Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH:15]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40].[Cl-].[NH4+]>ClCCl>[C:1]([O:5]/[N:6]=[C:7]1\[CH:8]=[C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)[O:10][C:11]2[C:16]\1=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:13][CH:12]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(CCCCO)cc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)O/N=c1\cc(-c2cc3cccn3cn2)oc2ccc(CCCCOS(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A ice-cooled solution of 6-(4-Hydroxy-butyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (115 mg, 0.28 mmol) (example 102B) in dichloromethane (5 ml) was treated with triethylamine (100 μl, 0.7 mmol) and dropwise with methanesulfonyl chloride (26 μl, 0.34 mmol). The mixture was stirred at room temperature for 3 hours and treated with a saturated solution of ammonium chloride, extracted with dichloromethane, washed with brine, dried over sodium sulfate and concentrated to dryness. The crude mesylate was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](Cl)=[N:11][CH:12]=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1[C:27]2[CH:28]=[C:29]([NH2:32])[CH:30]=[CH:31][C:26]=2[N:25]=[CH:24]1.C(O[Na])(C)(C)C>C1(C)C=CC=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]>[CH2:1]([O:8][C:9]1[C:10]([NH:32][C:29]2[CH:30]=[CH:31][C:26]3[N:25]=[CH:24][O:23][C:27]=3[CH:28]=2)=[N:11][CH:12]=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ncnc(Cl)c2OCc2ccccc2)cc1
Reactant: Nc1ccc2ncoc2c1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ncnc(Nc3ccc4ncoc4c3)c2OCc2ccccc2)cc1
Temperature: 115 °C
Yield: 25.9 %

Procedure:
5-(benzyloxy)-4-chloro-6-p-tolylpyrimidine (50 mg, 0.161 mmol) was dissolved in PhMe, to this was added benzo[d]oxazol-6-amine (23.7 mg, 1.1 eq), Pd(dba)2 (4.6 mg, 0.05 eq), t-BuONa (31 mg, 2 eq), and (±)-BINAP (15 mg, 0.15 eq). The mixture was degassed and heated at 115° C. overnight. The mixture was cooled to room temperature, diluted with EtOAc and washed with H2O. Preparative TLC gave 17 mg of the title compound.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[C:19]([C:21](O)=[O:22])[N:18]=[CH:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:24])[C:8](=[O:25])[C@H:7]2[CH2:26][CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:32]>>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[C:19]([C:21]([NH2:32])=[O:22])[N:18]=[CH:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:24])[C:8](=[O:25])[C@H:7]2[CH2:26][CH3:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [NH4+]
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3cnc(C(=O)O)c3)nc2N1C1CCCC1
Agent: CC(=O)[O-]
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3cnc(C(N)=O)c3)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 39, with (R)-1-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)-1H-imidazole-4-carboxylic acid (Example 37) used instead of (R)-1-(8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)-1H-pyrazole-4-carboxylic acid (Example 44) and ammonium acetate instead of dimethylamine hydrochloride. LCMS: 370.2 m/z (M+H)+; ret. Time: 3.97 (Analytical Method D).
Reaction SMILES: CI.[C:3]([O-])([O-])=O.[K+].[K+].[OH:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([OH:20])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14]>>[CH3:16][O:15][C:13](=[O:14])[C:12]1[CH:11]=[C:10]([O:9][CH3:3])[CH:19]=[C:18]([OH:20])[CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: [K+]
Solvent: CI
Product: COC(=O)c1cc(O)cc(OC)c1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1a, from methyl iodide (6.44 mL, 104 mmol), K2CO3 (28.8 g, 208.15 mmol), and methyl 3,5-dihydroxybenzoate (17.5 g, 64 mmol). Purification by column chromatography eluting with 15% EtOAc in hexanes gave a pale yellow solid (7.51 g, 40% yield). 1H NMR (400 MHz, CDCl3) δ 7.16 (dd, J=4.80, 2.27 Hz, 2 H) 6.63 (t, J=2.27 Hz, 1 H) 5.36 (s, 1H) 3.92 (s, 3 H) 3.83 (s, 3 H).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C([Li])CCC.[Cl:14]C(F)(Cl)C(F)(F)Cl>C1COCC1>[Cl:14][C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=1
Reactant: FC(F)(Cl)C(F)(Cl)Cl
Reactant: CC(C)n1cncn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)n1ncnc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 141 %

Procedure:
Under an atmosphere of nitrogen a solution of 1-isopropyl-1H-[1,2,4]triazole (19 mmol) in THF (50 mL) at −78° C. was treated with n-butyllithium (11.4 mL, 2.5 M, 28.5 mmol) dropwise giving a cream yellow suspension. Further n-butyllithium (3.8 mL, 2.5 M, 9.5 mmol) was added after 1 h and stirring continued for a further 1.5 h. 1,1,2-trichlorotrifluoroethane (4.57 mL, 38 mmol) was added dropwise giving a dark brown solution. The resultant reaction mixture was stirred for 15 min before being quenched by the addition of saturated aqueous NaHCO3 (20 mL) then allowed to warm to RT. The resultant mixture was extracted twice with diethyl ether, the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo to give 5-Chloro-1-isopropyl-1H-[1,2,4]triazole as a dark oil (3.9 g) which was used in the subsequent step without further purification. 1H NMR δ (ppm) (CDCl3): 7.85 (1H, s), 4.73-4.63 (1H, m), 1.54-1.46 (6H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:19][C@H:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][C:11]=3[CH3:21])[N:7]([C:22]#N)[CH2:6]1)=[O:4].[CH2:24](I)[CH2:25]C>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:19][C@H:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][C:11]=3[CH3:21])[N:7]([CH2:22][CH2:24][CH3:25])[CH2:6]1)=[O:4]
Reactant: CCCI
Reactant: COC(=O)[C@@H]1C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]2N(C#N)C1
Product: CCCN1C[C@H](C(=O)OC)C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]21
Yield: 54 %

Procedure:
As described at the beginning, the noncrystalline compound can be prepared from 6-cyano-2-methyl-8beta-ergoline-carboxylic acid methyl ester by reduction and alkylation with n-propyliodide in a 54% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[C:18]([N+:30]([O-:32])=[O:31])=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:28])([CH3:27])[C:21]=3[CH:29]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH:33]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[C:18]([N+:30]([O-:32])=[O:31])=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:27])([CH3:28])[C:21]=3[CH:29]=2)=[O:33])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(SCCCCOc2cc3c(cc2[N+](=O)[O-])NC(=O)OC3(C)C)cc1OC
Reactant: OO
Product: COc1ccc(S(=O)CCCCOc2cc3c(cc2[N+](=O)[O-])NC(=O)OC3(C)C)cc1OC

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dimethoxy-phenylmercapto)-butoxy]-7-nitro-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[CH:31]([NH2:34])([CH3:33])[CH3:32]>C(O)C>[CH:31]([NH:34][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1)([CH3:33])[CH3:32]
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)Nc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1
Reaction time: 2 h

Procedure:
To a solution of 100 mg (0.225 mmol) of the oxadiazole from Example 23A in 1.5 ml of ethanol were added 266 mg (4.50 mmol) of isopropylamine, and then the reaction mixture was stirred in the microwave at 80 for 2 h. Another 266 mg (4.50 mmol) of isopropylamine were added and the mixture was stirred in the microwave at 80° C. for a further 2 h. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 69.0 mg (66% of theory)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:24]=[CH:25][C:26]2[O:31][CH2:30][CH:29]([C:32](O)=[O:33])[O:28][C:27]=2[CH:35]=1>>[OH:22][C:23]1[CH:24]=[CH:25][C:26]2[O:31][CH2:30][CH:29]([C:32]([N:12]3[CH2:11][CH2:10][N:9]([CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH2:14][CH2:13]3)=[O:33])[O:28][C:27]=2[CH:35]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=C(O)C1COc2ccc(O)cc2O1
Product: O=C(C1COc2ccc(O)cc2O1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 65 %

Procedure:
That compound is obtained in a yield of 65% starting from 1-[bis(4-fluorophenyl)methyl]piperazine and 7-hydroxy-2,3-dihydro-1,4-benzodioxin-2-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])=O)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:25]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.C(Cl)Cl.[NH2:51][NH2:52]>O1CCOCC1.CO.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15](=[N:51][NH2:52])[NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:25]=1
Reactant: O=C(Nc1ccccc1Cl)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: NN
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: NN=C(Nc1ccccc1Cl)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Temperature: 80 °C

Procedure:
To a solution of 8-bromo-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide in dry 1,4-dioxane was added Lawesson's reagent. The 50 mL round-bottom was sealed and heated at 80° C. for 3 h. The reaction mixture was cooled to room temperature and concentrated to give the crude thioamide. The bright yellow crude solid thus obtained was taken up in methanol and methylene chloride and treated with hydrazine. Reaction progress was monitored by LCMS. Upon completion, the mixture was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated to give crude 8-bromo-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbohydrazonamide as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:21])=[CH:7][C:8]([NH:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1OB(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:21])=[CH:7][C:8]([NH:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccccc1OB(O)O
Reactant: Cc1cc(Nc2ccc(C#N)cc2)nc2cc(Br)ccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccccc1-c1ccc2c(C)cc(Nc3ccc(C#N)cc3)nc2c1

Procedure:
Prepared analogously to Example 27e from 4-[(7-bromo-4-methyl-quinolin-2-yl)-amino]-benzonitrile, 2-methylphenylboric acid, tetrakis-(triphenylphosphine)-palladium (0) and sodium carbonate in toluene/water.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:17][CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[C:5]2[N:6]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[NH:67]1[CH2:71][CH2:70][CH2:69][CH2:68]1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[CH2:18][O:17][C:4]1[C:5]2[N:6]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=[C:2]([N:67]2[CH2:71][CH2:70][CH2:69][CH2:68]2)[CH:3]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(Br)cn12
Reactant: C1CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(N3CCCC3)cn12
Reaction time: 16 h

Procedure:
500 mg of ethyl 6-bromo-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate (1.18 mmol, 1 equivalent), 43 mg of tris(dibenzylideneacetone)dipalladium (0.047 mmol, 4 mol %), 158 mg of sodium tert-butoxide (1.65 mmol, 1.4 equivalents), 67 mg of XPHOS (0.141 mmol, 12 mol %) and 294 μl of pyrrolidine (3.5 mmol, 3 equivalents) were dissolved in 30 ml of dry toluene and reacted in an oil bath preheated to 100° C. After 16 h at this temperature, the reaction mixture was cooled, filtered through kieselguhr, concentrated and chromatographed (Biotage Isolera Four; cyclohexane/ethyl acetate gradient as mobile phase). This gave 100 mg (19% of theory) of the title compound.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:41])([CH3:40])[C@@H:14]([O:32]CC1C=CC=CC=1)[C:15]([O:17][CH2:18][CH2:19][O:20][C:21](=[O:31])[CH2:22][O:23]CC1C=CC=CC=1)=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2].CO>[Pd].C(OCC)(=O)C>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:41])([CH3:40])[C@@H:14]([OH:32])[C:15]([O:17][CH2:18][CH2:19][O:20][C:21](=[O:31])[CH2:22][OH:23])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](OCc1ccccc1)C(=O)OCCOC(=O)COCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OCCOC(=O)CO
Reaction time: 8 h
Yield: 72.6 %

Procedure:
Following the general procedure of hydrogenolysis of benzyl ethers of Description 18, a mixture of [2-(phenylmethoxy)acetyloxy]ethyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoate (45a) (0.10 g, 0.17 mmol) and 0.1 g of 10 wt.-% of palladium on activated carbon in 6 mL of a mixture of methanol (MeOH) and ethyl acetate (EtOAc) was stirred overnight under a hydrogen atmosphere. After work-up and further purification by mass-guided preparative HPLC, 51 mg (73% yield) of the title compound (45) was obtained as a colorless, viscous oil after lyophilization of the solvents. 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.02-1.05 (2s, 3H), 1.10-1.13 (2s, 3H), 1.60 (t, J=5.2 Hz, 3H), 2.01 (s, 3H), 2.05-2.12 (m, 2H), 2.84-3.03 (br. m, 1H), 3.14-3.26 (m, 2H), 3.34-3.46 (m, 2H), 3.97-4.16 (m, 3H), 4.22 (s, 2H), 5.56-5.96 (br. m, 1H), 7.00-7.08 (m, 1H) ppm. MS (ESI) m/z: 414.02 (M+H)+, 435.96 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[ClH:16].[CH2:17](O)[CH3:18]>>[ClH:16].[CH2:17]([O:14][C:13](=[O:15])[C@H:2]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)[NH2:1])[CH3:18]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@@H](N)Cc1c[nH]c2ccccc12

Procedure:
A mixture of L-tryptophan (14.3 g, 0.07 mol) in 200 ml of ethanol containing ~7 g of anhydrous HCl was refluxed for 5 hours. The mixture was cooled and the solid which separated was recrystallized from ethanol/ether. Yield 17.4 g (92.5%), m.p. 226°-228° C. The product has the formula: ##STR1587## The product may also be named ethyl L-2-amino-3-indolepropionate.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=O)[CH3:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12].C1C=CC=CC=1>O>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(CC(C)NCC(O)c2ccccc2)cc1

Procedure:
2-Hydroxy-2-phenylethanamine (2.15 g) and 1-(4-carbomethoxyphenyl)propan-2-one (3.0 g) were heated in refluxing benzene (100 ml) under a Dean and Stark head until the theoretical amount of water had been collected. The solvent was replaced by methanol and the mixtue was stirred and cooled during the portionwise addition of sodium borohydride (3.0 g). The mixture was stirred for 2 hours, the solvent was evaporated and the residue was partitioned between water and chloroform. The organic extract was dried, evaporated and recrystallised from hexane, mp 82°-84°, (45:55 mixture of diastereoisomers) and from benzene/hexane, mp 121°-122°, (80:20 mixture of diastereoisomers). τ(CDCl3) 8.97 (3H, d, J=6 Hz), 6.85-7.60 (7H, m), 6.15 (3H, s), 5.33 (1H, m), 2.81 (2H, d, J=8 Hz), 2.70 (5H, m), 2.04 (2H, d, J=8 Hz). 13C NMR (d6DMSO)ppm. 20.15, 19.90; 53.82, 53.64; 55.03 54.86; 71.91, 71.73.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1.[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][OH:33]>>[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][O:33][CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CCl)n1
Reactant: OCc1ccccc1F
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(COCc2ccccc2F)n1
Yield: 61 %

Procedure:
As described for Example 157, 4-[2-chloromethyl-1-(4-nitro-phenyl)-1H-imidazol-4-yl]-5-methyl-3-phenyl-isoxazole (100 mg, 0.25 mmol), using 2-fluorobenzyl alcohol instead of 3-chlorobenzyl alcohol, was converted to the title compound (75 mg, 61%) which was obtained as a light yellow foam. MS: m/e=485.5 [M+H]+.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:35][C:36]#[N:37]>CN(C)C=O>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:35][C:36]#[N:37])[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#CCBr
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCn1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(C(=O)N3CCN(C4CCC4)CC3)ccc21
Yield: 7 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), sodium hydride and bromoacetonitrile in N,N-dimethylformamide, to give the desired product as a yellow gum (7%).
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[N:6]1[CH:7]=[CH:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12>C(Cl)(Cl)Cl>[N:6]1[CH:7]=[C:8]([S:2]([OH:5])(=[O:4])=[O:3])[N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12
Reactant: c1ccn2ccnc2c1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)c1cnc2ccccn12
Temperature: 25 °C
Yield: 0.1 %

Procedure:
Chlorosulfonic acid (0.170 mL, 2.55 mmol) was dissolved in chloroform (1 mL) and this solution was added dropwise to imidazo[1,2-a]-pyridine (0.100 g, 0.85 mmol) in chloroform (4 mL) over 10 min. The reaction mixture was heated to reflux for 24 h, then allowed to cool to RT and concentrated to dryness under vacuum. The crude oily product was treated with diethyl ether (10 mL) and ethanol (5 mL) resulting in a white precipitate. The solid was collected by filtration, washed with EtOH and dried to yield imidazo[1,2-a]-pyridine-3-sulfonic acid (0.128 mg). MS (ESI−) for m/z 131 (M−H)−.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:26][C:27]([F:42])([F:41])[C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:30]5[CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=[C:28]([C:27]([F:26])([F:42])[F:41])[CH:29]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 397, starting from 2-[(S)-1-Phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine and 3,5-bis(trifluoromethyl)phenyl boronic acid. Mass spectrum (ESI) 528.3 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[C:10]1[NH:11][C:12]2[CH:18]=[C:17]([C:19](Cl)=[O:20])[CH:16]=[CH:15][C:13]=2[N:14]=1.[CH2:22]([NH2:25])[CH2:23][CH3:24].CCN(C(C)C)C(C)C.CO>C(#N)C>[CH2:22]([NH:25][C:19]([C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([C:4]3[C:5]([Cl:9])=[CH:6][CH:7]=[CH:8][C:3]=3[Cl:2])[NH:11][C:12]=2[CH:18]=1)=[O:20])[CH2:23][CH3:24]
Reactant: O=C(Cl)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: CCCN
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1

Procedure:
A suspension of 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carbonyl chloride hydrochloride salt in acetonitrile (0.2 M, 0.10 mL) was added to a vial containing n-propylamine (0.2 M in toluene, 0.11 mL) and DIPEA (0.5M in toluene, 0.10 mL). After incubation on a shaker at ambient temperature overnight, the mixture was diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid propylamide: MS (m/z) 347.95 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2C(=O)C3C=CC=CC=3OC2(C)C)=[N:7][CH:8]=1)[CH3:2].Cl>>[NH2:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=1
Reactant: CCc1ccc(N2C(=O)c3ccccc3OC2(C)C)nc1
Agent: Cl
Product: CCc1ccc(N)nc1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
Following the general method of K. Wachi and A. Terada (Chem. Pharm. Bull., 1980, 28, 465-472), a mixture 81 mg (0.29 mmoles) of 3-(5-ethyl-2-pyridinyl)-2,2-dimethyl-2.3-dihydro-(4H)-1,3-benzoxazin-4-one and 2.0 mL of concentrated hydrochloric acid was heated to reflux for 8 h. The reaction was cooled to room temperature and the solvent was evaporated. The residue was dissolved in 4 mL ethyl acetate and washed with 3×1 mL of a 1:1 mixture of 10% of aqueous sodium hydroxide solution and saturated aqueous sodium chloride. The organic solution was dried (sodium sulfate), decanted, and evaporated to give 26 mg (84% yield) of 2-amino-5-ethylpyridine as an amber oil.