Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C=CC=CC=1/C=[N:5]\[C@@H:6]1[C:13](=[O:14])[N:12]2[C@@H:7]1[S:8][CH2:9][C:10]([CH2:27][S:28][C:29]1[S:30][C:31]([CH3:34])=[N:32][N:33]=1)=[C:11]2[C:15]([O:17]CC1C=CC(OC)=CC=1)=[O:16].O.CS([O:44][C:45](=O)[CH2:46][N:47]1[CH:51]=[N:50][N:49]=[N:48]1)(=O)=O.ClCCl>C(OC)(C)(C)C>[N:47]1([CH2:46][C:45]([NH:5][C@@H:6]2[C:13](=[O:14])[N:12]3[C@@H:7]2[S:8][CH2:9][C:10]([CH2:27][S:28][C:29]2[S:30][C:31]([CH3:34])=[N:32][N:33]=2)=[C:11]3[C:15]([OH:17])=[O:16])=[O:44])[CH:51]=[N:50][N:49]=[N:48]1
Reactant: COc1ccc(COC(=O)C2=C(CSc3nnc(C)s3)CS[C@@H]3[C@H](/N=C\c4ccccc4O)C(=O)N23)cc1
Reactant: CS(=O)(=O)OC(=O)Cn1cnnn1
Solvent: ClCCl
Solvent: COC(C)(C)C
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)Cn4cnnn4)[C@H]3SC2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A reactor is charged with (6R,7R)-4-methoxybenzyl 7-((Z)-(2-hydroxybenzylidene)amino)-3-(((5-methyl-1,3,4-thiadiazol-2-yl)thio)methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (1 eq), water (6-9 weight % relative to the Schiff base), 2-(1H-tetrazol-1-yl)acetic methanesulfonic anhydride (2.5 eq) and dichloromethane (1.75 mL per gram of Schiff base). The mixture is stirred for three hours at room temperature, then added to methyl tertiary butyl ether over the course of 2-3 hours, resulting in the formation of a solid. The solid is filtered and the filter cake was washed with additional methyl tertiary butyl ether. The filtered solid is deprotected using conventional methods and dried under vacuum to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[I:11].[F:12][C:13]([F:23])([F:22])[O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([O:14][C:13]([F:12])([F:22])[F:23])=[CH:16][CH:17]=2)=[O:8])=[CH:4][C:3]=1[I:11]
Reactant: O=C(O)c1ccc(Br)c(I)c1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(Br)c(I)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 1.2 using 4-bromo-3-iodobenzoic acid and 4-(trifluoromethoxy)aniline to afford a white solid. UPLC-MS (condition 1) tR=3.64 min, m/z=485.7 [M+H]+, m/z=483.8 [M−H]−; Br pattern. 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.38 (d, J=8.3 Hz, 2H) 7.82-7.93 (m, 4H) 8.47 (d, J=1.7 Hz, 1H) 10.52 (s, 1H).
Reaction SMILES: [ClH:1].[Cl-:2].[NH2:3][C:4]([CH3:17])([CH3:16])[CH2:5][CH2:6][N+:7]1([CH3:15])[CH2:12][CH2:11][C:10]([F:14])([F:13])[CH2:9][CH2:8]1.C(O[Cl:23])(C)(C)C.O>CO>[Cl-:23].[Cl:1][N:3]([Cl:2])[C:4]([CH3:17])([CH3:16])[CH2:5][CH2:6][N+:7]1([CH3:15])[CH2:12][CH2:11][C:10]([F:14])([F:13])[CH2:9][CH2:8]1
Reactant: Cl
Reactant: CC(C)(N)CC[N+]1(C)CCC(F)(F)CC1
Reactant: CC(C)(C)OCl
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CC(C)(CC[N+]1(C)CCC(F)(F)CC1)N(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(3-Amino-3-methylbutyl)-4,4-difluoro-1-methylpiperidinium chloride hydrochloride (0.57 g, 1.94 mmol) in methanol (15 mL) was cooled in an ice bath for 15 min. t-BuOCl (0.69 mL, 3 equiv, 5.82 mmol) was added in one portion via syringe to the colorless solution to give a deep yellow solution. The reaction mixture was stirred for 30 min at 0° C., and then concentrated under reduced pressure to yield a colorless oil. This oil was dissolved into water and purified via reverse phase chromatography on a Shimadzu Prep-LC utilizing water/acetonitrile and 0.05% acetic acid as modifier. Fractions were collected monitoring UV absorbance at 215 nm. Fractions were pooled and concentrated via rotovap with the water bath set at 25° C. to give a white solid, (0.52 g, 83.1%). 1H NMR (D2O, 400 MHz): δ 1.47 (s, 6H), 2.27-2.32 (m, 2H), 2.422-2.56 (m, 4H), 3.10 (s, 3H), 3.55-3.61 (m, 2H), 3.65-3.69 (m, 4H). LRMS (ESI+) for C11H21Cl2F2N2+ (289.1); Found: 289 (M+).
Reaction SMILES: [I:1][C:2]1[N:6]2[CH:7]=[C:8]([C:11]3[C:12]([C:35]4[CH:40]=[CH:39][C:38]([S:41][CH3:42])=[CH:37][CH:36]=4)=[N:13][N:14]([C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[OH:43]OS([O-])=O.[K+].[OH2:49]>O1CCCC1.CO>[I:1][C:2]1[N:6]2[CH:7]=[C:8]([C:11]3[C:12]([C:35]4[CH:36]=[CH:37][C:38]([S:41]([CH3:42])(=[O:43])=[O:49])=[CH:39][CH:40]=4)=[N:13][N:14]([C:16]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: O=S([O-])OO
Reactant: CSc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(I)n3c2)cc1
Reactant: O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(I)n3c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.7 g 3-iodo-6-{3-[4-(methylsulfanyl)phenyl]-1-trityl-1H-4-pyrazolyl}imidazo[1,2-a]pyridine obtained in Example 42 was dissolved in a solvent mixture of 30 mL tetrahydrofuran and 30 mL methanol, and then 20 mL aqueous solution of 3.1 g oxone was added in divided portions thereto. The mixture was stirred at room temperature for 2 hours, then water was added thereto, and the reaction solution was extracted with ethyl acetate and dried over magnesium sulfate. The product was purified by NH silica gel (hexane/ethyl acetate) to give 1.67 g of the title compound as a colorless amorphous.
Reaction SMILES: [Cl:1][CH:2]1[CH2:5][CH:4]([CH2:6][OH:7])[CH2:3]1.[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[H-].[Na+].O>CN(C)C=O>[Cl:1][CH:2]1[CH2:5][CH:4]([CH2:6][O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1
Reactant: BrCc1ccccc1
Reactant: OCC1CC(Cl)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: ClC1CC(COCc2ccccc2)C1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
A mixture of 3-chlorocyclobutanemethanol (17.3 g, 0.143 mole) and benzylbromide (29.96 g, 0.1576 mole) in dry dimethylformamide (123 ml) was stirred at room temperature under an argon atmosphere and a 60% suspension of sodium hydride (6.31 g) was added. The reaction was stirred at ambient temperature for 22.5 hours. The reaction mixture was poured into 600 ml of water and the aqueous mixture extracted with ethyl acetate (4×500 ml). The ethyl acetate extracts were combined and dried over anhydrous sodium sulfate and the ethyl acetate evaporated in vacuo yielding the crude product as a yellow oil. The material was purified on a 2-liter Merck silica gel column eluting with 3 liters of hexane, followed by 5% ethyl acetate/hexane. The fractions containing the desired product were combined and the volatiles evaporated in vacuo yielding 28.6 g of the title compound as a pale yellow oil.
Reaction SMILES: CC(C)([O-])C.[K+].Cl[C:8]1[N:13]=[CH:12][N:11]=[C:10]([NH:14][S:15](=[O:25])(=[O:24])[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1.C(O)(=O)C[C:35](CC(O)=O)([C:37](O)=[O:38])[OH:36]>C(O)CO>[OH:36][CH2:35][CH2:37][O:38][C:8]1[N:13]=[CH:12][N:11]=[C:10]([NH:14][S:15](=[O:25])(=[O:24])[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1
Reactant: O=S(=O)(NCc1ccccc1)Nc1ncnc(Cl)c1-c1ccc(Cl)cc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: OCCO
Product: O=S(=O)(NCc1ccccc1)Nc1ncnc(OCCO)c1-c1ccc(Cl)cc1
Temperature: 102 °C

Procedure:
Potassium tert.-butoxide (3.5 g) was dissolved in ethyleneglycol (35 ml), benzyl sulfamic acid-[6-chloro-5-(4-chlorophenyl)-4-pyrimidinyl]-amide (1.8 g, Referential Example 15) was added and the mixture was heated to 102° C. for 11 h. The mixture was poured onto ice/water and acidified to pH=4 with solid citric acid. The precipitated product was filtered off, washed with water and dried at HV to give benzyl sulfamic acid-[6-(2-hydroxy-ethoxy)-5-(4-chlorophenyl)-4-pyrimidinyl]-amide (1.77 g). tR=4.36 (LC); [M+H]+=435.09 (ES+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4]([OH:13])[CH:3]=1.[Br:14][CH2:15][CH2:16]Br>>[Br:14][CH2:15][CH2:16][O:13][C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2
Reactant: BrCCBr
Reactant: Cc1ccc2c(O)cc(Cl)cc2n1
Product: Cc1ccc2c(OCCBr)cc(Cl)cc2n1

Procedure:
The title compound was prepared from 7-chloro-5-hydroxy-2-methylquinoline and 1,2-dibromoethane using a similar procedure to Description 16.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH2:24]>>[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: Cc1ccc(O)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Product: Cc1ccc(O)cc1Nc1cc(C(F)(F)F)nc(-c2cnccn2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol) and 5-hydroxy-2-methylaniline (34 mg, 0.231 mmol) similar to Example 190 and was isolated as a solid (3 mg). 1H NMR (CDCl3): 9.74 (d, J=1.2 Hz, 1H), 8.76-8.71 (m, 2H), 7.30 (brs, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.87 (brd, 1H), 6.78 (dd, J=8.4, 2.4 Hz, 1H), 6.73 (s, 1H), 2.21 (s, 3H).
Reaction SMILES: C(OP([CH:9]([F:11])[F:10])(=O)OCC)C.C([N-]C(C)C)(C)C.[Li+].[CH3:20][O:21][C:22]1[CH:40]=[CH:39][C:38]2[C@@H:37]3[C@H:27]([C@H:28]4[C@@:32]([CH2:35][CH2:36]3)([CH2:33][CH3:34])[C:31](=O)[CH2:30][CH2:29]4)[CH2:26][CH2:25][C:24]=2[CH:23]=1>O1CCCC1.C(OCC)(=O)C>[F:11][C:9]([F:10])=[C:31]1[CH2:30][CH2:29][C@H:28]2[C@H:27]3[C@H:37]([CH2:36][CH2:35][C@:32]12[CH2:33][CH3:34])[C:38]1[CH:39]=[CH:40][C:22]([O:21][CH3:20])=[CH:23][C:24]=1[CH2:25][CH2:26]3
Reactant: CCOP(=O)(OCC)C(F)F
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CCC2=C(F)F
Reaction time: 1 h
Yield: 80.8 %

Procedure:
A solution of 9.4 g of diethyl-(difluoromethyl)-phosphonate in 150 ml of tetrahydrofuran is slowly mixed with 25 ml of 2 M lithium diisopropylamide solution at a bath temperature of -50° C., and it is stirred for 1 hour. Then, a solution of 6 g of 3-methoxy-18-methyl-estra-1,3,5(10)-trien-17-one in 173 ml of tetrahydrofuran is slowly added, stirred for 15 minutes, slowly heated at a bath temperature of from -50° C. to 100° C. and refluxed for 6 hours. For working-up, it is diluted with ethyl acetate, washed with water as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 5.4 g of 17-difluoromethylene-3-methoxy-18-methyl-estra-1,3,5(10)-triene is obtained as colorless crystals with a melting point of 145-146° C., [α]D22 =+40.2° (c=0.515% in pyridine).
Reaction SMILES: CS(O[CH2:6][C@H:7]([N:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:34])[C:15]=2[NH:19][C:20](=[O:33])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:32])[CH:23]=2)[C:10]1=[O:35])[CH3:8])(=O)=O.Cl.[OH:37][CH:38]1[CH2:41][NH:40][CH2:39]1.C(N(CC)CC)C.C(Cl)Cl>>[F:32][C:24]1[CH:23]=[C:22]([CH2:21][C:20]([NH:19][C:15]2[C:14]([CH3:34])=[CH:13][CH:12]=[C:11]3[C:16]=2[CH:17]=[CH:18][N:9]([C@H:7]([CH3:8])[CH2:6][N:40]2[CH2:41][CH:38]([OH:37])[CH2:39]2)[C:10]3=[O:35])=[O:33])[CH:27]=[CH:26][C:25]=1[C:28]([F:31])([F:29])[F:30]
Reactant: OC1CNC1
Reactant: Cc1ccc2c(=O)n([C@H](C)COS(C)(=O)=O)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(=O)n([C@H](C)CN3CC(O)C3)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1

Procedure:
A solution of (R)-2-(5-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamido)-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl methanesulfonate (100 mg, 0.2 mmol), 3-hydroxyazetidine hydrochloride (120 mg, 1.1 mmol), triethylamine (200 mg, 2 mmol) and methylene chloride (1 mL, 20 mmol) was stirred at room temperature overnight. The volatiles were removed and the residue was purified by reverse phase preparative HPLC to afford the desired product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[N:8][N:9]=1
Reactant: COc1ccc2c(-c3ccc(C(F)(F)F)cc3)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(-c3ccc(C(F)(F)F)cc3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-methoxy-4-(4-trifluoromethylphenyl)-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[CH3:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][CH:18]=[CH:17]2.[I:24]I>ClC1C=CC=CC=1>[I-:24].[F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]3[C:19]4[CH:18]=[CH:17][C:16]5[CH:15]=[C:14]([CH3:13])[CH:23]=[CH:22][C:21]=5[N+:20]=4[CH:12]=[C:7]3[CH:6]=[CH:5][C:4]=2[CH:3]=1
Reactant: II
Reactant: Cc1ccc2ncccc2c1
Reactant: Cc1ccc2cc(F)ccc2n1
Solvent: Clc1ccccc1
Product: Cc1ccc2c(ccc3n4c(ccc5cc(F)ccc54)c[n+]23)c1
Product: [I-]

Procedure:
A mixture of 24.2 g. of 6-fluoroquinaldine, 86 g. of 6-methylquinoline, 100 ml. of chlorobenzene and 76 g. of iodine is stirred at 20°-25° C. until solution is obtained, then heated at 95°-100° C. for 3 days. The mixture is cooled and the precipitate of 10-fluoro-3-methylimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration, washed with chlorobenzene, then with methanol and dried; m.p. 360° C. after crystallization from dimethylformamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH:5]=[CH:6][C:7]1=[N:8][CH2:9][CH2:10][N:11]([CH3:25])[C:12]2[CH:17]=[C:16]([O:18]C3CCCCO3)[CH:15]=[CH:14][C:13]1=2.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH:5]=[CH:6][C:7]1=[N:8][CH2:9][CH2:10][N:11]([CH3:25])[C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:13]1=2
Reactant: CN1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2ccc(OC3CCCCO3)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CN1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2ccc(O)cc21
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
To a solution of 74 mg (0.17 mmol) of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-8-(tetrahydro-2(RS)-pyranyloxy)-1-methyl-1H-1,4-benzodiazepine (prepared in EXAMPLE 114) in methanol (5 ml) was added 33 mg (0.17 mmol) p-toluenesulphonic acid and the solution stirred at room temperature for 1 hour. A further 33 mg (0.17 mmol) of p-toluenesulphonic acid was added and the solution stirred for a further 2 hours. The solvent was removed by evaporation and the residue partitioned between water and ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulphate, filtered and evaporated to dryness. The residue was chromatographed on silica gel using first dichloromethane/methanol (95:5), and then dichloromethane/methanol (9:1) for the elution. The product was dissolved in a solution of hydrogen chloride in ether and evaporated to dryness. After trituration there was obtained 8 mg of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-8-ol hydrochloride as a dark orange solid MS: m/e 347.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)[CH3:12].[C-:22]1([NH2:27])[CH:26]=[CH:25][CH:24]=[CH:23]1.[CH-:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1.[Fe+2:33]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:27][C-:22]2[CH:26]=[CH:25][CH:24]=[CH:23]2)[CH3:20])[N:14]=1)[CH3:12].[CH-:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1.[Fe+2:33]
Reactant: N[c-]1cccc1
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: Cc1ccccc1
Product: CC(=Nc1c(C)cc(C)cc1C)c1cccc(C(C)=N[c-]2cccc2)n1
Reaction time: 16 h

Procedure:
Monoimine 2-[1-(2,4,6-trimethylphenylimino)ethyl]-6-acetylpyridine (1, 263 mg, 0.94 mmol) and ferrocenylamine (280 mg, 1.03 mmol) were dissolved in 40 ml of toluene. To this solution, molecular sieves (4 Å) were added. After standing for 16 hours the mixture was filtered. The solvent was removed in vacuo. The residue was recrystallised from ethanol. Yield 180 mg (41%) of mixed diimine 6.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]([C:22]2[CH:23]=[N:24][C:25]([NH:28][NH2:29])=[CH:26][CH:27]=2)[C:18]([F:21])([F:20])[F:19])[CH2:13]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])N.[CH3:34][O:35][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[N:44]=[C:43]([CH:46]=O)[CH:42]=[CH:41]2>>[F:1][CH2:2][CH2:3][N:4]([C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]([C:22]2[CH:27]=[CH:26][C:25]3[N:24]([C:46]([C:43]4[CH:42]=[CH:41][C:40]5[C:45](=[C:36]([O:35][CH3:34])[CH:37]=[CH:38][CH:39]=5)[N:44]=4)=[N:29][N:28]=3)[CH:23]=2)[C:18]([F:21])([F:19])[F:20])[CH2:13]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N(CCF)[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: COc1cccc2ccc(C=O)nc12
Agent: NC(=O)[O-]
Product: COc1cccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](N(CCF)C(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12

Procedure:
Prepared as described in Example 9B, Step F, using tert-butyl 2-fluoroethyl((S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-yl)carbamate (0.10 g, 0.237 mmol) in place of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-yl)carbamate and 8-methoxyquinoline-2-carbaldehyde (0.044 g, 0.237 mmol). LCMS APCI (+) m/z 589 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[C:13]([NH:16][CH2:17][CH2:18][NH2:19])(=[O:15])[CH3:14]>C(O)C>[CH3:12][O:11][C:4]1[N:3]=[C:2]([NH:19][CH2:18][CH2:17][NH:16][C:13](=[O:15])[CH3:14])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CC(=O)NCCN
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(NCCNC(C)=O)n1
Temperature: 0 °C
Yield: 72.5 %

Procedure:
4 g (0.0212 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 50 ml of ethanol and 4.51 ml (0.0424 mol) of N-acetylethane-1,2-diamine are placed in a fully equipped round-bottomed flask. The mixture is refluxed for 2 hours with stirring and is then poured onto an ice/water mixture with stirring. The precipitate formed is filtered off by suction and dried under vacuum to constant weight. 3.9 g of yellow powder are obtained, ie a yield of 72.5%.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[F:9][C:10]([F:21])([F:20])[O:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]>[N+](C)([O-])=O>[N+:7]([C:17]1[CH:18]=[CH:19][C:12]([O:11][C:10]([F:9])([F:20])[F:21])=[C:13]([CH:16]=1)[CH:14]=[O:15])([O-:8])=[O:6]
Reactant: O=Cc1ccccc1OC(F)(F)F
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: C[N+](=O)[O-]
Product: O=Cc1cc([N+](=O)[O-])ccc1OC(F)(F)F
Reaction time: 2 h
Yield: 60.8 %

Procedure:
Nitronium tetrafluoroborate (14.0 g, 105 mmol) was added to a solution of 2-trifluoromethoxy-benzaldehyde (10.0 g, 52.6 mmol) in nitromethane (30 mL) at room temperature. The mixture was stirred for 2 h and was then quenched with ice water and extracted with ether (100 mL). The organic layer was separated, washed with water, dried over MgSO4 and chromatographed with 5% EtOAc/hexanes to afford 7.52 g of 5-nitro-2-trifluoromethoxy-benzaldehyde (60.8%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21]#[N:22])=[O:15])[C@H:12]2[CH2:23][C@@H:9]1[C@H:10]([O:24][CH2:25][C:26](O)=[O:27])[CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31].N12CCCN=C1CCCCC2>CN(C)C=O>[C:21]([C@@H:17]1[CH2:18][CH2:19][CH2:20][N:16]1[C:14]([C@@H:13]1[C@H:12]2[CH2:23][C@H:9]([C@H:10]([O:24][CH2:25][C:26]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[O:27])[CH2:11]2)[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:15])#[N:22]
Reactant: CS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2OCC(=O)O)[C@H]1C(=O)N1CCC[C@H]1C#N
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2OCC(=O)NS(C)(=O)=O)[C@H]1C(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [((1R,3S,4S,6R)-2-(tert-butoxycarbonyl)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.1]hept-6-yl)oxy]acetic acid obtained in Example 15-2 (195 mg) in dimethylformamide (2.5 mL), was added 1,1′-carbonyldiimodazole (165 mg). The mixture was stirred at room temperature. After 30 minutes, methanesulfonamide (66 mg) and 1,8-diazabicyclo[5,4,0]undec-7-ene (106 mg) were added, and the resulting mixture was stirred at room temperature for 12 hrs.
Reaction SMILES: [OH:1][CH:2]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])[CH2:7][C@@H:6]1[C:22]([O:24]C)=[O:23].[OH-].[Na+].CCCCC>O1CCOCC1.C(OC(C)C)(C)C>[OH:1][CH:2]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])[CH2:7][C@@H:6]1[C:22]([OH:24])=[O:23]
Reactant: COC(=O)[C@H]1CN(CC#Cc2c(F)cccc2F)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Solvent: CCCCC
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CC#Cc4c(F)cccc4F)C[C@@H]3C(=O)O)c2c1
Temperature: 60 °C
Reaction time: 15 h
Yield: 56.7 %

Procedure:
A solution of 0.531 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,6-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylate in 5.3 cm3 of dioxane to which had been added 0.84 cm3 of 5N aqueous sodium hydroxide solution was stirred for 15 hours at a temperature in the region of 60° C. After cooling to a temperature in the region of 20° C., the reaction mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μm; diameter 3 cm; 20 g), elution was carried out with a dichloromethane/methanol (90/10 by volume) mixture, and first a fraction of 100 cm3 was collected, followed by 25-cm3 fractions. Fractions 1 to 12 were combined and then concentrated as above. A foam was obtained, which product was taken up with stirring in 15 cm3 of diisopropyl ether for 15 minutes. After adding 15 cm3 of pentane and stirring for an additional 10 minutes, the crystallized product formed was filtered off, washed with 2 times 10 cm3 of a diisopropyl ether/pentane (50/50 by volume) mixture, and then 3 times 20 cm3 of pentane, and dried in the air. 0.293 g of (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,6-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid was obtained in the form of a solid with a cream color melting at 107° C.