Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[CH2:2]([N:9]1[CH:14]=[CH:13][C:12](OCC2C=CC=CC=2)=[C:11]([N+:23]([O-:25])=[O:24])[C:10]1=[O:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>ClCCl>[NH2:1][C:12]1[CH:13]=[CH:14][N:9]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:10](=[O:26])[C:11]=1[N+:23]([O-:25])=[O:24]
Reactant: N
Reactant: O=c1c([N+](=O)[O-])c(OCc2ccccc2)ccn1Cc1ccccc1
Solvent: ClCCl
Product: Nc1ccn(Cc2ccccc2)c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
20 ml of a saturated ethanolic ammonia solution were added to a solution of 5.5 g (16.3 mmol) of 1-benzyl-4-benzyloxy-3-nitro-pyridin-2-one in 50 ml dichloromethane and stirred for 3 days at ambient temperature in the sealed flask. The solution was evaporated to dryness, the residue was triturated with diethyl ether, suction filtered and dried.
Reaction SMILES: [C:1]([NH:5][NH2:6])(=[O:4])[CH2:2][CH3:3].C(O[C:10]([C:12]1[N:13]([CH3:20])[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=1)=[NH:11])C>>[CH3:20][N:13]1[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=[C:12]1[C:10]([NH:6][NH:5][C:1](=[O:4])[CH2:2][CH3:3])=[NH:11]
Reactant: CCC(=O)NN
Reactant: CCOC(=N)c1ncc([N+](=O)[O-])n1C
Product: CCC(=O)NNC(=N)c1ncc([N+](=O)[O-])n1C

Procedure:
Similarly, 2-propionylhydrazine is reacted with ethyl-1-methyl-5-nitro-2-imidazolecarboximidate to afford 2-(1-methyl-5-nitro-2-imidazolecarboximidoyl)-1-propionylhydrazine (IIIO).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N+:10]([C:13]1[CH:14]=[C:15]([C@@H:19]([OH:22])[CH2:20][CH3:21])[CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[S:24]([O:22][C@H:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=1)[CH2:20][CH3:21])(=[O:26])(=[O:25])[CH3:23]
Reactant: CC[C@H](O)c1cccc([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](OS(C)(=O)=O)c1cccc([N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
Diisopropylethylamine (1.07 g, 8.3 mmol) is added to a mixture of (S)-1-(3-nitrophenyl)propanol (XXI, PREPARATION 1, 1 g, 5.5 mmol) in methylene chloride (20 mL). The mixture is cooled to −20° and methanesulfonyl chloride (0.69 g, 6.02 mmol) is added. The reaction is held at −20° for 10 min, then held at 0° for 40 min. The reaction is diluted with methylene chloride, sodium bicarbonate (5%) is added and the phases are separated. The methylene chloride is evaporated to give the title compound, [α]D=−79.9° (ethanol, c=1); TLC (silica gel GF, ethyl acetate/hexane, 20/80) Rf=0.19; NMR (CDCl3, TMS) 0.96-1.01, 1.88-2.17, 2.89, 5.54-5.59, 7.57-7.62, 7.70-7.73 and 8.20-8.24 δ.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1C(C)C)([CH3:3])[CH3:2].C(C1C(C(C)C)=C(C(C)C)C=CC=1)(C)C>>[C:4]1([CH:1]([CH3:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)c1ccccc1C(C)C
Agent: CC(C)c1cccc(C(C)C)c1C(C)C
Product: CC(C)c1ccccc1

Procedure:
The diisopropylbenzene and a portion of the heavies (triisopropylbenzene and heavier) could be recycled to yield additional cumene. The undesirable cumene contaminant n-propylbenzene could not be detected in the product at the ppm level.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([C:10]2[N:15]3[CH:16]=[CH:17][N:18]=[C:14]3[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[N:12][CH:11]=2)=[N:7][CH:6]=1)=O.[NH4+:32].[OH-].[NH4+].[Cl-]>CO>[N:26]1([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:13]3[C:14]4[N:15]([CH:16]=[CH:17][N:18]=4)[C:10]([C:8]4[S:9][C:5]([C:3]([NH2:32])=[O:2])=[CH:6][N:7]=4)=[CH:11][N:12]=3)=[CH:25][CH:24]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: [NH4+]
Reactant: COC(=O)c1cnc(-c2cnc(Nc3ccc(N4CCOCC4)cc3)c3nccn23)s1
Agent: [Cl-]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cnc(-c2cnc(Nc3ccc(N4CCOCC4)cc3)c3nccn23)s1
Yield: 6 %

Procedure:
A solution of 2-[8-(4-morpholin-4-yl-phenylamino)-imidazo[1,2-a]pyrazin-5-yl]-thiazole-5-carboxylic acid methyl ester (90 mg, 0.21 mmol), 35% NH4OH (2.5 mL), and NH4Cl (0.2 g), in MeOH (12 mL) is heated at 85° C. in a stem tube for 48 hours. The mixture is concentrated in vacuo and purified by silica gel column chromatography eluting with 99:1 and 97:3 DCM:NH3 (7M in MeOH). Trituration with diethyl ether-MeOH gives the title compound (4.9 mg, 6%). LCMS: Rt 2.52 min (90%), m/z (ES+) 422 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 3.13 (4H, m), 3.79 (4H, m), 7.00 (2H, d), 7.75 (1H, br s), 7.81 (1H, s), 7.91 (2H, d), 8.25 (1H, s), 8.28 (1H, br s), 8.55 (1H, s), 9.08 (1H, s), 10.05 (1H, s).
Reaction SMILES: [CH3:1][CH:2]1[CH2:19][C@@H:5]2[C@@H:6]3[N:10]([C:11](=O)[C@@H:4]2[CH2:3]1)[C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:8][CH2:7]3.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1.C(Cl)Cl.CO>[CH2:9]([N:10]1[CH2:11][C@H:4]2[C@H:5]([CH2:19][CH:2]([CH3:1])[CH2:3]2)[C@H:6]1[CH2:7][OH:8])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC1C[C@@H]2[C@H]3CO[C@H](c4ccccc4)N3C(=O)[C@@H]2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1C[C@H]2CN(Cc3ccccc3)[C@H](CO)[C@H]2C1
Temperature: 0 °C

Procedure:
To a cold (0° C.) solution of (1R,3aS,3bS,6aR)-5-methyl-1-phenyl-hexahydro-2-oxa-7a-aza-cyclopenta[a]pentalen-7-one (470 mg) in anh. THF (7 mL) was added LAH (160 mg, 2.3 eq) in small portion. The mixture then refluxed for 6 h before cooled to 0° C. To the reaction mixture were carefully added water (0.3 mL), aqueous NaOH solution (15%) (0.9 mL) and water (0.3 mL). The resulting solid was removed by filtration and the filtrate was concentrated in to yield a crude oil. FC (DCM/MeOH: 97/3 to 93/7) gave the title compound as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:40][OH:41]>O>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:40][OH:41])=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1C=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1C=NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
Intermediate (17b) (4.3 g, 10 mmol) was dissolved in pyridine (40 mL, 500 mmol). Hydroxylamine hydrochloride (1.7 g, 25 mmol) was added, followed by the addition of water (20 mL, 1000 mmol). The mixture was stirred at room temperature overnight. Water (30 mL) was added and the mixture was stirred for 20 minutes. The precipitant was filtered off and dried to yield intermediate (17c) (3.5 g). MS m/z: [M+H+] calcd for C26H29N2O4, 448.2; found 448.3.
Reaction SMILES: F[C:2]1C=CC(CCN2CCC(N3C4C(=CC=C(CN)C=4)C=C3)CC2)=CC=1.[F:27][C:28]1[CH:57]=[CH:56][C:31]([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([N:40]3[C:48]4[C:43](=[CH:44][CH:45]=[C:46]([CH2:49][NH:50][C:51](=[O:55])[CH2:52][CH2:53]Br)[CH:47]=4)[CH:42]=[CH:41]3)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1.BrCCC(Cl)=O.C(N(CC)CC)C>C(#N)C>[F:27][C:28]1[CH:57]=[CH:56][C:31]([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([N:40]3[C:48]4[C:43](=[CH:44][CH:45]=[C:46]([CH2:49][N:50]5[CH2:2][CH2:53][CH2:52][C:51]5=[O:55])[CH:47]=4)[CH:42]=[CH:41]3)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1
Reactant: NCc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Reactant: O=C(CCBr)NCc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Agent: O=C(Cl)CCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCCN1Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Yield: 156.5 %

Procedure:
1H-NMR(400 MHz,DMSO-d6); δ(ppm) 1.40-1.50(2H,m), 1.60-1.71(4H,m), 2.00-2.08(2H,m), 2.12-2.26(2H,m), 2.37-2.52(2H,m), 2.70-3.10(8H,m), 3.39-3.49(2H,m), 3.52-3.63(2H,m), 4.42(2H,d,J=6.0 Hz), 4.45-4.58(1H,m), 6.43(1H,d,J=3.2 Hz), 6.96(1H,d,J=8.0 Hz), 7.10-7.19(2H,m), 7.26-7.34(2H,m), 7.44(1H,d,J=3.2 Hz), 7.47(1H,s), 7.49(1H,d,J=8.0 Hz), 8.76(1H,t,J=6.0 Hz). m.p.: 113-114° C. Mass: FAB+477(M+H). Example 377: Synthesis of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-bromopropionylamino)methylindole 1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (370 mg) obtained in Example 322-3), 3-bromopropionyl chloride (240 mg), triethylamine (140 mg) and acetonitrile (10 ml) were treated as in Example 373 to give the title compound (290 mg) as an oil (yield: 57%). 1H-NMR(400 MHz,CDCl3); δ(ppm) 2.02-2.10(2H,m), 2.14-2.26(2H,m), 2.29-2.40(2H,m), 2.68-2.76(2H,m), 2.80(2H,t,J=6.4 Hz), 2.85-2.92(2H,m), 3.18-3.26(2H,m), 3.70(2H,t,J=6.4 Hz), 4.20-4.30(1H,m), 4.62(2H,d,J=6.0 Hz), 6.15(1H,br-s), 6.50(1H,d,J=3.2 Hz), 6.96-7.04(3H,m), 7.16-7.24(2H,m), 7.25(1H,d,J=3.2 Hz), 7.37(1H,s), 7.58(1H,d,J=8.0 Hz). Example 378: Synthesis of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(3-N,N-dimethylaminopropionyl)aminomethylindole
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1.[NH2:28][CH2:29][CH2:30][CH2:31][OH:32]>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13]([NH:28][CH2:29][CH2:30][CH2:31][OH:32])[C:12]=2[CH2:11][CH2:10]1
Reactant: NCCCO
Reactant: Cc1cccc(N2CCc3c(Cl)nc4c(OC(F)(F)F)cccc4c32)c1C
Product: Cc1cccc(N2CCc3c(NCCCO)nc4c(OC(F)(F)F)cccc4c32)c1C

Procedure:
1-(2,3-Dimethylphenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(500 mg, 1.3 mmol) was dissolved in 3-amino-1-propanol(6 ml) in the pressure tube, then reacted at the same condition of Step 3 in the Example 14 to obtain 300 mg of desired compound as solid in 56% of yield.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[N:22]=[C:21]5[CH:23](O)[NH:24][C:25](=[O:26])[C:20]5=[CH:19][CH:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[N:22]=[C:21]5[CH2:23][NH:24][C:25](=[O:26])[C:20]5=[CH:19][CH:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C1NC(O)c2nc(Oc3ccc4c(c3)CCN(C3CCC3)CC4)ccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2nc(Oc3ccc4c(c3)CCN(C3CCC3)CC4)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (E234) (90 mg, 0.25 mmol) and triethylsilane (0.1 ml) in trifluoroacetic acid (0.1 ml) was vigorously stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the residue purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90); MS (ES+) m/e 350 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]([C:12]1[N:13]=[C:14]([CH2:17]Br)[S:15][CH:16]=1)=[O:11])[CH3:8].[I:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>CC(C)=O>[CH2:7]([O:9][C:10]([C:12]1[N:13]=[C:14]([CH2:17][O:26][C:23]2[CH:24]=[CH:25][C:20]([I:19])=[CH:21][CH:22]=2)[S:15][CH:16]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1csc(CBr)n1
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Yield: 57.6 %

Procedure:
Ground potassium carbonate (3.4 g, 24.6 mmol) was added to a solution of 2-bromomethyl-thiazole-4-carboxylic acid ethyl ester (12.83 g, 56 mmol; from Step 1 above) and 4-iodophenol (5.5 g, 25 mmol; available from Aldrich Chemical Company, Inc., Milwaukee, Wis.) in acetone (440 mL). The reaction mixture was heated at reflux for 15 h and then it was filtered and water was added to the filtrate until it turned cloudy. The filtrate was left on ice and then the resulting white solid was filtered off, washed with acetone/hexanes (2:1) and dried to give 2-(4-iodo-phenoxymethyl) -thiazole-4-carboxylic acid ethyl ester (5.6 g, 65%) as a white solid. 1HNMR (CDCl3): δ 1.4 (t, 3H, J=7 Hz), 4.46 (q, 2H, J=7 Hz), 5.4 (s, 2H), 6.7 (d, 2H, J=9 Hz), 7.6 (d, 2H, J=9 Hz), 8.2 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:20])[C:5]([C:9]2[C:13]([CH3:14])=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[N:11]([CH3:19])[N:10]=2)=[N+:6]([O-])[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:24]>CN(C)C=O>[Cl:1][C:2]1[C:7](=[O:24])[NH:6][C:5]([C:9]2[C:13]([CH3:14])=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[N:11]([CH3:19])[N:10]=2)=[C:4]([F:20])[CH:3]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1c(-c2c(F)cc(Cl)c[n+]2[O-])nn(C)c1S(C)(=O)=O
Solvent: CN(C)C=O
Product: Cc1c(-c2[nH]c(=O)c(Cl)cc2F)nn(C)c1S(C)(=O)=O
Temperature: 22 °C
Reaction time: 8 h

Procedure:
2.6 go 5-chloro-3-fluoro-2-(5-methanesulfonyl-1,4-dimethyl-[1H]-pyrazol-3-yl)-pyridine-1-oxide (Example P40) are introduced into 35 ml of dry dimethylformamide. At a temperature of 10° C., 16.8 g of trifluoroacetic anhydride are added dropwise and the mixture is then stirred overnight at 22° C., subsequently poured into 2 liters of ice-water and extracted with tert-butyl methyl ether. After drying over magnesium sulfate, filtering and concentrating to dryness by evaporation in vacuo, 1.8 g of the desired compound are obtained as crude product, which can be used directly in the next step.
Reaction SMILES: [CH2:1]([C@:5]12[CH2:13][CH2:12][C:11]3[C:14]4[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[CH:18][C:19]=4[CH2:20][CH2:21][C:10]=3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])[CH:2]([CH3:4])[CH3:3].N.NC1C=CC=CC=1.[Li].[Cl-].[NH4+]>O1CCCC1.O>[CH2:1]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C:14]4[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[CH:18][C:19]=4[CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc2c(c1)CCC1=C2CC[C@]2(CC(C)C)[C@@H](O)CC[C@@H]12
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(CC(C)C)[C@@H](O)CC[C@@H]12
Yield: 76 %

Procedure:
Add a solution of 13β-isobutyl-3-methoxygona-1,3,5(10),8-tetraen-17β-ol (17.0 g.) in dry tetrahydrofuran (125 cc.; distilled) slowly to a mixture of liquid ammonia (680 cc., distilled), aniline (85 cc., distilled) and tetrahydrofuran (125 cc.) with stirring. Then add lithium (7.9 g.) in small portions. After the addition of lithium is completed, stir the blue mixture for another 3 hours. Discharge the blue color by the cautious addition of ammonium chloride followed by warm (50°) water. Extract the crude product with benzene. Wash the extracts with water, hydrochloric acid, (20%) sodium bicarbonate, water and dry. Evaporate the solvent in vacuo to obtain a gum which on crystallization from ether-petroleum ether gives 13β-isobutyl-3-methoxygona-1,3,5(10)-trien-17β-ol (13.0 g.; 76%); m.p. 103°-104° C.: ultraviolet absorption peak at 2.78 mμ (ε 1,975); infrared absorption peak at 2.83 μ.
Reaction SMILES: [OH:1][C@H:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][N:4]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH2:28]([O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[O:38])[CH3:29].ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CN(C)C=O>[CH2:28]([O:30][C:31]1[CH:32]=[C:33]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][N:4]([CH2:3][C@H:2]([OH:1])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:16][CH:17]=2)[CH:34]=[CH:35][C:36]=1[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[O:38])[CH3:29]
Reactant: CCOc1cc(B(O)O)ccc1C(=O)NS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N(CCOc1ccc(I)cc1)C[C@H](O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1cc(-c2ccc(OCCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(C)(=O)=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
A mixture of tert-butyl [(2R)-2-hydroxy-2-phenylethyl][2-(4-iodophenoxy)ethyl]carbamate (250 mg), [3-ethoxy-4-[[(methylsulfonyl)amino]carbonyl]phenyl]boronic acid (223 mg), [1,1′-bis(diphenylphosphino]ferrocene]-dichloropalladium(II), complex with dichloromethane (1:1, 114 mg), 1,1′-bis(diphenylphosphino)ferrocene (32 mg), N,N-dimethylformamide (5 ml), and 2N sodium carbonate solution (0.99 ml) was stirred at 80° C. for 1 hour. After cooling to room temperature, the mixture was quenched by the addition of 1N hydrochloric acid (1.99 ml) and partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was separated, washed with water (20 ml×2) and brine (20 ml), and dried over magnesium sulfate. Filtration followed by evaporation gave a brown foam which was chromatographed on silica gel (eluent: hexane/ethyl acetate) to give tert-butyl [2-[[3′-ethoxy-4′-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]oxy]ethyl][(2R)-2-hydroxy-2-phenylethyl]carbamate (84.5 mg) as a pale orange solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13](NC1C=CC(C(O)=O)=CN=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].[CH2:34]([O:36][C:37](=[O:47])[CH:38]=[CH:39][C:40]1[CH:41]=[N:42][C:43]([NH2:46])=[CH:44][CH:45]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:47])[CH:38]=[CH:39][C:40]1[CH:41]=[N:42][C:43]([NH:46][C:13](=[O:14])[CH2:12][CH2:11][CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:7](=[O:33])[N:8]2[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[CH:44][CH:45]=1)[CH3:35]
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Reactant: CCOC(=O)C=Cc1ccc(N)nc1
Product: CCOC(=O)C=Cc1ccc(NC(=O)CCC2c3c(F)cccc3C(=O)N2Cc2ccc(F)cc2)nc1

Procedure:
The product of Example 11, Part D (137 mg, 0.41 mmol) and 3-(6-amino-pyridin-3-yl)-acrylic acid ethyl ester (80 mg, 0.41 mmol) were converted to the title compound in a manner analogous to the method described in Example 27 (90.8 mg, 43%). 1H NMR (400 MHz, CDCl3) δ 8.3 (s, 1H), 8.18 (d, J=8.7 Hz, 1H), 8.03 (s, 1H); 7.89-7.86 (d, J=8.6 Hz, 1H); 7.71 (d, J=7 Hz, 1H); 7.62 (d, J=16 Hz, 1H), 7.49-7.44 (m, 1H); 7.34 (m, 2H); 7.23 (t, J=8.75 Hz, 1H); 7.04 (t, J=8.8 Hz, 2H); 6.44 (d, J=16 Hz, 1H); 5.28 (d, J=15 Hz, 1H), 4.70 (m, 1H), 4.29-4.23 (m, 3H); 2.57-2.50 (m, 2H); 2.04-1.93 (m, 2H); 1.36 (t, J=7.4 Hz, 3H) MS: m/z (MH+) 506.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[CH2:17]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]1[C:33]([NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:30]2[CH2:31][CH2:32][N:27]([C:25]([O:24][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:26])[C@H:28]([C:33]([NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]2)[N:3]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1CNCCN1C(=O)OCc1ccccc1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2nc(N3CCN(C(=O)OCc4ccccc4)[C@H](C(=O)NC(C)(C)C)C3)nc(N)c2cc1OC

Procedure:
A solution of 4-amino-2-chloro-6,7-dimethoxyquinazoline (0.78 g, 3.2535 mmol) and (S)-4-[(benzyloxy)carbonyl]-3-(1,1-dimethylethylamino) carbonyl piperazine (see Askin, D. et al., Tetrahedron Letters 1994, 35, 673-676) (1.04 g, 3.2535 mmol) in 2-propanol (6 mL) was heated at 90° C. (24 h). The solvent was removed in vacuo and the residue subjected to SGC (SiO2, 40 mm×240 mm, 0-10% MeOH/CH2Cl2) which afforded (S)-1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-[(benzyloxy)carbonyl]-3-(1,1-dimethylethylamino)carbonyl piperazine.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[SH:33].C(N(CC)CC)C>CO>[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33][CH:17]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C@@H:12]([C:13]([O:15][CH3:16])=[O:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: Nc1ccccc1S
Reactant: COC(=O)/C(=C/c1ccc(Cl)c(Cl)c1)NC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Sc1ccccc1N)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a deoxygenated solution of methyl (2Z)-2-{[(benzyloxy)carbonyl]amino}-3-(3,4-dichlorophenyl)acrylate (10a) (2.17 g, 5.7 mmol) in anhydrous methanol (40 ml) (warmed to dissolve) under nitrogen was added the 2-aminothiophenol (3.1 ml, 28.5 mmol) followed by addition of triethylamine (400 ul, 2.85 mmol). The mixture stirred 3 days at ambient temperature, concentrated to ca. 10 mL, partitioned between cold 1N hydrochloric acid (75 mL) and ethyl acetate (100 mL). The organic phase was separated and consecutively washed with 1N hydrochloric acid (4×), dilute aqueous sodium bicarbonate and brine, dried, filtered and evaporated to give the title compound (10b) as an 4:1 mixture (erythro:threo) (2.8 g, 96%). A 100 mg sample was converted to the HCl salt to provide an analytically pure title compound (32 mg) as a (4:1) mixture. MS APCI, m/z=505 (M+1), 507 (M+3). LC/MS: 2.94 min.
Reaction SMILES: P(=O)(O)(O)O.[CH3:6][C:7]1[CH2:12][CH2:11][C:10]([CH3:15])([CH:13]=[CH2:14])[CH2:9][CH:8]=1>C1(C)C=CC=CC=1>[CH3:6][C:7]1[CH:12]2[CH2:11][C:10]([CH3:15])([CH2:9][CH:8]=1)[CH2:13][CH2:14]2
Reactant: C=CC1(C)CC=C(C)CC1
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Product: CC1=CCC2(C)CCC1C2

Procedure:
Phosphoric acid (H3PO4, 145 g, 1.48 mol) was added to a solution of 1,4-dimethyl-4-vinyl-cyclohexene (403 g, 2.96 mol, commercially available from Evonik Industries) in toluene (500 mL) and refluxed for 6 hours. The reaction mixture was subsequently quenched with a solution of sodium hydroxide (NaOH). The organic layer was separated, dried over sodium sulfate (Na2SO4), and fractionated to provide 2,5-dimethyl-bicyclo[3.2.1]oct-2-ene (280 g) having a boiling point of 87° C. at a pressure of 27 mmHg
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[O:10][CH2:11][C:12]1[N:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[CH:14][CH:13]=1.CS(C)=O.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[CH:3]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[O:10][CH2:11][C:12]1[N:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[CH:14][CH:13]=1)=[O:2]
Reactant: COC(OC)c1ccncc1OCc1cccc(C(=O)O)n1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1ccncc1OCc1cccc(C(=O)O)n1
Temperature: 45 °C
Reaction time: 3.5 h

Procedure:
Into an 8-mL sealed tube, was placed a solution of 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-2-carboxylic acid (150 mg, 0.49 mmol, 1.00 equiv) in dichloromethane (4 mL) and trifluoroacetic acid (2 mL). The resulting solution was stirred for 3.5 h at 45° C. in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and MeCN (10% MeCN up to 35% in 4 min, up to 100% in 1 min, down to 10% in 1 min); Detector, Waters2545 UvDector 254&220 nm. This resulted in 49 mg (38%) of 6-[[(4-formylpyridin-3-yl)oxy]methyl]pyridine-2-carboxylic acid as a light yellow solid. LC-MS-PH-GBT-ZL-HS-19-0 (ES, m/z): 259 [M+1]+ H-NMR-PH-GBT-ZL-HS-19-0 (300 MHz, DMSO, ppm): 10.52 (s, 1H), 8.92 (s, 1H), 8.52 (d, J=4.8 Hz, 1H), 8.09 (m, 2H), 7.95 (m, 1H), 7.76 (d, J=4.8 Hz, 1H), 5.61 (s, 2H).