Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccccc2C(F)(F)F)C1
Yield: 84 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 2-trifluoromethylphenylboronic acid (173 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (200 mg, 84.0%) as an oil.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([C:11](OCC)=[O:12])[N:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([CH2:11][OH:12])[N:2]=1
Reactant: CCOC(=O)c1cc2c(cn1)CCCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc2c(cn1)CCCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.6 %

Procedure:
A solution of ethyl 5,6,7,8-tetrahydro-3-isoquinolinecarboxylate (1.27 g, 6.19 mmol) in THF (50 ml) at −78° C. under argon was treated with LiAlH4 (1M solution in THF, 6.19 ml, 6.19 mmol) and allowed warm to rt. After 10 min at rt, water (1 ml), 2M aq NaOH (1 ml) and water (1 ml) were sequentially added and the mixture stirred at rt for 0.5 h. The mixture was then filtered through a short pad of Kieselguhr, eluting with THF (50 ml), organic extracts were then evaporated, chromatographed (0-20% methanol/DCM) to give product as an orange oil (0.572 g, 57%).
Reaction SMILES: [Cl:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:24][CH:23]=[C:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1>[Pd].CO>[Cl:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: CCCC1=CCC(C(=O)NC(C(C)Cl)C2OC(SC)C(O)C(O)C2O)NCC1
Agent: [Pd]
Solvent: CO
Product: CCCC1CCNC(C(=O)NC(C(C)Cl)C2OC(SC)C(O)C(O)C2O)CC1

Procedure:
The unsaturated title compound from example 46 5-Propyl-2,3,6,7-tetrahydro-1H-azepine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide (433 mg, 0.99 mmol) and 10% Pd/C (80 mg), were taken MeOH (10 mL) hydrogenated at 50 psi overnight. The solvent was removed to obtain the crude material. Purification was carried by silica gel column chromatography (20% MeOH/DCM) followed by preparative HPLC (general method AC) to furnish isomer 1 Rt=18.3 min (10 mg, 2.3%) and isomer 2 Rt=18.6 min (58 mg, 13.3%).
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[CH3:19][S:20]([NH:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:22])=[O:21]>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]2[C:3](=[CH:2][C:26]3[CH:25]=[C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])[CH:29]=[CH:28][CH:27]=3)[C:4]3[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=3[CH2:6][CH2:7][C:8]=2[CH:13]=1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: Clc1ccc2c(c1)CCc1ccccc1C2=CBr
Product: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3cc(Cl)ccc32)c1

Procedure:
Following procedures essentially as described in Example 219, below, and using 5-bromomethylene-2-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (100 mg, 0.313 mmol) and 3-methanesulfonylaminophenylboronic acid (74 mg, 0.344 mmol), affords 37 mg (29%) of the Z-isomer (Example 206(a)) of the title compound as a colorless oil (MS (ES) 408 (M−H). HPLC shows 99% purity. Continue to elute and obtain 23 mg (18%) of the E-isomer (Example (b)) of the title compound as a colorless oil (MS (ES) 408 (M−H); HPLC shows 92% purity).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[N:8][NH:9][C:10]=2[CH:11]=[C:12]([Br:14])[CH:13]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.CN[C@@H]1CCCC[C@H]1NC>O.C(OCC)(=O)C.[Cu]I.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[N:8][N:9]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)[C:10]=2[CH:11]=[C:12]([Br:14])[CH:13]=1)=[O:4]
Reactant: Fc1ccc(I)cc1
Reactant: COC(=O)c1cc(Br)cc2[nH]ncc12
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)cc2c1cnn2-c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 6-bromo-4-indazolecarboxylic acid methyl ester (2.0 g, 7.8 mmol), copper(I) iodide (0.4 g, 0.2 mmol), potassium carbonate (1.2 g, 8.5 mmol) and 4-fluoroiodobenzene (1.8 g, 8.5 mmol) was charged in a sealed tube at room temperature. The tube was evacuated and back-filled with argon, and DMF (10 mL) and rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (0.20 g, 1.4 mmol) was added. The solution was stirred at 120° C. for 3 hours, cooled to room temperature, and diluted with water (30 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with brine (10 mL) and dried over sodium sulfate. The solvent was removed in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0-30% ethyl acetate in hexanes to afford 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([N:17]=[N+]=[N-])[C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=1[CH3:22]>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([NH2:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=1[CH3:22]
Reactant: COC(=O)[C@@H](CCCCOCc1ccc(F)c(C)c1)N=[N+]=[N-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](N)CCCCOCc1ccc(F)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of (R)-methyl 6-(4-fluoro-3-methylbenzyloxy)-2-azidohexanoate (0.141 g, 0.453 mmol) in 10 mL of ethyl acetate, Pd on BaSO4 (0.070 g) was added. The mixture was flushed with H2 for 15 min and stirred at room temperature under H2 for 1 h. The reaction mixture was then filtered through a pad of Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was used in the next step without further purification (0.128 g, >99% yield). GC-MS: tR=4.0 min; m/z 283 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[C:4](Cl)[N:3]=1.[CH2:15]([N:17](CC)[CH2:18][CH3:19])[CH3:16].N1CCCC1>C(#N)C>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[C:4]([N:17]2[CH2:18][CH2:19][CH2:16][CH2:15]2)[N:3]=1
Reactant: CCOC(=O)c1cc(F)c(Cl)nc1Cl
Reactant: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCNC1
Product: CCOC(=O)c1cc(F)c(N2CCCC2)nc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of ethyl 2,6-dichloro-5-fluoro-3-pyridinecarboxylate (3.00 g, 12.6 mmol: J. Med. Chem., 1986;29:2363) and triethylamine (2.63 mL, 18.90 mmol) in acetonitrile (15 mL) was added pyrrolidine (1.05 mL, 12.6 mmol) dropwise. After being stirred at 60° C. for 1 hour, the reaction mixture was evaporated, and the residue was dissolved in dichloromethane, washed with water, and dried over anhydrous sodium sulfate. The residue was purified on a silica gel column using hexane/dichloromethane (7:3) as eluent giving 2.5 g of the title compound as a solid, mp 95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[O:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[C:26](O)=[O:27]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:26]([CH:22]3[CH2:23][CH2:24][CH2:25][O:21]3)=[O:27])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCO1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Solvent: CO
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)C1CCCO1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and tetrahydro-2-furancarboxylic acid, (CAN 16874-33-2) as starting materials; enantiomers were separated by chiral HPLC (ChiralPak AD, 30% ethanol/n-heptane (−) enantiomer isolated; LC-MS (UV peak area/ESI) 100%, 401.0868 (M+H)+; αD20 (MeOH)=−16.8°
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1.[CH3:20][NH:21][CH3:22].Cl>>[CH3:20][N:21]([CH3:22])[CH2:2][CH2:3][O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=1
Reactant: Cc1cccc(C=Cc2ccccc2OCCCl)n1
Reactant: CNC
Agent: Cl
Product: Cc1cccc(C=Cc2ccccc2OCCN(C)C)n1

Procedure:
2-[o-(β-Dimethylamino-ethoxy)-styryl]-6-methyl-pyridine was prepared from 2-[o-(β-chloro-ethoxy)-styryl]-6-methyl-pyridine and dimethylamine, and the free base was converted into its monohydrochloride, yielding 45% of theory of the compound of the formula ##STR11## which had a melting point of 200° C.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.[CH3:14][O:15][C:16](=[O:28])[C:17]1[C:18](=[C:23](I)[CH:24]=[CH:25][CH:26]=1)[C:19]([O:21][CH3:22])=[O:20].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+]>C1(C)C=CC=CC=1.C(Cl)Cl.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.[Pd].[Pd]>[CH3:22][O:21][C:19](=[O:20])[C:18]1[C:17](=[C:26]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:13])[CH3:1])=[CH:7][CH:8]=2)[CH:25]=[CH:24][CH:23]=1)[C:16]([O:15][CH3:14])=[O:28]
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Nc2ccc(OCCN(C)C)cc2)c1C(=O)OC
Yield: 46 %

Procedure:
A mixture of 4-(2-dimethylamino-ethoxy)-phenylamine (0.56 g, 3.1 mmol), 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 16 hours. The reaction mixture was cooled, diluted with CH2Cl2 (10 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (30 mL). The filtrate was evaporated in vacuo, and the residue was purified by ISCO silica gel flash chromatography using a methylene chloride-methanol gradient, eluting 0.53 g of the product at 95:5 methylene chloride-methanol, in 46% yield, as a pale yellow solid; 1H NMR (CDCl3) δ 2.34 (s, 3H), 2.73 (t, J=5.7 Hz, 2H), 3.86 (s, 3H), 3.88 (s, 3H), 4.06 (t, J=5.7 Hz, 2H), 6.89-6.96 (m, 3H), 7.06-7.23 (m, 3H), 7.33-7.50 (m, 1H), 8.09 (s, 1H).
Reaction SMILES: [I:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=[O:15]>O1CCCC1.[Li+].[OH-].CO>[I:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1cnn(-c2cccc(F)c2)c1I
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnn(-c2cccc(F)c2)c1I
Reaction time: 8 h
Yield: 90 %

Procedure:
Ethyl 5-iodo-1-(3-fluorophenyl)-1H-pyrazole-4-carboxylate (589 mg, 1.64 mmol) was dissolved in a mixture of tetrahydrofuran (5 mL), 1.5 N LiOH (1.6 mL) and methanol (1.5 mL) and the mixture was stirred overnight. Most of the tetrahydrofuran was removed by gently blowing a stream of nitrogen over the reaction mixture. Water and 1 N HCl (2.4 mL) was added and the mixture was sonicated well to precipitate the carboxylic acid. The carboxylic acid was filtered and rinsed with water. After drying under vacuum, 5-iodo-1-(3-fluorophenyl)-1H-pyrazole-4-carboxylic acid was obtained (488 mg, 1.47 mmol, 90% yield). This material was used for the next step without further purification.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:21][C:22](=[O:52])[N:23]([CH2:36][C:37]2[CH:51]=[CH:50][C:40]([C:41]([NH:43][CH2:44][C@@H:45]([OH:49])[C:46]([OH:48])=[O:47])=[O:42])=[CH:39][CH:38]=2)C2C=CC(C3CCCCC3)=CC=2)[CH:13]=[CH:14][C:15]=1[O:16][C:17]([F:20])([F:19])[F:18])(C(C)(C)C)(C)C.[F-].[Cs+].[C:55](#N)[CH3:56].O>>[CH:10]1([C:56]2[CH:55]=[CH:39][C:38]([CH:36]([NH:23][C:22]([NH:21][C:12]3[CH:13]=[CH:14][C:15]([O:16][C:17]([F:20])([F:19])[F:18])=[C:10]([CH2:9][OH:8])[CH:11]=3)=[O:52])[C:37]3[CH:51]=[CH:50][C:40]([C:41]([NH:43][CH2:44][C@@H:45]([OH:49])[C:46]([OH:48])=[O:47])=[O:42])=[CH:39][CH:38]=3)=[CH:37][CH:36]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(NC(=O)N(Cc2ccc(C(=O)NC[C@@H](O)C(=O)O)cc2)c2ccc(C3CCCCC3)cc2)ccc1OC(F)(F)F
Reactant: CC#N
Agent: [Cs+]
Agent: [F-]
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)c(CO)c1)NC(c1ccc(C(=O)NC[C@@H](O)C(=O)O)cc1)c1ccc(C2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
(R)-3-{4-[3-[3-(tert-Butyldimethylsilanyloxymethyl)-4-trifluoromethoxyphenyl]-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid (17 mg, 0.023 mmol) was dissolved in acetonitrile:water (9:1) (2 mL) and caesium fluoride (35 mg, 0.35 mmol) added. The reaction mixture was stirred at 80° C. for 6 hours and additional amounts of caesium fluoride (35 mg) added. The mixture was stirred at 60° C. overnight, concentrated in vacuo and diluted with ethyl acetate (10 mL) and water (5 mL). The organic phase was washed with water (3×5 mL) and dried with magnesium sulphate and concentrated in vacuo. The residue was purified by preparative HPLC affording the title compound.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2].Cl[C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([C:30]4([OH:34])[CH2:33][O:32][CH2:31]4)[CH2:26][CH2:25]3)[N:19]2[CH3:22])=[C:15]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:14]=1>>[CH2:1]([C:3]1[N:4]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[C:18]([CH2:23][N:24]4[CH2:25][CH2:26][CH:27]([C:30]5([OH:34])[CH2:33][O:32][CH2:31]5)[CH2:28][CH2:29]4)[N:19]3[CH3:22])=[C:15]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:14]=2)[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: Cn1c(CN2CCC(C3(O)COC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CCc1nc2ccccc2[nH]1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C4(O)COC4)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-ethylbenzimidazole and 3-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)oxetan-3-ol were reacted to give 263. LCMS m/z: 533.3 (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:19]([O-:21])=[O:20])[C:11]=1[NH:12][C:13](=O)C(F)(F)F)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:19]([O-:21])=[O:20])[C:11]=1[NH:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)c(NC(=O)C(F)(F)F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: CNc1c(Br)cc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 45 °C
Reaction time: 0.33 h

Procedure:
To methyl 3-bromo-5-nitro-4-(2,2,2-trifluoroacetamido)-benzoate (9.69 g, 26.1 mmol) in 250 mL acetonitrile was added Cs2CO3 (10.2 g, 31.3 mmol) and methyliodide (3.3 mL, 52.2 mmol). The mixture was heated to 45° C. for 2 h. The solvent was removed in vac. Water and methanol were added and stirred for 20 minutes. The solid was filtered and washed with methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[S:27]([CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:29])=[O:28]>C(Cl)Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][S:27]([CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])(=[O:29])=[O:28])=[CH:3][C:4]=1[NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)NCCS(=O)(=O)Cl
Reactant: Cc1cc(C)nc(Nc2cc(N)cnc2C#N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(C)nc(Nc2cc(NS(=O)(=O)CCNC(=O)OC(C)(C)C)cnc2C#N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-amino-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carbonitrile (PrepEx 1.8) (150 mg, 0.63 mmol) in DCM (5 mL) was added triethylamine (0.26 mL, 1.88 mmol) followed by the dropwise addition of tert-butyl [2-(chlorosulfonyl)ethyl]carbamate (25% w/w in DCM, 920 mg, 0.94 mmol). The reaction mixture was stirred for 3 hours at room temperature. Additional tert-butyl [2-(chlorosulfonyl)ethyl]carbamate (25% w/w in DCM, 920 mg, 0.94 mmol) was added and the reaction mixture was stirred for 16 hours. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The organics were separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to afford tert-butyl [2-({6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}sulfamoyl)ethyl]carbamate. MS ESI calc'd. for C20H27N6O4S [M+H]+ 447. found 447. 1H NMR (500 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.19 (s, 1H), 8.50 (s, 1H), 8.01 (s, 1H), 6.86 (t, J=5.5 Hz, 1H), 6.73 (s, 1H), 6.65 (s, 1H), 3.41 (t, J=6.7 Hz, 2H), 3.32-3.29 (m, 2H), 2.31 (s, 3H), 2.22 (s, 3H), 1.30 (s, 9H).
Reaction SMILES: [F-].[K+].[Br:3][C:4]1[CH:5]=[CH:6][C:7](I)=[C:8]([CH3:10])[CH:9]=1.C[Si](C)(C)[CH:14]=[CH2:15]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].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.[Pd].C1(C)C=CC=CC=1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:14]=[CH2:15])=[C:8]([CH3:10])[CH:9]=1
Reactant: Cc1cc(Br)ccc1I
Reactant: C=C[Si](C)(C)C
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(Br)cc1C
Temperature: 25 °C
Yield: 76.1 %

Procedure:
KF (870 mg, 15 mmol), n-Bu4NCl (2.77 g, 10 mmol), Pd(dba)2 (145 mg, 0.25 mmol), molecular sieves (4 Ang, 200 mg, activated balls), 5-bromo-2-iodo-1-methylbenzene (1.49 g, 5 mmol), trimethyl(vinyl)silane (2.7 mL, 20 mmol), and toluene (10 mL) were added to a pressure vessel and sparged with Ar. The vial was sealed and microwaved at 170° C. for 30 min. The mixture was cooled to ambient temperature, diluted with hexanes, filtered and concentrated. The crude oil was purified by flash chromatography (100% hexanes) to yield 30A (750 mg, 76%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.31 (s, 3 H) 5.31 (dd, J=10.99, 1.10 Hz, 1 H) 5.62 (dd, J=17.59, 1.10 Hz, 1 H) 6.84 (dd, J=17.04, 10.99 Hz, 1 H) 7.26-7.35 (m, 3 H).
Reaction SMILES: CC1(C)O[CH:5]([O:7][C:8](=[O:30])[CH:9](C)[O:10][C:11]2[CH:23]=[C:22]3[C:14]([C:15]4[C:20]([CH2:24][CH3:25])([CH2:21]3)[CH2:19][CH2:18][C:17](=[O:26])[CH:16]=4)=[C:13]([Cl:27])[C:12]=2[Cl:28])[CH2:4][O:3]1.Cl.[C:33](=O)(O)[O-:34].[Na+].[Cl-].[Na+]>CC(C)=O>[Cl:27][C:13]1[C:12]([Cl:28])=[C:11]([O:10][CH2:9][C:8]([O:7][CH2:5][CH:4]([OH:3])[CH2:33][OH:34])=[O:30])[CH:23]=[C:22]2[C:14]=1[C:15]1[C:20]([CH2:24][CH3:25])([CH2:21]2)[CH2:19][CH2:18][C:17](=[O:26])[CH:16]=1
Reactant: O=C([O-])O
Reactant: CCC12CCC(=O)C=C1c1c(cc(OC(C)C(=O)OC3COC(C)(C)O3)c(Cl)c1Cl)C2
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OCC(O)CO)c(Cl)c1Cl)C2
Reaction time: 2 h

Procedure:
A mixture of 165 mg of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetate from Example 109, Step A is dissolved in 100 ml. of 0.075 N hydrochloric acid and 20 ml. of acetone and heated, with stirring at 50°-55° C. for 2 hours. The mixture is cooled and neutralized with a solution of sodium bicarbonate. The solution is saturated with sodium chloride and extracted two times with 100 ml. portions of 20% tetrahydrofuran in ether. The extract is dried over Na2SO4. After filtration, the filtrate was concentrated to a yellow oil that solidified on standing. After recrystallization from tetrahydrofuran-ether-petroleum ether, there is obtained 110 mg. of product, m.p. 135°-138° C.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH3:12].C(O)(=O)CCCCCCCCC=CC>>[C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCC=CCCCCCCCC(=O)O
Agent: CC=CCCCCCCCCC(=O)O
Product: CCCCC=CCCCCCC(=O)O

Procedure:
9-dodecenoic acid; 10-dodecenoic acid;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8]C(=O)OC(C)(C)C)[C:3]=1[I:16].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[I:16]
Reactant: CC(C)(C)OC(=O)Nc1nccc(Cl)c1I
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1nccc(Cl)c1I
Reaction time: 1.5 h
Yield: 65 %

Procedure:
A 250 mL round bottom flask was charged with tert-butyl (4-chloro-3-iodopyridin-2-yl)carbamate (4.5 g, 12.69 mmol) and dissolved in DCE (50.8 mL). To that stirring solution was added anisole (2.77 mL, 25.4 mmol) followed by TFA (14.67 mL, 190 mmol) at rt. After 1.5 hours, LCMS showed clean and complete consumption of the starting material to a large peak with the desired mass (m/z=254 [M+H]+Methanol/Water/TFA Phenomenex Luna C18, 30×2 mm, 3u ES+/−). The mixture was concentrated under reduced pressure into a collection bulb that was pretreated with 3.0 M NaOH. The crude mixture was then redissolved in toluene to aid in the removal of any volatiles. The crude solid was then diluted with EtOAc and sat'd sodium bicarbonate. The mixture was stirred for 15 min. The contents of the flask were transferred into a separatory funnel where the aqueous layer was extracted twice with EtOAc and discarded. The combined organics were washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure. The crude material was dissolved in a small amount of ethanol and then heated with a heat gun. The mixture was let sit and then after 5 min cooled in an acetone dry ice bath. The solids were sonicated and collected by filtration. The mother liquor was concentrated and the above procedure was repeated. 4-chloro-3-iodopyridin-2-amine (2.1 g, 65% yield) was collected as a solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.88 (d, J=5.3 Hz, 1H), 6.74 (d, J=5.3 Hz, 1H), 5.20 (br. s., 2H).