Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]Br)[C:5]([Br:10])=[CH:4][C:3]=1[CH2:11]Br.[P:13]([O:20][CH2:21][CH3:22])([O:17]CC)[O:14][CH2:15][CH3:16]>>[Br:10][C:5]1([P:13]([O:14][CH2:15][CH3:16])(=[O:17])[O:20][CH2:21][CH3:22])[C:4]([P:13]([O:20][CH2:21][CH3:22])(=[O:17])[O:14][CH2:15][CH3:16])=[C:3]([CH3:11])[C:2]([Br:1])=[CH:7][CH:6]1[CH3:8]
Reactant: BrCc1cc(Br)c(CBr)cc1Br
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(OCC)C1=C(C)C(Br)=CC(C)C1(Br)P(=O)(OCC)OCC
Temperature: 180 °C
Yield: 82.2 %

Procedure:
The mixture of 2, 5-dibromo-α,α′-dibromo-p-xylene (67) (7.58 g, 0.018 mol) and triethyl phosphite (60 ml) was refluxed at 180° C. overnight. The excess triethyl phosphite was removed under reduced pressure, 60 ml of hexanes was added, and white solid was formed. The solid was collected by filtration, washed three times with 20 ml of hexanes and gave 7.93 g (82.2%) of product.1H NMR (CDCl3, 500 MHz) δppm: 7.62 (s, 2H, Ar—H), 4.06 (m, 8H, CH2), 3.32 (d, J=20.5 Hz, 4H, CH2), 1.28 (t, J=7.0 Hz, 12H, CH3)13C NMR (CDCl3, 125.7 MHz) δppm: 135.2, 132.5, 123.6, 62.35, 62.32, 33.4, 32.2, 16.31, 16.28GC-MS (relative intensity %): 491 (M+, <5%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[CH2:13]([Mg]Cl)[CH:14]([CH3:16])[CH3:15]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:11])[CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(C)C[Mg]Cl
Product: COC(=O)c1ccc(C(O)CC(C)C)cc1

Procedure:
This compound is made from 4-formyl-benzoic acid methyl ester and isobutylmagnesium chloride following the general method exemplified in Preparation 1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:42])=[C:6]([C@:8]2([CH3:41])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH:17][C:18]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:9]2)[CH:7]=1.Br[C:44]1[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[CH:46][CH:45]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:18]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)([NH:17][C:10]2[CH2:11][O:12][CH2:13][C:14]([F:16])([F:15])[C@:8]([C:6]3[CH:7]=[C:2]([NH:1][C:44]4[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[CH:46][CH:45]=4)[CH:3]=[CH:4][C:5]=3[F:42])([CH3:41])[N:9]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(N)ccc3F)C(F)(F)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#Cc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Nc4ccc(C#N)cc4)ccc3F)C(F)(F)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 107.5 °C
Yield: 48.9 %

Procedure:
To a solution of [(R)-5-(5-amino-2-fluoro-phenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl]-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine (intermediate A12A) (40 mg, 69.5 μmol) in toluene (0.6 ml) in a sealable tube was added subsequently at 23° C. and under an argon atmosphere 4-bromobenzonitrile (25.3 mg, 139 μmol), sodium tert-butoxide (13.4 mg, 139 μmol), 2-di-t-butylphosphino-2′,4′,6′-triisopropylbiphenyl (2.95 mg, 6.95 μmol) and tris(dibenzylideneacetone) dipalladium chloroform adduct (2.16 mg, 2.08 μmol), the tube was sealed and heated to 105 to 110° C. for 17 h. The mixture was cooled to 23° C., partitioned between saturated aqueous NaHCO3 and ethyl acetate, the organic layer was dried and evaporated to give the crude product, which was purified by silica gel flash chromatography with n-heptane/ethyl acetate and trituration with diethyl ether/pentane to give the (R)-4-(3-(3-(bis(4-methoxyphenyl)(phenyl)methylamino)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-5-yl)-4-fluorophenylamino)benzonitrile (23 mg, 49%) as a light yellow crystalline. MS (ISN): m/z=675.5 [M−H]−.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([O:39][CH2:40][C@@H:41]1[O:46][CH2:45][C@@:44]([NH:55][C:56]([NH:58][C:59](=[O:66])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[S:57])([C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:48]=2[F:54])[C@H:43]([C@@H:67](O)[CH3:68])[CH2:42]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[CH2:32]([O:39][CH2:40][C@@H:41]1[O:46][CH2:45][C@:44]2([C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:48]=3[F:54])[N:55]=[C:56]([NH:58][C:59](=[O:66])[C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[S:57][C@H:67]([CH3:68])[C@@H:43]2[CH2:42]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: C[C@H](O)[C@@H]1C[C@H](COCc2ccccc2)OC[C@@]1(NC(=S)NC(=O)c1ccccc1)c1ccc(F)cc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](COCc3ccccc3)C[C@@H]12
Reaction time: 0.5 h

Procedure:
Diethyl azodicarboxylate (21.3 mL, 136 mmol) was added drop-wise to a solution of triphenylphosphine (35.7 g, 136 mmol) in tetrahydrofuran (850 mL), and the mixture was stirred for 30 minutes before being cooled in an ice bath. A solution of N-{[(3S,4R,6R)-6-[(benzyloxy)methyl]-3-(2,4-difluorophenyl)-4-[(1S)-1-hydroxyethyl]tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide (C20) (24.5 g, 45.3 mmol) in tetrahydrofuran (115 mL) was added drop-wise to the reaction mixture, which was then stirred for 1 hour under ice cooling. After concentration in vacuo, the residue was loaded onto a silica gel column that had been equilibrated with dichloromethane, and the column was eluted with 1:1 ethyl acetate/heptane. Fractions containing product were combined and concentrated under reduced pressure; the resulting material was triturated with 15% ethyl acetate in heptane, and the solid was removed via filtration. The filtrate was concentrated in vacuo and chromatographed on silica gel (Gradient: 20% to 40% ethyl acetate in heptane), affording the product as a white solid. Yield: 17.23 g, 32.97 mmol, 73%. LCMS m/z 523.2 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.23 (br d, J=6.5 Hz, 2H), 7.49-7.55 (m, 1H), 7.36-7.48 (m, 3H), 7.24-7.36 (m, 5H), 6.84-6.96 (m, 2H), 4.58 (AB quartet, JAB=12.0 Hz, ΔνAB=25.0 Hz, 2H), 4.18 (dd, J=12.2, 1.7 Hz, 1H), 3.87-3.94 (m, 1H), 3.84 (d, J=12.2 Hz, 1H), 3.63 (dd, half of ABX pattern, J=10.2, 6.4 Hz, 1H), 3.50 (dd, half of ABX pattern, J=10.2, 4.4 Hz, 1H), 3.23-3.31 (m, 1H), 2.88-2.96 (m, 1H), 1.61-1.79 (m, 2H), 1.25 (d, J=6.9 Hz, 3H).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[CH:25]([C:28]1[CH:33]=[CH:32][C:31]([NH:34]N)=[CH:30][CH:29]=1)([CH3:27])[CH3:26]>>[CH:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:30][CH:29]=1)([CH3:27])[CH3:26]
Reactant: CC(C)c1ccc(NN)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: CC(C)c1ccc(-n2nccc2-c2nn(-c3cccc(S(C)(=O)=O)c3)ccc2=O)cc1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and (4-isopropyl-phenyl)-hydrazine according to example 85 gave the desired product. MS: M=435.3 (M+H)+
Reaction SMILES: [F:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:10]1(B(O)O)[CH2:12][CH2:11]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[Cl:8][C:5]1[N:4]=[C:3]([CH:10]2[CH2:12][CH2:11]2)[C:2]([F:1])=[CH:7][N:6]=1
Reactant: OB(O)C1CC1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: Fc1cnc(Cl)nc1C1CC1
Temperature: 67 °C
Reaction time: 12 h
Yield: 79.6 %

Procedure:
5-Fluoro-2,4-dichloropyrimidine (5 g, 29.9 mmol), cyclopropyl boronic acid (2.57 g, 29.9 mmol), potassium phosphate tribasic (15.89 g, 74.9 mmol) and PdCl2(dppf)-dichloromethane adduct (1.22 g, 1.50 mmol) were added to a dry flask. The flask was degassed with argon and then tetrahydrofuran (150 ml) was added. The reaction mixture was degassed with argon for five minutes, and then heated to 67° C. After 12 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (1000 mL), washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc/hexane gradient) to afford 2-chloro-4-cyclopropyl-5-fluoropyrimidine (4.1 g, 23.8 mmol, 79% yield). MS ESI: [M+H]+ m/z 172.9. 1H NMR (500 MHz, DMSO-d6) δ 8.66 (d, J=2.0 Hz, 1H); 2.34-2.26 (m, 1H); 1.26-1.20 (m, 2H); 1.12-1.08 (m, 2H).
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[C:17]([C:22]4[N:23]=[CH:24][C:25]5[C:30]([CH:31]=4)=[CH:29][CH:28]=[C:27](OC(F)(F)F)[CH:26]=5)[C:18]([NH2:21])=[N:19][CH:20]=3)[CH:12]=[N:11]2)[CH2:6][CH2:5]1.[F:37]C1C=C2C(=CC=1)C=NC(OS(C(F)(F)F)(=O)=O)=C2>>[F:37][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[N:23][C:22]([C:17]1[C:18]([NH2:21])=[N:19][CH:20]=[C:15]([C:13]3[CH:12]=[N:11][N:10]([CH:7]4[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]4)[CH:14]=3)[CH:16]=1)=[CH:31]2
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2ccc(OC(F)(F)F)cc2cn1
Reactant: O=S(=O)(Oc1cc2cc(F)ccc2cn1)C(F)(F)F
Agent: Cl
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2cc(F)ccc2cn1

Procedure:
Following the procedure for 5-(1-Piperidin-4-yl-1H-pyrazol-4-yl)-3-(7-trifluoromethoxy-isoquinolin-3-yl)-pyridin-2-ylamine trihydrochloride, using trifluoromethanesulfonic acid 6-fluoroisoquinolin-3-yl ester, the title compound was obtained as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.27-2.39 (m, 4H), 3.18-3.26 (m, 2H), 3.51-3.60 (m, 2H), 4.57-4.70 (m, 1H), 7.79-7.86 (m, 1H), 7.96-8.04 (m, 2H), 8.36 (s, 1H), 8.40 (s, 1H), 8.56 (dd, J=9.2, 5.4 Hz, 1H), 8.70 (s, 1H), 8.74 (s, 1H), 9.77 (s, 1H). MS (ES+): m/z=389.18 [MH+]. HPLC: tR1.68 min (ZQ2, polar—5 min).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]2[N:27]([C@H:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:35][CH2:34][CH2:33]3)[CH:28]=[C:29]([C:30]#[N:31])[C:21]=12.CN(C)[CH:44]=[O:45]>O1CCCC1.O>[CH:44]([C:28]1[N:27]([C@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:35][CH2:34][CH2:33]2)[C:22]2=[N:23][C:24]([CH3:26])=[CH:25][C:20]([CH3:19])=[C:21]2[C:29]=1[C:30]#[N:31])=[O:45]
Reactant: Cc1cc(C)c2c(C#N)cn([C@@H]3CCCc4ccccc43)c2n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(C#N)c(C=O)n([C@@H]3CCCc4ccccc43)c2n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of diisopropylamine (3.72 ml, 28.4 mmol) in tetrahydrofuran (36 ml) was added a 1.6 N solution of butyllithium in hexane (17.7 ml, 28.4 mmol) at −78° C., and the mixture was stirred at −78° C. for 15 minutes. To the resultant solution was added dropwise 4,6-dimethyl-1-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (5.70 g, 18.9 mmol) in THF (60 ml) at −78° C., and the mixture was stirred at −78° C. for 30 minutes. Dimethylformamide (5.37 ml, 56.7 mmol) was added thereto, and the mixture was stirred at room temperature 1.5 hours, poured into iced water, and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the objective product as oily matter.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[C:18]([OH:26])(=[O:25])[C:19]([CH2:21][C:22](O)=[O:23])=[CH2:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:22](=[O:23])[CH2:21][CH:19]([C:18]([OH:26])=[O:25])[CH2:20]3)=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(/C=C/c2ccc(N)cc2)c1
Reactant: C=C(CC(=O)O)C(=O)O
Product: COc1cccc(/C=C/c2ccc(N3CC(C(=O)O)CC3=O)cc2)c1

Procedure:
In an analogous manner to that described in Example 36c), the reaction of (E)-4-[2-(3-methoxy-phenyl)-vinyl]-phenylamine with itaconic acid yields the (RS)-(E)-1-{4-[2-(3-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid as a brown solid; MS: m/e=336 (M−H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:21][OH:22])[CH2:4][O:5][C:6]1[C:13]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:12][C:9]([CH:10]=O)=[C:8]([O:19][CH3:20])[CH:7]=1.[C:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)(=[O:25])[CH3:24]>>[OH:1][CH2:2][CH:3]([CH2:21][OH:22])[CH2:4][O:5][C:6]1[C:13]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:12][C:9](/[CH:10]=[CH:24]/[C:23]([C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)=[O:25])=[C:8]([O:19][CH3:20])[CH:7]=1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OCC(CO)CO)c(-c2cccs2)cc1C=O
Product: COc1cc(OCC(CO)CO)c(-c2cccs2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 60 %

Procedure:
The title compound was prepared by condensing 4-(3-hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-50C) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 199–201° C., 60% yield. 1H-NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.23 (d, 2H, J=8.7 Hz), 8.06–8.11 (m, 3H), 7.93 (d, 1H, J=15.0 Hz), 7.71 (d, 1H, J=3.3 Hz), 7.54 (d, 1H, J=5.1 Hz), 7.13–7.16 (m, 1H), 6.87 (s, 1H), 4.62 (brs, 2H), 4.27 (d, 2H, J=5.1 Hz), 4.00 (s, 3H), 3.62 (brs, 4H), 2.11–2.15 (m, 1H). MS (ESI) m/z=469 ([M+H]+, 100%). Anal. Calcd. for C25H24O7S.¼H2O: C, 63.48; H, 5.22; S, 6.78. Found: C, 63.45; H, 5.29; S, 6.61.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].Cl.[O:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH2:30])[CH2:25][CH2:24]1>C1COCC1>[N+:19]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:9]=1[NH:30][CH2:29][CH:26]1[CH2:27][CH2:28][O:23][CH2:24][CH2:25]1)=[CH:17][CH:16]=[CH:15][CH:14]=2)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCC1CCOCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccccc2c1NCC1CCOCC1
Reaction time: 1 h
Yield: 89.2 %

Procedure:
Under a nitrogen atmosphere THF (90 mL) and triethylamine (17.5 mL, 125.6 mmol) were added sequentially to a mixture of crude 4-chloro-3-nitroquinoline (13.10 g, 62.81 mmol) and 1-tetrahydro-2H-pyran-4-ylmethylamine hydrochloride (10.0 g, 65.95 mmol). The reaction mixture was placed in an oil bath at 45° C. for 1 hour and then concentrated under reduced pressure. The residue was diluted with THF (30 mL) and water (200 mL). The THF was removed under reduced pressure. A solid was isolated by filtration and dried to provide 16.10 g of 3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)quinolin-4-amine as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C([O:47][C:48](=[O:68])[C@H:49]([OH:67])[CH2:50][C@H:51]([NH2:66])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([Cl:65])[CH:60]=2)=[CH:55][CH:54]=1)C.CCO.[Li+].[OH-].O>CN(C=O)C>[Cl:65][C:61]1[CH:60]=[C:59]([C:56]2[CH:55]=[CH:54][C:53]([CH2:52][C@@H:51]([NH:66][C:8]([C:4]3[CH:3]=[C:2]([OH:1])[N:6]([CH3:7])[N:5]=3)=[O:10])[CH2:50][C@@H:49]([OH:67])[C:48]([OH:68])=[O:47])=[CH:58][CH:57]=2)[CH:64]=[CH:63][CH:62]=1
Reactant: Cn1nc(C(=O)O)cc1O
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C(=O)N[C@H](Cc2ccc(-c3cccc(Cl)c3)cc2)C[C@@H](O)C(=O)O)cc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.4 %

Procedure:
5-Hydroxy-1-methyl-1H-pyrazole-3-carboxylic acid (19.6 mg, 138 μmol) was combined with HCTU (56.9 mg, 138 μmol) in DMF. The mixture was stirred for 10 minutes at room temperature before adding DIPEA (72 μL, 413 μmol) and (2R,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (50 mg, 0.1 mmol). The resulting mixture was stirred overnight at room temperature. EtOH (402 μL, 6.9 mmol) and 1 M LiOH in water (1.1 mL, 1.1 mmol) was added and the mixture was stirred at room temperature for 1 hour. The mixture was evaporated under reduced pressure and purified by preparative HPLC to yield the title compound (6.4 mg). MS m/z [M+H]+ calc'd for C22H22ClN3O5, 444.12. found 444.4.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].N1C=CC=CC=1>C(Cl)Cl>[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:2]([Cl:1])=[O:4])[CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CCN(C(=O)Cl)CC1
Temperature: 25 °C
Yield: 159.4 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (1.81 g, 6.09 mmol) in CH2Cl2 (30 ml) at 0° C., was added a solution of 1-methanesulfonyl-piperazine (2.0 g, 12.2 mmol) and pyridine (1.08 ml, 13.4 mmol) in CH2Cl2 (5 ml) over 30 minutes. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Purification by flash chromatography (SiO2, EtOAc) yielded 2.20 g (79%) of the title compound as white solid.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([OH:9])[C:5]([F:8])([F:7])[F:6].[F:10][C:11]1[C:12](F)=[C:13]([F:23])[C:14]([F:22])=[C:15]2C(=O)[O:19][C:17](=[O:18])[C:16]=12>O>[F:6][C:5]([F:8])([F:7])[CH2:4][O:9][C:12]1[C:11]([F:10])=[C:16]([CH:15]=[C:14]([F:22])[C:13]=1[F:23])[C:17]([OH:19])=[O:18]
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: OCC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(F)c(F)c(OCC(F)(F)F)c1F
Temperature: 70 °C
Yield: 51 %

Procedure:
An initial charge comprising a mixture of 7.6 g of water, 2.1 g of lithium hydroxide hydrate, 10 g of trifluoroethanol and 2.2 g (10 mmol) of tetrafluorophthalic anhydride is heated at 70° C. for 96 hours, after which the content of tetrafluorophthalic anhydride has fallen to below 1% (GC). The procedure described in Example 3 is then followed to give 1.4 g (5.1 mmol, corresponding to 51%) of 3-trifluoroethoxy-2,4,5-trifluorobenzoic acid.
Reaction SMILES: [S:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)[C:2]#N.[BH4-].[Na+].Cl[CH2:17][Si:18](C)([CH3:20])[CH3:19]>CC#N>[CH3:17][Si:18]([CH2:2][S:1][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)([CH3:20])[CH3:19]
Reactant: C[Si](C)(C)CCl
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: C[Si](C)(C)CSc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
To a stirred solution of 1.95 g of 4-thiocyanato-2-nitroaniline in 40 ml of CH3CN blanketed by nitrogen there is added in portions 0.5 g of NaBH4. The stirring is continued for one hour. At this time the color of the reaction mixture changes from yellow to dark purple. 1.4 ml of chloromethyltrimethylsilane is added with a syringe and the mixture is refluxed overnight. The solvent is evaporated and the residue is exhaustively extracted with petroleum ether. Evaporation of the solvent yields 1.9 g of the title A compound as a red solid.
Reaction SMILES: [CH:1]([C:13]([O:15]C)=O)([C:9]([O:11]C)=O)[CH2:2][CH2:3][C:4]([O:6][CH2:7]C)=[O:5].[C:17]1(/[CH:23]=[CH:24]/[C:25](=[NH:27])[NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C[O-].[Na+]>CO>[OH:15][C:13]1[N:26]=[C:25](/[CH:24]=[CH:23]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:27][C:9](=[O:11])[C:1]=1[CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CCOC(=O)CCC(C(=O)OC)C(=O)OC
Reactant: N=C(N)/C=C/c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCc1c(O)nc(/C=C/c2ccccc2)[nH]c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-Ethyl 1,1-dimethyl 1,1,3-propanetricarboxylate (23.8 g; 103 mmol) and (2E)-3-phenyl-2-propenimidamide (10.0 g; 68.4 mmol) were combined in MeOH (400 mL), treated with NaOMe in MeOH (31.0 g; 143 mmol) and the solution was stirred at room temperature for 2 days. The solution turned dark, and a dark green solid was filtered off. The solution was concentrated under vacuum, diluted with water, acidified to pH 2 with 6N HCl and the resulting yellow precipitate was filtered off. The aqueous mother liquor was extracted with EtOAc. During the extraction more yellow precipitate formed and was collected. The combined yellow solids were dried under vacuum and used without further purification (12.1 g, 59%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[CH2:15]([CH:17]([CH2:20][CH3:21])[CH:18]=O)[CH3:16].[BH4-].[Na+].O>C(O)C>[CH2:15]([CH:17]([CH2:20][CH3:21])[CH2:18][NH:14][CH2:13][CH2:12][CH2:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:18][CH:17]([CH2:20][CH3:21])[CH2:15][CH3:16])[CH2:10][CH2:9]1)[CH3:16]
Reactant: NCCCN1CCN(CCCN)CC1
Reactant: CCC(C=O)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC(CC)CNCCCN1CCN(CCCNCC(CC)CC)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.51 mL, 2.5 mmol) and 2-ethylbutyraldehyde (645 μL, 5.24 mmol) in absolute ethanol (20 mL), 3 Å molecular sieves are added. After stirring the mixture at room temperature for 12 h, NaBH4 (1.9 g, 49.92 mmol) was added portionwise and the mixture was stirred for 12 h at room temperature. The reaction was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL). Combined organic layers were extracted with HCl 1M. The combined aqueous layers were neutralized with NaOH 1M and extracted with CH2Cl2. Combined organic layers were dried over MgSO4. Crude compound is purified by flash chromatography on neutral aluminium oxide (CH2Cl2/MeOH).
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH3:23])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:9])=[O:8])(=[O:3])[NH2:2].[OH-].[Na+].O>C(O)C>[C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]2[C:5]=1[N:13]=[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][CH3:23])[NH:9][C:7]2=[O:8])(=[O:3])[NH2:2]
Reactant: CCOc1ccccc1C(=O)Nc1c(C(N)=O)cccc1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1ccccc1-c1nc2c(C(N)=O)cccc2c(=O)[nH]1
Yield: 0.1 %

Procedure:
A stirred mixture of 3-carbamoyl-2-(2-ethoxybenzamido)benzamide (Preparation 18; 1 g, 0,003 mol) sodium hydroxide (0.61 g, 0.015 mol), water (30 ml) and ethanol (7 ml) was heated under reflux for 1 hour. The cool solution was washed with dichloromethane (3×30 ml), acidified to pH 1 with 2N hydrochloric acid and the resulting precipitate collected by filtration. The solid was suspended in saturated aqueous sodium carbonate solution (60 ml) and this suspension extracted with dichloromethane-methanol (98: 2, 3×100 ml). The extracts were combined, dried (Na2SO4) and evaporated under vacuum, then the residue triturated with diethyl ether (50 ml) to give the title compound as a white solid (0.72 g, 78%), m.p. 252°-254° C. Found: C,66.28; H,4.97; N,13.65. C17H15H3O3 requires C,66.01; H,4.89; N,13.59%.