Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:57]=[CH:56][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:48][C:49]([O:51]C(C)(C)C)=[O:50])[C:24](=[O:47])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:46])[CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=4[C:42]([F:45])([F:44])[F:43])=[CH:27][N:26]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:48][C:49]([OH:51])=[O:50])[C:24](=[O:47])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:46])[CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=4[C:42]([F:43])([F:44])[F:45])=[CH:27][N:26]=3)=[CH:20][CH:21]=2)=[O:14])=[CH:56][CH:57]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4C(F)(F)F)cn3)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)O)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4C(F)(F)F)cn3)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
Prepared using General Procedure 8: To a stirred solution of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-5-(2-(4-methoxy-2 (trifluoromethyl)phenyl)acetamido)picolinamido)methyl)phenyl 4-(heptyloxy)benzoate INT-16 (18 mg, 0.02 mmol) in DCM (1 mL) was added a solution of TFA (0.1 mL) and DCM (0.2 mL). The reaction mixture was stirred at room temperature for 12 h. The solvent was evaporated under high vacuum to give 12 mg (75%) of 2-(N-(4-((4-(heptyloxy)benzoyl)oxy)benzyl)-5-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)picolinamido)acetic acid 298 as a white solid. LCMS-ESI (m/z) calculated for C39H40F3N3O8: 736; no m/z observed, tR=11.36 min (Method 2). 1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 10.60 (s, 1H), 8.72 (dd, J=11.1, 2.1 Hz, 1H), 8.19-8.09 (m, 1H), 8.09-7.97 (m, 2H), 7.71 (dd, J=28.2, 8.7 Hz, 1H), 7.43 (dd, J=16.8, 8.3 Hz, 3H), 7.27-7.15 (m, 4H), 7.10 (d, J=8.9 Hz, 2H), 4.75 (d, J=23.0 Hz, 2H), 4.30 (s, 1H), 4.08 (t, J=6.5 Hz, 2H), 3.97 (s, 1H), 3.89 (s, 2H), 3.82 (d, J=2.0 Hz, 3H), 1.73 (dd, J=14.5, 6.6 Hz, 2H), 1.50-1.15 (m, 8H), 0.87 (t, J=6.9 Hz, 3H).
Reaction SMILES: Cl.[C:2]([OH:8])(=[O:7])[CH2:3][CH2:4][C:5]#[CH:6]>C(O)CCC>[CH2:2]([O:7][C:2](=[O:8])[CH2:3][CH2:4][C:5]#[CH:6])[CH2:3][CH2:4][CH3:5]
Reactant: C#CCCC(=O)O
Agent: Cl
Solvent: CCCCO
Product: C#CCCC(=O)OCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HCl was bubbled into a n-butanol solution (200 mL) of pent-4-ynoic acid 6-3 (10 g, 102 mmol) for ten minutes. The solution was stirred overnight at room temperature. The solvent was removed in vacuo providing the crude ester 6-4 as a yellow liquid in quantitative yield.
Reaction SMILES: [CH3:1][C:2](=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=O.[Cl-].[CH2:13]([O:20][C:21]1[CH:46]=[CH:45][CH:44]=[CH:43][C:22]=1[CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N12CCCN=C1CCCCC2>C(#N)C>[CH2:13]([O:20][C:21]1[CH:46]=[CH:45][CH:44]=[CH:43][C:22]=1[CH:23]=[CH:3][C:2]([CH3:1])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(COc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C=O)=Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C=Cc1ccccc1OCc1ccccc1)=Cc1ccccc1
Yield: 90.2 %

Procedure:
Following a procedure similar to that described in the first part of Preparation 3, 1.32 g of α-methylcinnamaldehyde, 4.47 g of 2-benzyloxybenzyltriphenylphosphonium chloride (prepared as described in Preparation 1) and 1.37 g of 1,8-diazabicyclo[5,4,0]-undec-7-ene were reacted in acetonitrile. The crude product thus obtained was purified as described in the first part of Preparation 3, to give 2.66 g (yield 90%) of 1-(2-benzyloxyphenyl)-3-methyl-4-phenylbutadiene as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([OH:25])[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH:44]([CH3:46])[CH3:45]>CN(C)C=O.C(OCC)(=O)C>[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([O:25][CH:44]([CH3:46])[CH3:45])[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:37][CH:38]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:14])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)Br
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(O)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
Potassium carbonate (430 mg, 3.11 mmol) was added to a solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-ol (prepared as in Example 13, 325 mg, 0.62 mmol) in N,N-dimethylformamide (2 mL) at room temperature and stirred for 30 min and then 2-bromopropane (0.13 mL, 1.24 mmol) was added. The mixture was then heated to 60° C. and stirred for 3 h. The resulting mixture was diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-isopropoxy-1H-pyrrolo[2,3-b]pyridine (310 mg, 100%) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C30H32N2O5S2 [M+H]+ 565.73, observed 565.2.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].[OH-].[Na+].Cl.[CH3:12][S:13]([N:16]1[CH2:20][CH2:19][N:18]([C:21](Cl)=[O:22])[C:17]1=[O:24])(=[O:15])=[O:14]>O.CC(C)=O>[OH:4][C@@H:3]([CH3:5])[C@@H:2]([NH:1][C:21]([N:18]1[CH2:19][CH2:20][N:16]([S:13]([CH3:12])(=[O:15])=[O:14])[C:17]1=[O:24])=[O:22])[C:6]([OH:8])=[O:7]
Reactant: CS(=O)(=O)N1CCN(C(=O)Cl)C1=O
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: C[C@H](O)[C@@H](NC(=O)N1CCN(S(C)(=O)=O)C1=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
D-Threonine (5.0 g) was suspended in water (50 ml) and treated with 2M aqueous sodium hydroxide solution to pH 10, forming a clear solution. The pH was then re-adjusted to 7.5 with concentrated hydrochloric acid and the still clear solution cooled to 15°. 3-Methanesulphonyl-2-oxoimidazolidine-1-carbonyl chloride (9.5 g) was then added portionwise over 2 minutes, with simultaneous addition of 2M aqueous sodium hydroxide to maintain the pH at 6.0-7.5. Following this, acetone (30 ml) was added to give a clear solution which was then stirred at room temperature for 1 hour whilst still maintaining the pH at 6.0-7.5. After evaporation of the acetone in vacuo the aqueous residue was extracted well with ethyl acetate and the organic extracts were discarded. The pH of the aqueous phase was then adjusted to 1.5 with concentrated hydrochloric acid and the mixture was extracted using 3×50 ml portions of ethyl acetate:tetrahydrofuran (1:1). The organic extracts were dried and the solvent was evaporated to give the title compound as a white solid, (7.3 g).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[N:10]=[CH:9][C:8]=1[C:24]#[N:25].N1C=CC=CC=1.N>C(Cl)(Cl)Cl.C(O)C>[C:24]([C:8]1[CH:9]=[N:10][N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:21])([F:22])[F:20])=[CH:14][C:13]=2[Cl:23])[C:7]=1[NH:6][C:1](=[O:4])[CH2:2][CH3:3])#[N:25]
Reactant: N#Cc1cnn(-c2ccc(OC(F)(F)F)cc2Cl)c1N
Reactant: CCC(=O)Cl
Agent: N
Solvent: CCO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCC(=O)Nc1c(C#N)cnn1-c1ccc(OC(F)(F)F)cc1Cl
Reaction time: 20 h
Yield: 75.3 %

Procedure:
10 ml (0.11 mole) of propionyl chloride are added to 2.9 g (0.01 mole) of 5-amino-4-cyano-1-(2-chloro-4-trifluoromethoxy-phenyl)-pyrazole in 30 ml of chloroform at 0° C., with stirring, and a solution of 1.8 ml (0.02 mole) of pyridine in 15 ml of chloroform is then added, also at 0° C. When the addition has ended, stirring is continued at room temperature for 20 hours, the solvent is stripped off, the residue is taken up in 50 ml of ethanol, aqueous ammonia is added until the reaction is alkaline, the volatile constitutents are removed in vacuo, the residue is taken up in 100 ml of chloroform, the mixture is washed with water, then with 2N hydrochloric acid and again with water and dried over sodium sulphate and the solvent is removed in vacuo. 2.7 g (75.3% of theory) of 4-cyano-1-(2-chloro-4-trifluoromethoxy-phenyl)-5-propionylamino-pyrazole of melting point 127° C. are obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C@H:11]2[O:16][CH2:15][C@@H:14]3[CH2:17][NH:18][CH2:19][CH2:20][N:13]3[CH2:12]2)=[CH:4][CH:3]=1.OS(C(F)(F)F)(=O)=O.C1C(=O)N([I:36])C(=O)C1>>[F:1][C:2]1[C:3]([I:36])=[CH:4][C:5]([C@H:11]2[O:16][CH2:15][C@@H:14]3[CH2:17][NH:18][CH2:19][CH2:20][N:13]3[CH2:12]2)=[C:6]([CH3:10])[C:7]=1[C:8]#[N:9]
Reactant: Cc1c([C@@H]2CN3CCNC[C@H]3CO2)ccc(F)c1C#N
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Product: Cc1c([C@@H]2CN3CCNC[C@H]3CO2)cc(I)c(F)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-fluoro-2-methyl-3-((3R,9aS)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl)benzonitrile (600 mg, 2.18 mmol) was dissolved in triflic acid (5.80 mL, 65.4 mmol), and NIS (1226 mg, 5.45 mmol) was added at 0° C. The reaction mixture was stirred at rt overnight and quenched into ice water and basified with 5 N NaOH. The aqueous layer was extracted with DCM. The organic layer was washed with aqueous NaS2O3, NaHCO3, brine, dried and evaporated to give crude title compound, which was used without further purification. LC/MS: [(M+1)]+=402.1;
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27]3[C:36]([N+:37]([O-])=O)=[CH:35][CH:34]=[CH:33][C:28]=3[C:29]([O:31][CH3:32])=[O:30])=[CH:21][CH:20]=2)=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl>CO>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27]3[C:36]([NH2:37])=[CH:35][CH:34]=[CH:33][C:28]=3[C:29]([O:31][CH3:32])=[O:30])=[CH:21][CH:20]=2)=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NCc1ccc(-c2ccccc2-c2nnnn2Cc2ccccc2)cc1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2-c2nnnn2Cc2ccccc2)cc1
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A mixture of methyl 2-[({2′-[1-benzyl-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)amino]-3-nitrobenzoate (compound 21b, 8.396 g) and tin (II) chloride dihydrate (13.56 g) in methanol (155 mL) was heated under reflux for 2 hr. The reaction mixture was concentrated under reduced pressure, and to the concentrated residue were added saturated aqueous sodium hydrogen carbonate and ethyl acetate. The mixture was stirred for 1 hr, and filtered, and the insoluble material was washed with ethyl acetate. The filtrate and washing were combined, and concentrated under reduced pressure, and the concentrated solution was extracted with ethyl acetate. The ethyl acetate solution of the resultant product was dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the concentrated residue was purified by silica gel column (hexane→thexane:AcOEt=5:1→4:1→3:1→2:1→3:2) to give methyl 2-[({2′-[1-benzyl-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)amino]-3-aminobenzoate (compound 22b) (6.68 g, 84%) as a brown amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[O:17][N:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:14]=3[C:24]([F:27])([F:26])[F:25])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[CH2:28]O.P(Br)(Br)[Br:31]>ClCCl>[Br:31][CH2:28][C:3]1[CH:4]=[CH:5][C:6]([C:8]2[N:12]=[C:11]([C:13]3[O:17][N:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:14]=3[C:24]([F:25])([F:27])[F:26])[O:10][N:9]=2)=[CH:7][C:2]=1[F:1]
Reactant: BrP(Br)Br
Reactant: OCc1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1F
Solvent: ClCCl
Product: Fc1cc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)ccc1CBr
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
To a solution of (2-fluoro-4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)methanol (1.95 mL, 0.740 mmol) in dichloromethane (8 mL) at 0° C. was added phosphorus tribromide (1.0M in dichloromethane) (0.740 mL, 0.740 mmol). After 5 minutes, the ice bath was removed, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, washed with brine, and dried over anhydrous sodium sulfate. The residue was triturated with methanol with sonication, filtered, and washed with methanol. Analysis of the white solid by HPLC and LCMS indicated that there was no significant amount of the desired product present. The filtrate was concentrated under reduced pressure, and the compound was loaded with a minimum amount of dichloromethane on a fritted funnel containing a layer of CELITE® topped with a layer of silica gel. The plug column was eluted with dichloromethane to give 3-(4-(bromomethyl)-3-fluorophenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole (0.173 g, 0.370 mmol, 50% yield) as a white solid. The compound had an HPLC ret. time=3.72 min.−Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=468.0 and 470.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[N:9][N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:5]2=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].Br[C:43]1[CH:44]=[C:45]([NH:49][C:50](=[O:53])[CH2:51][CH3:52])[CH:46]=[N:47][CH:48]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.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].O.C(Cl)Cl>[CH:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:43]3[CH:44]=[C:45]([NH:49][C:50](=[O:53])[CH2:51][CH3:52])[CH:46]=[N:47][CH:48]=3)[CH:3]=2)[N:8]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:9]=1)=[O:12]
Reactant: CCC(=O)Nc1cncc(Br)c1
Reactant: O=Cc1nn(C2CCCCO2)c2ncc(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)Nc1cncc(-c2cnc3c(c2)c(C=O)nn3C2CCCCO2)c1
Temperature: 90 °C

Procedure:
A solution of 5-bromo-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-carbaldehyde (XI) (0.218 g, 0.70 mmol), bis(pinacolato)diboron (0.213 g, 0.84 mmol), and KOAc (0.206 g, 2.1 mmol) in DMF (10 ml) was purged with argon. PdCl2(dppf)2. DCM was added to the solution and purged again with argon. The solution was heated at 90° C. for 2 h under argon and cooled to the room temperature. N-(5-bromopyridin-3-yl)propionamide (XXXIII) (0.70 mmol), potassium phosphate (0.223 g, 1.05 mmol) and water (1 mL) was added to the solution and purged with argon. Pd(PPh3)4 was added to the solution and again purged with the argon. The solution was heated at 90° C. for 4 h under argon. The solution was filtered through a bed of Celite and the solvent was distilled under vacuum. The residue was treated with water and extracted with DCM. The combined organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (100% DCM 5:95 MeOH:DCM) to get N-(5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)propionamide (LX) as a off white solid (45% yield). 1H NMR (DMSO-d6) δ ppm 1.13 (t, J=7.55 Hz, 3H), 1.51-1.74 (m, 2H), 1.96-2.18 (m, 2H), 2.41 (q, J=7.55 Hz, 2H), 3.68 (m, 1H), 3.92 (m, 1H), 6.26 (dd, J=10.20, 2.14, 1H), 8.48 (m, 1H), 8.70 (m, 2H), 8.77 (m, 1H), 9.07 (m, 1 Hz), 10.17 (s, 1H), 10.24 (s, 1H); ESIMS found C20H21N5O3 m/z 380 (M+H).
Reaction SMILES: C(C1C(CC2C=CC(C)=CC=2)=CC2C(C)(C)CCC(C)(C)C=2C=1)=O.[CH3:25][C:26]1([CH3:60])[CH2:35][CH2:34][C:33]([CH3:37])([CH3:36])[C:32]2[CH:31]=[C:30](/[CH:38]=[CH:39]/[C:40]3[CH:50]=[CH:49][C:43]([C:44]([O:46]CC)=[O:45])=[CH:42][CH:41]=3)[C:29]([CH2:51][C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][C:53]=3[F:59])=[CH:28][C:27]1=2>>[CH3:25][C:26]1([CH3:60])[CH2:35][CH2:34][C:33]([CH3:36])([CH3:37])[C:32]2[CH:31]=[C:30](/[CH:38]=[CH:39]/[C:40]3[CH:50]=[CH:49][C:43]([C:44]([OH:46])=[O:45])=[CH:42][CH:41]=3)[C:29]([CH2:51][C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][C:53]=3[F:59])=[CH:28][C:27]1=2
Reactant: CCOC(=O)c1ccc(/C=C/c2cc3c(cc2Cc2ccc(F)cc2F)C(C)(C)CCC3(C)C)cc1
Agent: Cc1ccc(Cc2cc3c(cc2C=O)C(C)(C)CCC3(C)C)cc1
Product: CC1(C)CCC(C)(C)c2cc(Cc3ccc(F)cc3F)c(/C=C/c3ccc(C(=O)O)cc3)cc21
Yield: 72 %

Procedure:
Horner-Emmons olefination (following the procedure of Example) of 2-formyl-3-(4-methylbenzyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (239 mg, 0.69 mmol) followed by ester hydrolysis (following the procedure of Example) of ethyl 4-{(E)-2-[5,5,8,8-tetramethyl-3-(2,4-difluorobenzyl)-5,6,7,8-tetrahydro-naphthalen-2-yl]vinyl}benzoate gave 4-{(E)-2-[5,5,8,8-tetramethyl-3-(2,4-difluorobenzyl)-5,6,7,8-tetrahydro-naphthalen-2-yl]vinyl}benzoic acid (230 mg, 72%) as a white crystalline solid (m.p. 204.3-205.7° C.) recrystallized from (CH2Cl2/hexane) 43.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](O)=[O:25])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][NH:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](=[O:25])[N:28]([CH3:27])[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[CH:12][N:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)O)c2c1
Reactant: CNCCc1ccccn1
Product: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)N(C)CCc3ccccn3)c2c1

Procedure:
As described in example 1E, 100 mg of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid was coupled with methyl-(2-pyridin-2-yl-ethyl)-amine to give 66 mg of {6,8-dimethoxy-4-[methyl-(2-pyridin-2-yl-ethyl)-carbamoyl]-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C26H32N4O5+H 481.6; found 481.0.
Reaction SMILES: [CH2:1]([NH:3][C@H:4]1[C@H:8]([S:9][CH3:10])[CH2:7][NH:6][CH2:5]1)[CH3:2].[Cl:11][C:12]1[C:13](F)=[C:14]([F:29])[CH:15]=[C:16]2[C:21]=1[N:20]([CH:22]1[CH2:24][CH2:23]1)[CH:19]=[C:18]([C:25]([OH:27])=[O:26])[C:17]2=[O:28]>>[Cl:11][C:12]1[C:13]([N:6]2[CH2:7][C@@H:8]([S:9][CH3:10])[C@H:4]([NH:3][CH2:1][CH3:2])[CH2:5]2)=[C:14]([F:29])[CH:15]=[C:16]2[C:21]=1[N:20]([CH:22]1[CH2:24][CH2:23]1)[CH:19]=[C:18]([C:25]([OH:27])=[O:26])[C:17]2=[O:28]
Reactant: CCN[C@@H]1CNC[C@H]1SC
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Product: CCN[C@@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)C[C@H]1SC

Procedure:
The reaction is carried out analogously to Example 13 with trans-3-ethylamino-4-methylthio-pyrrolidine and 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid to give 8-chloro-1-cyclopropyl-7-(trans-3-ethylamino-4-methylthio-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting point: 217°-218° C. (with decomposition).
Reaction SMILES: [CH:1]([S:4]([O-:6])=[O:5])([CH3:3])[CH3:2].[Na+].CN1CCCC1=O.Cl[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]>O>[Cl:22][C:21]1[C:16]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)S(=O)[O-]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)S(=O)(=O)c1c(Cl)cccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
To a mixture of sodium isopropylsulfinate (3.3 g) and N-methyl-2-pyrrolidinone (20 mL), 2,3-dichloronitrobenzene (4 g) was added and stirred overnight at 70° C. The reaction mixture was diluted with water, and the precipitated solid was collected by filtration and washed with diethyl ether to give 3-chloro-2-isopropylsulfonyl-1-nitrobenzene (3.0 g) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[N+:6]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])([O-:8])=[O:7].ClC([O:19][CH2:20][CH2:21]Cl)=O.Cl>COCCOC.O>[OH:19][CH2:20][CH2:21][NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)OCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1ccccc1NCCO
Temperature: 80 °C

Procedure:
60.1 g of calcium carbonate are added to a solution of 138.1 g of 2-nitroaniline in 360 g of monoethylene glycol dimethylether and 60 g of water. 150.0 g of 2-chloroethyl chloroformate are then metered in at 80° C. and the reaction is brought to completion by subsequent stirring at 80° C. 100 g of water and 8.7 g of 35% strength hydrochloric acid are then added, up to a pH of 1, and the lower aqueous phase is separated off. The upper organic phase is diluted with 90 g of monoethylene glycol dimethylether, and 370.6 g of a 50% strength potassium hydroxide solution are added at 15° C. The reaction mixture is then heated to 85° C. and subsequently stirred at 85° C. for 4 hours. Thereafter, 250 g of water are added and the lower salt-containing aqueous phase is separated off. First 500 g of water and then 9 g of 10% strength sulphuric acid are added to the yellow-red organic phase, up to a pH of 8.5. After the monoethylene glycol dimethyl ether has been distilled off and the residue has been cooled to 10° C., the product is obtained in the form of yellow-red crystals.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH:25]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[C:30]#[N:31])=O>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:25][C:27]3[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=3)[C:30]#[N:31])[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: N#Cc1cccc(C=O)c1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: N#Cc1cccc(C=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)c1
Temperature: 25 °C
Yield: 68.5 %

Procedure:
The product of Example 268D (0.100 g, 0.27 mmol) was reacted with 3-formylbenzonitrile (0.362 g, 2.75 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.088 g, 69%).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[N:5]=1)([O-])=O.CO.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:9]([N:6]1[CH:7]=[CH:8][C:4]([NH2:1])=[N:5]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCn1ccc([N+](=O)[O-])n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCn1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
3-Nitro-1-hexyl-1H-pyrazole (118 mg, 0.60 mmol) was dissolved in ethyl acetate (3 mL) and methanol (3 mL) was added. Palladium, 10 wt. % on activated carbon, wet (˜50 mg) was added to the reaction. The vial was charged with hydrogen gas (via balloon) and the reaction stirred for 16 h at 25° C. The mixture was passed through a plug of celite and concentrated in vacuo afforded 1-hexyl-1H-pyrazol-3-ylamine (88 mg, 88%) as a golden oil: ESI-LRMS m/e calcd for C9H17N3 [M+] 167.15, found 168.4 [M+H+].