Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1C=CC=[C:2]1[C:6]1[N:10]([C:11]2[S:15][C:14]([CH2:16][NH:17][C:18](=[O:29])[C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])=[CH:13][CH:12]=2)[N:9]=[C:8]([C:30]([F:33])([F:32])[F:31])[CH:7]=1.P([O-])(O)(O)=[O:35].[Na+].Cl([O-])=O.[Na+]>C(#N)C.O>[C:24]([O:23][C:22]([NH:21][C@@H:19]([CH3:20])[C:18]([NH:17][CH2:16][C:14]1[S:15][C:11]([N:10]2[C:6]([C:2]([OH:35])=[O:1])=[CH:7][C:8]([C:30]([F:32])([F:31])[F:33])=[N:9]2)=[CH:12][CH:13]=1)=[O:29])=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccc(-n2nc(C(F)(F)F)cc2-c2ccco2)s1
Reactant: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccc(-n2nc(C(F)(F)F)cc2C(=O)O)s1
Temperature: 21 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
To a stirred solution of 24 (70 mg, 0.144 mmol) in acetonitrile (0.42 mL) at 0° C. was added a solution of sodium dihydrogen phosphate (87 mg, 0.722 mmol) in water (0.17 mL). Then a solution of sodium chlorite (131 mg, 1.44 mmol) in water (0.59 mL) was added drop wise. The mixture was allowed to reach 21° C., stirring for 3 h at 21° C. The mixture was quenched with 1N NaOH, washed with CH2Cl2 (2×), and the combined organic phase was extracted with 1N NaOH. The combined aqueous phase was acidified to pH 1 with 1N HCl, extracted with AcOEt, dried (MgSO4) filtered and concentrated to afford 25 (59 mg, 88%) as a yellow solid. LRMS (ESI): calc. 462.1; found 485.2 (MNa)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:31]1[CH2:36][CH2:35][S:34][CH2:33][CH2:32]1>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[C:15]2[O:14][CH:13]([CH2:12][N:31]3[CH2:36][CH2:35][S:34][CH2:33][CH2:32]3)[CH2:17][C:16]=2[CH:18]=1
Reactant: C1CSCCN1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Product: Cc1cccc(C)c1-c1cc(Cl)cc2c1OC(CN1CCSCC1)C2

Procedure:
The title compound was prepared (0.55 g, 39%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and thiomorpholine (0.72 g, 6.76 mmol). mp 224-226° C.
Reaction SMILES: [CH2:1]([N:4]([CH3:20])[CH2:5][CH:6]=[CH:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14][CH2:13]2)[CH:2]=[CH2:3].[CH2:21]([O:23][C:24](Cl)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([N:16]1[C:17]2[C:12](=[CH:11][C:10]([O:9][CH2:8][CH:7]=[CH:6][CH2:5][N:4]([CH2:1][CH:2]=[CH2:3])[CH3:20])=[CH:19][CH:18]=2)[CH2:13][CH2:14][CH2:15]1)=[O:25])[CH3:22]
Reactant: C=CCN(C)CC=CCOc1ccc2c(c1)CCCN2
Reactant: CCOC(=O)Cl
Product: C=CCN(C)CC=CCOc1ccc2c(c1)CCCN2C(=O)OCC

Procedure:
In analogy to example 3.9, Allyl-methyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-but-2-enyl]-amine and ethylchloroformate were converted to yield 6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester as brown oil, MS: 345 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18]C(=O)C(C)(C)C)=[N:4][C:5]([NH:13][C:14](=[O:17])[CH2:15]Cl)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]>C(O)(C)(C)C>[NH2:18][C:3]1[N:4]2[CH2:15][C:14](=[O:17])[N:13]=[C:5]2[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][C:2]=1[Cl:1]
Reactant: CCOC(=O)c1cc(Cl)c(NC(=O)C(C)(C)C)nc1NC(=O)CCl
Solvent: CC(C)(C)O
Product: CCOC(=O)C1=CC(Cl)=C(N)N2CC(=O)N=C12
Yield: 28.8 %

Procedure:
A solution of ethyl 5-chloro-2-[(chloroacetyl)amino]-6-[(2,2-dimethylpropanoyl)amino]nicotinate (EXAMPLE 24, Step 1, 6.55 g) in t-butyl alcohol (150 mL) was refluxed for 42 h. The formed precipitate was collected by filtration and washed with ethyl acetate to afford 1.28 g (29%) of the title compound as a pale purple solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:23](OCC)=[O:24])([CH3:22])[CH3:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>O1CCCC1>[C:7]([O:11][C:12]([N:14]1[CH2:15][CH2:16][N:17]([C:20]([CH3:22])([CH3:21])[CH2:23][OH:24])[CH2:18][CH2:19]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCOC(=O)C(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(C)(C)CO)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
To a suspension of lithium aluminium hydride powder (0.324 g) in anhydrous tetrahydrofuran (30 mL) at 0° C. under argon was added 4-(1-ethoxycarbonyl-1-methyl-ethyl)-piperazin-1-carboxylic acid tert-butyl ester (1.28 g). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours, then quenched with saturated aqueous ammonium chloride (10 mL). The reaction mixture was partitioned between water and dichloromethane and the combined organic layers washed with brine and dried (MgSO4). The solution was evaporated to give 4-(2-hydroxy-1,1-dimethyl-ethyl)-piperazin-1-carboxylic acid tert-butyl ester (0.43 g).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:13]2[CH:14]=[C:15]([C:18]3[C:19]([C:42]4[CH:47]=[CH:46][C:45]([NH:48][C:49]([N:51]5[CH2:56][CH2:55][O:54][CH2:53][CH2:52]5)=[O:50])=[CH:44][CH:43]=4)=[N:20][N:21]([C:23]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:22]=3)[CH:16]=[CH:17][C:12]2=[N:11][CH:10]=1.[CH3:57]I.O>CN(C)C=O.C(OCC)(=O)C>[CH3:57][N:48]([C:45]1[CH:44]=[CH:43][C:42]([C:19]2[C:18]([C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=5)=[CH:10][N:11]=4)[CH:14]=3)=[CH:22][N:21]([C:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:20]=2)=[CH:47][CH:46]=1)[C:49]([N:51]1[CH2:52][CH2:53][O:54][CH2:55][CH2:56]1)=[O:50]
Reactant: O=C(Nc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1)N1CCOCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)N1CCOCC1)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Reaction time: 0.33 h

Procedure:
6 mg sodium hydride was suspended in 2 mL N,N-dimethylformamide, then 3 mL of 64 mg morpholine-4-carboxylic acid {4-[4-(3-pyridin-2-ylimidazo[1,2-a]-pyridin-6-yl)-1-trityl-1H-pyrazol-3-yl]phenyl}amide (compound in Example 357) in N,N-dimethylformamide was added thereto under ice-coolingd water in a stream of nitrogen, and the reaction solution was returned to room temperature and stirred for 20 minutes. 7 μL methyl iodide was added thereto under ice-cooling and stirred for 20 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 55 mg of the title compound as a colorless amorphous.
Reaction SMILES: [ClH:1].COC[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[O:15][CH:16]1[CH2:19][NH:18][CH2:17]1.C1(C(C2C=CC=CC=2)N2C[CH:29]([O:31]C3C4C(=CC=CC=4)C=CC=3COC)C2)C=CC=CC=1>>[ClH:1].[CH3:29][O:31][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[O:15][CH:16]1[CH2:17][NH:18][CH2:19]1
Reactant: COCc1ccc2ccccc2c1OC1CNC1
Reactant: COCc1ccc2ccccc2c1OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Product: COc1ccc2ccccc2c1OC1CNC1

Procedure:
3-[(2-(Methoxymethyl)-1-naphthalenyl)oxy]-azetidine hydrochloride, mp 127° C. starting from 1-(diphenylmethyl)-3-[(2-(methoxymethyl)-1-naphtalenyl)oxy]-azetidine.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([S:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13]CC)=[O:12])[NH:4][N:3]=1.Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.Br.[OH-].[Na+]>C(O)(C)C.O>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:1][C:2]1[CH:6]=[C:5]([S:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([OH:13])=[O:12])[NH:4][N:3]=1
Reactant: CCOC(=O)c1cccc(Sc2cc(N)n[nH]2)c1
Reactant: Clc1ccccn1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)c1cccc(Sc2cc(Nc3ccccn3)n[nH]2)c1
Temperature: 175 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
A stirred solution of ethyl 3-(3-amino-1H-pyrazol-5-ylthio)benzoate (0.150 g, 0.57 mmol), 2-chloropyridine (0.130 g, 1.14 mmol) in isopropanol (2 mL) was treated with hydrobromic acid (0.150 mL) and heated at 175° C. in a microwave oven for 30 minutes. The mixture was then diluted with water (1.5 mL) and treated with sodium hydroxide (1 pellet). The reaction was stirred at room temperature overnight, then concentrated to dryness. The residue was dissolved in methanol, acidified with conc. hydrochloric acid and purified on Prep HPLC (MeCN/H2O/5 mM NH4OAc) to give the title material (0.113 g, 62%) as a solid. The compound was used as such in the next reaction.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:26][CH2:25][CH2:24][N:23](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:22][CH2:21][CH2:20][N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:18][CH2:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][CH2:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][CH2:11]2)(=O)=O)=CC=1.OS(O)(=O)=O.C(O)C>C(OCC)C>[NH:10]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)N2CCCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CCO
Product: C1CNCCCNCCNCCNCCNC1
Temperature: 100 °C
Yield: 39 %

Procedure:
A mixture of 1,4,7,10,14-penta(p-toluenesulfonyl)-1,4,7,10,14-pentaazacycloheptadecane prepared as in Example 12A (28.5 g, 0.0279 mole) and concentrated H2SO4 (100 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 72 H. To the resulting brown solution, ethanol (100 ml) was added dropwise with stirring at 0° C. followed by ethyl ether (1 l). The tan solid was filtered and washed thoroughly with ethyl ether. The solid was then dissolved in H2O (100 ml) and the resulting solution filtered and washed with ethyl ether. The pH of the solution was adjusted to 11 with 10N NaOH and the solvent was removed in vacuo. The resulting brown oily solid was extracted with hot THF (2×500 ml) and the THF extracts were filtered. The filtrates were combined and the solvent was removed in vacuo. The oily residue was dissolved in hot hexane and the insoluble impurities were removed by filtration. The solvent was removed in vacuo and the residual oil was purified by vacuum distillation to give 2.68 g (39% yield) of the product as a light yellow oil: bp 140°-5° C. (0.10 mm Hg); 1H NMR (CDCl3) δ 1.51 (br s, 5 H), 1.68 (quint, J=6.1 Hz, 4 H), 2.73 (m, 20 H); Exact mass (M+H)+ : calcd., 244.2501; Found: 244.2555 (C12H30N5).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[Br:10])=[O:4]>CO.O1CCCC1.[OH-].[Na+]>[Br:10][C:9]1[CH:8]=[CH:7][S:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1sccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
3-Bromo-2-thiophenecarboxylic acid methyl ester (7.74 g) was dissolved in a mixture of methanol (35 ml) and tetrahydrofuran (35 ml), and 1N aqueous sodium hydroxide (53 ml) was added. The mixture was stirred at room temperature for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-bromo-2-thiophenecarboxylic acid (7.05 g) as crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][C:23]([O:25]C)=[O:24])([CH2:18][CH2:19]3)[O:16][CH2:15]4)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH3:27][C:28]1[O:29][C:30]([C:36]([F:39])([F:38])[F:37])=[C:31]([C:33](O)=[O:34])[N:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Li+].[OH-]>CN(C=O)C.O.C1COCC1.C(O)(=O)C.CCN(CC)CC>[CH3:27][C:28]1[O:29][C:30]([C:36]([F:39])([F:37])[F:38])=[C:31]([C:33]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]45[CH2:21][CH2:20][C:17]([CH2:22][C:23]([OH:25])=[O:24])([CH2:18][CH2:19]4)[O:16][CH2:15]5)=[CH:10][CH:9]=3)=[N:6][CH:7]=2)=[O:34])[N:32]=1
Reactant: Cc1nc(C(=O)O)c(C(F)(F)F)o1
Reactant: COC(=O)CC12CCC(c3ccc(-c4ccc(N)cn4)cc3)(CC1)CO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nc(C(=O)Nc2ccc(-c3ccc(C45CCC(CC(=O)O)(CC4)OC5)cc3)nc2)c(C(F)(F)F)o1
Yield: 19 %

Procedure:
To a solution of methyl 2-(4-(4-(5-aminopyridin-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (212 mg, 0.602 mmol) in DMF (3 ml) at rt under N2 was added 2-methyl-5-(trifluoromethyl)oxazole-4-carboxylic acid (141 mg, 0.722 mmol) and Et3N (0.167 ml, 1.203 mmol. The mixture was stirred for 5 minutes before the addition of HATU (274 mg, 0.722 mmol) at room temperature. Upon completion of reaction, the mixture was diluted with H2O (25 ml) and extracted with EtOAc (50 ml). The organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated to afford the crude methyl ester. LC/MS, ESI-MS (+): 530.0, RT: 1.37 (Condition E). The crude methylester was suspended in THF (4 ml) and treated with 1N LiOH (0.722 ml, 0.722 mmol). Upon completion of reaction, the mixture was diluted with H2O and brought to pH 5 with acetic acid. The resulting slurry was filtered, washed with H2O and dried at 80° C. for several hours. The crude solid was triturated with hot EtOH, AcN, and Et2O to give the title compound as off-white solid after drying (65 mg, 19% yield). HR/MS (M+H)+ found 516.1749. calc. 516.1735, RT: 2.76 (Condition L). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.08 1 (s, 1H), 10.92 (s, 1H), 9.03 (s, 1H), 8.30 (d, J=8.0 Hz, 1H), 7.99 (d, J=16.0 Hz, 2H), 7.94 (d, J=16.0 Hz, 1H), 7.44 (d, J=8.00 Hz, 2H), 3.91 (s, 2H), 2.63 (s, 3H), 2.33 (s, 2H), 2.08-1.85 (m, 8H).
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C=CC(C2NC(C3C=CC(OC)=CC=3OCC)=NC2C)=CC=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[N:43]([C:44]([N:46]3[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]3)=[O:45])[C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:54]=3[O:61][CH2:62][CH3:63])=[N:41][CH:40]2[CH2:64]C2CCCC2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[N:43]([C:44]([N:46]3[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]3)=[O:45])[C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:54]=3[O:61][CH2:62][CH3:63])=[N:41][CH:40]2[CH3:64])=[CH:35][CH:34]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Agent: CCOc1cc(OC)ccc1C1=NC(C)C(c2ccc(Cl)cc2)N1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(OC)ccc1C1=NC(C)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1

Procedure:
[5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone was prepared from 5-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-1H-imidazole, trifluoroacetate salt (Example 17) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 471.2166, calculated for C25H32N4O3Cl [(M+H)+]471.2158.
Reaction SMILES: [NH2:1][CH:2]1[CH2:9][CH2:8][CH2:7][NH:6][C:4](=[O:5])[CH2:3]1.C(N(CC)CC)C.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>C(Cl)Cl>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][CH:2]1[CH2:9][CH2:8][CH2:7][NH:6][C:4](=[O:5])[CH2:3]1)=[O:21]
Reactant: O=C(Cl)c1ccccc1F
Reactant: NC1CCCNC(=O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CC(NC(=O)c2ccccc2F)CCCN1

Procedure:
3-Amino-ε-caprolactam (11.0 g) and triethylamine (15.7 ml) were added to 200 ml of methylenechloride. Then a solution of 2-fluorobenzoyl chloride (15.0 g) in methylenechloride (30 ml) was added dropwise to the mixture under ice-cooling and stirring. Thereafter, the mixture was stirred for 1.5 hrs. at room temperature, and the resultant precipitate was collected by filtration to give 3-(2-fluorobenzoyl)amino-ε-caprolactam as crude crystals. This crystals and phosphorus pentasulfide (16.5 g) were added to 200 ml of pyridine, and the whole was refluxed for 12 hrs. After cooling, the pyridine was removed by distillation, and to the residue was added a saturated sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed with water, dried, and the solvent was distilled off under reduced pressure. The residue was purified by a column chromatography on silica gel, and then recrystallized from ethyl ether to give the title compound (4.55 g, 24.7 %).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:16]2[NH:15][C:14](=[O:17])[O:13][C:12]([CH3:19])([CH3:18])[C:11]=2[CH:10]=[CH:9][CH:8]=1.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([S:26][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[C:16]3[NH:15][C:14](=[O:17])[O:13][C:12]([CH3:19])([CH3:18])[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1(C)OC(=O)Nc2c(OCCCCCl)cccc21
Reactant: Sc1ccccc1
Product: CC1(C)OC(=O)Nc2c(OCCCCSc3ccccc3)cccc21

Procedure:
Prepared analogously to Example 1 from 8-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and thiophenol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[O:5][CH:6]=1.[CH2:9]([O:11][C:12](=[O:17])[CH2:13][N:14]=[N+]=[N-])[CH3:10].[O-]CC.[NH4+].[Cl-].C([O-])(=O)C=C>O.CCOCC.C(O)C>[CH2:9]([O:11][C:12]([C:13]1[NH:14][C:3]2[C:2]([Br:1])=[CH:6][O:5][C:4]=2[CH:7]=1)=[O:17])[CH3:10]
Reactant: O=Cc1cc(Br)co1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: C=CC(=O)[O-]
Agent: CC[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1cc2occ(Br)c2[nH]1

Procedure:
4-Bromo-2-furaldehyde was annulated according to Procedure H (aldehyde and azido-acetic acid ethyl ester added as ethanol solution (1 M of ester) to −20° C. ethoxide solution; −20° C. 35 min, −5° C. 1.5 h, 5° C. 15 min; reaction poured into cold saturated aqueous NH4Cl; after ether extraction, acrylate organic phase washed with water until aqueous phase was neutral; 0.5 M solution of crude acrylate heated).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[C:12]2C=CC=C[C:11]=2N=N1.[C-]#N.[K+].C(Cl)(=O)C>C1(C)C=CC=CC=1.CCO>[N:1]1[CH:11]=[C:12]([NH2:8])[N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: c1ccc2[nH]nnc2c1
Reactant: Nc1ccccn1
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)Cl
Solvent: Cc1ccccc1
Product: Nc1cnc2ccccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of amino-pyridine derivative Gen-1 (1 eq.) in toluene are added the aldehyde RzCHO (1 eq.) and benzotriazole (1 eq.). The mixture is stirred at r.t. overnight. Additional aldehyde reagent (0.06 eq.) and benzotriazole (0.06 eq.) are added. After 4 h stirring, potassium cyanide (1.2 eq.) is added, followed by EtOH. The reaction mixture is stirred at r.t. for 5 days. The crude product mixture is then quenched with a 3 M NaOH solution. Solvents are evaporated carefully in vacuo. The residue is diluted with water and EtOAc. The aqueous layer is extracted with EtOAc. The combined organic layers are washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The crude product mixture is dissolved in EtOH and carefully added to a solution of acetyl chloride (2.1 eq.) in EtOH at 0° C. The resulting reaction mixture is stirred at r.t. overnight and then concentrated to dryness to afford the corresponding imidazo[1,2-a]pyridin-3-ylamine as hydrochloride salt.
Reaction SMILES: FC(F)(F)C(O)=O.[BH4-].[Na+].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][CH:19]=[C:20]([CH:22]([OH:25])[C:23]#[N:24])[N:21]=2)=[CH:13][CH:12]=1>C1COCC1>[NH2:24][CH2:23][CH:22]([C:20]1[N:21]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[O:18][CH:19]=1)[OH:25]
Reactant: N#CC(O)c1coc(-c2ccc(F)cc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: NCC(O)c1coc(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
Trifluoroacetic acid (0.35 mL, 4.60 mmol) was added dropwise to a suspension of NaBH4 (0.174 g, 4.60 mmol) in dry THF (10 mL) at 0° C., followed by addition of 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-hydroxyacetonitrile (0.20 g, 0.92 mmol) also portionwise. The reaction mixture was stirred at room temperature for 8 h, and then concentrated under reduced pressure and diluted with ice-water. The mixture was acidified to pH ˜2 using 1.5N HCl at 0° C. and then heated to 50° C. for 20 min. The solution was basified with aqueous NH4OH solution and the organic product was extracted with CHCl3. The combined extracts were washed with brine and concentrated under reduced pressure to afford 2-amino-1-(2-(4-fluorophenyl)oxazol-4-yl)ethanol (120 mg, crude), which was carried through without further purification. MS (ESI) m/z: Calculated for C11H11FN2O2: 222.08. found: 222.8 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]3[C:31]4[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=4)[N:25]([CH3:33])[N:24]=3)[N:21]=2)[N:16](COCC[Si](C)(C)C)[CH:15]=1)=[O:13])[CH2:5][CH2:6][S:7]([CH3:10])(=[O:9])=[O:8].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[CH3:10][S:7]([CH2:6][CH2:5][C@H:4]([NH:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]3[C:31]4[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=4)[N:25]([CH3:33])[N:24]=3)[N:21]=2)[NH:16][CH:15]=1)=[O:13])[CH2:3][O:2][CH3:1])(=[O:8])=[O:9]
Reactant: COC[C@H](CCS(C)(=O)=O)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@H](CCS(C)(=O)=O)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 43.6 %

Procedure:
In a 10 mL round-bottom flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1-methoxymethyl-3-methanesulfonyl-propyl)-amide (35 mg, 0.058 mmol) and TFA (0.5 ml, 6.5 mmol) were combined with dichloromethane (1.5 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (1 mL) and ethylenediamine (0.19 ml, 2.8 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (dichloromethane/heptane) to afford 12 mg (44%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-3-methanesulfonyl-1-methoxymethyl-propyl)-amide as a light yellow solid. MS: [M+Na]+=497; 1H NMR (300 MHz, DMSO-d6) δ: 12.87 (br. s., 1H), 9.12 (s, 1H), 8.54 (dd, J=8.7, 5.3 Hz, 1H), 8.47 (s, 1H), 8.28 (d, J=9.1 Hz, 1H), 7.69 (dd, J=9.8, 2.3 Hz, 1H), 7.19 (td, J=9.1, 2.3 Hz, 1H), 4.35-4.55 (m, 1H), 4.15 (s, 3H), 3.60 (dd, J=9.8, 4.2 Hz, 1H), 3.51 (dd, J=9.4, 4.2 Hz, 1H), 3.26 (s, 3H), 3.20-3.28 (m, 2H), 2.97 (s, 3H), 2.02-2.23 (m, 2H).