Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)[CH2:9]1)=O)(C)(C)C>C(O)=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:17]2[CH2:18][CH2:19][N:14]([CH:10]3[CH2:9][NH:8][CH2:12][CH:11]3[OH:13])[CH2:15][CH2:16]2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C(N2CCN(Cc3ccc(Cl)cc3)CC2)C1
Solvent: O=CO
Product: OC1CNCC1N1CCN(Cc2ccc(Cl)cc2)CC1

Procedure:
The desired compound was prepared from 3-[4-(4-Chloro-benzyl)-piperazin-1-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester in a manner similar to that described in Example 161. 1H-NMR (300 MHz, DMSO, HCl salt): δ 2.80-3,60 (m, 12H), 4.20-4.35 (m, 4H), 7.51 (d, 2H), 7.66 (d, 2H). Retention Time (LC, method: Formic acid polar): 0.68 min. MS (M+H+): 296
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])=[N:7][C:6]=2[C:5]([CH2:12][OH:13])=[CH:4][CH:3]=1>ClCCl.[O-2].[Mn+4].[O-2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[O:13])=[C:6]2[C:10]=1[O:9][C:8]([CH3:11])=[N:7]2
Reactant: Cc1nc2c(CO)ccc(Br)c2o1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1nc2c(C=O)ccc(Br)c2o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
To a solution of (7-bromo-2-methyl-benzo[d]oxazol-4-yl)methanol (Example 6.5) (5.16 g) in dichloromethane (300 ml) was added manganese(IV) oxide (59.9 g) and the suspension stirred at ambient temperature for 16 hours. The reaction mixture was filtered through a plug of silica gel and the filtrate concentrated to give 7-bromo-2-methyl-benzo[d]oxazole-4-carbaldehyde (3.23 g). LC-MS: RT=1.83 min, [M+H]+=240.0/242.0, method A.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:8])[CH2:4][CH2:3]1.[H-].[Na+].[Si:19]([O:26][CH2:27][C@H:28]1[CH2:39][CH2:38][C:37]2[S:36][C:35]3[N:34]=[CH:33][N:32]=[C:31](Cl)[C:30]=3[C:29]1=2)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C1COCC1>[Si:19]([O:26][CH2:27][C@H:28]1[CH2:39][CH2:38][C:37]2[S:36][C:35]3[N:34]=[CH:33][N:32]=[C:31]([O:1][CH:2]4[CH2:7][CH2:6][C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:8])[CH2:4][CH2:3]4)[C:30]=3[C:29]1=2)([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCc2sc3ncnc(Cl)c3c21
Reactant: CC1(NC(=O)OC(C)(C)C)CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CO[Si](C)(C)C(C)(C)C)CC4)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a solution of tert-butyl N-(4-hydroxy-1-methylcyclohexyl)carbamate (700 mg, 3.05 mmol, 1.00 equiv) in anhydrous THF (10 mL) was added sodium hydride (60% dispersion in mineral oil, 600 mg, 15.00 mmol, 4.91 equiv) at 0° C. under nitrogen. The resulting solution was stirred for 0.5 h at room temperature. To this was added (3S)-3-[[(tert-butyldimethylsilyl)oxy]methyl]-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene (1.18 g, 3.32 mmol, 1.09 equiv) and stirring was continued for 5 h at 30° C. The reaction was then quenched by the addition of 30 mL of NH4Cl (aq.) and extracted with 3×80 mL of ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/15) to yield 1.20 g (72%) of tert-butyl N-(4-[[(3S)-3-[[(tert-butyldimethylsilyl)oxy]methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)carbamate as a light yellow solid.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=O)=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(N=C=NC2CCCCC2)CCCCC1.ClCCl.[NH2:62][C@H:63]([C:76]([O:78][CH2:79][C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1)=[O:77])[CH2:64][CH2:65][C:66]([O:68][CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)=[O:67]>O1CCOCC1>[C:1]([O:18][CH:19]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]([NH:62][C@H:63]([C:76]([O:78][CH2:79][C:80]1[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=1)=[O:77])[CH2:64][CH2:65][C:66]([O:68][CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)=[O:67])=[O:28])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 46.6 %

Procedure:
N-(3-hexadecanoyloxyoctadecanoyl)-β-alanine (1.47 g) prepared by the method of Preparation B-5 and N,N'-dicyclohexylcarbodiimide (412 mg) were added to a mixed solution of dichloromethane (20 ml) and dioxane (20 ml). The resulting mixture was stirred for 15 minutes. Then, a solution of dibenzyl L-glutamate (650 mg) in dioxane (10 ml) was added thereto over a period of 30 minutes. The mixture was stirred for 2 hours at room temperature and allowed to stand overnight. The precipitated N,N'-dicyclohexylurea was removed off by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethanol to afford crystals of dibenzyl N-[N-(3-hexadecanoyloxyoctadecanoyl)-β-alanyl]-L-glutamate (850 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][O:14][C@H:13]([C@@H:17]([OH:30])[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:22]=3[Cl:29])=[O:19])[C:12]2=[O:31])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:32][OH:33]>CCO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][O:14][C@H:13]([C@@H:17]([OH:30])[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[N:32][OH:33])[NH2:28])=[CH:23][C:22]=3[Cl:29])=[O:19])[C:12]2=[O:31])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc(C#N)cc3Cl)C2=O)cc1
Reactant: NO
Solvent: CCO
Product: CC(C)(C)c1ccc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc(C(N)=NO)cc3Cl)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of compound 66-1 (60 mg) in EtOH (2 mL), was added 50% NH2OH aq. (22.4 microL). The reaction mixture was stirred at room temperature overnight. Then the mixture was concentrated in vacuo to obtain compound 66-2 (67 mg) as a colorless amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.C(C1NC(C=O)=C(C)N=1)C.[Cl:23][C:24]1[CH:29]=[C:28]([CH2:30][CH2:31][C:32]2([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:37][C:36](=[O:38])[CH2:35][C:34](=[O:39])[O:33]2)[CH:27]=[CH:26][C:25]=1[C:45]([CH3:49])([CH3:48])[C:46]#[N:47].C1(C2(CCC3C=CC(C(C)(C)C#N)=C(F)C=3)CC(O)=CC(=O)O2)CCCC1>>[Cl:23][C:24]1[CH:29]=[C:28]([CH2:30][CH2:31][C:32]2([CH:40]3[CH2:41][CH2:42][CH2:43][CH2:44]3)[CH2:37][C:36]([OH:38])=[C:35]([CH2:11][C:9]3[N:10]=[C:5]4[N:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]4[N:8]=3)[C:34](=[O:39])[O:33]2)[CH:27]=[CH:26][C:25]=1[C:45]([CH3:49])([CH3:48])[C:46]#[N:47]
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: Cc1cnc2nc(C=O)nn2c1
Agent: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(O)=CC(=O)O2)cc1F
Agent: CCc1nc(C)c(C=O)[nH]1
Product: Cc1cnc2nc(CC3=C(O)CC(CCc4ccc(C(C)(C)C#N)c(Cl)c4)(C4CCCC4)OC3=O)nn2c1

Procedure:
The title compound was prepared analogously to Example A(97) where 6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde and 2-{2-Chloro-4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propionitril from Example A(147) (was substituted in place of 2-{4-[2-(2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile. 1H NMR (400 MHz, CDCl3) δ: 1.17-1.59 (m, 8H), 1.59-1.62 (m, 2H)), 1.62 (s, 6H), 1.82-2.01 (m, 2H), 2.19 (s, 3H), 2.38-2.65 (m, 3H), 3.55 (d, J=16 Hz, 1H), 3.65 (d, J=16 Hz, 1H), 7.15-7.32 (m. 3H), 8.53 (d, J=2.3 Hz, 1H), 8.82 (s, 1H), 10.7 (s, 1H). C29H32ClN5O3: C, 65.22; H, 6.04; N, 13.11. Found: C, 65.15; H, 5.99; N, 13.10. MS (ESI): 535.2(M+H+).
Reaction SMILES: Cl.C(OC([NH:9][C@H:10]([C:36]([O:38]C(C)(C)C)=[O:37])[CH2:11][C@H:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][F:30])=[C:23]([O:31]C(C)(C)C)[CH:22]=1)[C:13]([O:15]C(C)(C)C)=[O:14])=O)(C)(C)C>O1CCOCC1>[F:30][CH2:29][CH2:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C@H:12]([C:13]([OH:15])=[O:14])[CH2:11][C@@H:10]([C:36]([OH:38])=[O:37])[NH2:9])=[CH:22][C:23]=1[OH:31]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCF)c(OC(C)(C)C)c1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](C[C@H](Cc1ccc(OCCF)c(O)c1)C(=O)O)C(=O)O
Reaction time: 4 h

Procedure:
A solution of hydrogen chloride in dioxane (0.25 ml, 4M) is added to 24 mg (0.041 mmol) di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-[3-tert-butoxy-4-(2-fluoroethoxy)benzyl]-L-glutamate. The reaction mixture is stirred for 4 hours and stored at −25° C. over night. The reaction mixture is concentrated in vacuo. Co. 3 ml dichloro methane is added and the solution is concentrate in vacuo. The last step is repeated. The crude product is purified by HPLC (column, XBrigde, C18, 5 μm 100×30 mm, H2O+0.1% trifluoroacetic acid, acetonitrile, flow 38 mL/min).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C@H:6]([NH2:8])[CH3:7].Br[CH2:14][CH3:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C@H:6]([NH:8][CH2:14][CH3:15])[CH3:7]
Reactant: C[C@@H](N)COc1ccccc1Br
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN[C@H](C)COc1ccccc1Br

Procedure:
(R)-2-(2-bromophenoxy)-1-methylethylamine, (Preparation 1A, Step 2) (1.68 g, 7.3 mmol) was dissolved in DMF (16 ml). The mixture was stirred with bromoethane (3.18 ml, 43 mmol) and K2CO3 (7.60 g, 55 mmoles) at r.t. under N2 for about 3 days. The mixture was concentrated, dissolved in EtOAc, washed with water and brine, dried over Na2SO4, and filtered. Solvent was removed and the residue was purified by flash chromatography (silica gel, 5% 2M NH3 in MeOH/CH2Cl2) to give about 2.08 g of a mixture of diethyl and monoethyl amine compounds with the mono ethyl as the minor product.
Reaction SMILES: C(OC([NH:8][C:9]([NH:23][CH2:24][CH3:25])=[N:10][CH:11]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]=2)[CH2:12]1)=O)(C)(C)C.[ClH:26]>C(O)C.O1CCOCC1>[ClH:26].[ClH:26].[CH2:24]([NH:23][C:9]([NH:10][CH:11]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]=2)[CH2:12]1)=[NH:8])[CH3:25]
Reactant: CCNC(=NC1CCN(c2cc(C)ccn2)C1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCNC(=N)NC1CCN(c2cc(C)ccn2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of N-(tert-butoxycarbonyl)-N′-ethyl-N″-(1-(4-methylpyridin-2-yl)pyrrolidin-3-yl)guanidine (200 mg) in ethanol (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 3 ml), and the mixture was stirred at ambient temperature for 6 hours. The solvent was evaporated under reduced pressure. To the residue was added 10% ethanol in ethyl acetate (50 ml), and the resultant precipitate was collected by filtration and dried under reduced pressure to give N-ethyl-N′-(1-(4-methylpyridin-2-yl)pyrrolidin-3-yl)guanidine dihydrochloride (120 mg).
Reaction SMILES: [C:1]([NH2:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CCN(CC)CC.[C:18](=S)=[S:19].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1>[N:10]([C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2])=[C:18]=[S:19]
Reactant: S=C=S
Reactant: CC(C)(N)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(N=C=S)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Cumylamine (5.32 mL, 37.0 mmol) (TCI America) and Et3N (16.97 mL, 122 mmol) (Aldrich) were mixed in THF (40 mL) at 0° C. under a nitrogen atmosphere. Carbon disulfide (2.224 mL, 37.0 mmol) (J.T.Baker) was added dropwise via syringe over the course of 10 min. The reaction was stirred at 0° C. for 1 h before being warmed to RT and stirred for 1 h. p-Toluenesulfonyl chloride (7.76 g, 40.7 mmol) (Fluka) was added, and the reaction was stirred at RT for 1 h. The mixture was quenched with 1 M HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated to give (2-isothiocyanatopropan-2-yl)benzene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=1)[C:10](=[O:17])[NH:11]2.I[CH3:33]>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=1)[C:10]([O:17][CH3:33])=[N:11]2
Reactant: COC(=O)COc1ccc(F)c2[nH]c(=O)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Reactant: CI
Product: COC(=O)COc1ccc(F)c2nc(OC)c(Cc3ccc(-n4cccn4)cc3)c(C)c12

Procedure:
The title compound was prepared by the method of Preparation 11e using [8-fluoro-4-methyl-2-oxo-3-(4-pyrazol-1-ylbenzyl)-1,2-dihydroquinolin-5-yloxy]acetic acid methyl ester and iodomethane.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:9][C:10]1[CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=[CH:12][C:11]=1[C:25]1[S:26][C:27]2[C:32]([N:33]=1)=[CH:31][CH:30]=[C:29]([C:34]1([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:36][CH2:35]1)[N:28]=2.FC(F)(F)S(O[C:49]1[CH2:53][N:52]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[C@H:51]([C:61]([O:63][CH3:64])=[O:62])[CH:50]=1)(=O)=O>CN(C=O)C>[F:9][C:10]1[CH:15]=[C:14]([C:49]2[CH2:53][N:52]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[C@H:51]([C:61]([O:63][CH3:64])=[O:62])[CH:50]=2)[CH:13]=[CH:12][C:11]=1[C:25]1[S:26][C:27]2[C:32]([N:33]=1)=[CH:31][CH:30]=[C:29]([C:34]1([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:35][CH2:36]1)[N:28]=2
Reactant: CC1(C)OB(c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)OC1(C)C
Reactant: COC(=O)[C@@H]1C=C(OS(=O)(=O)C(F)(F)F)CN1C(=O)OC(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C=C(c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A slurry of potassium phosphate (2.50 g, 11.8 mmol), (Amphos)2PdCl2 (0.125 g, 0.177 mmol), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (2.78 g, 5.89 mmol) and (S)-1-tert-butyl 2-methyl 4-(trifluoromethylsulfonyloxy)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (2.21 g, 5.89 mmol, synthesized according to literature reference: Bioorganic and Medicinal Chemistry Letters, 2007, 2715) in 15 mL DMF was flushed with argon, sealed, and heated to 80° C. After 6 h, the reaction was judged complete, cooled, and filtered through celite, rinsing with 200 mL EtOAc. The filtrate was washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography, EA/hexanes gradient, gave (2S)-1-tert-butyl 2-methyl 4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-2H-pyrrole-1,2(5H)-dicarboxylate as a light yellow solid. MS (ESI) m/z: Calculated: 571.2; Observed: 572.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([NH2:17])[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:18])=[CH:7][CH:8]=2)[N:3]=1.CCN(CC)CC.Cl[C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28]>ClCCl>[Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([NH:17][C:27](=[O:28])[O:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:18])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(Cl)nc2c1
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OCC(C)C)C3)nc(Cl)nc2c1
Reaction time: 0.08 h
Yield: 66 %

Procedure:
A solution of (R)-1-(2-chloro-7-methylquinazolin-4-yl)pyrrolidin-3-amine (100 mg, 0.38 mmol) in 2 mL of dichloromethane was cooled to −30° C. To it was added Et3N followed by the addition of isobutyl chloroformate dropwise. The reaction was complete after 5 minutes. The reaction was quenched with water, the layers separated, and the aqueous layer was twice extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 0%-10% EtOAc in DCM gave (R)-isobutyl 1-(2-chloro-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (90 mg, 66% yield). LC/MS: m/z 363.3 (M+H)+ at 2.74 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[CH2:20][N:19]3[CH2:26][CH:27]([NH2:31])[CH:28]([CH3:30])[CH3:29])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:32][C:33]1[N:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](O)=[O:36].CCN=C=NCCCN(C)C>N1C=CC=CC=1.O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:23][O:22][C:21]([CH3:24])([CH3:25])[CH2:20][N:19]3[CH2:26][CH:27]([NH:31][C:35]([C:34]3[C:33]([CH3:32])=[N:41][CH:40]=[CH:39][CH:38]=3)=[O:36])[CH:28]([CH3:29])[CH3:30])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: Cc1ncccc1C(=O)O
Reactant: CC(C)C(N)CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ncccc1C(=O)NC(CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12)C(C)C
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 76.7 %

Procedure:
To a solution of 4-(2-amino-3-methyl-butyl)-6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-β-carbolin-8-yl)-amide (1.47 g, 3.31 mmol) in pyridine (35 mL) was added 2-methyl-nicotinic acid (544 mg, 3.97 mmol) and EDCI (1.02 g, 5.30 mmol). The solution was stirred 6.5 hours at room temperature, then diluted with water (100 mL). The mixture was poured into a separatory funnel and diluted further with water (50 mL) and EtOAc (150 mL). The layers were shaken and separated. The aqueous layer was extracted with EtOAc (3×50 mL), then the combined organic layers were washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated to yield an orange semi-solid residue which was purified via column chromatography. The resulting yellow solid was placed on the high-vacuum pump overnight, after which 1.43 g of 6,6-dimethyl-4-{3-methyl-2-[(2-methyl-pyridine-3-carbonyl)-amino]-butyl}-morpholine-3-carboxylic acid (6-chloro-9H-β-carbolin-8-yl)-amide was obtained (77% yield).
Reaction SMILES: [CH:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]2[C:10]([O:12][C:13](=[O:14])[C:3]=2[CH:2]=1)=O.[NH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(O)(=O)C>[O:21]1[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][N:15]2[C:10](=[O:12])[C:4]3[C:3](=[CH:2][CH:1]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=3)[C:13]2=[O:14])[CH2:19][CH2:20]1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)C(=O)N(CCN1CCOCC1)C2=O
Temperature: 25 °C
Yield: 81.8 %

Procedure:
1,2,4-Benzenetricarboxylic anhydride (356, 0.487 g, 2.53 mmol) and 4-(2-aminoethyl)morpholine (0.33 g, 2.53 mmol) were allowed to stir 2 hours at 130° C. in acetic acid (10 mL). The reaction mixture was then cooled to room temperature and the precipitated solid was collected by filtration, washed with H2O and dried under vacuum, to afford title compound 357 as a white powder (0.63 g, 82% yield). 1H NMR (DMSO) δ (ppm): 8.26 (dd, J=7.6, 1.4 Hz, 1H), 8.15 (dd, J=1.4, 0.6 Hz, 1H), 7.92 (dd, J=7.6, 0.6 Hz, 1H), 3.73 (t, J=6.5 Hz, 2H), 3.50 (t, J=4.5 Hz, 4H), 2.59 (t, J=6.5 Hz, 2H), 2.47 (overlapped with DMSO, 4H). MS: 304.3 (calc), 305.1 (obs).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]1.C(N(CC)CC)C>C(O)C>[C:11]1([C:10]2[C:3]3[C:2]([N:17]4[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]4)=[N:7][CH:6]=[N:5][C:4]=3[S:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)C1CCNCC1
Reactant: Clc1ncnc2scc(-c3ccccc3)c12
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(O)C1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Temperature: 140 °C
Yield: 101.4 %

Procedure:
4-Chloro-5-phenylthieno[2,3-d]pyrimidine (1.5 g, 6.1 mmol), piperidine-4-carboxylic acid (0.86 g, 6.7 mmol) and triethylamine (2.6 mL, 18 mmol) were suspended in dry ethanol (15 mL). The reaction was heated at 140° C. in a microwave for 10 min. The reaction was partitioned between water and DCM. The product was purified by column chromatography using a gradient of 10% methanol in DCM to 100% methanol to give the target compound as an off-white solid (yield=2.1 g). LCMS [M+H]+=440; RT=4.04 min.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)=O.[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][N:14]=1>CC(C)=O>[F:11][C:7]1[CH:6]=[C:5]([C:3]2[N:12]=[C:13]3[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][N:14]3[CH:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1ccnc(N)n1
Reactant: O=C(CBr)c1cccc(F)c1
Solvent: CC(C)=O
Product: Nc1ccn2cc(-c3cccc(F)c3)nc2n1

Procedure:
2-Bromo-1-(3-fluorophenyl)ethanone (10.9 g, 50 mmol) was added to a solution of 2,4-diaminopyrimidine (3.70 g, 34 mmol) in acetone (185 ml), and the mixture was heated to reflux for 6 h. The cooled suspension was filtered and the precipitate was washed with acetone (50 ml). The solid was re-suspended in water (35 ml) and NH4OHaq. (25%, 50 ml), then it was collected over a glass fiber paper and the filtrate was washed with H2O (75 ml). After drying under vacuum, the product was obtained (5.56 g, 72%) as a yellow solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][OH:18])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:19]([O:22][CH2:23][C:24]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=[CH:26][C:25]=1[N:39]1[CH2:51][CH2:50][N:42]2[C:43]3[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=3[CH:49]=[C:41]2[C:40]1=[O:52])(=[O:21])[CH3:20].CC(O[Na])=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:19]([O:22][CH2:23][C:24]1[C:25]([N:39]2[CH2:51][CH2:50][N:42]3[C:43]4[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=4[CH:49]=[C:41]3[C:40]2=[O:52])=[CH:26][CH:27]=[CH:28][C:29]=1[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][OH:18])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:21])[CH3:20]
Reactant: Cn1cc(Br)nc(Nc2cnn(CCO)c2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)O[Na]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3cnn(CCO)c3)n2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 43.9 %

Procedure:
A mixture of 140a (595 mg, 1.9 mmol), 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a (882 mg, 1.9 mmol), CH3COONa (309 mg, 3.8 mmol), PdCl2(dppf) (153 mg, 0.19 mmol) and K3PO4 (1 g, 3.8 mmol) suspended in CH3CN (30 mL) and H2O (2 mL) was heated at 110° C. for 15 h under argon atmosphere. After reaction CH3CN was evaporated and the residue was purified by reverse phase Combi-flash eluting with 0.3% NH4HCO3 in 1:4 water/CH3CN to give 140b as a brown solid (477 mg, 44%). LCMS: [M+H]+572.