Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH:13]=[CH:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O.CCO.[Pd]>[C:2]1([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CC(c2ccccc2)CCN1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: c1ccc(C2CCNCC2)cc1
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A mixture of 20.5 g (104.9 mmol) of 4-phenyltetrahydropyridine hydrochloride (Aldrich) and 0.5 g of 10% Pd/C in 40 mL of H2O and 160 mL of EtOH was stirred under hydrogen at 45 psi for 2 h. The reaction mixture was then filtered though a thin pad of celite eluting with EtOH and H2O. The filtrate was concentrated and the residue was stirred in 75 mL of ether. To it at 0° C. was added 5 g of solid NaOH. The layers were separated and the aqueous layer was extracted with ether. The combined organic fractions were washed with sat'd NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was crystalized from cold heptane to give 10 g of the title compound. 1H NMR (CDCl3) δ7.33 (t, 2H, J=7.7 Hz), 7.25-7.28 (m, 3H), 6.90 (bs, 1H), 3.65 (d, 2H, J=12.6 Hz), 3.04 (d of d,2H, J=13.0, 2.5 hz), 2.78 (t of d, 1H, J=12.1, 3.2 Hz), 2.21-2.30 (m,2H), 2.05 (d, 2H, J=14.0 Hz).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:11](=[S:12](=[O:14])=[O:13])[C:10]([O:15][CH3:16])=[C:9]([CH3:17])[CH:8]=[C:4]1[C:5]([OH:7])=O.CC(C)=O.ClC(OCC)=O.[CH:28]1([N:36]2[CH2:40][CH2:39][CH2:38][CH:37]2[CH2:41][NH2:42])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(N(CC)CC)C.O>[CH:28]1([N:36]2[CH2:40][CH2:39][CH2:38][CH:37]2[CH2:41][NH:42][C:5](=[O:7])[C:4]2[CH:3]([O:2][CH3:1])[C:11](=[S:12](=[O:14])=[O:13])[C:10]([O:15][CH3:16])=[C:9]([CH3:17])[CH:8]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COC1=C(C)C=C(C(=O)O)C(OC)C1=S(=O)=O
Reactant: NCC1CCCN1C1CCCCCCC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: COC1=C(C)C=C(C(=O)NCC2CCCN2C2CCCCCCC2)C(OC)C1=S(=O)=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
13 g of 2,4-dimethoxy-5-methyl sulphonyl benzoic acid, 150 ml of acetone, 28 ml of water and 7 ml of triethylamine (density 0.726) are placed in a 250 ml flask fitted with an agitator, a thermometer, a condenser and a dropping funnel. The suspension is cooled to from 0° to +5° C., then 5.4 g of ethyl chloroformate is added drop by drop. The mixture is agitated for 45 minutes at room temperature and cooled to about 0° C., then 13.8 g of 1-cyclooctyl-2-aminomethyl-pyrrolidine is added drop by drop. There is complete solubilisation. The reaction medium is agitated at room temperature then left to stand. The solvents are evaporated under vacuum and the residue is dissolved in 100 ml of water and 20 ml of hydrochloric acid (density 1.18). The organic phase is extracted 3 times with 50 ml of methylene chloride, dried over magnesium sulphate, filtered and evaporated to dryness under vacuum. The residue is dissolved in 100 ml of water. The solution is filtered in the presence of carbon black and the filtrate made alkaline with 10 ml of ammonia. A gum is precipitated. This is extracted 3 times with 50 ml of methylene chloride, and the organic solution is washed twice with 50 ml of water and dried over magnesium sulphate. It is filtered, then the solvent is evaporated under vacuum and the residue re-crystallised in 200 ml of isopropanol. The crystals are filtered off, washed twice with a little iced isopropanol and dried in an oven at 50° C.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH2:11]([O:18][NH:19][CH2:20][C:21]1([C:29]([OH:31])=[O:30])[CH2:26][C@H:25]([CH3:27])[CH2:24][C@H:23]([CH3:28])[CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH2:11]([O:18][N:19]([CH2:20][C:21]1([C:29]([OH:31])=[O:30])[CH2:26][C@H:25]([CH3:27])[CH2:24][C@H:23]([CH3:28])[CH2:22]1)[CH:1]=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CO
Reactant: C[C@@H]1C[C@H](C)CC(CNOCc2ccccc2)(C(=O)O)C1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: C[C@@H]1C[C@H](C)CC(CN(C=O)OCc2ccccc2)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a cold solution of formic acid (15.5 mL, 0.40 mol) in dichloromethane (75 mL) at 0° C. under a nitrogen atmosphere was added acetic anhydride (5.9 mL, 62 mmol). After 1 h, a solution of (3S,5R)-1-(Benzyloxyamino-methyl)-3,5-dimethyl-cyclohexanecarboxylic acid (1.8 g, 6.2 mmol) in dichloromethane (75 mL) was added. The reaction was stirred at room temperature for 18 h and was concentrated in vacuo. Water (150 mL) was added and the mixture was extracted with dichloromethane (75 mL×5). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo to yield the title compound as a yellow solid (1.59 g, 80%). MH+320.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:19][C@H:20]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C@H:20]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.7 %

Procedure:
To a mixture of 2,4-dichloro-5-fluoro-pyrimidine (1.75 g, 10.48 mmol) and iPr2NEt (3.27 mL, 18.78 mmol) in THF (50 mL) was added tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (1.83 mL, 10.48 mmol) in THF (2 mL). The resulting solution was allowed to stir at room temperature for 2 hours. The mixture was concentrated to dryness, diluted with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford 3.41 g of 7a, as a white foamy solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42](Cl)=[O:43]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:42]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=3)=[O:43])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)C(=O)c3ccccn3)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, picolinoyl chloride hydrochloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([OH:19])=[O:18])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][C:38]([NH:40][O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)=[O:39])=[CH:31][CH:30]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([O:19][C:29]2[CH:30]=[CH:31][C:32]([CH2:35][CH2:36][CH2:37][C:38](=[O:39])[NH:40][O:41][C@@H:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:33][CH:34]=2)=[O:18])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(OCc2ccccc2)cn1)C(=O)O
Reactant: O=C(CCCc1ccc(O)cc1)NOC1CCCCO1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(Cc1ccc(OCc2ccccc2)cn1)C(=O)Oc1ccc(CCCC(=O)NO[C@@H]2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(R)-3-(5-(Benzyloxy)pyridin-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid (0.19 g, 0.5 mmol), 4-(4-hydroxyphenyl)-N-(tetrahydro-2H-pyran-2-yloxy)-butanamide (0.14 g, 0.5 mmol), and DMAP (0.06 g, 0.5 mmol) were added into DCM (10 mL) and stirred at 0° C. for 10 min. A solution of DCC (0.12 g, 0.6 mmol) in DCM (5 mL) was added to the above-mentioned solution dropwise. The mixture was stirred from 0° C. at room temperature for 1 h (monitored by TLC). The white solid was removed and the filtrated was then evaporated in vacuo. Ethyl acetoacetate was added and the solid was again removed. The solution was evaporated in vacuo. The residue was purified by chromatography (EA:Hex=1:5) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][CH:8]([CH:13]1[C:26]3[CH:25]=[CH:24][C:23]([C:27]#[N:28])=[CH:22][C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[O:4].[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+].O>CN(C=O)C>[F:30][C:2]([F:29])([F:1])[C:3]([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][CH:8]([CH:13]1[C:26]3[CH:25]=[CH:24][C:23]([C:27]4[NH:33][N:32]=[N:31][N:28]=4)=[CH:22][C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[O:4]
Reactant: N#Cc1ccc2c(c1)Oc1ccccc1C2C1CC2CCC(C1)N2C(=O)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N1C2CCC1CC(C1c3ccccc3Oc3cc(-c4nnn[nH]4)ccc31)C2)C(F)(F)F
Temperature: 120 °C
Yield: 86 %

Procedure:
To a solution of 9-[8-(2,2,2-trifluoroacetyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-9H-xanthene-3-carbonitrile, 3j (0.35 g; 0.848 mmol) in DMF (10 mL) were added sodium azide (0.165 g, 2.54 mmol) and ammonium chloride (0.136 g; 2.5 mmol), and the mixture was heated at 120° C. for 3 h. The mixture was allowed to cool to rt, poured into water, and the solid was separated via filtration, yielding 0.33 g (86%) of title compound 2,2,2-trifluoro-1-{3-[3-(1H-tetrazol-5-yl)-9H-xanthen-9-yl]-8-aza-bicyclo[3.2.1]oct-8-yl}-ethanone, 4j
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]2([CH3:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[NH:9]1)=[O:7])(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]3([CH3:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC1(CC2NC(C(=O)OC(C)(C)C)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(CC2NC(C(=O)O)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)CCCCC1

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 102b (3 g, 5.3 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (3.3 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]([CH3:15])[CH2:9][NH:10][C:11](=[O:14])[CH2:12]Cl)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.O>FC(F)(F)C(O)=O>[CH3:15][C@H:8]1[CH2:9][NH:10][C:11](=[O:14])[CH2:12][N:7]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:16]
Reactant: C[C@@H](CNC(=O)CCl)NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C[C@H]1CNC(=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
(S)-tert-butyl(1-(2-chloroacetamido)propan-2-yl)carbamate (7.5 g, 29.9 mmol) was dissolved in trifluoroacetic acid (30 mL) and stirred for 10 minutes. The reaction mixture was concentrated, dissolved in THF (321 mL) and potassium carbonate (20.7 g, 149.5 mmol) was added and the reaction mixture was refluxed for 12 hours. To the reaction mixture was added (Boc)2O (7.7 mL, 35.9 mmol) and the reaction mixture was refluxed for an additional 5 hours. The reaction mixture was cooled to rt and water was added. The reaction mixture was extracted with EtOAc. The organic layers were combined, dried with Na2SO4, filtered, concentrated and purified by flash column chromatography (0-100% EtOAc in hexanes) to provide the desired compound (5 g, 78%). 1H NMR (600 MHz, DMSO) δ 8.00 (s, 1H), 4.17 (s, 1H) 3.94 (d, J=17.8 Hz, 1H), 3.58 (d, J=17.9 Hz, 1H), 3.43-3.34 (m, 1H), 3.98 (ddd, J=12.7, 4.9, 2.5 Hz, 1H), 1.43-1.38 (s, 9H), 1.10 (d, J=6.7 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:41]=[CH:40][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[CH:20][C:19]=3[N:31]([CH3:39])C(=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1>Cl.O1CCOCC1>[CH3:39][N:31]1[C:19]2[CH:20]=[C:21]([S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:22]=[CH:23][C:18]=2[N:17]=[C:15]1[CH2:14][O:13][C:12]1[CH:40]=[CH:41][C:9]([CH2:8][CH:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[O:7])=[CH:10][CH:11]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Sc2ccccn2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Sc3ccccn3)cc21
Yield: 39.6 %

Procedure:
In a similar manner to that described in Example (2-2a), a reaction was carried out using t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(pyridin-2-ylthio)phenyl}-N-methylcarbamate (0.63 g) and 4N hydrogen chloride/dioxane (20 ml) and the reaction mixture was purified to give the title compound (0.20 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[C:27](O)=[O:28]>>[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[C:27]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:28]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cc5ccccc5o4)cc23)CC1
Yield: 83.5 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 24.0 mg (0.15 mMol) benzofuran-2-carboxylic acid, 15.6 mg (84%) of the title compound were recovered.
Reaction SMILES: C([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[N+:19]([O-:21])=[O:20])[CH:12]=[CH:11][C:10]=1[NH:22][C:23]([C:25]([O:27]CC)=O)=[O:24])(C(OCC)=O)=O>Cl>[OH:27][C:25]1[C:23]([OH:24])=[N:22][C:10]2[CH:11]=[CH:12][C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[C:18]=3[C:9]=2[N:8]=1
Reactant: CCOC(=O)C(=O)Nc1ccc2cccc([N+](=O)[O-])c2c1NC(=O)C(=O)OCC
Agent: Cl
Product: O=[N+]([O-])c1cccc2ccc3nc(O)c(O)nc3c12
Reaction time: 2 h
Yield: 89.4 %

Procedure:
A suspension of 1,2-diethoxalylamino-8-nitro-naphthalene (0.40 g, 1 mmol) in 20 ml of 4M hydrochloric acid was refluxed with stirring for 21/2 h. The mixture was cooled, and the product was filtered off, washed with water, and dried to give 0.23 g (88%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[C:13]([O:32][NH2:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O.O.CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][C:10]([NH:33][O:32][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(O)CSc1ccc(F)cc1
Reactant: NOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(CSc1ccc(F)cc1)NOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (4-fluoro-phenylsulfanyl)-acetic acid (1.52 g, 8.17 mmol) from step B and O-Trityl-hydroxylamine (2.26 g, 10 mmol) in dry DMF was sequentially added NMP (3.0 ml), EDCl (2.05 g, 10.7 mmol), and HOBT (1.45 g, 10.74 mmol). The resulting mixture was stirred at room temperature for overnight. The reaction was diluted with EtOAc and water. The organic layer was washed sequentially with 1N HCl solution, 10% aqueous Na2CO3, water and saturated NaCl solution. The organic portion was dried over anhydrous Na2SO4 and concentrated under reduced pressure to gave a crude material, which was then purified by a column chromatography with 0˜25% EtOAc in hexanes. MS: 466.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([NH2:27])[CH:23]=[N:22]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[CH:7][C:2]([NH:27][C:24]2[CH:23]=[N:22][N:21]([CH3:20])[C:25]=2[CH3:26])=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Reactant: Cc1c(N)cnn1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1cc(Nc2cnn(C)c2C)ncc1Cl
Temperature: 150 °C
Yield: 11.5 %

Procedure:
To a 10 mL sealable tube was added 2-[(2,5-dichloro-4-pyridinyl)amino]-N-methylbenzamide (95 mg, 0.321 mmol), 1,5-dimethyl-1H-pyrazol-4-amine (35.7 mg, 0.321 mmol), BINAP (20 mg, 0.032 mmol), cesium carbonate (314 mg, 0.964 mmol), and palladium(II) acetate (7.21 mg, 0.032 mmol) in 1,4-dioxane (5 mL). The reaction vessel was sealed and heated at 150° C. for 1 hr. The reaction mixture was purified using a prep HPLC (0.1% formic acid, 5 to 95% water:acetonitrile). Fractions were combined and evaporated. 2-({5-Chloro-2-[(1,5-dimethyl-1H-pyrazol-4-yl)amino]-4-pyridinyl}amino)-N-methylbenzamide (16 mg, 0.037 mmol, 11.38% yield) was isolated as yellow oil LCMS (M+H)+=371.1; 1H NMR (400 MHz, MeOD) ppm 2.17 (s, 3 H) 2.91 (s, 3 H) 3.78 (s, 3 H) 6.47 (s, 1 H) 7.13-7.24 (m, 1 H) 7.40 (s, 1 H) 7.46-7.57 (m, 2 H) 7.67 (dd, J=7.83, 1.26 Hz, 1 H) 7.82 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCNCC1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(Cl)cc1)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Yield: 72.8 %

Procedure:
Using the procedure from Example 7A, 4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 2-chloro-5-(trifluoromethyl)pyridine (138 mg, 0.76 mmol), DIEA (0.27 ml, 1.52 mmol) and 1,4-dioxane (0.3 ml) at 190° C. to afford the title compound (112 mg), a white solid, in 73% yield.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]1[CH2:15][CH2:14][CH2:13][C:12]([CH3:17])([CH3:16])[C:11]=1/[CH:18]=[CH:19]/[C:20](/[CH3:29])=[CH:21]/[CH:22]=[CH:23]/[C:24](/[CH3:28])=[CH:25]/[CH2:26][OH:27].C(N(CC)CC)C>ClCCl>[CH3:28]/[C:24](/[CH:23]=[CH:22]/[CH:21]=[C:20](\[CH3:29])/[CH:19]=[CH:18]/[C:11]1[C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][CH2:15][C:10]=1[CH3:9])=[CH:25]\[CH2:26][O:27][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Reactant: O=C1CCCC(=O)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/COC(=O)CCCC(=O)O)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 208.5 %

Procedure:
Glutaric anhydride (115 mg, 1.01 mmol) and retinol (240 mg, 0.838 mmol) were dissolved in dichloromethane (3 mL) in an amber-colored vial. Triethylamine (257 ul, 1.84 mmol) was added and the vial was flushed with argon. Reaction was allowed to stir at room temperature overnight. The reaction mixture was concentrated and then purified via silica gel chromatography with a dichloromethane/methanol gradient to yield 5-(((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraen-1-yl)oxy)-5-oxopentanoic acid as a yellowish oil (700 mg, 78%). Material characterized by NMR.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:24].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1>C1COCC1>[N:32]1([C:29]2[CH:28]=[CH:27][C:26]([NH:25][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])[CH:10]=4)[NH:5][C:4]3=[O:24])=[CH:31][CH:30]=2)[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)c1
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CNc2ccc(N4CCOCC4)cc2)C(=O)N3)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 68.9 %

Procedure:
A small screw cap test tube was charged with N-[3-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-acetamide (prepared below, 52 mg, 0.161 mmol) and THF (2 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (43 mg, 0.242 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 69% (54 mg, 0.111 mmol) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[CH:11][C:10]([C:20]([O:22]CC)=[O:21])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[CH:11][C:10]([C:20]([OH:22])=[O:21])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(F)c2)n(-c2ccc(Cl)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2cccc(F)c2)n(-c2ccc(Cl)cc2)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
43.0 g (125 mmol) of the compound of Example 56A are provided in 504 ml of 1,4-dioxane, 94 ml (188 mmol) of a 2N solution of lithium hydroxide in water are added, and the mixture is stirred at 70° C. for 2 h. The mixture is concentrated, a conc. aqueous hydrogen chloride solution is subsequently added to the residue until the pH is acidic, the mixture is extracted with dichloromethane, and the organic phase is dried over magnesium sulfate, filtered and concentrated. 39.5 g (100% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH3:12])[CH:8]=[C:9]([Cl:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH2:12][Br:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)cc(C(C)(C)C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(Cl)cc(CBr)c1

Procedure:
3-t-Butyl-5-chlorotoluene (5.7 g) was dissolved in carbon tetrachloride (80 ml) and N-bromosuccinimide (5.56 g) was added followed by benzoyl peroxide (750 mg). This mixture was heated at reflux for 6 h. The mixture was cooled, filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica using hexane as eluent to afford 3-t-butyl-5-chlorobenzyl bromide as a colourless liquid. 1H NMR (360 MHz, CDCl3) δ1.31 (9H, s, (CH3)3), 4.42 (2H, s, CH2), 7.20 (1H, t, J=1.5 Hz, ArH), 7.26 (1H, t, J=1.5 Hz, ArH), 7.28 (1H, t, J=1.5 Hz, ArH).