Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH2:22]1[C:24]2([CH2:28][CH:27]([C:29]([NH2:31])=[O:30])[NH:26][CH2:25]2)[CH2:23]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH:27]([C:29]([NH2:31])=[O:30])[CH2:28][C:24]4([CH2:22][CH2:23]4)[CH2:25]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: NC(=O)C1CC2(CC2)CN1
Agent: Cl
Product: NC(=O)C1CC2(CC2)CN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Yield: 37.1 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 18.6 mg, 106 μmol) was reacted with 5-azaspiro[2.4]heptane-6-carboxamide hydrochloride (Example 135 b, 18.6 mg, 106 μmol) to obtain the title compound (16 mg, 56%) as colorless liquid, MS (EI): m/e=407.3 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6](Cl)[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.C(N(C(C)C)C(C)C)C.[C:22]([O:26][CH3:27])(=[O:25])[CH2:23][SH:24]>C(Cl)Cl>[CH3:27][O:26][C:22](=[O:25])[CH2:23][S:24][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([Cl:1])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: COC(=O)CS
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CSc1nc(SC)nc(Cl)c1C=O
Temperature: 25 °C

Procedure:
To an ice-cooled solution (−10° C.) of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde (2.0 g, 8.97 mmol) and iPr2EtN (0.82 mL, 8.97 mmol) in DCM (40 mL) was added methyl thioglycolate (1.56 mL, 8.97 mmol) in DCM (20 mL) over 15 min. The reaction mixture was let warm to RT, then washed with sat. NaHCO3, dried over MgSO4, filtered, and concentrated. The product was used without further purification. ESIMS calcd 293 (M++H), found 293 (M++H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:21][CH2:20][CH2:19][CH2:18][C:9]=2[N:10]=[C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:12]=1)(=O)=O.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([NH2:34])=[O:33])=[CH:27][CH:26]=1>>[CH:13]1([C:11]2[N:12]=[C:7]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([CH2:31][C:32]([NH2:34])=[O:33])=[CH:29][CH:30]=3)[C:8]3[S:21][CH2:20][CH2:19][CH2:18][C:9]=3[N:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=S(=O)(Oc1nc(C2CCCC2)nc2c1SCCC2)C(F)(F)F
Reactant: NC(=O)Cc1ccc(N)cc1
Product: NC(=O)Cc1ccc(Nc2nc(C3CCCC3)nc3c2SCCC3)cc1
Yield: 54.3 %

Procedure:
Following general procedure H, 2-cyclopentyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (0.133 g, 0.36 mmol) was reacted with 2-(4-aminophenyl)acetamide (0.063 g, 0.43 mmol) to afford the title compound (0.072 g, 54%) as an off-white solid. MW=368.50. 1H NMR (DMSO-d6, 300 MHz) δ 7.91 (s, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.44 (s, 1H), 7.16 (d, J=8.5 Hz, 2H), 3.31 (s, 2H), 3.13-3.07 (m, 2H), 3.00 (quin, J=8.0 Hz, 1H), 2.75 (t, J=6.5 Hz, 2H), 2.17-2.06 (m, 2H), 1.97-1.48 (m, 8H); APCI MS m/z 369 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](=[O:12])C)=[CH:4][CH:3]=1.[Cl-].C(OC(=O)C[N+:19]1[CH:24]=[CH:23]C=CC=1)C.[C:26]([O-])(=O)C.[NH4+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:26]=[C:24]([CH3:23])[NH:19][C:10](=[O:12])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C[n+]1ccccc1
Reactant: CC(=O)/C=C/c1ccc(Cl)cc1
Reactant: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1cc(-c2ccc(Cl)cc2)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47 %

Procedure:
A suspension of (E)-4-(4-chlorophenyl)but-3-en-2-one (5.42 g, 30 mmol, Aldrich Chemical Co.), 1-(2-ethoxy-2-oxoethyl)pyridinium chloride (6.05 g, 30 mmol) (prepared according to the procedure described in WO 94/04502) and ammonium acetate (46.3 g, 0.6 mol) in ethanol (150 mL) was stirred at room temperature for 15 min, then at reflux for 4 h. The reaction mixture was allowed to cool and stand at room temperature overnight. The resulting precipitate was collected by filtration, and the collected solid was washed with ethanol, then water, and dried in a vacuum oven at 45° C. for 16 h to afford 3.1 g (47%) of the title compound as an off-white solid. HPLC/MS: retention time=2.86 min, [M+H]+=220.3.
Reaction SMILES: NC[C@@H]1C[C@H](O)C1.CS([O:12][C@H:13]1[CH2:16][C@@H:15]([CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])[CH2:14]1)(=O)=O.[Cl:27][C:28]1[CH:29]=[C:30](O)[CH:31]=[C:32]([F:40])[C:33]=1[CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O.O>[Cl:27][C:28]1[CH:29]=[C:30]([CH:31]=[C:32]([F:40])[C:33]=1[CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)[O:12][C@H:13]1[CH2:16][C@H:15]([CH2:17][N:18]([CH3:19])[C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:14]1
Reactant: Oc1cc(F)c(CN2CCCC2)c(Cl)c1
Reactant: CN(C[C@H]1C[C@@H](OS(C)(=O)=O)C1)C(=O)OC(C)(C)C
Agent: NC[C@H]1C[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CN(C[C@H]1C[C@H](Oc2cc(F)c(CN3CCCC3)c(Cl)c2)C1)C(=O)OC(C)(C)C
Temperature: 92.5 °C

Procedure:
A mixture of intermediate 6, cis-3-{[(tert-butoxycarbonyl)(methyl)amino]methyl}cyclobutyl methanesulfonate (1.5 g, 5.2 mmol), intermediate 18, 3-chloro-5-fluoro-4-(pyrrolidin-1-ylmethyl)phenol (2.38 g, 10.4 mmol) and Cs2CO3 (3.38 g, 10.4 mmol) in DMSO (20 mL) was heated at 90-95° C. for 4 h under vigorous stirring in a flow of argon, then cooled. Water (40 ml) and EtOAc (40 ml) were added, and the layers were separated. The water layer was extracted with ether (20 ml), the combined organic layers were washed with 1N NaOH (3×25 mL), brine, dried with Na2SO4, and evaporated to give the title compound (1.8 g, 82%) as a yellow oil. LC/MS data: 427.6, 429.6, 430.5 (M+H) (calculated for C22H32CFIN2O3 426.96). 1H NMR-data (DMSO-d6): 6.76 (br. s, 1H, Ar—H); 6.71 (dd, 1H, J1=2.2 Hz, J2=11.5 Hz, Ar—H); 4.79-4.92 (m, 1H); 3.65 (s, 2H); 3.32 (d, 2H, J=8.0 Hz); 2.78 (s, 3H, NCH3); 2.38-2.62 (m, 5H+DMSO); 2.20-2.28 (m, 2H); 2.05-2.17 (m, 2H); 1.58-1.73 (m, 4H); 1.41 (s, 9H, Boc).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH3:21][C:15]1[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:19][CH:18]=[C:17]([CH3:20])[N:16]=1
Reactant: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(N2CCNCC2)c(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 141.8 %

Procedure:
To a mixture of 3-bromo-2,6-dimethylpyridine (2.0 g), t-Boc-piperazine (2 g), palladium(II) acetate (0.12 g), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.31 g) and sodium tert-butoxide (1.34 g) was added toluene (35 mL), and the mixture was stirred with heating under reflux for 9 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give 4-(2,6-dimethylpyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (3.06 g). The obtained 4-(2,6-dimethylpyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (2.16 g) was dissolved in chloroform (21 mL), 4N hydrogen chloride/ethyl acetate solution (10 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with aqueous potassium carbonate solution, the mixture was extracted with ethyl acetate, and the solvent was evaporated to give the title compound (2.01 g).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:12]#[N:13])[CH2:5][C:6]1([CH3:11])[O:10][CH2:9][CH2:8][O:7]1.[C:15]([NH2:23])(=[NH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1CCN2C(=NCCC2)CC1>CN(C=O)C.C(Cl)(Cl)Cl>[NH2:13][C:12]1[N:23]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:22]=[C:3]([OH:2])[C:4]=1[CH2:5][C:6]1([CH3:11])[O:7][CH2:8][CH2:9][O:10]1
Reactant: COC(=O)C(C#N)CC1(C)OCCO1
Reactant: N=C(N)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(Cc2c(N)nc(-c3ccccc3)nc2O)OCCO1

Procedure:
A solution of acetal (2) (1 g, 5.02 mmol), benzamidine (786 mg, 5.02 mmol), and DBU (1.5 mL, 10.04 mmol) in dry DMF (15 mL) was heated to 85° C. for 15 h. The mixture was diluted with CHCl3 (30 mL) and washed with 0.5 N NaOH (10 mL) and H2O (20 mL). The organic fraction was dried, filtered and concentrated to a brown oil. Flash chromatography (SiO2; 1/9 EtOAc/CH2Cl2, Rf 0.35) was attempted, but material crystallized on the column. The silica gel was washed with MeOH. Fractions containing the product (3) were concentrated and used without further purification (783 mg, 54.3%):
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH2:9][N:8]([CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:7]2=[O:21].[CH3:22]C(N(C)C)=O.CI>O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:22])[CH2:9][N:8]([CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:7]2=[O:21]
Reactant: CC(=O)N(C)C
Reactant: O=C1c2cc(Cl)ccc2NCN1CCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN1CN(CCN2CCCC2)C(=O)c2cc(Cl)ccc21
Reaction time: 0.5 h
Yield: 14 %

Procedure:
543 Milligrammes (22.5 mmoles) of 60% sodium hydride are added to 3.50 grammes (12.5 mmoles) of 6-chloro-2,3-dihydro-3-[2-(pyrrolidino)ethyl]-4(1H)-quinazolinone in 25 mlof anhydrous dimethylacetamide and the solution is left at room temperature, in agitation and in an inert gas atmosphere, for 30 minutes. 0.86 Ml (13.8 mmoles) of methyl iodide are slowly dripped and the reactionmixture is kept for 6 hours at room temperature. The reaction mixture is then diluted with water and ice and the product is extracted with ethyl ether and recovered through evaporation of the organic solvent, obtaining an oily substance, with a yield of 14%, presenting the following chemical-physical characteristics:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[C:12]1([CH:18]([CH3:22])[C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[C:9]([C:19](=[O:20])[CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:22])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C)[nH]1
Reactant: CC(C(=O)Cl)c1ccccc1
Product: CCOC(=O)c1cc(C(=O)C(C)c2ccccc2)c(C)[nH]1

Procedure:
5-Methyl-4-(2-phenyl-propionyl)-1H-pyrrole-2-carboxylic acid ethyl ester (138) was synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and 2-phenyl-propionyl chloride following the procedure described in Example 32. Reaction conditions: 1,2-dichloromethane/−40° C.→RT. Purification: no purification. LC/MS: 86%.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]2[C:14]([CH2:15][OH:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:7][CH:6]=[N:5]1)[CH3:3].[H-].[Na+].Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH3:27])[C:21]=1[CH:28]=[O:29]>CN(C)C=O>[CH:2]([N:4]1[C:8]([C:9]2[C:14]([CH2:15][O:16][C:20]3[C:21]([CH:28]=[O:29])=[C:22]([NH:26][CH3:27])[N:23]=[CH:24][CH:25]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:7][CH:6]=[N:5]1)([CH3:1])[CH3:3]
Reactant: CNc1nccc(Cl)c1C=O
Reactant: CC(C)n1nccc1-c1ncccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1nccc(OCc2cccnc2-c2ccnn2C(C)C)c1C=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Steps 3 & 4. Into a 100-mL round-bottom flask, was placed a solution of [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methanol (1.15 g, 5.29 mmol, 1.00 equiv) in N,N-dimethylformamide (40 mL). This was followed by the addition of sodium hydride (530 mg, 13.25 mmol, 2.50 equiv, 60%) at 0° C. The mixture was stirred for 15 min at 0° C. To this was added 4-chloro-2-(methylamino)pyridine-3-carbaldehyde (900 mg, 5.28 mmol, 1.00 equiv). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 5×30 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-020): Column, SunFire Prep C18 OBD Column, 5 um, 19*100 mm, mobile phase, water with 0.1% TFA and MeCN (3.0% MeCN up to 20.0% in 5 min, up to 95.0% in 2 min, down to 3.0% in 1 min); Detector, waters 2489 254&220 nm. This resulted in 107.1 mg (6%) of 2-(methylamino)-4-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methoxy)pyridine-3-carbaldehyde as a yellow solid. 1HNMR (400 MHz, DMSO, ppm): 8.72 (m, 1H), 8.17 (s, 1H), 7.91 (m, 1H), 7.52 (m, 3H), 6.56 (s, 1H), 6.26 (d, J=4.2 Hz, 1H), 6.15 (d, J=3.3 Hz, 1H), 5.43 (m, 1H), 5.12 (m, 1H), 4.60 (m, 1H), 2.87 (d, J=3.3 Hz, 1H), 1.46 (d, J=5.1 Hz, 1H), 1.35 (d, J=5.1 Hz, 1H); (ES, m/z): 352.1 [M+1]+
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:11].[N+](C1C=C(C=CC=1)C(Cl)=O)([O-])=O>C(Cl)Cl.C(N(CC)CC)C>[C:6]1(=[O:11])[C:7]2[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=2)[CH2:4][NH:5]1
Reactant: O=C1NCc2c(O)cccc21
Agent: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1NCc2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 0 %

Procedure:
To a solution of 4-hydroxy isoindolinone 27 (0.100 gm, 0.67 mmol) in methylene chloride (5 ml) and triethylamine (0.2 ml), was added m-nitrobenzoyl chloride (0.125 gm, 0.67 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 5 hr. After the usual workup, the resulting residue was purified by PTLC plate (solvent was 10% methanol-methylene chloride) to give 2,3-dihydro-1H-isoindol-1-one 32 (0.025 mg, 28%).
Reaction SMILES: N.[C:2]1([CH3:8])[CH:7]=CC=[CH:4][CH:3]=1.S(Cl)(Cl)=[O:10].C[N:14]([CH:16]=[O:17])C>>[CH3:4][C@H:3]1[C@@H:2]([CH3:8])[C:7](=[O:10])[NH:14][C:16]1=[O:17]
Reactant: CN(C)C=O
Reactant: Cc1ccccc1
Reactant: O=S(Cl)Cl
Agent: N
Product: C[C@@H]1C(=O)NC(=O)[C@@H]1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a cooling bath, ammonia gas was introduced into a toluene (5 ml) solution of 390 mg of cis-2,3-dimethylsuccinic anhydride for 30 minutes. The solvent was evaporated away under reduced pressure to obtain a white solid. This was dissolved in 10 ml of DMF, and at −78° C., 0.5 ml of thionyl chloride was added to it and stirred at 0° C. for 2 hours. The reaction liquid was restored to room temperature, the solvent was evaporated away under reduced pressure, ethyl acetate was added to the residue, and washed with aqueous saturated sodium hydrogencarbonate solution. After dried, the solvent was removed, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=7/3 to 0/1) to obtain 269 mg of the entitled compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[OH-].[Na+].C([O:18][C:19](OC(OC(C)(C)C)=O)=[O:20])(C)(C)C.O.[C:30](O)([CH3:33])([CH3:32])[CH3:31]>>[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([NH2:1])[C:19]([OH:20])=[O:18])([O:11][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:10]
Reactant: CC(C)(C)O
Reactant: NCCCCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)CCCCCCC(N)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8-Aminocaprylic acid (970.3 mg, 6.1 mmol) was dissolved in tert-butylalcohol (14.7 ml), 5N NaOH (1.44 ml, 6.1 mmol) was added thereto, and the mixture was stirred at room temperature for 10 minutes. Di-tert-butyl-dicarbonate (1.46 g, 6.7 mmol) dissolved in tert-butylalcohol (10 ml) was added thereto and stirred at room temperature for 24 hours. Then, water (10 ml) was added thereto and the mixture was concentrated under a reduced pressure, cooled to 0° C., and then, 2N H2SO4 was added thereto dropwise until pH of the mixture became 2. The resultant was extracted with ethyl acetate, the extract was washed with H2O, dried over MgSO4 and concentrated. The concentrate was purified using column chromatography (ethyl acetate:toluene:acetic acid=20:10:0.3) to obtain the title compound (1.78 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[N:13]=2)=[N:6][CH:7]=1.C(N(C(C)C)C(C)C)C.[SH:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47]>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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1>[CH3:49][O:48][C:46](=[O:47])[CH2:45][CH2:44][S:43][C:2]1[CH:3]=[C:4]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[N:13]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)CC1
Reactant: COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCSc1cnc(Nc2nc(C3CCN(C(=O)OC(C)(C)C)CC3)cs2)c(Oc2ccccc2)c1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A 100 mL round-bottomed flask was charged with tert-butyl 4-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate (1.6 g, 3.0 mmol), N-ethyl-N-isopropylpropan-2-amine (1.0 mL, 6.0 mmol), Xantphos (0.087 g, 0.15 mmol), and Dioxane (25 mL). Nitrogen was bubbled through the solution for 10 minutes. Methyl 3-mercaptopropanoate (0.40 mL, 3.6 mmol) and Pd2dba3 (0.068 g, 0.075 mmol) were added and the reaction was plunged into a 95° C. oil bath for 6 hours. The reaction was cooled to room temperature and the solids filtered through celite and concentrated. The residue was purified on silica (30% EtOAc in hexanes) to afford tert-butyl 4-(2-(5-(3-methoxy-3-oxopropylthio)-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate (1.4 g, 81.48% yield) as a white foam.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]([NH2:27])=[O:26])=[N:4][C:5]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].N[C:29]1C(C(OCC)=O)=NC(NC2C=CC=C(O)C=2)=NC=1NC1C=CC=CC=1OC.N>CO>[OH:24][C:20]1[CH:19]=[C:18]([NH:17][C:5]2[N:6]=[C:7]3[C:2]([N:1]=[CH:29][N:8]3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:3]([C:25]([NH2:27])=[O:26])[N:4]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1nc(Nc2cccc(O)c2)nc(Nc2ccccc2OC)c1N
Reactant: COc1ccccc1Nc1nc(Nc2cccc(O)c2)nc(C(N)=O)c1N
Agent: N
Solvent: CO
Product: COc1ccccc1-n1cnc2c(C(N)=O)nc(Nc3cccc(O)c3)nc21
Temperature: -78 °C
Yield: 87 %

Procedure:
5-Amino-2-(3-hydroxyphenylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carbox-amide. In a sealed tube, ethyl 5-amino-2-(3-hydroxyphenylamino)-6-(2-methoxyphenyl-amino)pyrimidine-4-carboxylate (See example 36.B) (76.4 mg, 0.193 mmol) was dissolved in anhydrous methanol (5 mL) and was chilled to −78° C. The solution was then saturated with ammonia gas. The reaction vessel was sealed at −78° C. and allowed to warm to room temperature. After 18 h the reaction was chilled to −78° C. and opened to atmosphere. The volatiles were evaporated and the resulting material was purified by column chromatography (100% ethyl acetate) to provide the title compound (61.5 mg, 0.168 mmol, 87% yield). MS (ESI) m/z 367.2 [M+1]+.
Reaction SMILES: Cl[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]([CH2:21][CH3:22])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11](=[O:23])[NH:10][C:9]1=[O:24])=[O:3].[N:25]1([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C.ClCCl>C(Cl)(Cl)Cl>[CH2:34]([O:33][C:31]([N:25]1[CH2:30][CH2:29][N:28]([C:2]([CH2:4][CH2:5][CH2:6][CH2:7][N:8]2[C:13](=[O:14])[C:12]([CH2:21][CH3:22])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11](=[O:23])[NH:10][C:9]2=[O:24])=[O:3])[CH2:27][CH2:26]1)=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CCC1(c2ccccc2)C(=O)NC(=O)N(CCCCC(=O)Cl)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCC1(c2ccccc2)C(=O)NC(=O)N(CCCCC(=O)N2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The acid chloride of step 3 (0.2 mole) in chloroform (75 mL) was added dropwise over 15 minutes to a mixture of benzyl 1-piperazinecarboxylate (6.0 g, 0.030 mole) and triethylamine (4.0 g, 0.04 mole) in chloroform (100 mL). This mixture was stirred at room temperature for 20 hrs, and dichloromethane was then added (300 mL). The mixture was washed with 10% hydrochloric acid solution (3×100 mL), washed with saturated sodium chloride solution (100 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed. The residue was then chromatographed on SiO2 to give a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:17]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]([CH2:29][CH2:30]S(C)(=O)=O)[CH2:21]1)(=[O:19])[CH3:18].C([O-])([O-])=O.[K+].[K+]>CC(CC(C)C)=O>[C:17]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]([CH2:29][CH2:30][N:14]2[CH2:13][CH:12]=[C:11]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][CH:7]=3)[CH2:16][CH2:15]2)[CH2:21]1)(=[O:19])[CH3:18]
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: CC(=O)N1CC(CCS(C)(=O)=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CC(=O)N1CC(CCN2CC=C(c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Yield: 10.4 %

Procedure:
A mixture of of 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.6 g), 19a (2.0 g), K2CO3 (4.0 g), and methylisobutylketone (20 ml) was refluxed for 16 hours. The mixture was filtered and evaporated in vacuo, and the residue was purified on silica gel eluted with ethyl acetate-methanol-triethylamine (90:5:5). Crystallization from ethanol gave the title product (0.3 g).
Reaction SMILES: [CH2:1]1[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][N:2]1C(OC(C)(C)C)=O.[Cl-:17].[Cl:18][C:19]1[CH:24]=[CH:23][NH+:22]=[CH:21][CH:20]=1>>[ClH:18].[ClH:17].[N:22]1[CH:23]=[CH:24][C:19]([N:7]2[CH2:6][CH2:5][C:4]3([CH2:1][NH:2][CH2:3]3)[CH2:9][CH2:8]2)=[CH:20][CH:21]=1
Reactant: [Cl-]
Reactant: Clc1cc[nH+]cc1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Product: Cl
Product: c1cc(N2CCC3(CC2)CNC3)ccn1

Procedure:
The synthesis was carried out analogously to the synthesis of amine AMN-07. For this, in step (i) tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate was reacted with 4-chloropyridinium chloride and in step (ii) the Boc protective group was split off in order to obtain the amine AMN-08.