Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22]C(=O)C)=[C:18]([CH2:26][CH3:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH2:26][CH3:27])[CH:17]=3)[O:7][C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 299 %

Procedure:
A mixture of acetic acid 4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-ethyl-phenyl ester (0.92 g, 2.47 mmol, from Step 3), potassium carbonate (0.68 g, 4.9 mmol) in MeOH (10 mL) was stirred at rt for 1 h. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated to a yellow oil. The oil was purified by silica gel chromatography (20% to 40% EtOAc in hexanes) to give the title compound (2.44 g, 59%). 1H NMR (CDCl3): δ 1.22 (t, 3H, J=7.6 Hz), 1.43-1.78 (br m, 8H), 1.87-2.01 (m, 2H), 2.28 (m, 1H), 2.57-2.63 (m, 4H), 2.76 (s, 2H), 3.42 (s, 2H), 4.63 (s, 1H), 6.68 (d, 1H, J=8.1 Hz), 6.84 (d, 1H, J=8.1 Hz), 6.90 (s, 1H). Anal. Calcd. For C20H26O4.0.25H2O: C, 71.72; H, 7.98. Found: C, 71.10; H, 7.99.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:16]([CH:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:27](Cl)=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].O>O1CCCC1>[CH2:16]([CH:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:27]([NH:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCC(CCCCCCCCCC)C(=O)Cl
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCC(CCCCCCCCCC)C(=O)Nc1cc(C(=O)OC)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethyl 5-aminoisophthalate (Aldrich, 4.40 g, 21.0 mmol) is suspended in dry tetrahydrofuran (100 mL) in a 250 mL round bottom flask under an inert atmosphere. The dimethyl 5-aminoisophthalate suspension is cooled to 0° C. for at least 30 min., and an ice cold suspension of 2-decyltetradecanoyl chloride in of dry tetrahydrofuran (80 mL) is added slowly, dropwise. The reaction is then allowed to slowly warm to room temperature and stir overnight. Deionized water (10 mL) is added and the tetrahydrofuran is removed by rotary evaporation. The crude residue is then dissolved in 250 mL of ethyl acetate, and is washed with 3 successive 100 mL portions of deionized water. The ethyl acetate is then removed from the organic phase by rotary evaporation and the product is dried in vacuo to give crude dimethyl 5-(2′-decyltetradecanamido)isophthalate (12.56 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=3)[CH:9]=[CH:10][C:4]=2[O:3]1.CN(C)C=O.C(N(CC)CC)C.[CH3:34][O:35][N:36]([CH3:40])[C:37](Cl)=[O:38]>O>[CH3:1][C:2]1([CH3:21])[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:37]([N:36]([O:35][CH3:34])[CH3:40])=[O:38])=[CH:16][N:15]=3)[CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: CON(C)C(=O)Cl
Reactant: CC1(C)Cc2cc(CCOc3ccc(N)cn3)ccc2O1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)Nc1ccc(OCCc2ccc3c(c2)CC(C)(C)O3)nc1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
2.2 g of 2-[2-(2,3-dihydro-2,2-dimethyl-5-benzofuranyl)ethoxy]-5-aminopyridine was dissolved into 10 ml of N,N-dimethylformamide, and 0.9 g of triethylamine was added thereto. 1.2 g of N-methoxy-N-methylcarbamoyl chloride was slowly added dropwise thereto. After the mixture was stirred at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate and ethyl acetate was dried off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (2/3) as a developer to obtain 2.1 g of 1-{2-[2-(2,3-dihydro-2,2-dimethyl-5-benzofuranyl)ethyloxy]-5-pyridyl}-3-methoxy-3-methylurea.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH2:5][OH:6].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[O:10][CH:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:14]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COc1cc(CO)cc(Cl)c1O
Reactant: COC(=O)Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(Oc1c(Cl)cc(CO)cc1OC)c1ccccc1
Temperature: 25 °C
Yield: 63.9 %

Procedure:
To a solution of 0.500 g (2.65 mmol) of 3-chloro-4-hydroxy-5-methoxybenzyl alcohol (Bader) and 0.668 g (1.1 eq) of methyl 2-bromophenylacetate dissolved in 5 mL acetone was added 0.733 g (2 eq) of anhydrous potassium carbonate and the reaction mixture was stirred and refluxed overnight. The reaction mixture was cooled to room temperature, filtered and evaporated in vacuo. The residual oil was purified on a silica gel flash chromatography column eluted with 35% ethyl acetate/hexane to afford 0.570 g (64%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Br:11])[C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Br:11])[C:3]=1[CH2:12][Br:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Br)cc([N+](=O)[O-])cc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(Br)c(CBr)c(Br)c1
Temperature: 25 °C
Reaction time: 3.75 h

Procedure:
To a mixture of 2,6-dibromo-4-nitrotoluene (5.00 g, 16.95 mmol) in CCl4 (131 mL) was added N-bromosuccinimide (4.22 g, 23.73 mmol) and dibenzoyl peroxide (411 mg, 1.70 mmol). The mixture was evacuated and flushed with argon three times, then heated using an oil bath. At reflux azo-bis-isobutyronitrile (278 mg, 1.695 mmol) was added. The reaction was stopped after 3.75 h, cooled to rt and filtered washing with CCl4. The filtrate was concentrated under reduced pressure to give a yellow solid, which was purified using flash chromatography on Biotage 40M column, eluting with 90:10 hexanes-CH2Cl2 to yield 1,3-dibromo-2-(bromomethyl)-5-nitrobenzene. 1H NMR (500 MHz, CDCl3): δ 4.8 (s, 2H), 8.4 (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=2)[C:4](=[O:22])[CH:3]=1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C(Cl)Cl.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>[OH:19][C:16]([CH3:18])([CH3:17])[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:35])[F:36])=[CH:31][CH:30]=3)=[CH:3][C:4]2=[O:22])=[CH:9][C:10]=1[O:20][CH3:21]
Reactant: COc1cc(-n2ccc(Cl)cc2=O)ccc1OCC(C)(C)O
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(-n2ccc(-c3ccc(OC(F)(F)F)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 60 °C
Reaction time: 17 h
Yield: 63.6 %

Procedure:
A mixture of 4-chloro-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridin-2(1H)-one Part D (25 mg, 0.08 mmol), 4-(trifluoromethoxy)phenylboronic acid (28 mg, 0.14 mmol), tribasic potassium phosphate (49 mg, 0.23 mmol), and palladium tetrakis (9 mg, 7.7 μmol) in DMF (0.4 mL) was stirred at 60° C. under nitrogen for 17 hours. The reaction mixture was diluted with CH2Cl2, filtered and concentrated. The crude was purified using preparative HPLC (C18 column/10:90:0.1 to 90:10:0.1 MeOH—H2O-TFA). This material further purified by ISCO flash chromatography (silica gel/hexanes-ethyl acetate 100:0 to 0:100 gradient) to afford the title compound 1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-4-(4-(trifluoromethoxy)-phenyl)pyridin-2(1H)-one B-1 (23.2 mg, 0.049 mmol, 63.6% yield) as a light yellow solid. LC/MS 450 (M+H)+, tR 0.95 min (method 5). 1H NMR (500 MHz, chloroform-d) δ 7.65 (2H, d, J=8.88 Hz), 7.43 (1H, d, J=7.49 Hz), 7.34 (2H, d, J=8.05 Hz), 6.97-7.02 (2H, m), 6.93 (1H, dd), 6.85 (1H, s), 6.48 (1H, dd), 3.89 (3H, s), 3.88 (2H, s), 1.37 (6H, s).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:7][C:8]=1[CH2:9]O)([CH3:3])[CH3:2].CCN(CC)CC.CS(Cl)(=O)=O.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([C@@H:40]2[CH2:42][C@H:41]2[C:43]([OH:45])=[O:44])=[CH:36][CH:35]=1>ClCCl.O>[CH:1]([C:4]1[N:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:7][C:8]=1[CH2:9][NH:33][C:34]1[CH:35]=[CH:36][C:37]([C@@H:40]2[CH2:42][C@H:41]2[C:43]([OH:45])=[O:44])=[CH:38][CH:39]=1)([CH3:3])[CH3:2]
Reactant: Nc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 19.7 %

Procedure:
To a solution of {(4-isopropyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol (0.10 g, 0.331 mmol) in dichloromethane (3 mL) was added Et3N (0.04 g, 0.39 mmol) and the mixture cooled to 0° C. The mixture stirred for 15 min after which methanesulfonyl chloride (0.04 g, 0.36 mmol) was added followed 30 min later by the addition of racemic-(trans)-2-(4-aminophenyl)cyclopropanecarboxylic acid (I-1) (0.09 g, 0.49 mmol). The solution stirred for 24 h after which it was poured into H2O, the organics extracted with dichloromethane, dried over MgSO4, and the solvents reduced in vacuo. The crude material was purified on silica gel eluting with an increasing gradient from hexanes to 30% ethyl acetate/hexanes to give the title compound as a yellow powder (0.03 g, 16%). 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=8.3 Hz, 2H), 7.65 (d, J=8.2 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 6.62 (d, J=8.6 Hz, 2H), 4.47 (s, 2H), 3.50-3.47 (m, 1H), 3.18-3.15 (m, 1H), 2.53-2.51 (m, 1H), 1.80-1.77 (m, 1H), 1.61-1.58 (m, 1H), 1.37-1.26 (m, 7H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])([O:12][CH3:13])[C:10]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:9][C:8](OC)([CH3:24])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[Cl-].[Al+3].[Cl-].[Cl-]>CCOCC>[CH2:20]([O:19][C:10]1[C:11]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])([O:12][CH3:13])[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][C:8](=[CH2:24])[CH:9]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCOC1=CC(C)(OC)C=C(OCCCC)C1(OC)OCCCC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: C=C1C=C(OCCCC)C(OC)(OCCCC)C(OCCCC)=C1
Yield: 87.8 %

Procedure:
The procedure of Example 9 was repeated by using 334 mg of 1,5,6-tributoxy-3,6-dimethoxy-3-methyl-1,4-cyclohexadiene, 10 ml of ether and 15 mg of aluminum chloride, recovering 290 mg of an oily crude product. The crude product was purified by silica gel column chromatography using a 20:1 benzene-ethyl acetate mixture, giving 268 mg of 1,5,6-tributoxy-6-methoxy-3-methylidene-1,4-cyclohexadiene in 89% of the theoretical yield. The compound thus obtained was identified by NMR.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[C:27](Cl)(=[O:30])[CH2:28][CH3:29].C(N(CC)CC)C>C(Cl)Cl>[CH3:26][C:24]1[CH:23]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:25]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: Cc1cc(C)cc(Oc2ccc(C#N)cc2S(=O)(=O)N2CCNCC2)c1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCN(S(=O)(=O)c2cc(C#N)ccc2Oc2cc(C)cc(C)c2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of compound 24 (0.102 g, 0.27 mmol) in CH2Cl2 (2 mL) was added propionyl chloride (0.035 g, 0.38 mmol) and triethylamine (0.039 g, 0.38 mmol). The reaction mixture was stirred at room temperature for 20 hrs, whereupon the starting material was consumed (TLC, 1% MeOH in CH2Cl2). The reaction mixture was concentrated in vacuo, redissolved in a minimal amount of CH2Cl2, and chromatographed over normal phase silica (MeOH/CH2Cl2). The fractions containing the desired product were combined and concentrated in vacuo to yield a white powder, which was then triturated with CH2Cl2/diisopropyl ether and vacuum filtered to yield the desired product as a powder. The powder was redissolved in CH2Cl2 and chromatographed for a second time over normal phase silica (MeOH/CH2Cl2). The fractions containing the desired product were combined and concentrated in vacuo to yield a white powder. The powder was triturated with diisopropyl ether and vacuum filtered to yield compound 57 (0.061 g, 52.1% yield, 96.6% HPLC purity). 1H NMR (500 MHz, CDCl3): 8.27 (d, J=2 Hz, 1H), 7.67 (dd, J1=9 Hz, J2=2 Hz, 1H), 6.94 (s, 1H), 6.90 (d, J=9 Hz, 1H), 6.68 (s, 2H), 3.71 (m, 2H), 3.54 (m, 2H), 3.35 (m, 4H), 2.34 (s, 6H), 2.32 (m, 2H), 1.13 (t, J=7 Hz, 3H); MS (ESI, EI+): m/z=428 (MH+).
Reaction SMILES: C([BH3-])#N.[Na+].[ClH:5].[O:6]([C:13]1([OH:24])[CH:23]=[CH:22][C:16]([C:17]([CH3:21])([CH3:20])[CH2:18][NH2:19])=[CH:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO.CCOCC>[ClH:5].[CH2:25]([NH:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]1[CH:15]=[CH:14][C:13]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([OH:24])[CH2:23][CH:22]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(CN)C1=CCC(O)(Oc2ccccc2)C=C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CC(C)(CNCc1ccccc1)C1=CCC(O)(Oc2ccccc2)C=C1
Reaction time: 1 h

Procedure:
Sodium cyanoborohydride (10 mg, 0.17 mmol) was added to a solution of 83 (30 mg, 0.11 mmol) and benzaldehyde (12 μl, 0.12 mmol) in MeOH (2 ml). After 1 hour stirring, the reaction mixture was diluted with ether and washed with water. The aqueous was extracted with ether and then combined organic layers were washed with water, and brine, then dried over MgSO4. The crude product was purified via flash SiO2 (eluted with hexane/ethyl acetate (10:1)) to give the protected amine as a white solid. The protected amine was dissolved in 3 N HCl solution in ethylacetate (2 ml) and the reaction mixture was stirred at ambient temperature for 15 hours. The crude reaction mixture was concentrated in vacuo and dried under high vacuum pressure to give 84 as a white solid (25 mg, 61% yield). 1H-NMR (400 MHz, DMSO-d6) δ 8.83 (brd s, 2H), 7.52-7.32 (m, 10H), 7.15 (d, J=7.6 Hz, 1H), 7.02-6.95 (m, 3H), 4.09 (s, 2H), 3.34 (s, 2H), 1.35 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:15]([CH:16]3[CH2:18][CH2:17]3)[C:14]3[C:19]([C:23]([NH:25][CH3:26])=[O:24])=[CH:20][CH:21]=[CH:22][C:13]=3[N:12]=2)[CH3:10])[C:3]=1I.C([O-])([O-])=O.[Na+].[Na+].[CH3:34][S:35]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)(=[O:37])=[O:36]>COCCOC.O.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]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:15]([CH:16]3[CH2:18][CH2:17]3)[C:14]3[C:19]([C:23]([NH:25][CH3:26])=[O:24])=[CH:20][CH:21]=[CH:22][C:13]=3[N:12]=2)[CH3:10])[C:3]=1[C:41]1[CH:42]=[CH:43][C:38]([S:35]([CH3:34])(=[O:37])=[O:36])=[CH:39][CH:40]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CNC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3I)n(C3CC3)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CNC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3-c3ccc(S(C)(=O)=O)cc3)n(C3CC3)c12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-2-(1-(6-amino-5-iodopyrimidin-4-ylamino)ethyl)-1-cyclopropyl-N-methyl-1H-benzo[d]imidazole-7-carboxamide (Prepared in Example 20, 50.4 mg, 0.106 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (17.25 mg, 0.021 mmol), Na2CO3 (0.026 ml, 0.634 mmol), 4-(methanesulfonyl)-benzeneboronic acid (52.8 mg, 0.264 mmol) in anhydrous 1,2-dimethoxyethane (5 mL) and water (1 mL) was heated to 80° C. under N2. After 1 h, the mixture was cooled to rt and filtered. The filtrate was concentrated under reduced pressure, and purified by column chromatography on a silica gel column using 0 to 10% gradient of MeOH in DCM-EtOAc (1:1) as eluent to give 2-((1S)-1-((6-amino-5-(4-(methylsulfonyl)phenyl)-4-pyrimidinyl)amino)ethyl)-1-cyclopropyl-N-methyl-1H-benzimidazole-7-carboxamide: 1H NMR (400 MHz, DMSO-d6) δ 8.42-8.37 (m, 1H), 8.06 (d, J=8 Hz, 2H), 8.01 (s, 1H), 7.61 (d, J=8 Hz, 2H), 7.56 (d, J=8 Hz, 1H), 7.20 (d, J=8 Hz, 1H), 7.15 (dd, J=8, 8 Hz, 1H), 5.85-5.75 (m, 2H), 3.28 (s, 3H), 2.83 (d, J=4 Hz, 3H), 1.49 (d, J=8 Hz, 3H), 1.18-1.08 (m, 2H), 0.98-0.92 (m, 1H), 0.83-0.75 (m, 1H); LC-MS (ESI) m/z 506.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16].Cl.[NH2:20][OH:21].O.O.O.C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[N:20][OH:21])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16]
Reactant: NO
Reactant: Cc1ccsc1C(=O)Cc1ccccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccsc1C(Cc1ccccc1[N+](=O)[O-])=NO
Yield: 76.7 %

Procedure:
A mixture of 22.0 g of 1-(3-methyl-2-thienyl)-2-(2-nitrophenyl)ethanone in 210 ml of 95% ethanol, 11.7 g of hydroxylamine hydrochloride in 28 ml water, and 25.04 g of sodium acetate trihydrate in 28 ml water was refluxed overnight. The mixture was allowed to cool. The precipitate was collected and crystallized from 95% ethanol to give 17.85 g of product, mp 105°-100° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:16][C:17]([CH:19]1[C:24](=O)[C@:23]2([CH3:29])[C:26]([CH3:28])([CH3:27])[C@H:20]1[CH2:21][CH2:22]2)=[O:18])=O)(C)(C)C>ClCCl>[CH2:30]([N:15]1[C:24]2[C@:23]3([CH3:29])[C:26]([CH3:28])([CH3:27])[C@@H:20]([CH2:21][CH2:22]3)[C:19]=2[C:17](=[O:18])[NH:16]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)NC(=O)C1C(=O)[C@@]2(C)CC[C@@H]1C2(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)[nH]n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 7.2 %

Procedure:
Trifluoroacetic acid (25.5 mL) was added to a solution of N-benzyl-N′-((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (˜30 mmol) in dichloromethane (25.5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, at room temperature for 2 h, heated in a flak equipped with a reflux condenser at an oil-bath temperature of 80° C. for 6 h, and then at an oil-bath temperature of 100° C. overnight in the presence of molecular sieves. The molecular sieves were filtered off and washed with dichloromethane. The filtrate was washed with water until the washings were neutral. The organic layer was dried (sodium sulfate), filtered, evaporated, and purified using a Biotage system with a 330 g column, eluting with 2-5% methanol/dichloromethane, to give (4R,7S)-1-benzyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (610 mg, 7%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[C:21]1([C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:20])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Brc1ccccn1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
A solution of 2-bromopyridine (5 g, 0.032 mol) in dry THF (150 mL) was cooled to −70° C. To this cooled solution was added n-BuLi (2.8 M, 12.4 mL, 0.034 mol) over a period of 20 min and allowed to stir for 2 h under N2 atmosphere. A solution of benzophenone (5.8 g, 0.032 mol) in dry THF (50 mL) was added to the solution at the same temperature over a period of 30 min. The reaction mixture was warmed slowly to RT and allowed to stir another 5 h at RT. The reaction mixture was concentrated under vacuum and the residue was washed with petroleum ether. The organic layer was filtered and the filtrate was concentrated under vacuum to give the title compound (8 g, 95%).
Reaction SMILES: C(O[C:9]([N:11]([C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[C:18]2[S:23]([NH:26][C:27]1[C:32]([O:33][CH3:34])=[N:31][C:30]([Br:35])=[CH:29][N:28]=1)(=[O:25])=[O:24])[CH3:12])=O)C1C=CC=CC=1.[OH-].[Na+]>Br.C(O)(=O)C.O>[CH2:9]([N:11]([C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[C:18]2[S:23]([NH:26][C:27]1[C:32]([O:33][CH3:34])=[N:31][C:30]([Br:35])=[CH:29][N:28]=1)(=[O:25])=[O:24])[CH3:12])[C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:14]=1
Reactant: COc1nc(Br)cnc1NS(=O)(=O)c1cccc2c(N(C)C(=O)OCc3ccccc3)cccc12
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1nc(Br)cnc1NS(=O)(=O)c1cccc2c(N(C)Cc3ccccc3)cccc12
Reaction time: 1 h
Yield: 51.6 %

Procedure:
5-(N-Benzyloxycarbonyl-N-methylamino)-N-(5-bromo-3-methoxy-2-pyrazinyl)-1-naphthalenesulphonamide (0.40 g) was suspended in 33% hydrobromic acid in acetic acid (5 ml) and the mixture was stirred for 1 hour. Evaporation afforded a yellow residue which was dissolved in water (20 ml ), basified to pH 10 with 1N aqueous sodium hydroxide and extracted with ethyl acetate (3×25 ml). The combined organic extracts were dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel (30 g), eluting with a gradient of 20-50% ethyl acetate in hexane, affording 5-(N-benzyl-N-methyl-amino)-N-(5-bromo-3-methoxy2-pyrazinyl)-1-naphthalenesulphonamide (0.095 g); 1H NMR (d6DMSO): 2.72 (s,3H), 3.90 (s,3H), 4.25 (s,2H), 7.2-7.4 (m,6H), 7.58 (t,1H), 7.68 (t,1H), 7.80 (s,1H), 8.32 (dd,1H), 8.46 (d,1H), 8.64 (d,1H), 11.48 (br,1H); mass spectrum (+ve FAB, methanol/NBA); 513(M+H)+.
Reaction SMILES: O.O.[Sn](Cl)(Cl)(Cl)Cl.[Cl:8][C:9]1[N:14]=[C:13]([C:15]#[N:16])[C:12]([N+:17]([O-])=O)=[C:11]([NH:20][CH2:21][CH3:22])[CH:10]=1.[OH-].[K+]>Cl.CN(C=O)C>[NH2:17][C:12]1[C:13]([C:15]#[N:16])=[N:14][C:9]([Cl:8])=[CH:10][C:11]=1[NH:20][CH2:21][CH3:22]
Reactant: CCNc1cc(Cl)nc(C#N)c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNc1cc(Cl)nc(C#N)c1N
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 79.5 %

Procedure:
At 0° C., a solution of tin chloride dihydrate (25.9 g) in concentrate aqueous HCl (76 mL) was added dropwise over 40 minutes to a solution of 6-chloro-4-ethylamino-3-nitro-pyridine-2-carbonitrile (2.9 g) in DMF (70 mL). The mixture was stirred for 2.5 hours, then poured to a mixture of ice (400 g) and 50% potassium hydroxide (400 mL), extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with 2N sodium hydroxide (700 mL), then brine (3×100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (eluent: dichloromethane/ethyl acetate 9/1) to afford the title compound (2.0 g) as white crystals (mp=150° C.). 1H NMR (DMSO-d6) δ: 6.46 (s, 1H); 6.42 (br.s, 1H); 6.02 (br.s, 2H); 3.20 (q, J=8 Hz, 2H); 1.26 (t, J=8 Hz, 3H). MS m/z: 197/199 (M+1).