give 15 g (1st crop) of the title compound as a solid after crystallization from EtOAc.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:24])[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])([OH:3])=O.S(Cl)([Cl:27])=O>ClC(Cl)C>[Cl:27][C:10]1([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])[C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[O:3])[O:24]1
Reactant: O=S(Cl)Cl
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C(=O)c1ccccc1C(=O)O
Solvent: CC(Cl)Cl
Product: O=C1OC(Cl)(C(=O)OCc2ccc([N+](=O)[O-])cc2)c2ccccc21

Procedure:
In 15 ml of dichloroethane was dissolved 580 mg of Compound (97), followed by addition of 0.58 ml of thionyl chloride. The mixture was heated for one hour under reflux. The solvent was evaporated off, and the residue was treated with isopropylether to give 500 mg of the subject Compound (98) as colorless crystals, m.p. 132°-134° C.
Reaction SMILES: COC(=O)NC(C(N1CCC(C2NC(C3C=CC([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[NH:34][C:35]([CH:38]6[CH2:42][CH2:41][CH2:40][N:39]6[C:43](=[O:53])[CH:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:47])[CH3:46])=[N:36][CH:37]=5)=[CH:29][CH:28]=4)=CC=3)=CN=2)C1)=O)C(C)C.C(O[C:60]([N:62]1[CH2:66][CH2:65][CH2:64][CH:63]1[C:67]1[NH:68][C:69]([C:72]2[CH:77]=[CH:76][C:75]([O:78]C3C=CC=C(C4NC(C5CCCN5C(OC(C)(C)C)=O)=NC=4)C=3)=[CH:74][CH:73]=2)=[CH:70][N:71]=1)=[O:61])(C)(C)C>>[CH3:52][O:51][C:49](=[O:50])[NH:48][CH:44]([C:60]([N:62]1[CH2:66][CH2:65][CH2:64][CH:63]1[C:67]1[NH:68][C:69]([C:72]2[CH:77]=[CH:76][C:75]([O:78][C:28]3[CH:27]=[CH:32][CH:31]=[C:30]([C:33]4[NH:34][C:35]([CH:38]5[CH2:42][CH2:41][CH2:40][N:39]5[C:43](=[O:53])[CH:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:46])[CH3:47])=[N:36][CH:37]=4)[CH:29]=3)=[CH:74][CH:73]=2)=[CH:70][N:71]=1)=[O:61])[CH:45]([CH3:47])[CH3:46]
Reactant: COC(=O)NC(C(=O)N1CCC(c2ncc(-c3ccc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)cc3)[nH]2)C1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Oc3cccc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)c3)cc2)[nH]1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Oc3cccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)c3)cc2)[nH]1)C(C)C

Procedure:
Following the procedure used to prepare compound (1-{3-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester, except that 2-[5-(4-{3-[2-(1-Boc-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenoxy}-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester was used instead of 2-(5-{4′-[2-(1-Boc-pyrrolidin-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester. 1H-NMR (300 MHz, CD3OD) δ 7.80-7.10 (m, 10H), 5.30-5.15 (m, 2H), 4.30-4.20 (m, 2H), 4.18-4.05 (m, 2H), 3.95-3.80 (m, 2H), 3.70-3.60 (m, 6H), 2.65-2.45 (m, 2H), 2.40-2.00 (m, 8H), 1.05-0.85 (m, 12H); m/z 755.3 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:10])[C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+].Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:18][CH2:17]1.C(OCC)(=O)C.ClCCl>CS(C)=O>[Cl:29][C:24]1[CH:23]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:1]3[C:9]4[CH2:8][CH2:7][CH2:6][C:5](=[O:10])[C:4]=4[CH:3]=[CH:2]3)[CH2:21][CH2:20]2)[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: O=C1CCCc2[nH]ccc21
Reactant: ClCCN1CCN(c2ccc(Cl)c(Cl)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1CCCc2c1ccn2CCN1CCN(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of 1,5,6,7-tetrahyroindol-4-one (107 mg) in DMSO (2 mL) was added powdered sodium hydroxide (33 mg) and the mixture was stirred at ambient temperature for 0.5 hours. 1-(2-Chloroethyl)-4-(3,4-dichlorophenyl)piperazine (220 mg) from step 1 was then added as a solution in DMSO (2 mL) and the resulting mixture stirred at ambient temperature for 24 hours then heated to approximately 60° C. for 2 hours, after which time thin layer chromatography (TLC) (ethyl acetate:dichloromethane 1:1) showed complete reaction. The reaction was poured into ice cold water (15 mL) and stirred for 0.5 hours. A solid mass formed and was separated by decanting the water. The aqueous layer was extracted with dichloromethane (10 mL). The solid mass was dissolved with dichloromethane (5 mL) and the combined organics were dried with sodium sulfate and the solvent removed under vacuum to obtain an oil (250 mg) as the titled compound.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1.S(Cl)(Cl)=O.[CH3:19]O>>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:19])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1
Reactant: CO
Reactant: O=C(O)c1ccc2c(=O)[nH]cnc2c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2c(=O)[nH]cnc2c1
Temperature: 80 °C
Yield: 70 %

Procedure:
A mixture of 4-oxo-3,4-dihydroquinazoline-7-carboxylic acid (2.5 g, 13.15 mmol) in 80 mL of methanol was added thionyl chloride (2.5 mL) at 5° C. and then refluxed at 80° C. over night. The reaction mixture was concentrated under vacuum and the residue dissolved in ethyl acetate. The organic layer was washed with 10% aqueous NaHCO3, water, brine and dried. The solvent was removed to give methyl 4-oxo-3,4-dihydroquinazoline7-carboxylate in 70% yield as solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:26])[C@@H:20]([NH2:25])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:13]([OH:27])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[O:42]1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[CH:44]=[C:43]1[C:51](O)=[O:52]>ClCCl.CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:26])[C@@H:20]([NH:25][C:51]([C:43]2[O:42][C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[CH:44]=2)=[O:52])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:13]([OH:27])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: CC(C)C[C@H](N)C(=O)NC1CCCN(C(=O)OCc2ccccc2)CC1O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CO
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CCCN(C(=O)OCc2ccccc2)CC1O

Procedure:
To a solution of 4-((S)-2-amino-4-methyl-pentanoylamino)-3-hydroxy-azepane-1-carboxylic acid benzyl ester of Example 78a (3.2 g) in dichloromethane (200 mL) was added EDC (1.48 g), HOBt (1.05 g), TEA (1.29 mL) and benzofuran-2-carboxylic acid. The reaction was stirred until complete. Workup and column chromatography (2% methanol:dichloromethane) provided the title compound (3.78 g): MS(EI) 521 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH:18]4[CH2:20][O:19]4)[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH:18]([OH:19])[CH2:20][N:24]4[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]4)[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=c1c2cc(C3CO3)ccc2ccc2ncc(Cl)cc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CC(O)c2ccc3ccc4ncc(Cl)cc4c(=O)c3c2)CC1

Procedure:
3-chloro-7-oxiran-2-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (60 mg, 0.21 mmol) was suspended in 2.5 mL of methanol. tert-Butyl piperazine-1-carboxylate (98 mg, 0.53 mmol) was added and the reaction was heated to reflux for 8 hours. The resulting mixture was concentrated in vacuo and purified directly via flash chromatography (15-100% ethyl acetate/hexanes) to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 9.79 (d, 1H); 8.49 (d, 1H); 8.22 (d, 1H); 7.77 (dd, 1H); 7.60 (d, 1H); 7.31 (d, 1H); 7.25 (d, 1H); 4.91 (dd, 1H); 3.50-3.45 (m, 4H); 2.72 (broad s, 2H); 2.63 (dd, 1H); 2.50 (dd, 1H); 2.44 (broad s, 2H); 1.46 (s, 9H). Hydroxyl proton was not observed. LRMS (APCI) calc'd for (C25H29ClN3O4) [M+H]+, 470.2; found 470.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[C:12]([OH:15])(=[O:14])C>[Pd]>[C:4]([O:15][C:12]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1)=[O:14])([CH3:7])([CH3:5])[CH3:3]
Reactant: CC(=O)O
Reactant: O=C(O)C=Cc1ccncc1
Agent: [Pd]
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(4-pyridyl)-2-propenoic acid (10 g) , 10% Pd—C (1 g) in acetic acid (40 ml) was hydrogenated (3.0 kg/cm2) at 65° C. for 8 hours. After the catalyst was removed by filtration, the filtrate was concentrated in vacuo. The residue was resolved in toluene (30 ml) and concentrated in vacuo. The residue was resolved in water (30 ml) and tetrahydrofuran (50 ml), cooled to 0° C., and triethylamine (33 g) was added dropwise at 5° C. Di-t-butyl dicarbonate (18.3 g) was added to the mixture at 20° C. and stirred overnight. PH was adjusted to 7 with HCl, organic layer was washed with 10% aqueous citric acid (40 ml), 5% aqueous sodium chloride (40 ml), dried over magnesium sulfate (5 g) and concentrated in vacuo. The residue was resolved in toluene (20 ml), concentrated in vacuo to 25 ml. The mixture was stirred at 40° C. for 3 hours, n-heptane (20 ml) was added to the mixture and stirred at 0° C. overnight. The precipitate was separated and dried to give 3-(1-tert-butoxycarbonyl-4-piperidyl)propionic acid as white solid (12.8 g).