Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](/[C:3](=[C:5]1/[C:6]2[CH:35]=[CH:34][CH:33]=[CH:32][C:7]=2[O:8][CH2:9][C:10]2[CH:15]=[C:14]([CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([C:26](O)=[O:27])[C:20]=4[N:19]=[C:18]3[CH2:29][CH2:30][CH3:31])[CH:13]=[CH:12][C:11]/1=2)/[CH3:4])#[N:2].[OH:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C=O)C>[OH:36][CH:37]1[CH2:42][CH2:41][N:40]([C:26]([C:25]2[C:20]3[N:19]=[C:18]([CH2:29][CH2:30][CH3:31])[N:17]([CH2:16][C:14]4[CH:13]=[CH:12][C:11]5/[C:5](=[C:3](/[CH3:4])\[C:1]#[N:2])/[C:6]6[CH:35]=[CH:34][CH:33]=[CH:32][C:7]=6[O:8][CH2:9][C:10]=5[CH:15]=4)[C:21]=3[CH:22]=[CH:23][CH:24]=2)=[O:27])[CH2:39][CH2:38]1
Reactant: OC1CCNCC1
Reactant: CCCc1nc2c(C(=O)O)cccc2n1Cc1ccc2c(c1)COc1ccccc1/C2=C(\C)C#N
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCc1nc2c(C(=O)N3CCC(O)CC3)cccc2n1Cc1ccc2c(c1)COc1ccccc1/C2=C(\C)C#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.1 %

Procedure:
[step 1] (E)-1-[11-(1-Cyanoethylidene)-6,11-dihydrodibenzo[b,e]oxepin-8-yl]methyl-2-propylbenzimidazole-4-carboxylic acid (220 mg, 0.48 mmol) obtained in Example 100, step 2 was dissolved in DMF (4.0 mL), 4-hydroxypiperidine (96 mg, 0.95 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (109 mg, 0.57 mmol) and 1-hydroxybenzotriazole (87 mg, 0.57 mmol) were added, and the mixture was stirred at room temperature for 15 hr. Saturated aqueous sodium hydrogen carbonate solution (15 mL) was added to the mixture, and the precipitated solid was collected by filtration. The residue was purified by silica gel column chromatography (chloroform/methanol=99/1 to 93/7) to give (E)-2-{8-[4-(4-hydroxy-1-piperidinecarbonyl)-2-propylbenzimidazol-1-yl]methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene}propiononitrile (260 mg, 100%). [step 2] Using (E)-2-{8-[4-(4-hydroxy-1-piperidinecarbonyl)-2-propylbenzimidazol-1-yl]methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene}propiononitrile (260 mg, 0.48 mmol) obtained in step 1 and in the same manner as in Example 5, the title compound (compound 101) (85 mg, 30%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([CH3:15])=[C:8]([CH2:12][C:13]#[N:14])[CH:9]=[CH:10][CH:11]=1.[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>CN(C=O)C.CCCCCC>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([CH3:15])=[C:8]([CH:9]=[CH:10][CH:11]=1)[CH2:12][C:13]1[NH:23][N:22]=[N:21][N:14]=1
Reactant: Cc1cccc(C)c1COc1cccc(CC#N)c1C
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cccc(C)c1COc1cccc(Cc2nnn[nH]2)c1C
Temperature: 90 °C

Procedure:
A mixture of 2-(3-(2,6-Dimethylbenzyloxy)-2-methylphenyl)acetonitrile (Step E, 2.70 g, 10.19 mmol), sodium azide (0.795 g, 12.23 mmol) and ammonium chloride (0.653 g, 12.22 mmol) in dry DMF (20 ml) was heated under argon at 90° C. for 16 hours or until all the starting material is consumed, the reaction mixture was cooled, diluted with water and extracted with EtOAc (30 ml×4). The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol 92.5:7.5) to give semi solid product. The semi solid was stirred with 1:2 ethyl acetate:hexane (15 ml) for 10 minutes, and filtered to give product as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[CH3:13][C:14]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=1)=[O:15].[OH-].[Na+]>CO>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:13]/[C:14]([C:16]2[CH:17]=[C:18]([O:24][CH3:25])[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=2)=[O:15])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C=O)cc1
Reactant: COc1cc(OC)cc(C(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOc1ccc(/C=C/C(=O)c2cc(OC)cc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a stirred solution of 4-propoxybenzaldehyde (0.5 g, 3.1 mmol) and 3,5-dimethoxyacetophenone (0.55 g, 3.1 mmol) in methanol (10 ml) was added 50% w/v of aqueous sodium hydroxide (2.4 ml, 0.031 mol). The reaction mixture was stirred for 2 h at room temperature and then extracted with ethyl acetate (3×20 ml), the combined organic layers were dried over magnesium sulphate and reduced in vacuo. The product was recrystallised from ethanol to give 0.978 g (93%) of off-white crystals. 1H-NMR (CDC3) δ 7.8 (d, 1H), 7.6(d, 2H), 7.3 (d, 1H), 7.15 (d, 2H), 6.9 (d, 2H), 6.65 (t, 1H), 4.0 (t, 2H), 3.9 (s, 6H), 1.85 (m, 2H), 1.05 (t, 3H). 13C-NMR (CDCl3) δ 190.2, 161.3, 160.8, 144.9, 140.6, 130.2, 127.4, 119.6, 114.9, 106.3, 104.8, 69.7, 55.6, 22.5, 10.4. Mass Spectrum m/e (M+1)327.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[N+:13]([O-])([OH:15])=[O:14].O>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([NH2:12])(=[O:10])=[O:11]
Reactant: NS(=O)(=O)c1c(Cl)cccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
Into a solution of 2,6-dichlorobenzenesulfonamide (7.8 g, 34.5 mmol) in 30 mL of concentrated sulfuric acid at 0°, nitric acid (1.74 mL, 41.4 mmol) was added dropwise. The mixture was stirred at 0° C. for 2 hours, then 200 mL of water was added to produce a precipitate. The resulting mixture was filtered. The white solid was collected, washed with water and dried in vacuo to give the desired product (7.17 g, 76%). 1H NMR (DMSO-d6): δ8.25 (s, 2H), 8.20 (d, 1H), 7.92 (d, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[C@@H:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:4][CH2:3]1.[CH3:18][Al](C)C.C1(C)C=CC=CC=1>ClCCl>[OH:1][C:2]1([CH3:18])[N:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[C@@H:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:4][CH2:3]1
Reactant: C[Al](C)C
Reactant: C=CCOC(=O)N1C(=O)CC[C@@H]1C(=O)OCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=CCOC(=O)N1[C@@H](C(=O)OCC)CCC1(C)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-1-Allyl 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate (9.1 g, 38 mmol) was dissolved in dichloromethane (100 mL) and cooled to 0° C. before trimethylaluminum—2 M in toluene (94 mL, 190 mmol) was added. The reaction was stirred at ambient temperature for 16 h. The reaction mixture was quenched with a minimal amount of ammonium chloride (saturated, aqueous) to form a white solid, which was filtered off to give crude product. The crude was purified by chromatography to obtain the title compound. Found MS (ES+): 258(M+H)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:18]1[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[C:21]([CH3:43])[CH:22]2[Si:28]([CH:31]1[C:39]2[C:34](=[C:35](Br)[C:36]([CH3:40])=[CH:37][CH:38]=2)[CH:33]=[C:32]1[CH3:42])([CH3:30])[CH3:29]>C1COCC1.[Cl-].[Cl-].[Zn+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:18]2[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]3[C:19]=2[CH:20]=[C:21]([CH3:43])[CH:22]3[Si:28]([CH:31]2[C:39]3[C:34](=[C:35]([C:5]4[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=[C:3]([C:2]([F:1])([F:16])[F:15])[CH:4]=4)[C:36]([CH3:40])=[CH:37][CH:38]=3)[CH:33]=[C:32]2[CH3:42])([CH3:30])[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC1=Cc2c(ccc(C)c2Br)C1[Si](C)(C)C1C(C)=Cc2c1ccc(C)c2Br
Reactant: FC(F)(F)c1cc([Mg]Br)cc(C(F)(F)F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC1=Cc2c(ccc(C)c2-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1[Si](C)(C)C1C(C)=Cc2c1ccc(C)c2-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
In an argon atmosphere, to a solution of 15 mL of THF with 29.0 ml of 0.5 M ZnCl2 (14.5 mmol) in THF, 13.0 ml of 1.0 M 3,5-bis(trifluoromethyl) phenylmagnesium bromide (13.0 mmol) in THF was added at ambient temperature. This mixture was stirred for 1 hour, and, then, 10.0 ml of 0.02 M Pd(PtBu3)2 (0.20 mmol, 4 mol. %) in THF and 2.51 g (5.0 mmol) of 2 were added. The resulting mixture was stirred for 5 hours at reflux. The product was isolated by flash chromatography on Silica Gel 60 (40-63 μm, d 30 mm, l 100 mm; eluent: hexanes). Yield 3.65 g (95%) of white solid of ca. 1 to 1 mixture of rac- and meso-compounds.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]2[C:19](OCC)=[C:18]([C:23](=[O:27])[N:24]([CH3:26])[CH3:25])[S:17](=[O:29])(=[O:28])[N:16]=2)=[CH:7][CH:6]=1)[CH3:3].C(#[N:32])C>>[CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]2[C:19]([NH2:32])=[C:18]([C:23](=[O:27])[N:24]([CH3:26])[CH3:25])[S:17](=[O:29])(=[O:28])[N:16]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: CC#N
Reactant: CCOC1=C(C(=O)N(C)C)S(=O)(=O)N=C1NCCSCc1ccc(CN(C)C)o1
Product: CN(C)Cc1ccc(CSCCNC2=NS(=O)(=O)C(C(=O)N(C)C)=C2N)o1

Procedure:
Into a solution of 3-[2-[(5-dimethylaminomethyl-2-furanyl)methylthio]ethyl]amino-4-ethoxy-5-dimethylcarbamylisothiazole-1,1-dioxide (1.4 g, 3.2 mmol) in acetonitrile (12 ml) warmed at 65° C., ammonia gas was slowly bubbled over a 1-2 hour period. Solvent was evaporated, residue chromatographed on silica gel eluting with 3-5% methanol/chloroform to give 0.96 g of title compound which could be crystallized from nitromethane/ether, mp 101°-104°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.CN.Cl.[CH3:15][N:16](C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:16][CH3:15])=[O:11]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)Cc1ccccc1Br
Agent: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)Cc1ccccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
To a solution of 2-bromophenyl acetic acid (2.15 g) in dichloromethane (100 ml) was added methylamine (2M solution in tetrahydrofuran, 6 ml), 4-dimethylaminopyridine (1.32 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.055 g). The mixture was left to stir at room temperature for 16 hours, after which the organic portion was washed with 2M aqueous hydrogen chloride, dried over magnesium sulfate and filtered. The filtrate was concentrated to give a solid (2.04 g)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].S(Cl)(Cl)=O>>[CH:6]([NH:9][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)([CH3:7])[CH3:5]
Reactant: O=C(O)CCCCc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: CC(C)NC(=O)CCCCc1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution containing 0.5 g of the product obtained in Example 24 in 2.5 mlof thionyl chloride was refluxed for 10 min. The excess of thionyl chloridewas evaporated in vacuo and the residue dissolved in 25 ml of dichloromethane. To this solution 0.47 g of isopropylamine was added and the mixture was Stirred for 1 h at 20° C. Dichloromethane phase waswashed with 1 N hydrochloric acid and evaporated in vacuo. The residue was crystallized from toluene. Yield 0.44 g (75%), m.p. 113°-115° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][P:4](=O)([OH:7])[O:5][CH3:6].[CH2:9]([OH:12])[C:10]#[CH:11]>>[CH3:2][O:3][P:4](=[O:7])([O:5][CH3:6])[O:12][CH2:9][C:10]#[CH:11]
Reactant: COP(=O)(O)OC
Reactant: C#CCO
Agent: [Cl-]
Product: C#CCOP(=O)(OC)OC

Procedure:
1 mole of phosphoric acid dimethyl ester-chloride was reacted with 1 mole of propargyl alcohol analogously to Example 9.
Reaction SMILES: [CH3:1][Mg+].[Br-].CON(C)[C:7]([C:9]1[C:14](=[O:15])[C:13]([CH2:16][O:17][CH3:18])=[CH:12][N:11]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:10]=1)=[O:8]>C1COCC1>[C:7]([C:9]1[C:14](=[O:15])[C:13]([CH2:16][O:17][CH3:18])=[CH:12][N:11]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=2)[N:10]=1)(=[O:8])[CH3:1]
Reactant: C[Mg+]
Reactant: COCc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)N(C)OC)c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: COCc1cn(-c2cccc(C(F)(F)F)c2)nc(C(C)=O)c1=O
Reaction time: 1 h
Yield: 82.9 %

Procedure:
MeMgBr (1 M solution in THF, 16 mL, 16 mmol) was added dropwise at −78° C. to a solution of N-methoxy-5-(methoxymethyl)-N-methyl-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide (1.95 g, 5.25 mmol) in THF (50 mL). After stirring for 1 h, the reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt and recrystallized from hexane/AcOEt to give the title compound (1.42 g, 83% yield) as a pale yellow solid: mp 141-143° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.68 (3H, s), 3.54 (3H, s), 4.50 (2H, d, J=1.5 Hz), 7.66-7.74 (2H, m), 7.81-7.87 (1H, m), 7.89 (1H, s), 8.38 (1H, t, J=1.5 Hz). Anal. Calcd for C15H13F3N2O3: C, 55.22; H, 4.02; N, 8.59. Found: C, 55.26; H, 3.95; N, 8.58.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:23]=[N:24][NH:25][CH:26]=4)=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:27][CH2:28][C:29]1[C:30](=[O:37])[NH:31][C:32]([CH3:36])=[CH:33][C:34]=1[CH3:35].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:35][C:34]1[CH:33]=[C:32]([CH3:36])[NH:31][C:30](=[O:37])[C:29]=1[CH2:28][NH:27][C:13]([C:12]1[C:7]2[CH:6]=[N:5][N:4]([CH:2]([CH3:3])[CH3:1])[C:8]=2[N:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:26]=[N:25][NH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH:11]=1)=[O:15]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccc(-c4cn[nH]c4)cc3)nc21
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(-c4cn[nH]c4)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 109 using 1-(1-methylethyl)-6-[4-(1H-pyrazol-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (20 mg, 0.058 mmol), DMSO(1 mL), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (16.29 mg, 0.086 mmol), N-methylmorpholine (0.025 mL, 0.230 mmol), 1-hydroxy-7-azabenzotriazole (15.67 mg, 0.115 mmol) and EDC (22.07 mg, 0.115 mmol). The final product was collected as 12 mg (43%). LCMS E-S (M+H)=482.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (d, J=6.4 Hz, 6 H), 2.14 (s, 3 H), 2.24 (s, 3 H), 4.42 (d, J=4.8 Hz, 2 H) 5.27-5.47 (m, 1 H), 5.91 (s, 1 H), 7.79 (d, J=8.3 Hz, 2 H), 8.04 (br. s., 1 H), 8.15-8.21 (m, 1 H), 8.27 (d, J=8.3 Hz, 2 H), 8.35-8.42 (m, 1 H), 8.99 (t, J=4.8 Hz, 1 H), 11.58 (br. s., 3 H).
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.S(=O)(=O)(O)O.[N+:25]([O-])([O-:27])=[O:26].[K+].[OH-].[NH4+]>>[N:1]1([CH:6]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:14]([N+:25]([O-:27])=[O:26])[CH:15]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)Nc1ccc(C(C(C)C)n2ccnc2)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: CC(=O)Nc1ccc(C(C(C)C)n2ccnc2)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 80 %

Procedure:
(a-3) To a stirred and cooled (0° C.) mixture of 21.5 parts of N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]acetamide and 183 parts of concentrated sulfuric acid were added portionwise 8.6 parts of potassium nitrate at 0°~5° C. The reaction mixture was poured into ice water and treated with ammonium hydroxide. The product was extracted three times with 150 parts of trichloromethane. The combined extracts were dried, filtered and evaporated, yielding 20 parts (80%) of N-[4-[1(1H-imidazol-1-yl)-2-methylpropyl]-2-nitrophenyl]acetamide as a residue (int. 103).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:15][CH2:16][O:17][C:18](=[O:39])[C@H:19]([OH:38])[CH2:20][C@H:21]([NH2:37])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=2[F:36])=[CH:25][CH:24]=1)(=[O:14])[CH2:11][CH2:12][CH3:13].[OH:40][N:41]1[CH:45]=[C:44]([C:46](O)=[O:47])[N:43]=[N:42]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C>>[C:10]([O:15][CH2:16][O:17][C:18](=[O:39])[C@H:19]([OH:38])[CH2:20][C@H:21]([NH:37][C:46]([C:44]1[N:43]=[N:42][N:41]([OH:40])[CH:45]=1)=[O:47])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=2[F:36])=[CH:25][CH:24]=1)(=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC(=O)OCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Reactant: O=C(O)c1cn(O)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[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: CCCC(=O)OCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cn(O)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.9 %

Procedure:
DIPEA (35.8 μL, 206 μmol) was added to a solution of (2R,4R)-4-amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxypentanoic acid butyryloxymethyl ester (30.0 mg, 68.5 μmol), 1-hydroxy-1H-1,2,3-triazole-4-carboxylic acid (13.3 mg, 103 μmol) and HATU (39.1 mg, 103 μmol) in DMF (500 μL, 6.5 mmol). The resulting mixture was stirred at room temperature for 30 minutes, then concentrated in vacuo to yield a clear yellow liquid. The crude liquid was purified by preparative scale HPLC (C18 column chromatography, small column, using 30-90% MeCN in water with 0.05% TFA) to yield the title compound as a white solid (9.0 mg). MS m/z [M+H]+ calc'd for C25H26ClFN4O7, 549.15. found 549.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[OH:12][C:3]1[C:2]([NH:1][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)=[CH:26][CH:27]=2)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(N)c1O
Reactant: O=C(Cl)c1ccc(-c2ccccn2)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NC(=O)c2ccc(-c3ccccn3)cc2)c1O
Temperature: 70 °C
Reaction time: 4 h
Yield: 76.6 %

Procedure:
Thionyl chloride (10 mL) was added to 4-(pyridin-2-yl)benzoic acid (1.8 g, 9 mmol) and the mixture was stirred under reflux overnight. The solvent was evaporated under reduced pressure and the residue was dried in vacuum to give crude 4-(pyridin-2-yl)benzoyl chloride. To a solution of methyl 3-amino-2-hydroxybenzoate (1 g, 6 mmol) and pyridine (480 mg, 6 mmol) in toluene (50 mL) were added the crude 4-(pyridin-2-yl)benzoyl chloride (1.3 g, 6 mmol) portion wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (100 mL×4), the organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain yellow solid of methyl 2-hydroxy-3-(4-(pyridin-2-yl)benzamido)benzoate (1.6 g, yield 76%). LC-MS (ESI) m/z: 349 (M+1)+. (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23]Cl)[CH3:20]>C1(C)C(C)=CC=CC=1.O>[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH3:20]
Reactant: N#Cc1ccc(O)cc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCN(CC)CCOc1ccc(C#N)cc1
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
A solution of 8.04 g (67 mmol) of 4-cyanophenol in 100 ml of xylene was treated with a solution of 2.99 g (74 mmol) of sodium hydroxide in 20 ml of water and the mixture was stirred for 30 minutes. To this mixture were added 13.88 g (100 mmol) of potassium carbonate and 12.83 g (75 mmol) of 2-diethylaminoethyl chloride hydrochloride. The resulting mixture was then heated at reflux for 3 hours, subsequently left to cool, washed twice with 50 ml of water each time, dried over magnesium sulfate, filtered and evaporated to give 10.93 g (74%) of 4-(2-diethylaminoethoxy)benzonitrile as a colorless mobile liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[NH:11][C:10](=O)[C@@H:9]3[CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:8]3[C:7]=2[CH:6]=[CH:5][CH:4]=1.CN(C=O)C.[Br:29]N1C(=O)CCC1=O>C1COCC1.O.C(OCC)(=O)C>[Br:29][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]2[NH:11][CH2:10][C@@H:9]3[CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:8]3[C:7]=2[CH:6]=1
Reactant: COc1cccc2c1NC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(Br)cc2c1NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Temperature: -30 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of (±)-cis tert-butyl 6-methoxy-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate from Example 10, Part B (0.39 g, 1.28 mmol) in 8 mL of THF and 4 mL of DMF at −30° C. was added N-bromosuccinimide (0.15 g, 1.34 mmol). The reaction was stirred at −30° C. for 1 h and then was diluted with water and ethyl acetate. The organics were washed with water and brine, dried (Na2SO4) and concentrated in vacuo to afford 0.41 g (83%) of the title compound which was used without purification.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4]([OH:6])=[O:5].[C:10]([OH:13])(=[S:12])[CH3:11]>>[C:10]([S:12][CH2:7][CH:3]([C:2]([F:9])([F:8])[F:1])[C:4]([OH:6])=[O:5])(=[O:13])[CH3:11]
Reactant: CC(O)=S
Reactant: C=C(C(=O)O)C(F)(F)F
Product: CC(=O)SCC(C(=O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a 50 mL round bottom flask was added 2-(trifluoromethyl)acrylic acid (6 g, 42.8 mmol), followed by thioacetic acid (4.59 ml, 64.3 mmol). The reaction was slightly exothermic. The mixture was then stirred at 25° C. overnight. NMR showed some starting material (˜30%). One more equiv of thioacetic acid was added and the mixture was heated at 95° C. for 1 hour, then allowed to cool to room temperature. Mixture was purified by vacuum distillation at 2.1-2.5 mm Hg, fraction distilled at 80-85° C. was mostly thioacetic acid, fraction distilled at 100-110° C. was almost pure product, contaminated by a nonpolar impurity (by TLC). It was again purified by flash chromatography (0-20% MeOH/DCM), to give 2-(acetylthiomethyl)-3,3,3-trifluoropropanoic acid (7.78 g, 36.0 mmol, 84% yield) as colorless oil, which solidified under high vacuum to give a white solid: mp 28-30° C.; 1H NMR (400 MHz, CDCl3) δ 7.52 (brs, 1H), 3.44 (dt, J=7.5, 3.5 Hz, 2H), 3.20 (dd, J=14.9, 11.1 Hz, 1H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 194.79, 171.14, 123.44 (q, J=281.6 Hz), 50.47 (q, J=27.9 Hz), 30.44, 24.69 (q, J=2.6 Hz); 19F NMR (376 MHz, CDCl3) δ −67.82.