Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7](=[O:23])[N:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[S:9](=[O:18])(=[O:17])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:24]([NH:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7](=[O:23])[N:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[S:9](=[O:18])(=[O:17])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCCCNCc1ccccc1
Reactant: CC(C)(C)N1C(=O)C(NCCCBr)=C(c2ccccc2)S1(=O)=O
Product: CCCCN(CCCNC1=C(c2ccccc2)S(=O)(=O)N(C(C)(C)C)C1=O)Cc1ccccc1

Procedure:
The title compound was prepared from 4-[(3-bromopropyl)amino]-2-tert-butyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and N-benzylbutan-1-amine in a similar manner as described for Example 5. 1H NMR (500 MHz CDCl3): δ 7.52-7.44 (m, 2H), 7.42-7.38 (m, 3H), 7.33-7.30 (m, 2H), 7.30-7.24 (m, 3H), 6.36 (t, 1H), 3.48 (s, 2H), 2.86-2.78 (m, 2H), 2.40-2.12 (m, 4H), 1.76 (s, 9H), 1.56-1.44 (m, 4H), 1.36-1.24 (m, 2H), 0.91 (t, 3H); 13C NMR (125 MHz CDCl3): δ 159.8, 139.4, 135.6, 131.8, 129.4, 129.2, 128.9, 128.4, 127.2, 125.7, 106.3, 61.5, 59.2, 54.1, 52.0, 44.3, 29.2, 27.8, 26.3, 20.9, 14.3; Mass Spectrum: M+H+ 484.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[N:8][C:6]=2[N:7]=1.[NH2:19][CH3:20].CO.[BH4-].[Na+]>C1(C)C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH:19][CH3:20])=[N:8][C:6]=2[N:7]=1
Reactant: O=Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Reaction time: 48 h

Procedure:
To 5-chloro-7-morpholinothiazolo[4,5-d]pyrimidine-2-carbaldehyde 43 in 50 mL Toluene and 50 mL THF was added 30 mL of NH2Me (40% in water) and the mixture stirred under N2 for two days. The mixture was concentrated in vacuo and redissolved in 50 mL THF and 50 mL MeOH followed by the portionwise addition of 1.6 g (4.0 eq) NaBH4 and the reaction mixture stirred overnight at room temperature. Complete reaction was confirmed by LCMS and the mixture was concentrated in vacuo and purified by flash chromatography (95/5% EtOAc/EtOH 20 min followed by a gradient up to 100% EtOH over 30 min more) to give 1-(5-chloro-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)-N-methylmethanamine 60.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:8](=[O:24])[CH:7]=1.[Cl:30]N1C(=O)CCC1=O.ClC(Cl)C(O)=O>ClC(Cl)C>[Cl:30][C:7]1[C:8](=[O:24])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Agent: O=C(O)C(Cl)Cl
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Temperature: 50 °C

Procedure:
The title compound was prepared by taking up methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate (1.46 g, 3.66 mmol) in dichloroethane (25 ml) and adding N-chlorosuccinimide (0.49 g, 3.66 mmol), dichloroacetic acid (catalytic), and heating to 50° C. for 6 hours. At this time, the solvent was removed in vacuo and the residue taken up in diethyl ether. The precipitate was collected on a filter pad. 1H NMR (300 MHz, CDCl3) δ 8.07 (dd, J=7.85, 1.61 Hz, 11), 7 80 (d, J=1.81 Hz, 2H), 7.62 (app q, J=846 Hz, 1H), 7.48 (d, J=7.85, 1H), 7.05-6.95 (m, 1H), 6.93-6 89 (m, 1H), 6.19 (s, 1H), 5.30 (s, 2H), 3.93 (s, 3H), 2.17 (s, 3H), 1.97 (s, 3H). ES-HRMS m/z 434.0932 (M+H calcd for C22H19ClF2NO4 requires 434.0965).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH:15]=1)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1.C(OCC)(=O)C>[CH2:31]([CH:18]1[CH:19]=[C:14]([C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH3:13])[CH2:15][CH2:16][C:17]1=[O:20])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C1=CCC(=O)CC1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OCc1ccccc1)C1=CC(Cc2ccccc2)C(=O)CC1
Temperature: -78 °C
Reaction time: 6 h

Procedure:
To a stirred solution of the above ketone (33) (14.93 g) in dry THF (200 mL) at -78° C. under Ar was added a solution of lithium bis-trimethylsilylamide (55 mL, 1N in THF). After stirring for 20 min benzylbromide (35 mL) was added and the reaction stirred for an additional 6 h at -78° C. then allowed to slowly warm to room temperature. The reaction was taken up in ethyl acetate, washed with 1N HCl, saturated NaCl, dried over MgSO4 and evaporated. The product (34) was obtained by flash chromatography on silica gel eluted with 20 to 25% ethyl acetate in n-hexane (6.09 g, 31%): TLC Rf 0.17 (20% ethyl acetate, n-hexane); 1H NMR (CDCl3) δ1.12 (3H, d, J=7 Hz), 2.0-3.2 (7H, m), 4.18(1H, q), 5.1(2H, s), 5.33(1 H, dd), 5.55(1H, br s), 7.22 (5H, m), 7.32 (5H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[C:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[F:27])(=[O:20])[CH3:19]>>[C:18]([C:21]1[CH:22]=[C:23]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=3[CH:17]=2)[CH:24]=[CH:25][C:26]=1[F:27])(=[O:20])[CH3:19]
Reactant: CC(=O)c1cc(B(O)O)ccc1F
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3ccc(F)c(C(C)=O)c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 3-acetyl-4-fluorophenylboronic acid according to the coupling procedure described in example 1. MS (ESI) m/z 371 ([M+H]+); MS (ESI) m/z 369 ([M−H]−); High Resolution Mass Spectrometry (HRMS): calcd for C21H23FN2O3, 370.1693; found (ESI+), 371.17619; Anal. calcd for C21H23FN2O3: C, 68.09; H, 6.26; N, 7.56. Found: C, 67.36; H, 6.45; N, 7.65.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([N:39]=[C:40]=[O:41])=[O:38])=[CH:32][CH:31]=1>O1CCCC1.C(N(C(C)C)CC)(C)C>[CH3:26][N:24]([CH3:25])[CH2:23][CH2:22][N:19]1[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:40]([NH:39][C:37](=[O:38])[CH2:36][C:33]4[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=4)=[O:41])=[CH:28][CH:27]=3)[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:21][CH2:20]1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3)ccn2)CC1
Reaction time: 8 h
Yield: 29 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(2-dimethylaminoethyl)piperazin-1-yl]carbonylamino}pyridine (86.7 mg) in tetrahydrofuran (2.5 ml) were added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 5.4 ml) and diisopropylethylamine (0.235 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5) to provide the titled compound (36.2 mg, 29%) as white powder.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([OH:12])=[CH:5][C:6]([CH3:11])=[C:7]([CH:10]=1)[CH:8]=[O:9])[CH3:2].[H-].[Na+].[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20]Cl>C1COCC1>[CH2:1]([C:3]1[C:4]([O:12][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:5][C:6]([CH3:11])=[C:7]([CH:10]=1)[CH:8]=[O:9])[CH3:2]
Reactant: CCc1cc(C=O)c(C)cc1O
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc(C=O)c(C)cc1OCOCCOC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
A solution of 5-ethyl-4-hydroxy-2-methyl-benzaldehyde (0.9 g, 5.5 mmol) dissolved in THF (10 mL) was added to a cooled 0° C. suspension of NaH (0.29 g, 7.2 mmol, 60% dispersion in mineral oil) in THF (5 ml). After the addition was complete the reaction mixture was warmed up to room temperature and stirred for 30 mins. 2-Methoxyethoxymethyl chloride (0.82 mL, 7.1 mmol) was added and the reaction was stirred for 4 hours. The reaction mixture was quenched with 1N HCl and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to a yellow oil. Purification by flash column chromatography (10% to 20% EtOAc in hexanes) gave the title compound as a clear oil (0.89 g, 65%). 1H NMR (400 MHz, CDCl3): δ 1.21 (t, J=7.3 Hz, 3H), 2.63 (m, 5H), 3.39 (s, 3H), 3.57 (m, 2H), 3.84 (m, 2H), 5.37 (s, 2H), 6.95 (s, 1H), 7.62 (s, 1H), 10.15 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:22]=[CH:21][C:10]([C:11]([NH:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:23][S:24]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])=[O:25].[C:33]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:33]1([N:30]2[CH2:29][CH2:28][CH:27]([S:24]([CH2:23][C:3]3[N:4]=[C:5]([C:7]4[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]5[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=5)=[O:12])=[CH:21][CH:22]=4)[O:6][C:2]=3[CH3:1])(=[O:25])=[O:26])[CH2:32][CH2:31]2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C1CCCCC1
Reactant: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCN(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
A solution of 4-[5-methyl-4-[(piperidine-4-sulfonyl)methyl]-1,3-oxazol-2-yl]-N-(pyridin-3-ylmethyl)benzamide (300 mg, 0.66 mmol, 1.00 equiv), cyclohexanone (98 mg, 1.00 mmol, 1.51 equiv) and acetic acid (120 mg, 2.00 mmol, 3.03 equiv) in 1,2-dichloroethane (10 mL) was stirred for 4 h at room temperature. To this was added sodium triacetoxyborohydride (420 mg, 1.98 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature and then concentrated under vacuum. The residue was purified on a silica gel column with water/acetonitrile (95/5-20/80) to give 350 mg (99%) of 4-[4-[(1-cyclohexylpiperidine-4-sulfonyl)methyl]-5-methyl-1,3-oxazol-2-yl]-N-(pyridin-3-ylmethyl)benzamide as a white solid. LC-MS (ES, m/z): 537 [M+H]+; 1HNMR (300 MHz, CD3OD, ppm) δ 8.60 (s, 1H), 8.47 (d, 1H), 8.11 (d, 2H), 8.00 (d, 2H), 7.89 (d, 1H), 7.47-7.43 (m, 1H), 4.65 (s, 2H), 4.40 (s, 2H), 3.14 (d, 3H), 2.50 (d, 3H), 2.41-2.33 (m, 3H), 2.25 (d, 2H), 1.92-1.83 (m, 6H), 1.67 (d, 1H), 1.29-1.09 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[C:13]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:21][C:20]1[CH:22]=[CH:23][C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:18][CH:19]=1)=[N:7][N:6]=[CH:5]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(Nc2nncc3cc(Br)ccc23)cc1

Procedure:
Heat a mixture of 6-bromo-1-chloro-phthalazine (500 mg, 2.05 mmol) and 4-(tert-butyl)aniline (611 mg, 4.10 mmol) in 2-propanol (10 mL) at reflux for 3 hours. Evaporate the mixture, add 1M NaOH (10 mL), extract twice with EtOAc (10 mL each), dry (Na2SO4), and evaporate to provide the crude product. Purify by silica gel chromatography, eluting with dichloromethane followed by 95% CH2Cl2-MeOH to provide (6-Bromo-phthalazin-1-yl)-(4-tert-butyl-phenyl)-amine as a white solid.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=4)=[N:11][C:10]=3[N:9]([CH3:27])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][N:29]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([N:32]5[CH2:33][CH2:34][CH2:35][N:29]([CH3:28])[CH2:30][CH2:31]5)(=[O:25])=[O:24])=[CH:19][CH:18]=4)=[N:11][C:10]=3[N:9]([CH3:27])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCCNCC1
Reactant: Cn1nc(C2CCCCC2)c2c(=O)[nH]c(-c3ccc(S(=O)(=O)Cl)cc3)nc21
Product: CN1CCCN(S(=O)(=O)c2ccc(-c3nc4c(c(C5CCCCC5)nn4C)c(=O)[nH]3)cc2)CC1
Yield: 45 %

Procedure:
The same reaction procedure as in Example 49 was performed, except that the compound obtained in Example 181 was used in place of the compound obtained in Example 48, and N-methyl-1,4-diazacycloheptane was used in place of N-methylpiperazine. In this manner, 110 mg (45%) of the captioned compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=O.[CH2:14]([CH:16]([CH2:21][CH3:22])[C:17](OC)=[O:18])[CH3:15].O.[NH2:24][NH2:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[C:16]([CH2:21][CH3:22])([CH2:14][CH3:15])[C:17](=[O:18])[NH:24][N:25]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CCC(CC)C(=O)OC
Reactant: NN
Solvent: O
Product: CCC1(CC)C(=O)NN=C1c1ccc(OC)c(OC)c1

Procedure:
Prepared analogously as described for the example C5 using 3,4-dimethoxybenzoyl chloride, methyl 2-ethylbutanoate and hydrazine hydrate as starting compounds.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=1.C(N(CC)CC)C>C1COCC1>[N:4]1([CH2:3][CH2:2][NH:1][S:16]([C:14]2[S:15][C:11]([Cl:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: NCCN1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCN1CCOCC1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
To a stirred solution of 4-(2-aminoethyl)-morpholine (1.80 g, 13.8 mmol) in THF (20 mL) was added at 0° C. (ice water bath) commercially available 5-chloro-thiophene-2-sulfonyl chloride (1.0 g, 4.61 mmol) and triethylamine (0.71 mL, 5.07 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) to yield the title compound (1.34 g, 93%) as a colorless oil. MS (ISN) 309.0 [(M−H)−].
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][N:22]1[C:34]2[CH:33]=[CH:32][C:31]([CH:35]=O)=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:35][C:31]2[CH:32]=[CH:33][C:34]3[N:22]([CH3:21])[C:23]4[C:28]([C:29]=3[CH:30]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: Cn1c2ccccc2c2cc(C=O)ccc21
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc2c(c1)c1ccccc1n2C

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 9-methyl-9H-carbazole-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.94 min.; [M+H]+: 429.05 g/mol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.[C:9]1([C:15]2([NH2:19])[CH2:18][CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN1C(=O)CCC1>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:19][C:15]2([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:16][CH2:17][CH2:18]2)[CH:3]=1
Reactant: Clc1cc(Br)ccn1
Reactant: NC1(c2ccccc2)CCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Brc1ccnc(NC2(c3ccccc3)CCC2)c1
Temperature: 120 °C
Reaction time: 72 h
Yield: 9.2 %

Procedure:
To a 20 dram vial was added 4-bromo-2-chloropyridine (250 mg, 5.0 mmol, 1.0 equiv), 1-phenylcyclobutanamine (1.0 g, 7 mmol, 1.4 equiv), and NMP (1 mL). The reaction was heated to 120° C., stirred for 72 h, and then diluted with water (20 mL) and ethyl acetate (50 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer. The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography, affording 139 mg (9%) of 4-bromo-N-(1-phenylcyclobutyl)pyridin-2-amine as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][C@@H:13]2[CH2:15][C@H:10]1[CH2:11][N:12]2[CH3:16])[NH2:5].C(OC(N[C:25](=[N:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:26]1C=CC=N1)=O)(C)(C)C.[OH2:39]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:5]=[C:25]([NH2:26])[N:31]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:39])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][C@@H:13]2[CH2:15][C@H:10]1[CH2:11][N:12]2[CH3:16]
Reactant: Cc1cc(N)ccc1N1C[C@@H]2C[C@H]1CN2C
Reactant: O
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Solvent: CN(C)C=O
Product: Cc1cc(N=C(N)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1N1C[C@@H]2C[C@H]1CN2C
Temperature: 25 °C
Reaction time: 36 h
Yield: 97 %

Procedure:
On a larger scale, 3-methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]aniline (10.0 g, 45.8 mmol) and 1-(tert-butoxycarbonylamino(tert-butoxycarbonylimino)methyl)pyrazole (15.0 g, 48.2 mmol) were combined in DMF (25 mL) and stirred at ambient temperature. The progress of homogenous reaction was monitored by LC/MS. After 36 h, the reaction mixture was added slowly to water (300 mL) in a beaker with vigorous stirring, whereupon a precipitate formed. The reaction flask was rinsed with DMF (2×5 mL) and transferred to the beaker. Suction filtration of the suspension, further washing of the resulting filter cake with water (200 mL) and air drying under suction provided 20.5 g (97%) of [3-methyl-4-((1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptan-5-yl)phenyl][N,N-bis(tert-butoxycarbonyl)]guanidine (Ja) as a off-white purple solid; LCMS: purity: 96%; MS (m/e): 449 (MH+).
Reaction SMILES: C(OC(=O)[N:7]([C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1)[C:8]1[C:9]2[N:10]([CH:27]=[CH:28][N:29]=2)[C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:12][N:13]=1)(C)(C)C.C(OC([N:51]1[C:55]([C:56]([F:59])([F:58])[F:57])=[C:54](Br)[CH:53]=[N:52]1)=O)(C)(C)C.C(Cl)Cl>CN(C=O)C.C(O)(C(F)(F)F)=O.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>[NH3:7].[CH3:42][N:39]1[CH2:40][CH2:41][N:36]([C:33]2[CH:34]=[CH:35][C:30]([NH:7][C:8]3[C:9]4[N:10]([CH:27]=[CH:28][N:29]=4)[C:11]([C:54]4[C:55]([C:56]([F:59])([F:58])[F:57])=[N:51][NH:52][CH:53]=4)=[CH:12][N:13]=3)=[CH:31][CH:32]=2)[CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)n1ncc(Br)c1C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)c2ccc(N3CCN(C)CC3)cc2)c2nccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2ccc(Nc3ncc(-c4c[nH]nc4C(F)(F)F)n4ccnc34)cc2)CC1
Product: N
Yield: 4.2 %

Procedure:
In the same way as described for Compound 145, step 2 using [4-(4-methyl-piperazin-1-yl)-phenyl]-(5-tributylstannanyl-imidazo[1,2-a]pyrazin-8-yl)-carbamic acid tert-butyl ester (0.38 g, 0.78 mmol) in DMF (6 mL), 4-bromo-5-trifluoromethyl-pyrazole-1-carboxylic acid tert-butyl ester (0.49 g, 0.15 mmol) and Pd(PPh3)4 (0.09 g, 0.15 mmol). The crude mixture is stirred in (1:1) TFA:DCM (2 mL) at room temperature for 3 hours. Purification by silica gel column chromatography eluting with DCM followed by a mixture of 99:1 and 95:5 DCM:NH3 (7M in MeOH) affords the title compound (2.79 mg, 1%). LCMS: Rt 1.90 min (96%) m/z (ES+) 443 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.26 (3H, s), 2.49-2.54 (4H, m), 3.09-3.14 (4H, m), 6.96 (2H, d), 7.31 (1H, s), 7.63 (2H, d), 7.89 (2H, d), 8.37 (1H, s), 9.44 (1H, s).
Reaction SMILES: C(OC([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](/C=C/C(OC)=O)[CH:18]=2)[NH:13][C:12]=1[CH3:26])=O)C1C=CC=CC=1.CO.[BH4-].[Li+].CCCCCC.[C:37](OCC)(=[O:39])[CH3:38]>C1COCC1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:12]1[CH2:26][CH2:38][CH2:37][OH:39]
Reactant: CCOC(C)=O
Reactant: COC(=O)/C=C/c1ccc2[nH]c(C)c(C(=O)OCc3ccccc3)c2c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCCCc1cc2ccccc2[nH]1
Temperature: 4 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
5-((E)-2-Methoxycarbonyl-vinyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.200 g, 0.573 mmol, 1 eq) was suspended in dry THF (10 mL) under Ar. Methanol (0.116 mL, 2.87 mmol, 5.0 eq) was added followed by cooling to 4° C. and the addition of lithium borohydride (1.40 mL of 2 M, 2.87 mmol, 5.0 eq). The reaction mixture was stirred and allowed to warm to room temperature, then heated to reflux. The reaction was followed by TLC (CH2Cl2/MeOH 9/1). After 24 hours, the reaction was quenched with brine and extracted with ethyl acetate (3×). The combined organic extracts were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with CH2Cl2/MeOH 9/1. 0.149 g (81% yield) of the indole-propanol was obtained as a white solid, with some contamination by the E-allylic alcohol (20%-30%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:21]=[C:15]3[CH2:16][N:17]([CH3:20])[CH2:18][CH2:19][N:14]3[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C([O:25][CH2:26][C:27]1[C:28]([N:42]2[CH2:54][CH2:53][N:45]3[C:46]4[CH2:47][CH2:48][CH2:49][CH2:50][C:51]=4[CH:52]=[C:44]3[C:43]2=[O:55])=[N:29][CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1)(=O)C>>[OH:25][CH2:26][C:27]1[C:28]([N:42]2[CH2:54][CH2:53][N:45]3[C:46]4[CH2:47][CH2:48][CH2:49][CH2:50][C:51]=4[CH:52]=[C:44]3[C:43]2=[O:55])=[N:29][CH:30]=[CH:31][C:32]=1[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:21]=[C:15]3[CH2:16][N:17]([CH3:20])[CH2:18][CH2:19][N:14]3[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: CN1CCn2nc(Nc3cc(Br)nn4ccnc34)cc2C1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Product: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)nn4ccnc34)cc2C1
Yield: 10 %

Procedure:
Following the procedure described in Example 123, and starting with 124g (900 mg, 2.60 mmol) and 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 114e (1.01 g, 2.6 mmol), 124 was obtained as a white solid (147 mg, 10%). MS-ESI: [M+H]+ 565.3. 1H NMR (500 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.56 (d, J=5.0 Hz, 1H), 8.17 (s, 1H), 7.75 (s, 1H), 7.66 (s, 1H), 7.46 (d, J=5.0 Hz, 1H), 6.58 (s, 1H), 6.03 (s, 1H), 4.73 (t, J=5.0 Hz, 1H), 4.62-4.58 (m, 1H), 4.40-4.37 (m, 1H), 4.27-4.19 (m, 2H), 4.10-4.08 (m, 1H), 4.00-3.93 (m, 3H), 3.54 (s, 2H), 2.82 (t, J=5.0 Hz, 2H), 2.64-2.56 (m, 2H), 2.47-2.46 (m, 2H), 2.37 (s, 3H), 1.79-1.68 (m, 4H).