Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:38]2[CH2:37][CH2:36][N:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[O:28][CH3:27])[CH2:40][CH2:39]2)=[O:26])[C:11]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(Oc2ccccc2)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3OC)CC2)c(Oc2ccccc2)nc1C
Yield: 88 %

Procedure:
Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1([C:27](Cl)=[O:28])[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2>>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:27]([C:14]2([CH2:13][CH2:12][CH2:11][CH2:10][Br:9])[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:28])=[CH:4][CH:5]=1
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: NCc1ccncc1
Product: O=C(NCc1ccncc1)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 4-(aminomethyl)-pyridine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [C:1]1([C:11](Cl)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH2:18]([O:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH3:19]>ClCCCl>[CH2:18]([O:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([C:31]=1[C:11]([C:1]1[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=1)=[O:12])=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH3:19]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)c1[nH]c2ccccc2c1C(=O)c1cccc2ccccc12

Procedure:
1. To a solution of naphthalene-1-carbonyl chloride (3.43 g) and AlCl3 (2.40 g) in 1,2-dichloroethane (7 ml) was added at 0° C. a solution of 1H-indole-2-carboxylic acid ethyl ester (1.70 g) in 1,2-dichloroethane (7 ml) and the mixture was heated at reflux temperature for 2 h. The mixture was partitioned between ice cold water and AcOEt, the organic layer was washed with aqueous Na2CO3, dried and evaporated. The residue was chromatographed on silica (n-heptane/AcOEt, 5:1) to give 3-(naphthalene-1-carbonyl)-1H-indole-2-carboxylic acid ethyl ester as pale yellow solid. MS: 344.1 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[CH2:13][CH3:14])[C:6]=2[C:5](=[O:18])[NH:4][C:3]1=[O:19].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][C:27](=[O:29])[CH3:28].O>CS(C)=O>[O:29]=[C:27]([CH3:28])[CH2:26][CH2:25][CH2:24][CH2:23][N:4]1[C:5](=[O:18])[C:6]2[N:7]([C:11](=[O:17])[C:12]([CH3:15])([CH3:16])[CH2:13][CH3:14])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:19]
Reactant: CCC(C)(C)C(=O)n1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCC(C)(C)C(=O)n1cnc2c1c(=O)n(CCCCC(C)=O)c(=O)n2C
Reaction time: 0.25 h
Yield: 49.7 %

Procedure:
3-Methyl-7-(methylpivaloyl)xanthine (406 mg, 1.5 mmol) was added to a stirring suspension of NaH (36 mg, 1.5 mmol) in DMSO (20 ml) and stirred for 15 min. 6-Bromo-2-hexanone (260 mg, 1.5 mmol) was added and the reaction mixture was stirred for 20 hrs. The reaction mixture was poured into 100 ml of water and extracted with 25% ethanol/dichloromethane (3×40 ml). The combined organic extracts were combined, dried with magnesium sulfate and the solvent was removed under vacuum to give a brown oil. The brown oil was chromatographed (10 g silica gel, ethyl acetate) to give 1-(5-oxohexyl)-3-methyl-7-(methylpivaloyl)xanthine (270 mg, 49% yield)
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23][CH:24]([C:28](O)=[O:29])[C:25](O)=[O:26])[CH2:15][CH3:16]>>[OH:29][C:28]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:9][C:25](=[O:26])[C:24]=1[S:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:14][CH2:15][CH3:16]
Reactant: CCCc1ccccc1SC(C(=O)O)C(=O)O
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Product: CCCc1ccccc1Sc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (0.990 mL, 4.83 mmol) and diethyl ester of [(2-propylphenyl)thio]propanedioic acid (1.00 g, 3.22 mmol). m.p. 158°-160° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.972 (t, 3H), 1.64 (m, 2H), 2.71 (t, 2H), 6.87 (s, 1H), 6.92 (m, 1H), 7.06 (m, 2H), 7.16 (m, 1H), 7.55 (m, 3H), 7.85 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[N:17]1([C:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)=[CH:13][CH:12]=2)=[O:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccc(O)cc2)cc1)N1CCOCC1
Reaction time: 16 h
Yield: 83.2 %

Procedure:
To a solution of 4-hydroxy-biphenyl-4′-carboxylic acid (5.35 g, 25.0 mmol), morpholine (2.39 g, 27.5 mmol) and triethylamine (3.5 mL, 25 mmol) in dichloromethane (100 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. The mixture was stirred for 16 hours, diluted with aqueous NaH2PO4 and filtered. The solid was washed with 1:2 diethyl ether/water (100 mL) then with water (400 mL). The solid was dried in vacuo to give the titled compound (5.89 g, 83%). MS (DCI) m/z 284 (M+H)+;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][N:9]([S:13](Cl)(=[O:15])=[O:14])[CH2:8][C:7]=2[CH:17]=1.[NH2:18][C:19]1[C:24]2[CH:25]=[C:26]([CH2:28][CH:29]([NH:39]S(C3C=CC(OC4CCOCC4)=CC=3)(=O)=O)[C:30]([N:32]3[CH2:37][CH2:36][CH:35]([CH3:38])[CH2:34][CH2:33]3)=[O:31])[S:27][C:23]=2[CH:22]=[CH:21][N:20]=1>>[NH2:18][C:19]1[C:24]2[CH:25]=[C:26]([CH2:28][CH:29]([NH:39][S:13]([N:9]3[CH2:8][C:7]4[CH:17]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[O:12][CH2:11][CH2:10]3)(=[O:15])=[O:14])[C:30]([N:32]3[CH2:33][CH2:34][CH:35]([CH3:38])[CH2:36][CH2:37]3)=[O:31])[S:27][C:23]=2[CH:22]=[CH:21][N:20]=1
Reactant: CC1CCN(C(=O)C(Cc2cc3c(N)nccc3s2)NS(=O)(=O)c2ccc(OC3CCOCC3)cc2)CC1
Reactant: COc1ccc2c(c1)CN(S(=O)(=O)Cl)CCO2
Product: COc1ccc2c(c1)CN(S(=O)(=O)NC(Cc1cc3c(N)nccc3s1)C(=O)N1CCC(C)CC1)CCO2

Procedure:
This compound was prepared from 210 mg of 7-methoxy-2,3-dihydro-5H-benzo[f][1,4]oxazepine-4-sulfonyl chloride and 210 mg of 30a using the procedure described for 58c. Yield: 70 mg (oil), (+)-FAB-MS: 560 (MH+).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([NH:23][C:33](=[O:35])[CH3:34])[CH3:22])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3ccc(C(C)N)cc3)s2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(C)c1ccc(-c2cnc(Oc3ccc(OC(C)C)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
To a solution of Example 1F (0.15 g, 0.0004 mol) and excess triethylamine (2 mL) in methylene chloride (5 mL) was added excess acetic anhydride (1 mL) and the mixture was stirred at room temperature for 15 minutes. After quenching with methanol (5 mL), the solvent was concentrated and the residue was purified on silica gel (50˜75% ethyl acetate in hexane) to give 0.12 g of the title compound (76% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.35 (d, J=6.25 Hz, 6 H) 1.49 (d, J=6.99 Hz, 3 H) 2.00 (s, 3 H) 4.44-4.60 (m, 1 H) 5.06-5.20 (m, 1 H) 5.67 (d, J=6.99 Hz, 1 H) 6.87-6.97 (m, 2 H) 7.16-7.24 (m, 2 H) 7.27-7.34 (m, 2 H) 7.37 (s, 1 H) 7.38-7.44 (m, 2 H). MS (ESI), m/z 396.9 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([CH3:20])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[CH2:17][CH2:18][CH3:19])C.[Li+].[OH-]>C1COCC1.O>[CH3:20][C:5](=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][C:8]=1[CH2:17][CH2:18][CH3:19])[C:4]([OH:21])=[O:3]
Reactant: CCCc1cc(C(F)(F)F)ccc1C=C(C)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc(C(F)(F)F)ccc1C=C(C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
To a suspension of 2-methyl-3-(2-propyl-4-trifluoromethyl-phenyl)-acrylic acid ethyl ester (68 mg, 0.23 mmol) in THF (1 mL) was added a solution of 1N-LiOH (10 ml), and the mixture was stirred for 3 hours at room temperature. The resulting residue was dissolved in H2O and then washed three times with EtOAc, acidified with 1N HCl to pH 1-2. The solution was extracted three times with methylene chloride and then dried over anhydrous MgSO4 and concentrated in vacuo to give the title compound (60 mg, 96%).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:18]=[CH:19][C:20]([S:22]([N:25]3[CH:29]=[C:28]([CH:30]=[O:31])[CH:27]=[N:26]3)(=[O:24])=[O:23])=[CH:21][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:32]OS([O-])=O.[K+]>CN(C=O)C>[C:1]([C:5]1[N:9]([CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:18]=[CH:19][C:20]([S:22]([N:25]3[CH:29]=[C:28]([C:30]([OH:32])=[O:31])[CH:27]=[N:26]3)(=[O:24])=[O:23])=[CH:21][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C=O)cn3)ccc2n1C[C@H]1CC[C@H](F)CC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1C[C@H]1CC[C@H](F)CC1

Procedure:
1-({2-tert-Butyl-1-[(trans-4-fluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)-1H-pyrazole-4-carbaldehyde (130 mg, 0.291 mmol) and oxone (215 mg, 0.349 mmol) were stirred in 10 mL of DMF at rt overnight. The solvent was evaporated. The residue was dissolved in DCM and washed with water, brine and dried over anhydrous MgSO4. Yield: 135 mg (99%). MS (ESI) (M+H)+=463.06.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:12]([N:19]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(N(C)C)=O>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.O>[CH2:12]([N:19]1[CH:23]=[C:22]([C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH:21]=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: OB(O)c1cnn(Cc2ccccc2)c1
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: CC(=O)N(C)C
Solvent: O
Product: Nc1nc2cccc(-c3cnn(Cc4ccccc4)c3)n2n1
Temperature: 150 °C

Procedure:
A vial was charged with 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (2.00 g, 9.39 mmol), 1-benzylpyrazole-4-boronic acid, pinacol ester (3.20 g, 11.3 mmol), potassium phosphate (4.00 g, 18.8 mmol) and tetrakis(triphenylphosphine)palladium (1.10 g, 0.94 mmol). Dimethylacetamide (24 ml) and water (8 ml) were added and the reaction mixture was heated under microwave irradiation to 150° C. for 10 min. The mixture was partitioned between ethyl acetate and water, and the aqueous phase extracted with ethyl acetate. The combined organic phases were washed several times with water, once with brine, dried over magnesium sulfate and concentrated in vacuo. Trituration in the minimum amount of dichloromethane and diethyl ether afforded an orange solid which required no further purification. Yield: 1.82 g, 67%; LCMS method: 2, RT: 2.37 min, MI: 291 [M+1].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:6]([CH3:11])[C:7]=1[C:8](=[O:10])[CH3:9].[Br-:18].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:18][CH2:9][C:8]([C:7]1[C:6]([CH3:11])=[CH:5][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][C:2]=1[CH3:1])=[O:10]
Reactant: [Br-]
Reactant: CC(=O)c1c(C)cc(-c2ccccc2)cc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: Cc1cc(-c2ccccc2)cc(C)c1C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 125.2 %

Procedure:
To a solution of 1-(3,5-dimethyl-(1,1′-biphenyl)-4-yl)ethanone (1.89 g, 8.43 mmol) in acetonitrile (16.9 mL) was added tetrabutylammoniumtribromide (TBABr3, 4.07 g, 8.43 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(3,5-dimethyl-(1,1′-biphenyl)-4-yl)ethanone (3.2 g), which was used directly for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:31](I)=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[F:33].F[B-](F)(F)F.[C:39]([PH+](C(C)(C)C)C(C)(C)C)(C)(C)[CH3:40]>O1CCOCC1.CCOC(C)=O.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]>[NH2:1][C:2]1[C:31]([CH:39]=[CH2:40])=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[F:33]
Reactant: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Reactant: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4cc(F)c(N)c(I)c4)CS(=O)(=O)C[C@@H]32)c1
Agent: [Pd]
Agent: F[B-](F)(F)F
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=Cc1cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc(F)c1N

Procedure:
To a degassed solution of (3aR*,7S*,7aS*)-7-(4-amino-3-fluoro-5-iodo-benzyl)-3-(3-tert-butyl-benzyl)-5,5-dioxo-hexahydro-1-oxa-5lambda*6*-thia-3-aza-inden-2-one (example 1k) (0.60 g, 1 mmol) in anhydrous dioxane (4 mL) was added under argon Cs2CO3 (0.665 g, 2.0 mmol), 2,4,6-trivinyl-cyclotriboroxane pyridine complex (0.365 g, 1.5 mmol) and tri-tert-butyl-phosphonium tetrafluoroborate (0.044 g, 0.15 mmol) in dioxane was added under argon the Pd2(dba)3 (0.028 g, 0.03 mmol) and the reaction mixture was heated at reflux for 2 h. The reaction mixture was diluted with EtOAc and the organic layer was washed with water and brine, dried over MgSO4, filtered and evaporated. The title compound was obtained after flash-chromatography on silica gel (hexane-EtOAc 3:1 to 2:1) and crystallization from CH2Cl2-hexane as white crystals: HPLC RtA=2.22 min; ESIMS [M+NH4]+=504.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[S:10]1[CH:11]=[CH:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=3)[N:7]=2)=[CH:9]1
Reactant: Clc1nccc(-c2ccsc2)n1
Reactant: COC(=O)c1ccc(CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CNc2nccc(-c3ccsc3)n2)cc1
Temperature: 130 °C
Yield: 48 %

Procedure:
To a solution of 14 (680 mg, 3.46 mmol) and methyl 4-(aminomethyl)benzoate (686 mg, 4.51 mmol) in dry 1,4-dioxane (10 mL) was added DIPEA (1.50 mL, 8.65 mmol) and the mixture was heated for 48 h at 130° C. in a sealed tube. Solvents were removed under vacuum and the residue was triturated with a mixture of EtOAc/Et2O, to form a solid, which was collected by filtration and dried. This material was purified by flash chromatography on silica gel (EtOAc/CH2Cl2: 30/70) to afford the title compound 15 (540 mg, 1.66 mmol, 48% yield). 1H NMR: (400 MHz, DMSO-d6) δ (ppm): 8.29-8.23 (m, 2H), 7.88 (d, J=8.4 Hz, 2H), 7.84-7.77 (m, 1H), 7.69-7.59 (m, 2H), 7.52-7.43 (m, 2H), 7.03 (d, J=5.2 Hz, 1H), 4.60 (d, J=6.4 Hz, 2H), 3.81 (s, 3H).
Reaction SMILES: [O:1]1[C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:39])[CH:18]([C:29]1[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=1)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=1>O1CCCC1.[OH-].[OH-].[Pd+2]>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH:18]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:33][CH:34]=2)[C:17]([NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:2]2[O:1][C:6]3=[CH:7][CH:8]=[CH:9][C:5]3=[CH:4][CH:3]=2)=[O:39])=[CH:21][CH:22]=1
Reactant: CC(C)(C)c1ccc(C(Cc2ccc([N+](=O)[O-])cc2)C(=O)Nc2ccccc2-c2ccc3cccc-3o2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(Cc2ccc(N)cc2)C(=O)Nc2ccccc2-c2ccc3cccc-3o2)cc1
Reaction time: 16 h
Yield: 76.7 %

Procedure:
To N-(4-Benzofuran-2-yl-phenyl)-2-(4-tert-butyl-phenyl)-3-(4-nitro-phenyl)-propionamide (830 mg, 1.6 mmol) in tetrahydrofuran (20 ml) was added 20% palladium hydroxide on carbon (172 mg). The reaction mixture was stirred under hydrogen for 16 h, filtered and concentrated. Chromatography of the residue (20% ethyl acetate in hexane) afforded 3-(4-Amino-phenyl)-N-(4-benzofuran-2-yl-phenyl)-2-(4-tert-butyl-phenyl)-propionamide as a white solid (600 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][C:21]2[N:30]=[C:29]3[C:24]([CH2:25][CH2:26][C:27](=[O:31])[NH:28]3)=[CH:23][CH:22]=2)[CH2:12][CH2:11]1>[Ni].CCO.C1COCC1>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[N:30]=[C:29]3[C:24]([CH2:25][CH2:26][C:27](=[O:31])[NH:28]3)=[CH:23][CH:22]=2)[CH2:14][CH2:15]1
Reactant: Cc1c(F)ccc(N2CCN(CCCC=Cc3ccc4c(n3)NC(=O)CC4)CC2)c1Cl
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(F)ccc(N2CCN(CCCCCc3ccc4c(n3)NC(=O)CC4)CC2)c1Cl
Yield: 89.2 %

Procedure:
7-{5-[4-(2-Chloro-4-fluoro-3-methyl-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.382 g, 0.862 mmol) was hydrogenated using Ra—Ni (0.5 g) in 1:1 EtOH/THF (50 mL) for 12 h. The reaction was filtered and concentrated. Purification by liquid chromatography (SiO2, 5% MeOH/CH2Cl2 to 7% MeOH/CH2Cl2) gave the title compound as a light yellow foam (342 mg, 0.769 mmol, 89%). MS: APCI: M+1: 445.2 (Exact Mass: 444.21).
Reaction SMILES: CS(O[CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])(=O)=O.[Cl-:17].[Li+].O>CN(C)C=O>[Cl:17][CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC(CCCCC)OS(C)(=O)=O
Reactant: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCC(Cl)CCCCC
Temperature: 15 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
Thirty grams (0.12 mol) of 6-methanesulfonyloxyundecane was dissolved in 150 mL of N,N-dimethylformamide and 15.3 g (0.36 mol) of anhydrous lithium chloride was added to the solution under cooling with ice. The mixture was warmed to 50˜55° C. and stirred for 3 hours. Thereafter, the mixture was cooled to 15° C. and 300 mL of cold water was added. The reaction mixture was extracted three times with 150 mL of hexane and the organic layer was sequentially washed with 150 mL of water and 150 mL of a saturated aqueous solution of sodium chloride and thereafter dried over 6 g of anhydrous magnesium sulfate. After filtering off the anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 22.2 g (97.1% in yield) of 6-chloroundecane.
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].[CH3:4][C:5]([CH3:10])([CH3:9])[C:6](Cl)=[O:7]>C(OCC)C>[N+:1](=[CH:3][C:6](=[O:7])[C:5]([CH3:10])([CH3:9])[CH3:4])=[N-:2]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCOCC
Product: CC(C)(C)C(=O)C=[N+]=[N-]
Reaction time: 16 h
Yield: 100 %

Procedure:
To the diazomethane solution at 0° C. was added a solution of 1.23 mL (1.21 g, 10 mmol, Aldrich) of trimethylacetyl chloride in 1 mL of diethyl ether dropwise with stirring. The resulting mixture was kept at 0 ° C. for 16 h. The solution was sparged with argon to remove the excess diazomethane and diethyl ether was removed under reduced pressure to give 1.33 g (10 mmol, 100%) of crude 1-diazo-3,3-dimethyl-2-butanone as a yellow liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:24][C:25]2[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([C@H:14]3[CH2:18][O:17][C:16]4([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[O:15]3)[N:10]=2)=[N:6][CH:7]=1.[SH:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36].C(N(CC)C(C)C)(C)C>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]>[O:15]1[C:16]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[O:17][CH2:18][C@@H:14]1[C:11]1[N:10]=[C:9]([NH:8][C:5]2[N:6]=[CH:7][C:2]([S:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:3][C:4]=2[O:24][C:25]2[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[S:13][N:12]=1
Reactant: Cc1ncccc1Oc1cc(Br)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Reactant: COC(=O)CCS
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2cccnc2C)c1
Temperature: 80 °C
Yield: 68.9 %

Procedure:
To a solution of (S)—N-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (3.1 g, 6.14 mmol) in dioxanes (30 mL) continuously purged with nitrogen was added Xanphos (0.177 g, 0.303 mmol), Pd2dba3 (0.14 g, 0.153 mmol), methyl 3-mercaptopropanoate (0.73 g, 6.14 mmol) and N,N-diisopropylethylamine (1.17 mL, 6.45 mmol) and the reaction was heated overnight at 80° C. The reaction was concentrated in vacuo and the residue purified over silica gel (5% MeOH/CH2Cl2) to afford (S)-methyl 3-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)propanoate (2.3 g, 68%).
Reaction SMILES: C[CH2:2][N:3]=C=NCCCN(C)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=O)=[CH:15][CH:14]=1.C1C=CC2N(O)N=NC=2C=1.NC>CN(C=O)C.O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([NH:3][CH3:2])=[O:23])=[CH:15][CH:14]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)CCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
EDAC (1.56 g, 8.1 mmol) was added in one portion to 3-(4-bromophenyl)propanoic acid (2.5 g, 7.4 mmol) and HOBt (1.1 g, 8.1 mmol) in DMF (6 mL) and the reaction mixture was stirred for 2 h. The reaction mixture was cooled to 0° C. and NH2Me (2.0 M in MeOH, 29 mL, 58 mmol) was added dropwise. The solution was stirred at 0° C. for 30 min and 10 h at ambient temperature. The reaction mixture was diluted with water (25 mL), extracted with diethyl either (3×50 mL). The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to yield 22A (1.7 g, 67%) as an off-white solid. MS (ESI) m/z 242.22/244.22 (M+H)+.