Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:49][CH:48]=[CH:47][CH2:46][CH2:45][N:44]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:43]1=[O:57]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[CH2:49][CH:48]=[CH:47][CH2:46][CH2:45][N:44]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:43]1=[O:57])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: N[C@H]1CC=CCCN(Cc2ccccc2)C1=O
Agent: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3C/C=C\CCN(Cc4ccccc4)C3=O)Cc3ccccc3)C(=O)N21
Agent: N[C@H]1C/C=C\CCN(Cc2ccccc2)C1=O
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CC=CCCN(Cc4ccccc4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S,Z)-1-benzyl-2-oxo-1,2,3,4,7,8-hexahydroazocin-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (8.0 mg, 0.014 mmol) and Intermediate 44 (6.5 mg, 0.028 mmol) to give a white solid (6.8 mg, 61% yield). Anal. Calcd. for C45H54N4O6S m/z 778.7. found: 779.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.40-7.05 (m, 17H), 5.48-5.26 (m, 4H), 5.18-5.06 (m, 1H), 5.05-4.93 (m, 3H), 4.84 (d, J=14.8 Hz, 1H), 4.17 (d, J=14.8 Hz, 1H), 3.92-3.75 (m, 1H), 3.67 (s, 3H), 3.14 (dt, J=14.3, 8.7 Hz, 2H), 2.87-2.66 (m, 5H), 2.61-2.32 (m, 6H), 2.25 (dt, J=16.4, 8.0 Hz, 1H), 2.06-1.97 (m, 2H), 1.86-1.44 (m, 7H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][CH2:21][C:22](OCC)=[O:23])[CH:6]=[CH:7][C:8]=1[N:9]([CH3:19])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1.[OH-].[Na+].Cl.[CH2:30]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[C:31]1[CH:39]=[CH:38][C:37]2[O:36][CH2:35][O:34][C:33]=2[CH:32]=1>C(O)C.CN(C=O)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][CH2:21][C:22]([N:43]2[CH2:44][CH2:45][N:40]([CH2:30][C:31]3[CH:39]=[CH:38][C:37]4[O:36][CH2:35][O:34][C:33]=4[CH:32]=3)[CH2:41][CH2:42]2)=[O:23])[CH:6]=[CH:7][C:8]=1[N:9]([CH3:19])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1
Reactant: CCOC(=O)CCc1ccc(N(C)c2ccc([N+](=O)[O-])cn2)c(OC)c1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1cc(CCC(=O)N2CCN(Cc3ccc4c(c3)OCO4)CC2)ccc1N(C)c1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of ethyl 3-{3-methoxy-4-[methyl-(5-nitropyridin-2-yl)amino]phenyl}propionate (3.85 g, 11 mmol) in ethanol (80 mL) was added 2 N aqueous sodium hydroxide (6.4 mL, 13 mmol), and the resulting solution was stirred at room temperature for 2.5 hours. To the resulting reaction solution was added 6 N hydrochloric acid (2.2 mL, 13 mmol), and the solvent was removed under reduced pressure. To the residue were added THF (80 mL) and N,N′carbonyldiimidazole (2.08 g, 13 mmol), and the resulting solution was stirred at room temperature for 3 hours. To the resulting reaction solution were added 1-piperonylpiperazine (2.60 g, 12 mmol) and DMF (40 mL), and stirred at room temperature for 21 hours. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate), to thereby yield 4.59 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][N:8]=1)[CH3:2]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOCCOc1ccc(CO)cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCOCCOc1ccc(C=O)cn1

Procedure:
A total of 16 g of manganese dioxide is added in portions to a boiling solution of 8 g (40.6 mmol) of [2-(2-ethoxyethoxy)-5-pyridyl]-methanol in 200 ml of toluene within two hours. The mixture is then filtered hot and evaporated. Pale yellow oil, yield 7.1 g (90% of theory). 1H NMR (CDCl3 ; δ[ppm]): 1.2 (t, 3H); 3.6 (q, 2H); 3.8 (t, 2H); 4.6 (t, 2H); 6.9 (d, 1H); 8.1 (dd, 1H); 8.6 (d, 1H); 10.0 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[C:9]([C:25]([O:27]CC)=[O:26])[N:8]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:7]=12.CCO.O.[Li+].[OH-]>C1COCC1>[C:33]([O:32][C:30]([N:8]1[C:7]2=[C:2]([Cl:1])[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:16][CH:15]=2)=[C:9]1[C:25]([OH:27])=[O:26])=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CCOC(=O)c1c(CCOc2ccc(OC(F)(F)F)cc2)c2ccnc(Cl)c2n1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)n1c(C(=O)O)c(CCOc2ccc(OC(F)(F)F)cc2)c2ccnc(Cl)c21
Reaction time: 2.5 h
Yield: 99.8 %

Procedure:
To a solution of 1-tert-butyl 2-ethyl 7-chloro-3-{2-[4-(trifluoromethoxy)phenoxy]ethyl}-1H-pyrrolo[2,3-c]pyridine-1,2-dicarboxylate (33 mg, 0.06 mmol) in THF (1 mL) was added EtOH (0.2 mL)m and water (0.2 mL). Solid LiOH (30 mg, 1.2 mmol) was then added in a single portion. After 2.5 h, quenched with 5% potassium bisulfate until acidic (˜pH 3) and extracted with Et2O and then EtOAc. The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo to yield the title compound (30 mg). LRMS (ESI) calc (M+H)+=501.1. found 501.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[CH3:24][O:25][C:26]([C:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1)=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:31]([C:28]3([C:26]([O:25][CH3:24])=[O:27])[CH2:30][CH2:29]3)=[O:32])=[C:16]2[N:15]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: COC(=O)C1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.3 %

Procedure:
To a mixture of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 43 mg, 0.14 mmol), 1-(methoxycarbonyl)cyclopropanecarboxylic acid (24 mg, 0.16 mmol), and HATU (62 mg, 0.16 mmol) was added 0.7 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.053 mL, 0.30 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred for 10 minutes. The reaction mixture was diluted with EtOAc (15 mL), washed with water, brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 72% acetonitrile/water to yield the final product as a yellowish foamy powder (36 mg, 60% yield). MS (apci) m/z=442.2 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:18][CH2:17][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][C:9]=3[C:5]=2[CH2:4]1.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>>[N:24]1[CH:25]=[CH:26][C:21]([NH:20][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[O:7][C:6]4[CH2:17][CH2:18][CH:3]([N:2]([CH3:19])[CH3:1])[CH2:4][C:5]=4[C:9]=3[CH:10]=2)=[O:15])=[CH:22][CH:23]=1
Reactant: Nc1ccncc1
Reactant: CN(C)C1CCc2oc3ccc(C(=O)Cl)cc3c2C1
Product: CN(C)C1CCc2oc3ccc(C(=O)Nc4ccncc4)cc3c2C1
Yield: 38.8 %

Procedure:
Beginning with 0.011 gm (0.04 mMol) 2-dimethylamino-1,2,3,4-tetrahydrodibenzofuran-8-carbonyl chloride and 0.08 mMol 4-aminopyridine, 0.0052 gm (37%) of the title compound were recovered.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([C:11]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])=[C:4]([Cl:20])[CH:3]=1.[CH3:21][N:22](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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].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]>[Cl:20][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([Cl:8])[C:5]=1[C:9]([C:11]1[C:19]2[C:14](=[CH:15][N:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:10])[C:21]#[N:22]
Reactant: O=C(c1c(Cl)cc(Br)cc1Cl)c1c[nH]c2cnccc12
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1cc(Cl)c(C(=O)c2c[nH]c3cnccc23)c(Cl)c1
Temperature: 130 °C
Yield: 2 %

Procedure:
A mixture of (4-bromo-2,6-dichlorophenyl)(1H-pyrrolo[2,3-c]pyridin-3-yl)methanone (100 mg, 0.27 mmol) in dimethylformamide (3 mL) was treated with zinc cyanide (25.2 mg, 0.21 mmol), tris(dibenzylideneacetone)dipalladium (0) (6.21 mg, 0.006 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (5.6 mg, 0.01 mmol) followed by heating at 130° C. for 16 hours. The reaction mixture was diluted with ethyl acetate, filtered over celite, and the filtrate was concentrated under vacuum. The crude compound was purified by LC-MS to afford 3,5-dichloro-4-(1H-pyrrolo[2,3-c]pyridin-3-ylcarbonyl)benzonitrile (2 mg, 2%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:4]([Cl:8])[S:5][C:6]=1[Cl:7].[CH:13](OC)(OC)OC>>[Cl:7][C:6]1[S:5][C:4]([Cl:8])=[C:3]2[S:9](=[O:10])(=[O:11])[N:12]=[CH:13][NH:1][C:2]=12
Reactant: Nc1c(Cl)sc(Cl)c1S(N)(=O)=O
Reactant: COC(OC)OC
Product: O=S1(=O)N=CNc2c(Cl)sc(Cl)c21
Reaction time: 1.5 h

Procedure:
250 mg of the compound of Step C above are dissolved in 2.5 ml of trimethyl orthoformate. The solution is brought to boiling in an open vessel. After 1.5 hours, the reaction is complete. The solution is allowed to cool, yielding a beige precipitate which is collected by filtration, washed with diethyl ether and dried.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[OH-].[Na+].O.C(OCC)(=O)C.[CH:24]([C:36]([O:38][CH2:39][CH3:40])=[O:37])([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>O1CCCC1>[N+:8]([C:7]1[C:2]([C:24]([C:36]([O:38][CH2:39][CH3:40])=[O:37])([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:3][CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(C(=O)OCC)(C(=O)OCC)c1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.8 g of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine in 8 mL of tetrahydrofuran, 2.0 mL of triethyl 1,1,2-ethanetricarboxylate and 0.63 g of 60% sodium hydroxide were added under cooling with ice, and the mixture was stirred at room temperature for 2 hours. Thereto were added water and ethyl acetate, the organic layer was separated, and washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 3.5 g of triethyl 1-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)ethane-1,1,2-tricarboxylate as a brown oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:34](=[O:37])[CH2:35][CH3:36])[C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C@@H:11]([CH2:28][O:29]C(=O)CC)[CH2:10]2)=[CH:4][CH:3]=1.ClC1C=CC(N(C(=O)CC)[C@H]2C3C(=CC=C(OCC(O)=O)C=3)N(C(=O)C3C=CC(F)=CC=3)[C@@H](C)C2)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19](=[O:27])[C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C@@H:11]([CH2:28][OH:29])[CH2:10]2)[C:34](=[O:37])[CH2:35][CH3:36])=[CH:4][CH:3]=1
Reactant: CCC(=O)OC[C@H]1C[C@@H](N(C(=O)CC)c2ccc(Cl)cc2)c2ccccc2N1C(=O)c1ccc(F)cc1
Agent: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(OCC(=O)O)cc21
Product: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](CO)N(C(=O)c2ccc(F)cc2)c2ccccc21

Procedure:
(±)-Cis-N-(4-chloro-phenyl)-N-[1-(4-fluoro-benzoyl)-2-hydroxymethyl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide was prepared from (±)-cis-propionic acid 4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-1,2,3,4-tetrahydro-quinolin-2-ylmethyl ester using the saponification conditions utilized in the synthesis of (±)-cis-[4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yloxy]-acetic acid.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH2:19][CH2:20][CH2:21][Cl:22])[C@H:9]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(O)=[O:6].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Cl:22][CH2:21][CH2:20][CH2:19][N:10]1[C:9]2[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[C:5](=[O:6])[C:8]=2[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:18]
Reactant: COc1ccc([C@H]2[C@@H](C(=O)O)c3ccccc3C(=O)N2CCCCl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(c1)C(=O)c1c-2n(CCCCl)c(=O)c2ccccc12
Temperature: 25 °C
Yield: 17 %

Procedure:
Thionyl chloride (2 mL) was added to a solution of cis-4-carboxy-N-(3-chloropropyl)-3,4-dihydro-3-(4-methoxyphenyl)-1(2H)isoquinolone (8a) (0.510 g, 1.364 mmol) in benzene (40 mL). The reaction mixture was heated at reflux for 30 min, allowed to cool to room temperature, and concentrated. The residue was diluted with nitrobenzene (20 mL), chilled in an ice bath, and aluminum chloride (0.364 g, 2.728 mmol) was added. The reaction mixture was removed from the bath and heated at 100° C. for 1.5 h. Ice water (100 mL) was added and the solution was extracted with CHCl3 (3×50 mL). The combined organic layer was washed with sat NaHCO3 (3×50 mL), sat NaCl (50 mL), and dried over sodium sulfate. The solution was concentrated, hexanes (250 mL) were added, and liquid was decanted. The obtained solid was washed with hexanes (100 mL) and the liquid was again decanted. The solid was purified by flash column chromatography (SiO2), eluting with chloroform, to provide a purple-red solid (0.082 g, 17%) that was precipitated from EtOAc/hexanes: mp 195-198° C. IR (KBr) 1662, 1611, 1505, 1481, 1432, and 1299 cm−1; 1H NMR (CDCl3) δ 8.67 (d, J=8.1 Hz, 1 H), 8.31 (dd, J=8.2 Hz and 0.7 Hz, 1 H), 7.73 (m, 1 H), 7.66 (d, J=8.4 Hz, 1 H), 7.45 (m, 1 H), 7.22 (d, J=2.6 Hz, 1 H), 6.86 (dd, J=8.4 Hz and 2.6 Hz, 1 H), 4.67 (m, 2 H), 3.89 (s, 3 H), 3.83 (m, 2 H), 2.43 (m, 2 H); CIMS m/z (rel intensity) 354/356 (MH+, 100/30). Anal. (C20H16ClNO3) C, H, N.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][CH2:6][C@H:7]([OH:34])[CH2:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]2[N:21]=[C:20]([C:22]3[S:23][C:24]([CH2:28][NH:29][CH:30]([CH3:32])[CH3:31])=[C:25]([CH3:27])[CH:26]=3)[O:19][N:18]=2)=[CH:12][C:11]=1[CH3:33])=[O:4].[CH2:35](I)[CH3:36].CCN(C(C)C)C(C)C>CN(C=O)C.N>[NH3:5].[CH2:35]([N:29]([CH2:28][C:24]1[S:23][C:22]([C:20]2[O:19][N:18]=[C:17]([C:13]3[CH:14]=[C:15]([CH3:16])[C:10]([O:9][CH2:8][C@@H:7]([OH:34])[CH2:6][NH:5][C:3](=[O:4])[CH2:2][OH:1])=[C:11]([CH3:33])[CH:12]=3)[N:21]=2)=[CH:26][C:25]=1[CH3:27])[CH:30]([CH3:31])[CH3:32])[CH3:36]
Reactant: CCI
Reactant: Cc1cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(C)c3)no2)sc1CNC(C)C
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(Cc1sc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(C)c3)no2)cc1C)C(C)C
Reaction time: 20 h
Yield: 81.2 %

Procedure:
A solution of 2-hydroxy-N-[(2S)-2-hydroxy-3-(4-{5-[5-(isopropylamino-methyl)-4-methyl-thiophen-2-yl]-[1,2,4]oxadiazol-3-yl}-2,6-dimethyl-phenoxy)-propyl]-acetamide (284 mg, 0.448 mmol, Example 91), ethyl iodide (423 mg, 2.69 mmol) and DIPEA (354 mg, 2.69 mmol) in DMF (3 mL) is stirred at rt for 1 h, then at 40° C. for 17 h before another portion of DIPEA (54 mg, 0.421 mmol) and ethyl iodide (304 mg, 1.95 mmol) is added. Stirring is continued at 40° C. for 20 h. The mixture is diluted with aq. sat. NH3 (1 mL) and separated by prep. HPLC (Waters XBridge Prep C18, 75×30 mm ID, 10 μm, gradient of acetonitrile in water containing 0.5% of sat. aq. NH3) to give the title compound (94 mg) as a colourless resin; LC-MS*: tR=1.08 min; [M+1]+=517.32.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C@H:10]1[CH2:15][C@H:14]([NH:16][C:17]([C:19]2[CH:28]=[CH:27][C:22]3[O:23][CH2:24][CH2:25][O:26][C:21]=3[CH:20]=2)=[O:18])[CH2:13][CH2:12][N:11]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].Br[CH2:37][CH2:38][O:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][O:41]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[O:23]1[CH2:24][CH2:25][O:26][C:21]2[CH:20]=[C:19]([C:17]([NH:16][C@@H:14]3[CH2:13][CH2:12][N:11]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@@H:10]([C:2]4[N:3]([CH2:37][CH2:38][O:39][CH:40]5[CH2:45][CH2:44][CH2:43][CH2:42][O:41]5)[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[N:1]=4)[CH2:15]3)=[O:18])[CH:28]=[CH:27][C:22]1=2
Reactant: BrCCOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc3c(c2)OCCO3)C[C@@H]1c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc3c(c2)OCCO3)C[C@@H]1c1nc2ccccc2n1CCOC1CCCCO1
Temperature: 80 °C
Yield: 35.5 %

Procedure:
To a solution of (2R,4R)-tert-butyl 2-(1H-benzo[d]imidazol-2-yl)-4-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)piperidine-1-carboxyl ate (200 mg, 0.418 mmol) in DMF (2 mL) was added 2-(2-bromoethoxy)-tetrahydro-2H-pyran (114 mg, 0.543 mmol) and K2CO3 (116 mg, 0.836 mmol), and the reaction mixture was stirred at 80° C. for over night. Water and ethyl acetate were added to the mixture, organic layer was separated and dried over MgSO4 and concentrated. The residue was purified by HPLC with 0.1% HCOOH in water/0.1% HCOOH in ACN from 45-70% to give the named compound as white solid 90 mg (35%). LC-MS: 607.2 (t=2.9 min).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][NH2:31])=[CH:24][CH:23]=1>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:31][CH2:30][CH2:29][O:28][C:25]4[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: COc1ccc(OCCN)cc1
Product: COc1ccc(OCCNc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1

Procedure:
In like manner to the preparation of N4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 2-(4-methoxyphenyloxy)ethyl amine were reacted to give N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[(4-methoxyphenyloxy)ethyl]-2,4-pyrimidinediamine. LCMS: ret. time: 22.74 min.; purity: 91.9%; MS (m/e): 413.05 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[N:34]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[C:35]=[O:36].O>ClCCl>[CH2:37]([NH:34][C:35]([N:12]1[C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][C:4]=3[C:5]=2[N:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([C:22]#[N:23])([CH3:24])[CH3:25])=[CH:17][CH:16]=2)[C:13]1=[O:26])=[O:36])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: O=C=NCc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(C(=O)NCc3ccccc3)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (18 mg, 0.18 mmol) in dichloromethane (6 ml) was added (isocyanatomethyl)benzene (24.57 mg, 0.18 mmol). The reaction mixture was stirred at RT for 2 hours. Then the reaction mixture was poured on to water. The organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 1% MeOH in chloroform) to obtain the title compound. Yield: 18 mg (20%); 1H NMR (CDCl3, 300 MHz): δ 9.89 (s, 1H), 8.95 (t, 1H), 7.978-8.008 (d, 1H, J=9 Hz), 7.762-7.790 (d, 2H, J=8.4 Hz), 7.614-7.651 (dd, 1H, J=9, 1.8 Hz), 7.500-7.529 (d, 2H, J=8.7 Hz), 7.27-7.38 (m, 5H), 7.018-7.025 (d, 1H, J=2.1 Hz), 4.642-4.611 (d, 2H, J=5.7 Hz), 1.82 (s, 6H); MS: m/z 540 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][C:10]#[N:11].[CH2:12](N)[CH2:13][NH2:14]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][C:10]1[NH:14][CH2:13][CH2:12][N:11]=1
Reactant: Cc1cccc(Br)c1CC#N
Reactant: NCCN
Product: Cc1cccc(Br)c1CC1=NCCN1

Procedure:
2-(2-Bromo-6-methyl-benzyl)-4,5-dihydro-1H-imidazole was prepared from (2-bromo-6-methylphenyl)-acetonitrile and ethylene diamine in analogy to Example 19 b): off-white solid;
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([NH2:12])[C@H:9]([OH:13])[C@H:8]([OH:14])[CH:7]=1)=[O:5])[CH3:2].CS(O)(=O)=O>CCC(=O)CC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([NH2:12])[C@@H:9]2[O:13][C:6]([CH2:11][CH3:10])([CH2:7][CH3:8])[O:14][C@@H:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C[C@@H](O)[C@@H](O)[C@H](N)C1
Agent: CS(=O)(=O)O
Solvent: CCC(=O)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C[C@H]2OC(CC)(CC)O[C@H]2[C@H](N)C1
Temperature: 25 °C
Yield: 174.4 %

Procedure:
In a 25 ml two necked round bottom flask equipped with a dean stark separator, a reflux condenser, a thermometer, a magnetic stirrer and an inert gas supply, 0.90 g (4.47 mmol) (3R,4S,5R)-5-amino-3,4-dihydroxy-cyclohex-1-enecarboxylic acid ethyl ester was suspended in 9.0 ml 3-pentanon, 0.32 ml (4.92 mmol) methanesulfonic acid was added, the mixture was heated to reflux, with a dean stark separator for 2 hours. The reaction mixture was cooled to r.t., diluted with 9.0 ml ethyl acetate and the mixture was extracted with 9.0 ml 1M aqueous sodium hydrogen carbonate solution. The organic layer was dried over about 1 g sodium sulfate and filtered. The filter cake was washed with about 9 ml of ethyl acetate and the combined filtrates were evaporated in a rotary evaporator at 40° C./10 mbar to yield as the crude intermediate 1.05 g (3aR,7R,7aS)-7-amino-2,2-diethyl-3a,6,7,7a-tetrahydro-benzo[1,3]dioxole-5-carboxylic acid ethyl ester.