Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Na+].[CH3:44][NH:45][C:46](=[O:49])[CH2:47]Br.C(O)(=O)C>O1CCCC1.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:47][C:46]([NH:45][CH3:44])=[O:49])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CNC(=O)CBr
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC(=O)COc1ccc(C[C@H](NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H](O)CN(CC(C)C)S(=O)(=O)c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.1 %

Procedure:
To a solution of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate (60 mg, 0.1 mmol) in anhydrous tetrahydrofuran (1.5 mL) was added 60% sodium hydride/mineral oil dispersion (4 mg, 0.1 mmol). The mixture was stirred for 10 min at ambient temperature under nitrogen atmosphere and a solution of N-methyl-2-bromoacetamide (17 mg, 0.11 mmol) in anhydrous tetrahydrofuran (0.5 mL) was added. After 2 h, an additional portion of 60% sodium hydride/mineral oil dispersion (4 mg, 0.1 mmol) was added. After 15 min, acetic acid (0.1 mL) was added and the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate/water, dried (sodium sulfate), evaporated, and purified by chromatography (silica gel, ethyl acetate) to provide the title compound as a white solid (10 mg). 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d) 1.15-1.22 9 (1H, m), 1.2 (1H, quintuplet), 1.9-2.0 (1H, m), 2.35 (1H, t), 2.6 (3H, d), 2.65-2.80 (3H, m), 2.9 (1H, d), 2.95 (1H, dd), 3.2-3.3 (1H, m), 3.4-3.5 (1H, m) 3.5-3.6 (3H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.4 (2H, s), 4.8 (1H, dt), 5.0 (1H, d), 5.5 (1H, d), 6.2 (2H, s), 6.8 (2H, d), 7.0-7.2 (3H, m), 7.22 (1H, s), 7.25 (1H, d), 7.3 (1H, d), 8.0 (1H; br s); MS: 664 (MH+);
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17].C(=O)(O)[O-].[Na+]>O>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:17][CH:16]=[N:1]2)=[CH:7][CH:8]=1
Reactant: N=CN
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]cnc2cc(F)ccc12
Temperature: 165 °C
Yield: 91.6 %

Procedure:
A heterogeneous mixture of 2-amino-4-fluorobenzoic acid (8.7 g, 56 mmol) and formamidine acetate (29.2 g, 280 mmol) was stirred and heated at 165° C. for 2 h. The reaction mixture was suspended in H2O and the mixture was carefully basified with saturated sodium bicarbonate solution followed by stirring for 1 h. The brown solid was collected by filtration, washed with H2O and air dried to afford 8.42 g (91%) of 7-fluoroquinazolin-4(3H)-one. MS 165.0 (ES+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[CH3:16])[C:10](O)=[O:11])[N:5]=[CH:4][C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN=C=N[CH2:30][CH2:31][CH2:32][N:33](C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C1(N)CC1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[CH3:16])[C:10]([NH:33][CH:32]2[CH2:30][CH2:31]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:17](=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc(C(=O)O)cc1-n1ncc(C(=O)c2ccccc2)c1N
Reactant: CCN=C=NCCCN(C)C
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2ccccc2)c1N
Reaction time: 1 h

Procedure:
To a stirred solution of 3-(5-amino-4-benzoyl-pyrazol-1-yl)-4-methyl-benzoic acid 5 (Example 3, 700 mg, 2.18 mmol, 1.0 eq) in 30 mL of DMF was added EDCI (855 mg 4.35 mmol, 2.0 eq), HOBt (589 mg, 4.35 mmol, 2.0 eq), and diisopropylethylamine (1.59 mL, 8.71 mmol, 4.0 eq) and the solution was stirred for 15 minutes at room temperature when cyclopropylamine (302 μL, 4.35 mmol, 2.0 eq) was added and the reaction stirred for 1 hour. The mixture was diluted with EtOAc (300 mL) and washed with water (2×25 mL) and brine (25 mL), dried (Na2SO4) and concentrated. The product was purified by flash chromatography on silica gel eluted with 8/2 EtOAc/MeOH to provide the product as a brown oil. The product was further purified by trituration with 1/1/1 EtOAc/hexanes/CH2Cl2 and dried under vacuum to provide 3-(5-amino-4-benzoyl-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide 6 (387 mg, 50%) as a white powder: HPLC (4 minute gradient) tR 2.11 min; MS m/z 361 [M+H]+; 1H NMR (CD3OD, 300 MHz) δ 7.92 (d, J=7.6, 1 H), 7.81 (m, 4 H), 7.54 (m, 4 H), 2.85 (m, 1 H), 2.22 (s, 3 H), 0.80 (d, J=5.7, 2 H), 0.63 (s, 2 H) ppm; 13C NMR (CD3OD, 75 MHz) δ 191.2, 170.1, 153.8, 143.3, 142.0, 141.1, 136.9, 134.8, 132.9, 132.7, 130.1, 129.7, 129.2, 128.1, 104.8, 24.1, 17.7, 6.6 ppm.
Reaction SMILES: [OH:1][C@H:2]([CH3:35])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:16]3[CH:17]=[CH:18][NH:19][C:15]=3[N:14]3[N:20]=[CH:21][C:22]([C:23]4[CH:24]=[N:25][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:27][CH:28]=4)=[C:13]3[N:12]=2)[CH2:7][CH2:6]1)=[O:4].[OH:36][C@H](CO)C(O)=O>>[OH:1][C@H:2]([CH2:35][OH:36])[C:3]([N:5]1[CH2:6][CH2:7][CH:8]([C:11]2[C:16]3[CH:17]=[CH:18][NH:19][C:15]=3[N:14]3[N:20]=[CH:21][C:22]([C:23]4[CH:24]=[N:25][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:27][CH:28]=4)=[C:13]3[N:12]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: O=C(O)[C@H](O)CO
Reactant: C[C@@H](O)C(=O)N1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c3[nH]ccc23)CC1
Product: O=C([C@H](O)CO)N1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c3[nH]ccc23)CC1

Procedure:
The title compound was prepared in a similar way to compound 25, except that (R)-2,3-dihydroxypropanoic acid was used in place of D-lactic acid in Step C. LC/MS (10 min method) RT: 2.63 min, [M+]=482.21, [M+H]=483.21
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[Br:13])[C:6]([C:14]2[C:15](=[O:29])[NH:16][C:17](=[O:28])[C:18]=2[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[CH:5]1)[CH:2]=[CH2:3]>CO>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[Br:13])[C:6]([CH:14]2[CH:18]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[C:17](=[O:28])[NH:16][C:15]2=[O:29])=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cc(C2=C(c3c[nH]c4ccccc34)C(=O)NC2=O)c2cccc(Br)c21
Solvent: CO
Product: C=CCn1cc(C2C(=O)NC(=O)C2c2c[nH]c3ccccc23)c2cccc(Br)c21

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione may be prepared by reacting 1-allyl-7-bromo-1H-indole with (COCl)2 (oxalyl chloride) and sodium methoxide in a polar aprotic solvent such as dichloromethane to yield (1-allyl-7-bromo-1H-indol-3-yl)-oxo-acetic acid methyl ester, which is subsequently reacted with 2-(1H-indol-3-yl)-acetamide and tBuOK (potassium tert-butoxide) in THF to yield 3-(1-allyl-7-bromo-1H-indol-3-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione. Reduction of the 3-(1-allyl-7-bromo-1H-indol-3-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione by Mg in refluxing methanol, as in Example 2 procedure C, yields 3-(1-allyl-7-bromo-1H-indol-3-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione, which is treated with 9-BBN (9-borabicyclo[3.3.1]nonane) and Pd(PPh3)4(tetrakis(triphenylphosphine)palladium) to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]([CH2:34][CH3:35])([OH:33])[CH2:31][CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][CH:14]=2)[CH:12]=1.[Cl-].[NH4+]>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:39])=[O:4])[CH:8]=[N:9][CH:10]=2)=[CH:18][CH:17]=1)([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]([CH2:31][CH3:32])([OH:33])[CH2:34][CH3:35])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)OC)c3)cc2)cc1C)CC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)O)c3)cc2)cc1C)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.293 mL, 0.293 mmol) was added to a solution of [5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propyl}-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 144-(3); 48.7 mg, 0.098 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (37.6 mg, 79%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([C:13](=O)[NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:17][C:16]=2[NH2:28])=[N:10][NH:11][CH:12]=1)(C)(C)C.Cl.C([O-])([O-])=O.[Na+].[Na+]>CCOCC>[N:22]1([CH2:21][C:18]2[CH:19]=[CH:20][C:15]3[NH:14][C:13]([C:9]4[C:8]([NH2:7])=[CH:12][NH:11][N:10]=4)=[N:28][C:16]=3[CH:17]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)Nc1c[nH]nc1C(=O)Nc1ccc(CN2CCOCC2)cc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Temperature: 85 °C
Yield: 79.1 %

Procedure:
A mixture of [3-(2-amino-4-morpholin-4-ylmethyl-phenylcarbamoyl)-1H-pyrazol-4-yl]-carbamic acid tert-butyl ester (12.0 g, 28.8 mmol) and 2M aqueous HCl solution (50 mL) was heated at 85° C. for 14 h, then allowed to cool to ambient temperature. Solid Na2CO3 was carefully added until mixture was pH 8.5 and solution was saturated. A dark coloured gummy liquid was formed. The mixture was allowed to settle and the solvent decanted. To the remaining residue was added EtOH (60 mL), the mixture heated at reflux for 1 h and then hot filtered, washing with EtOH (2×20 mL), to remove inorganic residues. The filtrate was reduced in vacuo to give a glassy solid which was then stirred in Et2O (60 mL) for 1 h and the resultant purple coloured powder collected by filtration and dried in vacuo to give 3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine (6.8 g, 80%, ˜90% purity).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][O:6][C:7](=[O:25])[CH:8]=[C:9]1[CH2:14][CH2:13][N:12]([C:15]2[S:16][C:17]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:11][CH2:10]1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(=O)([O-])O.[Na+]>O1CCCC1.[Cu](I)I>[CH3:5][O:6][C:7](=[O:25])[CH2:8][C:9]1([CH2:1][CH3:2])[CH2:10][CH2:11][N:12]([C:15]2[S:16][C:17]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:13][CH2:14]1
Reactant: COC(=O)C=C1CCN(c2nc3ccc(Cl)cc3s2)CC1
Reactant: CC[Mg]Br
Agent: I[Cu]I
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CCC1(CC(=O)OC)CCN(c2nc3ccc(Cl)cc3s2)CC1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Copper iodide (1.77 g) was suspended in tetrahydrofuran (18 mL), and ethyl magnesium bromide (1.0 M tetrahydrofuran solution, 18.6 mL) was added thereto at −30° C. After stirring at −25° C. for 0.5 hour, the reaction solution was cooled to −78° C. To the mixture was added dropwise a solution of [1-(6-chlorobenzothiazole-2-yl)piperidine-4-ylidene]acetic acid methyl ester (1.00 g) in tetrahydrofuran (10 mL), and then added trimethylsilyl trifluoromethansulfonate (1.12 mL). After stirring at −78° C. for 2 hours, aqueous sodium hydrogencarbonate solution was added thereto. After filtration of the insoluble material, the filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (979 mg). Yield: 90%.
Reaction SMILES: [F-:1].[K+].C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1.Cl[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37][CH2:38][CH2:39][CH:40]1[O:44][CH2:43][CH2:42][O:41]1>C(#N)C>[F:1][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37][CH2:38][CH2:39][CH:40]1[O:44][CH2:43][CH2:42][O:41]1
Reactant: ClCc1ccccc1SCCC1OCCO1
Reactant: [F-]
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: [K+]
Solvent: CC#N
Product: FCc1ccccc1SCCC1OCCO1
Reaction time: 8 h

Procedure:
Potassium fluoride (3.5 mg, 0.060 mmol) and kryptofix 222 (22.5 mg, 0.060 mmol) were dissolved in acetonitrile (1 ml) and added to 2-[2-(2-chloromethyl-phenylsulfanyl)-ethyl]-[1,3]dioxolane (7.7 mg, 0.030 mmol) in acetonitrile (1 ml). The reaction mixture was heated to 70 degrees for 30 minutes. The crude product was purified by reverse phase preparative chromatography (Vydac 218TP1022 column; solvents A=water/0.1% TFA and B=CH3CN/0.1% TFA; gradient 40-80% B over 40 min; flow 10 ml/minute; detection at 254 nm). The fractions were left in the fridge overnight and to the acetonitrile phase was added diethyl ether, dried (Na2SO4) and evaporated under reduced pressure. (Analytical HPLC: Vydac 218TP54 column; solvents: A=water/0.1% TFA and B=CH3CN/0.1% TFA; gradient 40-80% B over 20 min; flow 1.0 ml/minute; retention time 9.200 minutes detected at 214 and 254 nm). Structure verified by NMR.
Reaction SMILES: BrC1C(=O)C(C(O)=O)=CN(C(C)C)C=1C.[Br:16][C:17]1[C:18](=[O:32])[C:19]([C:29]([OH:31])=O)=[CH:20][N:21]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:22]=1[CH3:23].Cl.CS(C1C=CC(CN)=CC=1)(=O)=O.[CH3:46][S:47]([C:50]1[CH:51]=[CH:52][C:53]([CH2:56][NH2:57])=[N:54][CH:55]=1)(=[O:49])=[O:48].BrBr>>[CH3:46][S:47]([C:50]1[CH:51]=[CH:52][C:53]([CH2:56][NH:57][C:29]([C:19]2[C:18](=[O:32])[C:17]([Br:16])=[C:22]([CH3:23])[N:21]([CH:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[CH:20]=2)=[O:31])=[N:54][CH:55]=1)(=[O:49])=[O:48]
Reactant: CS(=O)(=O)c1ccc(CN)nc1
Reactant: CCC(CC)n1cc(C(=O)O)c(=O)c(Br)c1C
Agent: BrBr
Agent: CS(=O)(=O)c1ccc(CN)cc1
Agent: Cc1c(Br)c(=O)c(C(=O)O)cn1C(C)C
Product: CCC(CC)n1cc(C(=O)NCc2ccc(S(C)(=O)=O)cn2)c(=O)c(Br)c1C

Procedure:
Preparation 23 is prepared following the procedure for preparation 5, substituting preparation 3c with preparation 15b and 4-methylsulfonylbenzylamine hydrochloride with C-(5-methanesulfonyl-pyridin-2-yl)-methylamine. ESI mass spectrum: [M+H]+=470 (bromine isotope pattern); Retention time HPLC: 0.91 min (Z018_S04).
Reaction SMILES: CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.[NH2:18][C@H:19]([C:24]([NH:26][C@H:27]([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22].Cl.[NH:37]([C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])[C@H:38]([C:54](O)=[O:55])[CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45].C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C.CN(C=O)C>[NH:37]([C:57]([O:59][CH2:60][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)=[O:58])[C@H:38]([C:54]([NH:18][C@H:19]([C:24]([NH:26][C@H:27]([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH:29]([CH3:30])[CH3:31])=[O:25])[CH2:20][CH:21]([CH3:22])[CH3:23])=[O:55])[CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]([O:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:45]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C
Reactant: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 19 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
4-Methylmorpholine (1.26 g, 12.5 mmol) and HOBt (1.69 g, 12.5 mmol) were added to a solution of H-Leu-Leu-OMe·HCl (4.04 g, 13.75 mmol) in ethyl acetate (160.0 g) and DMF (36.0 g) over 15 min. Z-Lys(Z)-OH (5.18 g, 12.5 mmol) was added to this stirred mixture over 15 min. A solution of DCC (3.10 g, 12.5 mmol) in ethyl acetate (10.0 g) was added dropwise at 18-20° C. over 30 min. The reaction mixture was stirred at 18-20° C. for 16 h and filtered. The filter cake was washed with ethyl acetate (100.0 g) and the combined filtrate was washed with aqueous NaHCO3. The resulting organic layer was washed with aqueous NaCl and concentrated under reduced pressure. The residue was dissolved in MeOH (80.0 g) at about 50° C. Water (160 g) was slowly added and the mixture was stirred for about 1 h at 20° C. The resulting solid was filtered, washed with H2O (80.0 g) and dried at 40° C. in a vacuum oven to give 8.16 g, 99.6% of the product Z-Lys(Z)-Leu-Leu-OMe.
Reaction SMILES: CCOC(C)=O.O.[C:8]([C:10]1[C:11]([CH3:30])=[N:12][C:13]([N:16]([CH2:20][CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)C(=O)C)=[N:14][CH:15]=1)#[N:9]>Cl>[CH3:30][C:11]1[C:10]([C:8]#[N:9])=[CH:15][N:14]=[C:13]([NH:16][CH2:20][CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[N:12]=1
Reactant: CC(=O)N(CCCC1CCN(C)CC1)c1ncc(C#N)c(C)n1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(NCCCC2CCN(C)CC2)ncc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The resultant mixture was treated at 20-25° C. with a dilute HCl solution (37% HCl (4.80 g) diluted with water (15.00 g)), followed by EtOAc (9.02 g) and water (10.00 g). The resultant mixture was settled and the top organic layer was removed. The acidic aqueous layer was stirred at room temperature for 1 h to yield a mixture (which contained the hydrolysis product, N-(5-cyano-4-methyl-pyrimidin-2-yl)-N-[3-(1-methyl-piperidin-4-yl)-propyl]-acetamide). The aqueous layer was extracted one time with EtOAc (9.02 g). 2-Methyl-THF (8.60 g) was added and the pH of the biphasic mixture was adjusted to about pH=12 by addition of 6N NaOH (9.69 g). The aqueous layer was removed and the 2-Me-THF layer was diluted with 2-MeT-HF (8.60 g) and dried with MgSO4 (1.0 g). The pH of the dried 2-MeTHF solution was adjusted to about pH=1 by dropwise addition of 5-6N HCl/IPA, whereupon the HCl salt of the title compound precipitated. The solid was filtered, dissolved in EtOH (3.95 g) and the pH was adjusted to about pH=12 using 6N NaOH (4.85 g). The solid which precipitated during the addition was filtered, washed with water (10.00 g) and dried in a vacuum oven at 60-70° C. for 5 h to yield the title compound as a solid.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:75]=[CH:74][CH:73]=[C:72]3[C:68]=2[CH:69]=[N:70][N:71]3[CH3:76])[C:56]=1[CH3:77].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:75]=[CH:74][CH:73]=[C:72]5[C:68]=4[CH:69]=[N:70][N:71]5[CH3:76])[C:56]=3[CH3:77])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Cc1c(-c2cccc3c2cnn3C)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccc3c2cnn3C)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.020 g, 0.042 mmol), 2,5-dimorpholinopyridin-3-amine (0.083 g, 0.32 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(1-methyl-1H-indazol-4-yl)quinoline (0.090 g, 0.26 mmol), Pd2dba3 (9.6 mg, 10.50 μmol) and sodium tert-butoxide (0.063 g, 0.66 mmol) in toluene (2.6 mL) at 120° C. for 3.3 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(1-methyl-1H-indazol-4-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 7.84 (1H, s), 7.80 (1H, br m), 7.65 (1H, d, J=2.5 Hz), 7.63 (1H, br. s.), 7.53 (4H, s), 7.54 (2H, m), 7.25 (1H, m), 7.05 (1H, ddd, J=13.4, 8.5, 2.7 Hz), 6.41 (1H, br. s.), 4.16 (3H, s), 3.92 (4H, app t, J=4.8 Hz), 3.85 (4H, app dd, J=5.7, 3.9 Hz), 3.25 (4H, br s.), 3.08 (11H, app dd, J=4.3, 2.3 Hz), 2.06 (3H, s). Mass Spectrum (ESI) m/e=572.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]2[N:24]=[C:25]([CH3:27])[O:26][C:22]=2[CH:21]=1.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:29]=[CH:28][C:23]3[N:24]=[C:25]([CH3:27])[O:26][C:22]=3[CH:21]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2ccc(N)cc2o1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc2ccc(NS(=O)(=O)c3cccc(Cl)c3C)cc2o1
Reaction time: 0.08 h
Yield: 65.2 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (163 mg, 0.723 mmol) in dichloromethane (3 mL) was added pyridine (140 μL, 1.72 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-amino-2-methylbenzoxazole (102 mg, 0.688 mmol) was added. The resulting mixture was stirred for 1 h at room temperature, then saturated NaHCO3 solution was added (8 mL) and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a white solid (151 mg, 65%), single spot at Rf 0.50 (60:40 hexane:ethyl acetate). mp 127.1-127.5° C., HPLC purity 97% (tR 2.05 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.85 (1H, dd, J=8.1, 1.1 Hz), 7.53 (1H, dd, J=8.1, 1.3 Hz), 7.45 (1H, d, J=8.4 Hz), 7.27 (1H, d, J=2.2 Hz), 7.17 (1H, t, J=7.9 Hz), 6.93 (1H, s, N—H), 6.86 (1H, dd, J=8.4, 2.2 Hz), 2.71 (3H, s), 2.58 (3H, s). LCMS: 335.14 (M−). FAB-MS (MH+, C15H13ClN2O3S): calcd 337.0413, found 337.0406.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[C:16]([CH:20]=O)=[CH:15][N:14]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([NH2:11])=[N:19][C:17]3[N:18]=[C:13]([NH2:12])[N:14]=[CH:15][C:16]=3[CH:20]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(CC#N)c1
Reactant: Nc1ncc(C=O)c(N)n1
Product: Cc1cc(C)cc(-c2cc3cnc(N)nc3nc2N)c1

Procedure:
The title compound was prepared according to Example 1, starting from 2.0 g of 3,5-dimethylphenyl-acetonitrile and 1.81 g of 2,4-diamino-5-pyrimidine-carboxaldehyde; mp 298°-302° C., MS(CI).