Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:33])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25](=[O:32])[N:26]([CH3:31])[CH:27]=[C:28]([Cl:30])[CH:29]=2)=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].O.[OH-].[Li+]>C1COCC1.O.C(O)(=O)C>[Cl:30][C:28]1[CH:29]=[C:24]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][C@@H:4]([C:3]([OH:33])=[O:2])[NH:5][C:6]([C:8]3([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:7])=[CH:23][CH:22]=2)[C:25](=[O:32])[N:26]([CH3:31])[CH:27]=1
Reactant: COCCC1(C(=O)N[C@@H](Cc2ccc(-c3cc(Cl)cn(C)c3=O)cc2)C(=O)OC)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(-c3cc(Cl)cn(C)c3=O)cc2)C(=O)O)CCCC1
Reaction time: 1 h
Yield: 71.8 %

Procedure:
A solution of 4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (69 mg, 0.145 mmol) in THF (3 mL) was treated with a solution of lithium hydroxide monohydrate (24.3 mg, 0.58 mmol) in water (1.0 mL). Sufficient THF was added to the mixture to effect solution. The mixture was stirred 1 hr and a few drops of acetic acid were added. The entire reaction mixture was applied to a 4×30 cm, C-18 reversed phase HPLC column and eluted with a linear gradient of acetonitrile in water of 5 to 95% over 35 min. The product containing fraction was lyophillyzed to give 4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-L-phenylalanine (48 mg, 72%) as a white solid. LR-Electrospray: m/z positive ion 943 (2M+Na), 483 (M+Na), 478, (M+NH4), 461 (M+H); negative ion 919 (2M−H), 521, 459 (M−H).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3](OC)=[O:4].C([N:11](CC)CC)C.[CH2:16]([CH2:22][CH2:23]N)[CH2:17][CH2:18][C:19]([OH:21])=[O:20].Cl>CO.C(OCC)(=O)C>[F:8][C:2]([F:1])([F:7])[C:3]([NH:11][CH:18]([CH2:17][CH2:16][CH2:22][CH3:23])[C:19]([OH:21])=[O:20])=[O:4]
Reactant: CCN(CC)CC
Reactant: NCCCCCC(=O)O
Reactant: COC(=O)C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCC(NC(=O)C(F)(F)F)C(=O)O
Reaction time: 8 h

Procedure:
Methyl trifluoroacetate (513 μL, 5.10 mmoles) and triethylamine (474 μL, 3.40 mmoles) were added to a suspension of aminocaproic acid (455 mg, 3.40 mmoles) in methanol (2 mL). After the mixture was stirred vigorously for 8 h, 1 N HCl was added dropwise until the a pH of 2 was obtained. The reaction was added to ethyl acetate (10 mL) was washed with 1 N HCl (2×2 mL), dried over MgSO4, and concentrated in vacuo to yield the amide as a white solid (745 mg, 3.49 mmoles, quant.). LRMS: not performed. 1H NMR: spectrum is consistent with the predicted structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]1[C:14]([NH:16][NH:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]1[C:14]1[N:19]2[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]2=[N:17][N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCOC[C@@H]1C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC[C@@H]1c1nnc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To a solution of Intermediate 83a (375 mg, 1.10 mmol), Ph3P (578 mg, 2.20 mmol) and Et3N (614 μL, 4.41 mmol) in THF (11.0 mL) at 0° C. was added hexachloroethane (523 mg, 2.20 mmol). The reaction was stirred at RT overnight then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was taken up in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH and eluted with 2M NH3 in MeOH; concentration in vacuo gave the title compound (297 mg, 84%). LCMS (Method 1): Rt 2.73, m/z 323.2 [MH+].
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH:14]([OH:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C:29](Cl)(=[O:31])[CH3:30].N1C=CC=CC=1>C1C=CC=CC=1>[F:1][C:2]([F:27])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH:14]([O:21][C:29](=[O:31])[CH3:30])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCOC(=O)CC(OC(C)=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
Ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-hydroxypentanoate is reacted with 1.1 equivalent of acetyl chloride and 1.0 equivalent of pyridine in benzene to yield ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-acetoxypentanoate. Similarly, using n-propanoyl chloride and isopropanoyl chloride yield the respective 3-n-propanate and 3-isopropanoate.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[NH:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][C:31](=[O:37])[NH:32]3)[CH2:24][CH2:23]1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=[C:30]1[C:29]2[C:33](=[CH:34][CH:35]=[CH:36][C:28]=2[CH:25]2[CH2:24][CH2:23][NH:22][CH2:27][CH2:26]2)[NH:32][C:31]1=[O:37]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Product: Cc1c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 42.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-piperidin-4-yl-1,3-dihydro-indol-2-one as starting materials to give 3-methyl-5-(2-morpholin-4-yl-ethyl)-2-(2-oxo-4-piperidin-4-yl-1,2-dihydro-indol-3-ylidenemethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (34 mg, 42.9%) as a yellow solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[N:28]([CH3:36])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=2)=[N:9]1)(=O)=O.C(N(CC)CC)C.[I-].[Na+].[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>CN(C=O)C>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][CH2:6][N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[N:28]([CH3:36])[C:29]5[C:34]([CH:35]=4)=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:26])=[C:20]([O:37][CH3:38])[CH:19]=3)[C:11]=12
Reactant: C1COCCN1
Reactant: COc1cc(-c2nn(CCOS(C)(=O)=O)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(-c2nn(CCN3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 60 °C
Yield: 14.5 %

Procedure:
To a mixture of 2-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-2-indolyl)carbonyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl methanesulfonate (Intermediate 4) (0.200 g, 0.373 mmol), triethylamine (0.052 mL, 0.37 mmol), and sodium iodide (0.056 g, 0.37 mmol) in DMF (5 mL) was added morpholine (0.039 mL, 0.45 mmol). The reaction mixture was heated at 60° C. for 60 h. Morpholine (0.100 mL, 1.15 mmol) was added and the reaction mixture was heated at 80° C. for 30 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. Water (5 mL) was added and the resulting precipitate was collected by filtration, washed with water (5 mL) and ether (10 mL), and dried in vacuo to afford a tan solid which was purified twice by silica gel chromatography (elution with 20% MeOH—CH2Cl2); the appropriate fractions were combined and concentrated to afford a beige solid which was triturated from ether and dried in vacuo to afford N2-{4-[4-amino-1-(2-morpholinoethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide as a white solid (0.048 g, 0.054 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.44 (1H, s), 8.26 (1H, s), 8.11 (1H, d, J=8.0 Hz), 7.70 (1H, d, J=7.6 Hz), 7.58 (1H, d, J=7.6 Hz), 7.29-7.35 (4H, m), 7.15 (1H, t, J=7.6 Hz), 4.48 (2H, t, J=6.4 Hz), 4.04 (3H, s), 3.96 (3H, s), 3.50-3.53 (4H, m), 2.82 (2H, t, J=6.2 Hz), and 2.47-2.51 (4H, m);); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile-0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.02 min. MS: M+ 527.3.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C@@H:11]([NH:14]S(C(C)(C)C)=O)[CH2:12][CH3:13])[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3].[ClH:21].O1CCOCC1>CO>[ClH:21].[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C@@H:11]([NH2:14])[CH2:12][CH3:13])[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3]
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1ccnc(S(C)(=O)=O)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC[C@H](N)c1ccnc(S(C)(=O)=O)c1
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid [(S)-1-(2-methanesulfonyl-pyridin-4-yl)-propyl]-amide (26 g, 82 mmol) in methanol (150 mL) was added a solution of 4 N HCl in dioxane (22.5 ml, 89.8 mmol) and stirred for 1 hour. The solution was concentrated to half the original volume and diluted with toluene (100 mL), and concentrated. The crude material was co-evaporated from toluene (3×100 mL) and dried in vacuo for 18 hours to afford the title compound as an off-white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][C:14]1([CH3:21])[C:19](=[O:20])[CH2:18][CH2:17][NH:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:16]2[CH2:17][CH2:18][C:19](=[O:20])[C:14]([CH3:21])([CH3:13])[CH2:15]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: CC1(C)CNCCC1=O
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCC(=O)C(C)(C)C2)ccc1[N+](=O)[O-]
Yield: 43.6 %

Procedure:
4-Fluoro-2-methoxy-1-nitrobenzene (1.550 g, 9.06 mmol), 3,3-dimethylpiperidin-4-one (INTERMEDIATE 38) (2.17 g, 9.06 mmol, TFA salt), and potassium carbonate (2.504 g, 18.12 mmol) in DMF (20 ml) were heated at 70° C. overnight. The reaction mixture was concentrated in vacuo to remove the solvent. The residue was partitioned between CH2Cl2 (100 mL) and water (30 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was purified using silica gel column (50%-100% CH2Cl2/Hexane) to obtain the title product (1.100 g, 43.6%).
Reaction SMILES: O1[CH2:6][CH2:5][O:4][CH2:3]C1.[C:7]([O:11][C:12](=[O:38])[NH:13][C:14]1C(OC)=[N:16][N:17]2[C:21]([C:22]3[C:27]([O:28][CH3:29])=[CH:26][C:25]([CH2:30][O:31][CH3:32])=[CH:24][C:23]=3[O:33][CH3:34])=[C:20](Br)[S:19][C:18]=12)([CH3:10])([CH3:9])[CH3:8].[CH2:39]([Zn]CC)[CH3:40]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CCCCCCC.C(OCC)(=O)C>[C:7]([O:11][C:12](=[O:38])[NH:13][C:14]1[C:6]([CH2:5][O:4][CH3:3])=[N:16][N:17]2[C:21]([C:22]3[C:23]([O:33][CH3:34])=[CH:24][C:25]([CH2:30][O:31][CH3:32])=[CH:26][C:27]=3[O:28][CH3:29])=[C:20]([CH2:39][CH3:40])[S:19][C:18]=12)([CH3:10])([CH3:9])[CH3:8]
Reactant: C1COCCO1
Reactant: COCc1cc(OC)c(-c2c(Br)sc3c(NC(=O)OC(C)(C)C)c(OC)nn23)c(OC)c1
Reactant: CC[Zn]CC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCc1sc2c(NC(=O)OC(C)(C)C)c(COC)nn2c1-c1c(OC)cc(COC)cc1OC
Temperature: 60 °C

Procedure:
To a dioxane (5 mL) solution of tert-butyl{2-bromo-3-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-6-methoxypyrazolo[5,1-b][1,3]thiazol-7-yl}carbamate (118 mg, 0.224 mmol), 1M diethyl zinc (0.448 mL, 0.448 mmol) and bis(tri-tert-butylphosphine)palladium(0) (5.70 mg, 0.011 mmol) were added, and the mixture was heated at 60° C. for one hour. After the reaction was completed, the solvent was directly distilled off under reduced pressure. The residue was purified by silica gel column chromatography (a mixed solvent of n-heptane and ethyl acetate: n-heptane/ethyl acetate=1/1) to obtain the title compound (84 mg, 0.176 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]([C:17]2[N:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][C:25]=1[F:33]>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([NH:14][C:15]([C:17]3[N:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:16])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:26][C:25]=1[F:33]
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnn1
Reactant: OB(O)c1ccc(Cl)c(F)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1)c1cccnn1

Procedure:
The title compound was synthesized in analogy to Example 39, using pyridazine-3-carboxylic acid[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 62 a) and B-(4-chloro-3-fluorophenyl)-boronic acid (CAN 137504-86-0) as starting materials; LC-MS (UV peak area/ESI) 100%, 425.0438 (M−H)−.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.[NH2:8][C@:9]([C:13]([OH:15])=[O:14])([CH3:12])[CH2:10][CH3:11].[Cl:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1.Cl>O.C(O)(C)C>[Cl:16][C:17]1[N:22]=[C:21]([NH:8][C@:9]([CH3:12])([CH2:10][CH3:11])[C:13]([OH:15])=[O:14])[CH:20]=[CH:19][N:18]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC[C@@](C)(N)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC[C@@](C)(Nc1ccnc(Cl)n1)C(=O)O
Temperature: 87.5 °C
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
To a solution of K2CO3 (526.2 mg, 3.80 mmol) in water (1.6 mL, 6 volume) was added isovaline-HCl (292.4 mg, 1.90 mmol). The resulting solution was stirred for 10 minutes. A solution of [14C] enriched 2,4-dichloropyrimidine (11a**) (0.261 g, 90 mCi) in isopropanol (5.2 mL, 20 volume) was added dropwise at room temperature, and the resulting mixture was heated at 85-90° C. for 18 hours. The mixture was then concentrated to 4 volumes, then 1N NaOH (6 mL) and isopropyl acetate (6 mL) were added. The aqueous phase was separated and the organic phase was extracted with 1N NaOH (6 mL×2). The combined aqueous layer was acidified to pH=3.0-3.5 using 6N HCl (aq). The resulting solution was extracted with isopropyl acetate (15 mL×3). The collected organic layer was concentrated to 3-4 volumes, then 1N HCl etherate (1.73 mL, 1.73 mmol) was added drop wise at 0° C. and stirred for 15 minutes. The organic solvent was decanted and the solid was washed with isopropyl acetate (5 mL×2). The solid was dried under vacuum and obtained 360 mg of (R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid (2a**) with 70% radiochemical purity by instant imager to provide (R)-2-(2-chloropyrimidin-4-ylamino)-2-methylbutanoic acid (2a**).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.Cl.[N+:43]([C:46]1[CH:51]=[CH:50][C:49]([C@@H:52]([NH2:54])[CH3:53])=[CH:48][CH:47]=1)([O-:45])=[O:44]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:54][C@H:52]([C:49]2[CH:48]=[CH:47][C:46]([N+:43]([O-:45])=[O:44])=[CH:51][CH:50]=2)[CH3:53])=[O:40])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@H](N)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@@H](C)c4ccc([N+](=O)[O-])cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 127 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (70 mg) was dissolved in chloroform (1 ml) and triethylamine (0.14 ml) to prepare a solution. A solution of triphosgene (33 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 75 min. Next, a solution of (1S)-1-(4-nitrophenyl)ethylamine hydrochloride (47 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (69 mg, yield 60%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.[C:12](=N)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[C:13]1([C:12](=[N:1][CH:2]2[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)C1CCCC(N)C1
Reactant: N=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COC(=O)C1CCCC(N=C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a flask, methyl 3-aminocyclohexanecarboxylate (3.86 g, 19.94 mmol) was dissolved in dichloromethane (80 mL). Benzophenone imine (3.33 mL, 19.94 mmol) was added to the reaction, and the reaction was stirred at room temperature for 24 hrs. Upon completion, the reaction was concentrated and triturated with diethyl ether. The suspension was filtered. This trituration process was done twice. The remaining filtrate was concentrated and progressed to the next step without further purification.
Reaction SMILES: C(OC(C1C=C(C2C=CC(C[S:19][CH2:20][CH2:21][OH:22])=CC=2)C=CC=1)=O)C.[CH2:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40]Br)[CH:35]=2)=[CH:30][CH:29]=1)=[O:27])[CH3:24].SCCO.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][S:19][CH2:20][CH2:21][OH:22])[CH:35]=2)=[CH:30][CH:29]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1ccc(-c2cccc(CBr)c2)cc1
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCO)cc2)c1
Agent: O=C([O-])[O-]
Agent: OCCS
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cccc(CSCCO)c2)cc1

Procedure:
3′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethyl ester was synthesized as described for 4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 3′-Bromomethyl-biphenyl-4-carboxylic acid ethyl ester (4.98 g, 15.6 mmol, 1 eq) in anhydrous DMF was treated with 2-mercaptoethanol (2.44 g, 31.20 mmol, 2 eq.) and potassium carbonate (6.47 g, 46.80 mmol, 3 eq.). When complete, the reaction was worked up as described leaving a yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][N:4]=1)#N.[OH-:13].[K+].Cl.[OH2:16]>>[CH3:10][O:9][C:8]1[C:3]([C:1]([OH:16])=[O:13])=[N:4][CH:5]=[CH:6][C:7]=1[O:11][CH3:12]
Reactant: COc1ccnc(C#N)c1OC
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: COc1ccnc(C(=O)O)c1OC

Procedure:
1 g of 3,4-dimethoxy-2-cyanopyridine obtained in Example e) and 3.5 g of potassium hydroxide in 15 mL of water are heated to 85° C. for half an hour. It is allowed to cool and in an ice bath hydrochloric acid is added gently to pH=2-3. After concentration to dryness, the residue is extracted three times with hot methanol, allowed to cool, filtered and concentrated. There is obtained a solid used crude.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4].C[O:28][C:29](=[O:39])[CH:30]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)O>>[CH2:1]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:30]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:29]([OH:39])=[O:28])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)C(O)Cc1ccccc1
Reactant: CCCCc1sc2ccccc2c1-c1ccc(-c2ccc(O)cc2)cc1
Product: CCCCc1sc2ccccc2c1-c1ccc(-c2ccc(OC(Cc3ccccc3)C(=O)O)cc2)cc1

Procedure:
The title compound was prepared from 4′-(2-butyl-benzo[b]-thiophen-3-yl)-biphenyl-4-ol, and 3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h, and was obtained as a white solid, mp.159-161° C.; MS m/e 507 (M+H)+;
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:26]=1[C:27](O)=[O:28]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:27](=[O:28])[C:26]5[C:25]([F:24])=[CH:33][CH:32]=[CH:31][C:30]=5[F:34])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4c(F)cccc4F)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-2,6-difluoro-benzamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.48 mmol) and 2,6-difluorobenzoic acid. The title compound was obtained as off-white powder (24 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1COCC1.Cl[C:15]1[CH:20]=[C:19]([Cl:21])[N:18]=[C:17]([NH2:22])[CH:16]=1.O>CS(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[CH:20]=[C:19]([Cl:21])[N:18]=[C:17]([NH2:22])[CH:16]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(O)cc1
Reactant: Nc1cc(Cl)cc(Cl)n1
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2cc(N)nc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 4-aminophenol (335 mg, 3.1 mmol) in anhydrous DMSO (8 ml) was flushed with nitrogen and treated with 1M KOBut/THF solution (3.1 ml, 3.1 mmol). The mixture was stirred at room temperature under nitrogen for 10 minutes. 4,6-dichloropyridin-2-ylamine (500 mg, 3.1 mmol) was added and the mixture was heated at 88° C. for 16 hours, cooled to room temperature and poured into 100 ml of water. The resulting precipitates were filtered, washed with water and dried to give the crude product, which was purified by silica gel chromatography with 2˜5% MeOH/CHCl3 to give 4-(4-aminophenoxy)-6-chloropyridin-2-amine as light brown solid. Yield: 350 mg, 49%.