Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][S:8]([CH:11]=[CH2:12])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C@H:34]([OH:42])[CH2:35][N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[CH:28][C:26]=2[N:27]=1>CCO>[OH:42][C@@H:34]([CH2:33][O:32][C:29]1[CH:30]=[CH:31][C:25]2[S:24][C:23]([CH3:22])=[N:27][C:26]=2[CH:28]=1)[CH2:35][N:36]1[CH2:37][CH2:38][N:39]([CH2:12][CH2:11][S:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])[CH2:40][CH2:41]1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Reactant: C=CS(=O)(=O)Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCS(=O)(=O)Nc4ccccc4)CC3)ccc2s1
Temperature: 85 °C

Procedure:
To a solution of phenyl(vinylsulfonyl)amine (141 mg, 0.77 mmol) and DIEA (0.47 mL, 4.9 mmol) in EtOH (7.5 mL) was added (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol (470 mg, 1.5 mmol, crude). The solution was heated for 2 hours at 85° C. on a J-Kem™ block. Upon cooling, the reaction mixture was concentrated to an oil and purified via flash column chromatography (4:1 EtOAc/MeOH) to afford [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]phenylamine.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH:14]=[C:13]([NH2:17])[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2].[CH3:21][C:22](=O)[CH2:23][C:24](=O)[CH3:25]>>[C:1]([O:4][C@H:5]([CH3:20])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:22]([CH3:21])=[CH:23][C:24]([CH3:25])=[N:17][C:13]=2[N:12]([CH3:18])[C:11]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)cc(N)n(C)c1=O
Reactant: CC(=O)CC(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(C)cc(C)nc2n(C)c1=O
Temperature: 145 °C

Procedure:
A mixture of (R)-3-(5-acetoxyhexyl)-6-amino-1-methyluracil (250 mg, 0.88 mmol), 2,4-pentanedione (2 ml, 19.5 mmol) and xylenes (3 ml) was heated to 145° C. for 18 hours. The mixture was concentrated under reduced pressure followed by coevaporation with toluene (2×5 ml) to remove the remaining 2,4-pentanedione to provide crude (R)-3-(5-acetoxyhexyl)-1,5,7-trimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[I:12])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>CN(C=O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][NH2:1])=[C:6]([I:12])[CH:7]=1
Reactant: [N-]=[N+]=NCc1ccc(F)cc1I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: NCc1ccc(F)cc1I
Temperature: 55 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
A solution of 1-(azidomethyl)-4-fluoro-2-iodobenzene (15.2 g, 54.8 mmol) in DMF (35 ml) at 0° C. was treated with triphenylphosphine (21.6 g, 81.2 mmol) and then stirred for 1 h. The reaction mixture was then treated with water (5 ml) and heated at 55° C. for 1 h. The DMF was concentrated in vacuo and the residue was diluted with ethyl acetate (200 ml). The organic phase was extracted with 0.5 N hydrochloric acid (140 ml) and the aqueous extract was washed with ethyl acetate. The aqueous phase was then adjusted to pH 9 with 1 N LiOH and extracted with ethyl acetate (2×200 ml). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated. The residue was diluted with ether (200 ml), filtered and concentrated. Distillation of the residue in vacuo gave 8.52 g (62% yield) of the title amine as a clear oil: bp 85° C./0.35 torr (bulb to bulb distillation air bath temperature). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 3.64 (2H, s, CH2), 7.27 (1H, m, aromatic), 7.53 (1H, dd, J=6 Hz and J=8.6H, aromatic), 7.83 (1H, dd, J=3 Hz and J=8 Hz, aromatic).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([OH:13])=O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([Cl:3])=[O:13]
Reactant: O=C(O)c1sccc1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1sccc1Cl
Temperature: 25 °C

Procedure:
Excess thionyl chloride (3.5 ml, 48.0 mmoles) was added to 0.85 g (5.2 mmoles) of 3-chloro-2-thiophenecarboxylic acid (prepared according to Corral, C., et al., Heterocycles 23:1431 (1985)) dissolved in 50 ml of toluene and stirring at room temperature. After addition the solution was refluxed for 3 hours to form 3-chloro-2-thiophenecarbonyl chloride. Concentration of the reaction solution gave the acid chloride as a white solid. The acid chloride was then dissolved in 4 ml of N,N-dimethylformamide and slowly added to a cooled (ice/water bath) stirring solution of 5-chloro-2-oxindole-1-carboxamide (1.0 g, 4.71 mmoles) and 4-(N,N-dimethylamino)pyridine (1.3 g, 10.5 mmoles) in 10 ml of N,N-dimethylformamide. After 45 minutes the solution was allowed to warm to room temperature and after 2 hours was worked-up by pouring into a mixed ice/6N hydrochloric acid solution. A yellow precipitate formed. The precipitate was filtered, washed with water and dried to give 1.3 g of impure product as a yellow solid. Recrystallization with acetic acid/heptane (2:1) gave 0.77 g (2.2 mmoles) of pure title compound as yellow needles, m.p. 222-224° C. Total yield of product was 42%.
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccccc1)N1CCNCC1
Reactant: O=Cc1ccccc1OCc1ccccc1
Product: O=C(Nc1ccccc1)N1CCN(Cc2ccccc2OCc2ccccc2)CC1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid phenylamide and 2-benzyloxybenzaldehyde. 1H NMR (400 MHz, CDCl3): 7.49-7.20 (m, 11H), 7.05-6.92 (m, 3H), 6.41 (s, 1H), 5.08 (s, 2H), 3.65 (s, 2H), 3.51-3.45 (m, 4H), 2.55-2.49 (m, 4H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([NH:16][C:17](=[O:35])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:20][CH:19]=2)[CH:4]=1.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:41]([O:40][C:38]([CH2:37][NH:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([NH:16][C:17](=[O:35])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:20][CH:19]=2)[CH:4]=1)=[O:39])[CH3:42]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)COc1ccc(N)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccc(OCC(=O)OCC)c(NC(=O)c2ccc(OCCCCc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
A mixture of 200 mg of ethyl 4-amino-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate hydrochloride, 70.4 mg of ethyl bromoacetate, 114 mg of anhydrous potassium carbonate and 5 ml of N,N-dimethylformamide was stirred at room temperature overnight. To the reaction mixture was added 30 ml of ethyl acetate. After washing with water, the system was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was applied to silica gel column chromatography and eluted with a toluene-ethyl acetate (4:1) mixture to obtain 140 mg of ethyl 4-(ethoxycarbonylmethylamino)-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate.
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=2[CH:7]=1)[CH:3]=O.[NH2:17][C:18]1[N:23]=[N:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1.O>C(O)CCC>[CH3:14][S:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([CH2:5][C:2]3[N:23]4[N:22]=[C:21]([C:24]#[N:25])[CH:20]=[CH:19][C:18]4=[N:17][CH:3]=3)[CH:16]=[CH:15][C:9]=2[N:10]=1
Reactant: N#Cc1ccc(N)nn1
Reactant: CSc1nc2ccc(CC(Cl)C=O)cc2s1
Solvent: O
Solvent: CCCCO
Product: CSc1nc2ccc(Cc3cnc4ccc(C#N)nn34)cc2s1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
A stirred mixture of 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal from Step 4 of Example 117 (1.3 g, 4.8 mmol) and 6-aminopyridazine-3-carbonitrile (0.8 g, 7.2 mmol) in 1-butanol (48 mL) was heated at reflux overnight. The mixture was cooled to rt and water (100 mL) was added. The mixture was extracted with EtOAc (3×60 mL, and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 3-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-b]pyridazine-6-carbonitrile as a yellow solid (0.7 g, 44%). 1H NMR (300 MHz, CDCl3) δ 8.09 (d, J=9.0 Hz, 1H), 7.83-7.78 (m, 2H), 7.69 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.29 (d, J=9.3 Hz, 1H), 4.46 (s, 2H), 2.78 (s, 3H). LCMS (ESI) m/z 338 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[N:5]=[C:4]([S:18][CH3:19])[N:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[N:5]=[C:4]([S:18][CH3:19])[N:3]=1
Reactant: CSc1nc(Cl)c(C=O)c(Nc2ccccc2Cl)n1
Reactant: OB(O)c1ccccc1Cl
Product: CSc1nc(Nc2ccccc2Cl)c(C=O)c(-c2ccccc2Cl)n1

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-chlorophenylboronic acid to give the title compound 4-(2-chloro-phenyl)-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 2.58 (s, 3H), 7.01-7.59 (m, 7H), 8.61 (d, 1H, J=4.7 Hz), 9.65 (s, 1H), 11.48 (br s, 1H). LC MS (m/e)=390 (MH+).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.Cl[C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11]>C1COCC1>[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCCN1C(=O)Oc1ccccc1
Temperature: -60 °C
Yield: 100.1 %

Procedure:
To a solution of 7.36 g (184 mmol) of NaH (60%) in 200 ml of THF was added 15.68 g (184 mmol) of 2-oxopyrrolidine with stirring under ice-cooling, and further the mixture was stirred at room temperature for 1 hr. until H2 gas ceased to evolve. The reaction solution was added to a solution of 29.7 g (190 mmol) of phenyl chloroformate in 100 ml of THF cooled at -60° C. and then stirred at room temperature for 4 hr. The reaction solution was poured into ice water, and then extracted with ethyl acetate. After drying, the solvent was removed by evaporation. When the crystalline residue was recrystallized from CH2Cl2 -ether, 37.8 g of the objective compound (II) melting at 120.0°-121.5° C. was obtained as crystals. Yield: 84.0%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:16]([S:18]([C:21]1[CH:26]=[CH:25][C:24](F)=[C:23]([Cl:28])[CH:22]=1)(=[O:20])=[O:19])[CH3:17]>>[Cl:28][C:23]1[CH:22]=[C:21]([S:18]([CH2:16][CH3:17])(=[O:20])=[O:19])[CH:26]=[CH:25][C:24]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)cc(C(F)(F)F)c2)c(Cl)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of example 25 step (iv) and the product of example 3 step (i).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][C@H:11]1[CH2:16][O:15][C@@H:14]([CH3:17])[O:13][C@H:12]1[CH2:18][N:19]1C(=O)C2=CC=CC=C2C1=O)=[O:4].O.NN>C(O)C>[NH2:19][CH2:18][C@H:12]1[C@@H:11]([CH2:10]/[CH:9]=[CH:8]\[CH2:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH2:16][O:15][C@@H:14]([CH3:17])[O:13]1
Reactant: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of (2R,4R,5S)-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-4-phthalimidomethyl-1,3-dioxane (54 mg) in ethanol (2 ml) was added hydrazine monohydrate (0.007 ml) and the mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo and the crude product was purified with preparative TLC (chloroform:methanol:conc.aqueous ammonia=85:15:0.1) to give (2R,4R,5S)-4-aminomethyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (13 mg).
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH:25]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]([CH3:29])([NH2:28])[CH3:27])=[CH:21][CH:22]=3)[CH:17]=[N:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C>CC#N>[CH3:29][C:26]([NH:28][S:4]([CH:1]1[CH2:3][CH2:2]1)(=[O:6])=[O:5])([CH3:27])[CH:25]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[N:15]([C:12]1[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=1)[N:16]=[CH:17]2
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(C)(N)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(NS(=O)(=O)C1CC1)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Cyclopropanesulfonyl chloride (155 μl, 1.52 mmol) was added to 1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-2-methyl-1-phenylpropan-2-amine (26a, 0.070 g, 0.19 mmol) triethylamine (80 μl, 0.57 mmol) in MeCN (3 ml) at room temperature. The reaction mixture was stirred over night, concentrated, diluted with 10% NaHSO4 (aq) and extracted with EtOAc. The organic phase was washed with 10% NaHSO4 (aq). The crude product was further purified by HPLC. Yield 25 mg (30%).
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[CH:4]1([Zr+3:9])[CH:8]=[CH:7][CH:6]=[CH:5]1.[CH3:10][Sn:11]([C:14]1[CH:15]([Sn](C)(C)C)[C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:13])[CH3:12]>C1(C)C=CC=CC=1>[Cl-:1].[Cl-:1].[CH3:10][Sn:11]([C:14]1[CH:15]([Zr+2:9][CH:4]2[CH:8]=[CH:7][CH:6]=[CH:5]2)[C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:13])[CH3:12]
Reactant: C[Sn](C)(C)C1=Cc2ccccc2C1[Sn](C)(C)C
Reactant: [Zr+3]C1C=CC=C1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: C[Sn](C)(C)C1=Cc2ccccc2C1[Zr+2]C1C=CC=C1
Yield: 177.1 %

Procedure:
Cyclopentadienylzirconium trichloride (CpZrCl3, 3.94 g, 15.0 mmol) which was slurrified by adding toluene of 70 ml was added into the mixed solution including bis(trimethylstannyl)indene (6.75 g, 15.28 mmol) and toluene of 100 ml, and then reacted for 21 hours at 85° C. Yellowish (trimethylstannyl-indenyl)(cyclopentadienyl)zirconium dichloride compound (6.71 g, yield: 86%) was obtained by a series of processes, such as removing toluene from reactant, slurrifying the obtained solid by adding hexane (100 ml) and filtering the slurry.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.[CH3:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[C:19](O)=[O:20].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)CCl>[CH2:1]1[O:2][C:3]2[C:8](=[CH:7][C:6]([C:19](=[O:20])[C:18]3[CH:22]=[CH:23][C:24]([N+:25]([O-:27])=[O:26])=[C:16]([CH3:15])[CH:17]=3)=[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:4]=2)[O:9]1
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCCl
Product: COC(=O)Cc1cc2c(cc1C(=O)c1ccc([N+](=O)[O-])c(C)c1)OCO2

Procedure:
The title compound was prepared from methyl 3,4-methylenedioxyphenylacetate (2.1 g, 11 mmol) in ClCH2CH2Cl (70 mL), 3-methyl-4-nitrobenzoic acid (3.7 g, 20 mmol) and P2O5 (6 g) as an oily solid (1.4 g, 3.9 mmol, 35%). 1H NMR (CDCl3) 7.99 (d, J=8.2, 1H), 7.74 (s, 1H), 6.69 (d, J=8.2, 1H), 6.84 (s, 1H), 6.83 (s, 1H), 6.07 (s, 2H), 3.86 (s, 2H), 3.64 (s, 3H), 2.63 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:29][C:30]([CH3:32])=O>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH:30]([CH3:32])[CH3:29])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: O=C(NC(COCC1CCNCC1)C1CCCC1)c1ccc2c(Cl)c[nH]c2c1
Reactant: CC(C)=O
Product: CC(C)N1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)C2CCCC2)CC1

Procedure:
Using alkylation method A, 3-chloro-N-[1-cyclopentyl-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (140 mg, 0.35 mmol) and acetone (0.25 mL, 3.5 mmol) afforded, after SCX purification, 67 g (44%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:11][NH2:12].[BH4-].[Na+]>C(O)C>[CH3:11][NH:12][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of p-methoxybenzaldehyde (25 ml; 200 mmol) and 8M methylamine in ethanol (100 ml; 800 mmol) in 100 ml of ethanol was stirred at rt for 18 hours. After removing the volatiles in vacuo, the residue was dissolved in 300 ml of fresh ethanol and sodium borohydride (8.5 g; 225 mmol) was added portionwise over 1.5 hr. Following the addition, the reaction mixture was concentrated to ˜⅓ volume and water (50 ml) was added. After cooling in an ice bath, the stirred mixture was carefully acidified to pH ˜2 with 5% aqueous H2SO4. After stirring 15 minutes, the mixture was basified to pH 14 with 6N NaOH and extracted with ethyl ether (400 ml). The ether layer was washed with water (200 ml), brine (100 ml) and dried over MgSO4. Concentration afforded 28.04 g (93%) of B51.1 as a colorless liquid. (M+H)+=152.13 (HPLC>94%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:6]=1[C:7]([N:9]1[CH2:13][CH2:12][CH:11]([O:14]S(C)(=O)=O)[CH2:10]1)=[O:8])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:29]=[C:30](O)[CH:31]=[CH:32][C:33]=1[Cl:34]>>[Cl:27][C:28]1[CH:29]=[C:30]([CH:31]=[CH:32][C:33]=1[Cl:34])[O:14][CH:11]1[CH2:12][CH2:13][N:9]([C:7]([C:6]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])=[O:8])[CH2:10]1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(OS(C)(=O)=O)C1
Reactant: Oc1ccc(Cl)c(Cl)c1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2ccc(Cl)c(Cl)c2)C1
Yield: 32 %

Procedure:
Prepared in analogy to Example 3(c) from rac-methanesulfonic acid 1-(2-isopropoxy-5-methanesulfonyl-benzoyl)-pyrrolidin-3-yl ester (Example 14(a)) and 3,4-dichlorophenol. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 32%). MS (m/e): 476.3 ({37Cl}M+H+, 10%), 474.3 ({37C,35Cl}M+H+, 80%), 472.2 ({35Cl}M+H+, 100%)
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:30]1[CH2:29][CH2:28][CH:27]([NH:26][C:24]([C:20]2[C:16]3=[N:17][CH:18]=[CH:19][C:14]([C:8]4[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)=[C:15]3[NH:22][C:21]=2[CH3:23])=[O:25])[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)NC1CCNCC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f7) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:29][C:30]([CH3:34])([CH3:33])[CH2:31][NH2:32]>>[CH3:29][C:30]([CH3:34])([CH3:33])[CH2:31][NH:32][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[C:8]([N:9]=1)=[C:7]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[N:6]=[C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])[N:4]=2
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CC(C)(C)CN
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNCC(C)(C)C)n(C)c2n1

Procedure:
Following General Procedure L for reductive amination, 9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purine-8-carbaldehyde and 2,2-dimethylpropan-1-amine were reacted to give 258. [M+H]+ 449.6.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[C:7]=1[N+:13]([O-:15])=[O:14].[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>>[NH2:12][C:8]1[C:7]([N+:13]([O-:15])=[O:14])=[C:6]([O:5][C:4]2[CH:16]=[CH:17][C:18]([Cl:19])=[C:2]([NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([O:22][C:21]([F:20])([F:32])[F:33])[CH:24]=3)[CH:3]=2)[CH:11]=[CH:10][N:9]=1
Reactant: Nc1cc(Oc2ccnc(N)c2[N+](=O)[O-])ccc1Cl
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Product: Nc1nccc(Oc2ccc(Cl)c(NC(=O)c3cccc(OC(F)(F)F)c3)c2)c1[N+](=O)[O-]
Yield: 33 %

Procedure:
Method H was used with 4-(3-amino-4-chlorophenoxy)-3-nitropyridin-2-amine and 3-(trifluoromethoxy)benzoyl chloride to afford the title compound as a yellow solid (0.153 g, 33%). 1H NMR δ (DMSO): 6.11 (d, 1H, Hpy,5, J=5.5 Hz), 7.18 (dd, 1H, Harom,5, J=3+9 Hz), 7.23 (s, 2H, NH2), 7.53 (d, 1H, Harom,2, J=3 Hz), 7.63 (dt, 1H, Harom, J=1+8 Hz), 7.66 (d, 1H, Harom,6, J=9 Hz), 7.70 (t, 1H, Harom,5, J=8 Hz), 7.91 (s, 1H, Harom,2′), 8.02 (dt, 1H, Harom, J=1+8 Hz), 8.07 (d, 1H, Hpy,6, J=5.5 Hz), 10.63 (s, 1H, NHamide). 19F NMR δ (DMSO): −56.37 (s, 3F, CF3).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][CH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1)[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[Br:24]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:24])[C:3](=[O:2])[N:13]([CH2:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[C:11]=1[CH3:12])=[O:8]
Reactant: COC(=O)C=CC(C(=O)OC)=C(C)NCc1nccs1
Reactant: O=C1CCC(=O)N1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(=O)n(Cc2nccs2)c1C
Temperature: 25 °C
Yield: 22.4 %

Procedure:
MeOH (60 mL) was added to a flask containing 4-{1-[(thiazol-2-ylmethyl)-amino]-ethylidene}-pent-2-enedioic acid dimethyl ester (2.12 g, 7.16 mmol). NaOMe solution (1.64 mL, 7.16 mmol, 4.375 M in MeOH) and N-bromosuccinimide (1.53 g, 8.59 mmol) were added, and the resulting mixture was refluxed for 1 h. After cooling to r.t., the solvent was evaporated in vacuo. Saturated NH4Cl was added, and the resulting mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (0-80% EtOAc/hexanes) to give 551 mg of the title compound as a yellow solid. MS: (+) m/z 343.11, 345.12 (M+1, 79/81Br).