Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9]([S:11][CH2:12][C:13]3[NH:14][CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=3)[N:10]=[C:6]2[CH:5]=[C:4]([CH3:24])[CH:3]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:25]([SH:11]([CH2:12][C:13]1[NH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)[C:9]1[N:10]=[C:6]2[CH:5]=[C:4]([CH3:24])[CH:3]=[C:2]([CH3:1])[N:7]2[N:8]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(C)n2nc(SCc3nc(-c4ccccc4)c[nH]3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)n2nc([SH](Cc3ccccc3)Cc3nc(-c4ccccc4)c[nH]3)nc2c1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of 5,7-dimethyl-2-(4-phenyl-1H-imidazol-2-ylmethylsulfanyl)-[1,2,4]triazolo[1,5-a]pyridine (15 mg, 0.045 mmol) in DMF (0.5 mL) was added benzyl bromide (5.4 μL, 0.045 mmol) and potassium carbonate (9.3 mg, 0.067 mmol) and the resulting mixture was stirred overnight at 75° C. Volatiles were evaporated and the residue was purified by preparative LC-MS to yield the title compound. LC-MS: m/z=426.3 (MH+), tR=1.06 min, method A.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[N:8]([CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[C:32]([F:31])[CH:33]=2)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2[nH]c1=O
Reactant: Fc1cccc(CBr)c1
Product: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2n(Cc2cccc(F)c2)c1=O

Procedure:
This compound was prepared from 6-fluoro-4-[4-(furan-2-carbonyl)-piperazin-1-yl]-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (81) and 3-fluorobenzyl bromide according to General Procedure B. Yield 421 mg (49%), MP 121° C.; 1H-NMR (DMSO-d6): δ 1.27 (t, J=7.2 Hz, 3H), 3.15 (m, 4H), 3.92 (m, 4H), 4.29 (q, J=7.2 Hz, 2H), 5.53 (s, 2H), 6.65 (dd, J=1.6, 3.2, Hz, 1H), 7.05 (m, 4H), 7.33 (m, 1H), 7.87 (d, J=1.6 Hz, 1H), 8.18 (dd, J=2.8, 8.8 Hz, 1H), 8.73 (d, J=2.8 Hz, 1H); EIMS: 523 (M+1). Anal. (C27H24F2N4O5) C, H, N.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[N:4]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:29]Br>C(O)(=O)C>[Br:29][CH2:2][CH2:1][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[N:4]=1
Reactant: CCc1nc(Nc2cccnc2)cc(-c2cccc(OC)c2)n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc(-c2cc(Nc3cccnc3)nc(CCBr)n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
[2-ethyl-6-(3-methoxyphenyl)pyrimidin-4-yl]-3-pyridylamine 14 (synthesized with a procedure similar to the one previously described) (1 eq) is dissolved in acetic acid, then sodium acetate (2 eq) is added. To this mixture, a solution of bromine (1 eq) in acetic acid is added dropwise. The reaction is stirred at room temperature for 3 h. The reaction mixture is concentrated under reduced pressure, water is added and the solution basified (pH ˜10-11) with sat. aq. Na2CO3 solution. The product 15 crashes out, is filtered off, dried, and used as is in the following step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CC(C)CCBr
Reactant: CCOC(=O)CSc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CSc1ccc(OCCC(C)C)cc1
Temperature: 25 °C

Procedure:
To stirred solution of (4-Hydroxy-phenylsulfanyl)-acetic acid ethyl ester (2.12 g, 10 mmol), K2CO3(anhydrous, 10 g) and 1-bromo-3-methyl butane (3 g, excess) was added in boiling acetone. The reaction mixture was refluxed for 24 hrs and cooled to room temperature. The reaction mixture was filtered and concentrated. The residue obtained was extracted with chloroform; washed well with water and concentrated. The crude product obtained was taken to next step with out purification. Yield 2.7 g (94%); (M+H)+ 283.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:27]([N:35]1[C:39](=[O:40])[C:38]([CH:42]([CH3:44])[CH3:43])([CH3:41])[N:37]=[C:36]1[C:45]1[N:54]=[CH:53][C:52]([CH3:55])=[CH:51][C:46]=1[C:47]([O:49][CH3:50])=[O:48])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:27]([N:35]1[C:39](=[O:40])[C:38]([CH:42]([CH3:44])[CH3:43])([CH3:41])[N:37]=[C:36]1[C:45]1[N:54]=[CH:53][C:52]([CH2:55][Br:1])=[CH:51][C:46]=1[C:47]([O:49][CH3:50])=[O:48])(=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(C)cnc1C1=NC(C)(C(C)C)C(=O)N1C(=O)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(CBr)cnc1C1=NC(C)(C(C)C)C(=O)N1C(=O)c1ccccc1
Temperature: 70 °C
Yield: 35.5 %

Procedure:
Solid N-bromosuccinimide (22.98 g, 0.129 mol) and benzoyl peroxide (3.12 g, 0.0129 mol) are added to a 25° C. solution of 2-(1-benzoyl-4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-5-methylnicotinic acid, methyl ester (46.2 g, 0.117 mol) in carbon tetrachloride. The reaction mixture is heated at 70° C. for 16 hours, cooled to room temperature, diluted with methylene chloride, washed sequentially with 5% sodium metabisulfite solution and water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give an oil. The oil is chromatographed using silica gel and hexanes/ethyl acetate (3:1) to (1:1) as eluant to give the title compound as a yellow solid (19.64 g, 35%), mp 88°-119° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].Cl.[NH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:12])=[CH:13][CH:14]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(O)c1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(O)c1ccc(C(=O)NCCC(=O)OCC)cc1
Reaction time: 16 h
Yield: 92.5 %

Procedure:
N,N-dimethylformamide (8.60 mL) was added to a vial containing 4-(1-hydroxybutyl)benzoic acid (250 mg, 1.29 mmol), ethyl 3-aminopropanoate hydrochloride (395 mg, 2.57 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′ tetramethyluronium hexafluorophosphate (979 mg, 2.57 mmol). Diisopropylethylamine (1.12 mL, 6.44 mmol) was then added. The reaction was stirred for 16 h, and was then concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) afforded ethyl 3-(4-(1-hydroxybutyl)benzamido)propanoate (350 mg, 93% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=8.2 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 6.84 (br. s., 1H), 4.74 (t, J=6.5 Hz, 1H), 4.23-4.07 (m, 2H), 3.72 (q, J=5.9 Hz, 2H), 2.64 (t, J=5.9 Hz, 2H), 1.85-1.72 (m, 1H), 1.72-1.58 (m, 1H), 1.52-1.37 (m, 1H), 1.37-1.30 (m, 1H), 1.28 (t, J=7.2 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H). MS (M+1) 294.3.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[C:11]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[C:31]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:30]=[CH:29][C:28]([C:24]2[O:25][C:26]([CH3:27])=[C:22]([CH2:21][CH2:20][O:19][C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=3[CH2:15][CH2:16][CH2:17][CH3:18])[O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:40])=[O:3])[N:23]=2)=[CH:33][CH:32]=1
Reactant: CCCCc1ccc(OC(C)(C)C(=O)OCC)cc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1ccc(OC(C)(C)C(=O)O)cc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Temperature: 55 °C
Yield: 75.5 %

Procedure:
A solution of 2-{3-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)-ethoxy]-4-butylphenoxy}-2-methylpropionic acid ethyl ester (0.12 g, 0.258 mmol) in ethanol (3 mL) was treated with 2 N aqueous NaOH (0.64 mL), and heated at 55° C. for 8 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with ethyl acetate (25 mL) and water (20 mL) and acidified to pH 1 with 1N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give a white solid (0.10 g, 88%). 1H NMR (400 MHz, CDCl3) δ8.05 (d, J 8.3 Hz, 2H), 7.69 (d, J=8.3 Hz, 2H), 7.64 (d, J=7.3 Hz, 2H), 7.47 (t, J=7.8 Hz, 2H), 7.38 (t, J=7.3 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 6.81 (s, 1H), 6.50 (d, J=8.3 Hz, 1H), 4.24 (t, J=7.6 Hz, 2H), 2.93 (t, J=7.6 Hz, 2H), 2.40 (s, 3H), 1.60 (s, 6H), 1.51 (penta, J=7.6 Hz, 2H), 1.39-1.26 (m, 2H), 0.91 (t, J=7.3 Hz, 3H), MS (ES) m/e 514 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:23]([O-:25])=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>CO.[OH-].[Na+]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]2([C:23]([OH:25])=[O:24])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[CH2:14][CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCN(CC2(C(=O)[O-])CCOCC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCN(CC2(C(=O)O)CCOCC2)CC1
Temperature: 60 °C
Reaction time: 7 h
Yield: 65.7 %

Procedure:
To a solution of Methyl 4-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl) methyl]tetrahydro-2H-pyran-4-carboxylate (6.47 g, 17.5 mmol, Step 10) in MeOH (32 mL), 5 N NaOH aq (10 mL) was added at room temperature (exothermic). The resulting solution was stirred at 60° C. for 7 h, then cooled to 5˜10° C. in ice-cold bath. To this solution, 5 N HCl aq (10 mL) was added and the resulting solution (pH value was ca.6) was concentrated. To the residue, 2-propanol (80 mL) was added. This solution was concentrated. To the residue, 2-propanol (80 mL) was added and it was concentrated again. The residue was diluted with EtOH (80 mL) and the mixture was stirred at room temperature for 2 h. It was filtered through a celite pad (5.0 g) to remove NaCl. The Celite pad was washed with EtOH (20 mL) and the combined filtrate was concentrated. To the residue, CH3CN (40 mL) was added and it was concentrated. During this procedure, the formation of white precipitate was noticed. To the residue CH3CN (40 mL) was added and the resulting suspension was stirred at room temperature for 2 h. This mixture was filtered and obtained solid was washed with CH3CN (10 mL), then dried under reduced pressure to give 4.1 g (65%) of the titled compound as white powder.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[OH:6][CH2:7][C@H:8]1[O:13][C:12]([CH3:15])([CH3:14])[O:11][C@@H:10]([CH2:16][C:17](OC)=[O:18])[CH2:9]1>>[CH2:1]([NH:5][C:17](=[O:18])[CH2:16][C@H:10]1[CH2:9][C@@H:8]([CH2:7][OH:6])[O:13][C:12]([CH3:14])([CH3:15])[O:11]1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Reactant: CCCCN
Product: CCCCNC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1

Procedure:
Mixture of n-butyl amine (100 grams), methyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (20 grams) was heated to reflux and stirred. After completion of the reaction, distilled off n-butylamine under reduced pressure at below 60° C. The obtained residue was further purified using mixture of cyclohexane and ethyl acetate.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2O.P(Cl)(Cl)([Cl:18])=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: Oc1ncnc2ccc(C(F)(F)F)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Yield: 54.2 %

Procedure:
6-Trifluoromethyl-quinazolin-4-ol (0.95 g, 4.44 mmol, 1 eq.), phosphorous oxychloride (2.48 mL, 26.6 mmol, 6 eq.) and triethylamine (3.71 mL, 26.6 mmol, 6 eq.) were refluxed for 2.5 hours. Stripped 3× from methylene chloride then dissolved in methylene chloride and rinsed 3× with saturated NaHCO3, 1× with brine. Dried and stripped in vacuo to give and amber oil. Purified over silica gel in 9:1 Hexanes/EtOAc. Obtained 560 mg of off-white solids as product. The product was used immediately in Ex 111 part C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][N:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2)#N.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:24]>C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:4]=[CH:5][N:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2)=[O:24]
Reactant: N#Cc1ccn2c1CCC2
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1ccn2c1CCC2
Temperature: -20 °C
Yield: 59 %

Procedure:
13.21 g (0.1 mol) of 7-cyano-2,3-dihydro-1H-pyrrolizine is dissolved in 150 ml of absolute toluene and cooled to -20° C. To this solution is added dropwise 108 ml (0.13 mol) of a 1.2-molar diisobutyl aluminum hydride solution in toluene; the mixture is then warmed to room temperature, stirred for another hour, and decomposed with 300 ml of 10% aqueous citric acid solution. The product is extracted with methylene chloride, the organic phase is dried, concentrated, and the residue recrystallized from ether, thus obtaining 8.0 g (59% of theory) of 7-formyl-2,3-dihydro-1H-pyrrolizine, mp 58° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([CH3:5])=O.[Cl:8][C:9]1[C:10]([NH:15][NH2:16])=[N:11][CH:12]=[CH:13][CH:14]=1>>[F:1][C:2]([F:7])([F:6])[C:3](=[N:16][N:15]=[C:10]1[C:9]([Cl:8])=[CH:14][CH:13]=[CH:12][NH:11]1)[CH3:5]
Reactant: CC(=O)C(F)(F)F
Reactant: NNc1ncccc1Cl
Product: CC(=NN=c1[nH]cccc1Cl)C(F)(F)F
Reaction time: 0.17 h
Yield: 66 %

Procedure:
1,1,1-Trifluoroacetone (7.80 g, 69.6 mmol) was added to (3-chloro-pyridin-2-yl)-hydrazine (alternatively named (3-chloro-pyridin-2-yl)-hydrazine) (10 g, 69.7 mmol) at 20-25° C. After the addition was complete, the mixture was stirred for about 10 minutes. The solvent was removed under reduced pressure, and the mixture was partitioned between ethyl acetate (100 mL) and saturated sodium carbonate solution (100 mL). The organic layer was dried and evaporated. Chromatography on silica gel (eluted with ethyl acetate) gave the product as an off-white solid (11 g, 66% yield), m.p. 64-64.5° C. (after crystallization from ethyl acetate/hexanes).
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:24][CH2:25][NH:26][CH:27]=O)=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>C1COCC1>[CH3:27][NH:26][CH2:25][CH2:24][O:23][C:16]1[C:15]2[C:14]3[C:22]4=[C:10]([O:9][CH2:8][CH:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:21]4[C:20]=2[CH:19]=[CH:18][CH:17]=1)[CH:11]=[CH:12][CH:13]=3
Reactant: O=CNCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Solvent: C1CCOC1
Solvent: CO
Product: CNCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 85 °C
Yield: 72.6 %

Procedure:
To a mixture of 2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethylformamide (0.769 g, 2.06 mmol) in dry THF (10 mL) is added borane-methylsulfide complex (0.59 mL, 6.2 mmol). The mixture is refluxed at 85° C. under an argon atmosphere for 19.5 h. The mixture is then cooled to room temperature and methanol is slowly added until gas evolution ceased. The solvents are removed under vacuum and methanol (10 mL) is added and then removed. The mixture is dissolved in methanol (15 mL), CH2C2 (5 mL) and conc. HCl (4 mL) and then heated at 65° C. for 1.5 h. The mixture is then neutralized with aqueous potassium carbonate and partitioned between water/CH2Cl2. The organic layer is washed with water, dried over magnesium sulfate and concentrated. Column chromatography (80 g silica gel) using CH2Cl2/hexane/CH3OH (80/17/3) as eluent gave N-methyl-2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine (0.536 g, 73%)
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f12) and commercially methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[N:1]1([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1
Reactant: CCOC(=O)CBr
Reactant: c1cnc2[nH]ncc2c1
Product: CCOC(=O)Cn1ncc2cccnc21

Procedure:
The title compound was prepared according to the method described for Preparation 93 using 1H-pyrazolo[3,4-b]pyridine and ethyl bromoacetate to afford the title compound as an off-white solid in 49% yield, 210 mg.
Reaction SMILES: [NH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:22])=[C:8]([NH:10][C:11]([C:13]2[N:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[O:12])[CH:9]=1)[C:2]#[N:3].[NH2:23][OH:24]>CCO>[OH:24][N:23]=[C:2]([NH2:3])[NH:1][C:4]1[CH:5]=[CH:6][C:7]([CH3:22])=[C:8]([NH:10][C:11]([C:13]2[N:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[O:12])[CH:9]=1
Reactant: NO
Reactant: Cc1ccc(NC#N)cc1NC(=O)c1cnc2ccccn12
Solvent: CCO
Product: Cc1ccc(NC(N)=NO)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of N-(5-cyanamido-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (68) 3.52 g (12.1 mmol) in 200 mL of EtOH was added 0.75 mL NH2OH (50 wt % in water, 12.1 mmol). The resulting mixture was stirred at room temperature overnight. The precipitate was filtered, washed with EtOH (10 mL) and air dried to give N-(5-(2-hydroxyguanidino)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (69) as a white solid, which was used directly in the next step without further purification. 1H NMR (400 MHz, d6-DMSO) δ 9.44 (s, 1H), 9.46 (dd, J=6.8, 0.8 Hz, 1 H), 8.54 (s, 1 H), 8.34 (s, 1 H), 7.76 (dd, J=7.2, 2.2 Hz, 1 H), 7.59 (s, 1 H), 7.52-7.43 (m, 2 H), 7.18-7.06 (m, 2 H), 2.13 (s, 3 H). MS m/z 325.1 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:10][C:11]1[C:12](Cl)=[N:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:25][C:26](=[O:45])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=1)[CH3:24].C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:23]([O:25][C:26](=[O:45])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([C:12]2[C:11]([CH2:10][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22])[CH2:8][CH3:9])=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:29]=1)[CH3:24]
Reactant: CCN(Cc1cc2ccccc2nc1Cl)C(=O)OC(C)(C)C
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)Cc1ccc(OC)c(-c2nc3ccccc3cc2CN(CC)C(=O)OC(C)(C)C)c1

Procedure:
(2-Chloro-quinolin-3-ylmethyl)-ethyl-carbamic acid tert-butyl ester (1.0 g, 3.11 mmol), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (1.07 g, 3.34 mmol), potassium carbonate (1.08 g, 7.8 mmol), and catalytic tetrakis(triphenylphosphine)palladium(0) were combined in 2:1 DME:H2O (18 mL), and stirred at 80° C. for 6 hours. After standard work-up, the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2([C:21]([O:23][CH3:24])=[O:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][C:2]2[C:3]([C:8]3([C:21]([O:23][CH3:24])=[O:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:37][CH:36]=1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: COC(=O)C1(c2nccnc2Cl)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C1(c2nccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Yield: 39.3 %

Procedure:
To a vial with 1-tert-butyl 4-methyl 4-(3-chloropyrazin-2-yl)piperidine-1,4-dicarboxylate (58 mg, 0.163 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (39.5 mg, 0.163 mmol), and cesium carbonate (106 mg, 0.326 mmol) under N2 is added DMSO (1.0 mL). The reaction is heated to 100° C. in an oil bath 3 h. The reaction was cooled to rt, added to H2O (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by RPHPLC to give 1-tert-butyl 4-methyl 4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidine-1,4-dicarboxylate (36 mg, 0.064 mmol, 39.3% yield) as a white solid. [M+1]=562.1. IC50 (uM) +++++.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:26])[N:25]=1)[C:20]([OH:22])=O>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:26])[N:25]=1)[C:20]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:22]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Product: Cc1cc(C(=O)N(C)c2cnccc2-c2ccccc2C)cc(Cl)n1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 2-chloro-6-methylisonicotinic acid (CAS RN 25462-85-5) after a reaction time of 64 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown foam (7%). MS (ESI): m/z=352.12 [M+H]+.