Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[OH:19].[H-].[Na+].Cl.Cl[CH2:24][C:25]1[N:26]=[CH:27][S:28][CH:29]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[N:8]([CH2:24][C:25]1[N:26]=[CH:27][S:28][CH:29]=1)[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2=[O:19]
Reactant: CCOC(=O)c1cnc2c(F)c(F)c(F)cc2c1O
Reactant: ClCc1cscn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2cscn2)c2c(F)c(F)c(F)cc2c1=O
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 22.6 %

Procedure:
1.5 g of ethyl 6,7,8-trifluoro-4-hydroxyquinoline-3-carboxylate was dissolved in 30 ml of DMF, and 0.43 g of 60% oily sodium hydride was added, followed by stirring at 80° C. in a nitrogen gas stream for 20 minutes. To this solution, 1.9 g of 4-chloromethylthiazole hydrochloride was added, followed by stirring at constant temperature for 15 hours, after which the reaction mixture was concentrated to dryness. The residue was dissolved in CHCl3 ; the organic layer was washed with water and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=1:2) to yield 0.46 g of ethyl 6,7,8-trifluoro-1-(4-thiazolylmethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate as a colorless powder. This product was suspended in a mixture of acetic acid and water (3 ml:3 ml); 0.33 ml of sulfuric acid was added, followed by stirring at 120° C. for 30 minutes. The reaction mixture was allowed to cool to room temperature, and the resulting crystal was collected by filtration to yield 0.38 g of the title compound as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[C:14]([N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([CH3:21])[CH2:16]2)=[CH:13][C:5]2[N:6]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[S:8][C:4]=2[CH:3]=1.C(=O)(O)[O-].[K+].[C:27](Cl)(Cl)=[S:28]>C(Cl)(Cl)Cl>[C:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:1]=[C:27]=[S:28])[C:14]([N:15]3[CH2:20][CH2:19][CH2:18][CH:17]([CH3:21])[CH2:16]3)=[CH:13][C:5]=2[N:6]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: S=C(Cl)Cl
Reactant: CC1CCCN(c2cc3nc(C(C)(C)C)sc3cc2N)C1
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC1CCCN(c2cc3nc(C(C)(C)C)sc3cc2N=C=S)C1
Reaction time: 0.5 h

Procedure:
To a cooled mixture of 1.5 g of 6-amino-2-tert-butyl-5-[3-methylpiperidin-1-yl]benzothiazole and 1.5 g of potassium bicarbonate in 50 ml of chloroform is added dropwise 0.6 g of thiophosgene in 5 ml of chloroform under stirring. The stirring is continued for 30 minutes maintaining the temperature at 0°-2°. The solid is filtered and the filtrate is evaporated. The residue thus obtained is dissolved in chloroform and filtered through a silica gel column. The filtrate is evaporated to give 2-tert-butyl-6-isothiocyanato-5-[3-methylpiperidin-1-yl]benzothiazole, melting at 47°-52°.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: CC(C)CCCBr
Product: CC(C)CCCN1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 41.9 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and 1-bromo-4-methyl pentane (103 mg, 0.690 mmol) gave 7-cyclopentyl-2-{5-[4-(4-methyl-pentyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (50 mg, 42%). MS(ESI) m/z 519.4 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[N:7]([CH2:27][C:26]2[CH:29]=[CH:30][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nn(Cc2ccc([N+](=O)[O-])cc2)c1=O
Yield: 92.6 %

Procedure:
Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and 4-nitrobenzyl chloride as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 92.6%.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[N:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:6]=1)[CH:2]=[CH2:3].[C:23]([O:27][C:28](=[O:36])[CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28](=[O:36])[CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][N:4]([CH2:1][CH:2]=[CH2:3])[C:5]1[CH:10]=[N:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:6]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)COCCCCBr
Reactant: C=CCNc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Product: C=CCN(CCCCOCC(=O)OC(C)(C)C)c1cnc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
In the same manner as in Example 22, except that 2-allylamino-5,6-diphenylpyrazine was used in place of 5,6-diphenyl-2-(methylamino)pyrazine and 2-(4-bromobutyloxy)acetic acid tert-butyl ester was used in place of 2-(4-bromobutyloxy)acetic acid methyl ester, the desired compound was prepared as a pale yellow oily substance.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:21])([F:20])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:3]=1.[I-].[K+].CCN(C(C)C)C(C)C.[CH3:33][C:34]1[NH:38][N:37]=[C:36]([NH2:39])[CH:35]=1>CN(C=O)C>[F:20][C:12]([F:21])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:4]1[N:3]=[C:2]([NH:39][C:36]2[CH:35]=[C:34]([CH3:33])[NH:38][N:37]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Fc1ccc(C(F)(F)c2nc(Cl)c3ccccc3n2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-2-(difluoro(4-fluorophenyl)methyl)quinazoline (0.150 g, 0.487 mmol) in DMF (2 mL) at rt were added potassium iodide (0.081 g, 0.487 mmol), DIEA (0.093 mL, 0.535 mmol) and 5-methyl-1H-pyrazol-3-amine (0.048 g, 0.487 mmol). After stirring the reaction mixture at rt overnight, the reaction was quenched by adding water (15 mL). The precipitate was collected by filtration and washed with H2O. The crude solid was triturated with MeOH. 2-(Difluoro(4-fluorophenyl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine was obtained as an off-white solid (0.125 g, 69%). 1H NMR (300 MHz, DMSO-d6) δ 2.24 (s, 3H), 6.31 (s, 1H), 7.34 (m, 2H), 7.68 (m, 3H), 7.87 (m, 2H), 8.68 (m, 1H), 10.69 (s, 1H), 12.20 (s, 1H); LC-MS (ESI) m/z 370 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:19]C3CCCCO3)[CH:14]=[C:15]([CH2:16]OC)[C:7]1=2)[CH3:2].B(Br)(Br)[Br:28].C(O)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:19])[CH:14]=[C:15]([CH2:16][Br:28])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(COC)c21
Reactant: BrB(Br)Br
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CC1OB(O)c2cc(O)cc(CBr)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [1-hydroxy-4-methoxymethyl-6-(tetrahydro-pyran-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester from step 1.10. (870 mg, 1.37 mmol) in DCM (10 mL) was added boron tribromide (0.46 mL, 3.02 mmol) slowly under −78° C. The reaction mixture was allowed to stir at room temperature for 1 h. Ethanol was added slowly and the solvent was removed under vacuum. The crude product was used for next step without further purification. 1H NMR (300 MHz, CD3CN) δ 7.13 (s, 1H), 7.01 (s, 1H), 5.62 (dd, 1H), 4.42-4.63 (dd, 2H), 4.14 (q, 2H), 3.18-3.24 (dd, 1H), 2.40-2.51 (m, 1H), 1.22 (t, 3H).
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]2[O:14][C:15](=[O:23])[C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[CH:18]=2)[CH:10]=[CH:9][C:8]=1[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:41]=[CH:40][C:34]2[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=2[C:32]=1[CH2:42][CH2:43][CH3:44])C.O.[OH-].[Li+].S(=O)(=O)(O)[OH:50]>C1COCC1.O>[C:15]([C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[CH2:18][C:13]([C:11]1[CH:10]=[CH:9][C:8]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:41]=[CH:40][C:34]3[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=3[C:32]=2[CH2:42][CH2:43][CH3:44])=[C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:45])[CH:12]=1)=[O:50])([OH:14])=[O:23]
Reactant: CCCc1c(OCCCCCOc2ccc(-c3cc4ccccc4c(=O)o3)cc2CCC(=O)OCC)ccc2c1OCCC2=O
Reactant: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCCCCCOc2ccc(C(=O)Cc3ccccc3C(=O)O)cc2CCC(=O)O)ccc2c1OCCC2=O
Reaction time: 47 h
Yield: 79.6 %

Procedure:
A mixture of 0.145 g (0.24 mmol) of 2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]-5-(1-oxo-1H-2-benzopyran-3-yl)benzenepropanoic acid ethyl ester in 5 mL of THF and 5 mL of water was treated with 29.8 mg (0.71 mmol) of lithium hydroxide monohydrate and the mixture was stirred for 47 hrs. After being acidified with 16 mL of 3N aqueous sulfuric acid, the resulting mixture was worked up in the usual manner. The crude product was crystallized from hexane-ethyl acetate to give 0.114 g (79.6%) of the title compound as a white solid, mp 178°-182° C.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(C)(=O)=O.[CH3:24][NH2:25]>N1C=CC=CC=1.CN(C=O)C>[CH:1]([N:14]1[CH2:17][CH:16]([NH:25][CH3:24])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CNC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-benzhydryl-azetidin-3-ol (15 g, 62.7 mmol) in pyridine (60 mL) was cooled to 0° C., treated with mesyl chloride (6.3 mL, 81 mmol) and stirred at room temperature for 3 hours. The mixture was partitioned between ether (300 mL) and H2O (150 mL). The ether layer was washed with H2O, washed with brine, dried (MgSO4), filtered and concentrated to provide a greenish solid. The solid (23.3 g) was mixed with methyl amine (40% in H2O, 90 mL) in DMF (60 mL), heated at 85° C. for 48 hours, cooled to room temperature, and partitioned between H2O (200 mL) and EtOAc (400 mL). The aqueous was extracted with additional EtOAc. The combined organics were extracted twice with 2 N HCl (200 mL). The combined 2M HCl layers were basified with NaOH (50%) and extracted with diethyl ether. The ether layer was washed with brine, dried (MgSO4), filtered, concentrated under reduced pressure and purified on a silica gel column eluting with NH4OH/MeOH/CH2Cl2 (0.4/4/96) to provide the title compound. NMR (CDCl3): δ 2.26 (s, 3H), 2.83 (t, J=6 Hz, 2H), 3.33 (m, 1H), 3.46 (t, J=6 Hz, 2H), 7.15-7.20 (m, 2H), 7.24-7.29 (m, 4H), 7.36-7.4 (m, 4H). MS (DCI-NH3) m/z 254 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[C:20](Cl)([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:21].[Cl-].C([NH+](CC)CC)C>O1CCCC1>[C:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([F:12])([F:10])[F:11])([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:21]
Reactant: Nc1ccc(Cl)cc1C(F)(F)F
Reactant: CCOC(=O)C(=O)Cl
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1ccc(Cl)cc1C(F)(F)F

Procedure:
A mixture of 2-amino-5-chlorobenzotrifluoride (14.4 ml, 0.1 mol) and triethylamine (14.0 ml, 0.1 mol) was dissolved in dry tetrahydrofuran, THF (250 ml). To this solution was added with stirring a solution of ethoxalyl chloride in THF (50 ml). After completion of the addition (30 min.) the mixture was stirred at ambient temperature for 3 h, whereafter the precipitated triethylammonium chloride was filtered off, and the filtrate was evaporated in vacuo. This left the crude title compound (24 g) as pale crystals. M.p. 55°-58° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][C@@:25]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)([CH3:35])[C:26]([NH:28][C:29]([CH3:34])([C:31]([OH:33])=O)[CH3:30])=[O:27])=[O:23])[N:9]=2)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=[N:56]C=2C=1.N>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:17])([F:16])[F:18])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][C@@:25]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:43])([F:45])[F:44])[CH:37]=3)([CH3:35])[C:26]([NH:28][C:29]([CH3:30])([C:31]([NH2:56])=[O:33])[CH3:34])=[O:27])=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)[C@](C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(NC(=O)[C@](C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1)C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 31 mg (47 μmol) of the compound of Example 21, 13 mg (70 μmol) of EDC and 9.4 mg (70 μmol) of HOBt in 2 ml of DMF was stirred at RT for 20 min and then poured into 2 ml of ammonia (35% strength solution in water). The reaction mixture was stirred at RT for 30 min, then briefly concentrated on a rotary evaporator, acidified with 1N hydrochloric acid and separated by preparative HPLC [Method 6]. The appropriate fraction was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 29 mg (92% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:33][CH2:32][N:31]([CH:34]([CH3:36])[CH3:35])[CH2:30][CH2:29]4)=[O:27])=[CH:22][CH:21]=3)[CH:17]=[N:18][CH:19]=2)[CH:3]=1.[CH:37]([OH:40])([CH3:39])[CH3:38]>>[CH:37]([O:40][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:33][CH2:32][N:31]([CH:34]([CH3:36])[CH3:35])[CH2:30][CH2:29]4)=[O:27])=[CH:22][CH:21]=3)[CH:17]=[N:18][CH:19]=2)[CH:3]=1)([CH3:39])[CH3:38]
Reactant: CC(C)O
Reactant: CC(C)N1CCN(C(=O)c2ccc(-c3cncc(-c4cc(Cl)nc(-c5ccccn5)n4)c3)cc2)CC1
Product: CC(C)Oc1cc(-c2cncc(-c3ccc(C(=O)N4CCN(C(C)C)CC4)cc3)c2)nc(-c2ccccn2)n1

Procedure:
This compound is prepared from {4-[5-(6-chloro-2-pyridin-2-yl-pyrimidin-4-yl)-pyridin-3-yl]-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone (Ex. 1) and isopropanol analogously to Example 2: [M+H]+=523 as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[C:5]([Cl:7])[N:6]=1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[Cl:7][C:5]1[N:6]=[C:2]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:3][CH:4]=1
Reactant: Clc1csc(Cl)n1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Clc1csc(N2CCOCC2)n1
Temperature: 110 °C
Yield: 91.2 %

Procedure:
In a 75 mL dry pressure vessel, 2,4-dichloro-thiazole (500 mg, 3.2 mmol) and morpholine (560 μL, 6.4 mmol) are dissolved in dry THF (2.0 mL). Cs2CO3 (1.56 g, 4.8 mmol) is added, and the reaction vessel is sealed. The reaction mixture is heated to 110° C. overnight. Solvent is removed via reduced pressure, and the crude reaction mixture is purified via silica gel chromatography to give the title compound (597 mg, 2.92 mmol, 91%). 1H-NMR (CDCl3), δ 3.45 (m, 4H), 3.79 (m, 4H), 6.31 (s, 1H) ppm. ES-MS (m/z): calcd for C7H9ClN2OS (M+H)+: 204.68; found: 205.2.
Reaction SMILES: [CH2:1]([N:3]([CH:11]1[CH2:15][CH2:14][CH:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:26]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[NH:27])[CH:23]=3)[NH:18][CH:17]=2)[CH2:12]1)C(=O)OC(C)(C)C)[CH3:2].C(O)(C(F)(F)F)=O.[NH4+].[OH-]>ClCCl>[CH2:1]([NH:3][CH:11]1[CH2:15][CH2:14][CH:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:26]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[NH:27])[CH:23]=3)[NH:18][CH:17]=2)[CH2:12]1)[CH3:2]
Reactant: CCN(C(=O)OC(C)(C)C)C1CCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC1CCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
tert-Butyl ethyl(3-(5-(thiophene-2-carboximidamido)-1H-indol-3-yl)cyclopentyl)carbamate (1.25 g, 2.76 mmol) was treated with 20% TFA solution (31 mL) in dichloromethane at 0° C. and the mixture left to stir for 2 hours at 0° C. The reaction then was neutralized with 10% NH4OH solution, the organic layer separated and evaporated. The crude was purified by column chromatography (20% 2N NH3 in MeOH: 80% CH2Cl2) to give the product as a yellow solid (0.87 g, 89%). 1H-NMR (DMSO-d6) δ 1.07 (t, 3H, J=7.2 Hz), 1.45-1.71 (m, 2H), 1.77-2.16 (m, 3H), 2.23-2.40 (m, 1H), 2.64-2.73 (m, 2H), 3.24-3.49 (m, 2H), 6.22 (brs, 2H, NH), 6.63 (d, 1H, J=8.1 Hz), 7.03-7.11 (m, 3H), 7.26 (d, 1H, J=8.4 Hz), 7.58 (d, 1H, J=5.1 Hz), 7.71 (d, 1H, J=3.6 Hz), 10.57 (s, 1H, NH); EI-MS (m/z, %) 352 (M+, 50), 243 (80), 158 (100), EI-HRMS (M+) calc. for C20H24N4S, calculated: 352.1722. found: 352.1725.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]3)=[CH:9][CH:8]=2)[N:5]=[C:4]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.[C:28](Cl)([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29].C([O-])(O)=O.[Na+]>CCOC(C)=O>[C:24]([C:4]1[CH:3]=[C:2]([C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29])[N:6]([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:14]3)=[CH:9][CH:8]=2)[N:5]=1)([CH3:26])([CH3:27])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(-n3nc(C(C)(C)C)cc3N)cc2C1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(-n3nc(C(C)(C)C)cc3C(=O)OCC(Cl)(Cl)Cl)cc2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.3 %

Procedure:
To a stirring solution of tert-butyl 7-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.50 g, 1.35 mmol) and Troc-Cl (0.19 ml, 1.38 mmol) in EtOAc (15 mL) was added satd. NaHCO3 (2.75 ml, 2.02 mmol). The resulting biphasic mixture was stirred at RT for 5 h. The layers were separated and the organic washed with sat'd. NaHCO3 (1×) and brine (1×), dried (Na2SO4) and concentrated in vacuo to obtain tert-butyl 7-(3-tert-butyl-5-((2,2,2-trichloroethoxy)carbonyl)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.69 g, 94% yield). MS (ESI) m/z: 545.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:41][C:42]1[CH:43]=[C:44]([N:49]([CH3:65])[C:50]2[N:55]=[C:54]3[S:56][C:57]([NH:59][C:60]([CH:62]4[CH2:64][CH2:63]4)=[O:61])=[N:58][C:53]3=[CH:52][CH:51]=2)[CH:45]=[CH:46][C:47]=1[F:48]>N1C=CC=CC=1>[Cl:1][C:2]1[C:10]([O:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:41][C:42]1[CH:43]=[C:44]([N:49]([C:50]2[N:55]=[C:54]3[S:56][C:57]([NH:59][C:60]([CH:62]4[CH2:63][CH2:64]4)=[O:61])=[N:58][C:53]3=[CH:52][CH:51]=2)[CH3:65])[CH:45]=[CH:46][C:47]=1[F:48])=[O:6]
Reactant: CN(c1ccc(F)c(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Reactant: CC(C)(C#N)Oc1cccc(C(=O)O)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Product: CN(c1ccc(F)c(NC(=O)c2cccc(OC(C)(C)C#N)c2Cl)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethoxy)benzoic acid (4.8 g, 20 mmol) produced in Example C70(iii) in pyridine (100 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (7.6 g, 20 mmol), and the mixture was stirred at room temperature for 2 hr. To the obtained solution was added N-{5-[(3-amino-4-fluorophenyl)(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (3.57 g, 9.99 mmol), and the mixture was stirred at 90° C. for 3 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (350 mL), and washed with water (350 mL). The aqueous layer was extracted with ethyl acetate (150 mL). The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (250 mL×2) and saturated brine (250 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=60/40→20/80), the obtained solution was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give the title compound (5.02 g, 87%) as a colorless powder.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1([F:28])[CH2:27][CH2:26][NH:25][CH2:24]1>C(#N)C>[F:22][C:23]1([F:28])[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:24]1
Reactant: FC1(F)CCNC1
Reactant: CCOC(=O)c1cccc(OCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cccc(OCCN2CCC(F)(F)C2)c1
Temperature: 70 °C
Reaction time: 36 h

Procedure:
To a suspension of ethyl 3-[(2-bromoethyl)oxy]benzoate D46 (476 mg) and potassium carbonate (481 mg, 3.48 mmol) in Acetonitrile (20 mL) stirred at 20° C. was added 3,3-difluoropyrrolidine (250 mg, 1.741 mmol). The reaction mixture was stirred at 70° C. for 36 h. After cooled to room temperature the mixture was filtrated and the filtrate was concentrated. The crude product was added to a silica gel column and was eluted with Hexane/EtOAc/TEA in ratio 50/50/0.5. Fractions isolated and solvent evaporated to afford the title product D49 in 400 mg as a yellow oil. LCMS Retention time=1.20 mins, [M+H]+300 (5 min run)
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@H:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].[NH:35]([C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48])[CH2:36][C:37]([O:39]N1C(=O)CCC1=O)=O>>[NH:35]([C:47]([O:49][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:48])[CH2:36][C:37]([NH:1][C@H:2]([C:11]([NH:13][C@H:14]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:39]
Reactant: CC(C)[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C(CNC(=O)OCc1ccccc1)ON1C(=O)CCC1=O
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C

Procedure:
A diester such as H-Gly-Asp(OtBu)-Val-OtBu can be prepared by condensing Z-Asp(OtBu)-OH and H-Val-OtBu to give Z-Asp(OtBu)-Val-OtBu, hydrogenolyzing the latter, coupling the resulting H-Asp(OtBu)-Val-OtBu with Z-Gly-OSu to give Z-Gly-Asp(OtBu)-Val-OtBu and hydrogenolyzing the latter.