Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]1[C:20]#[N:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:23].[Na+].[OH-].[Na+].OO>CC(C)=O.C(OCC)(=O)C>[C:1]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]1[C:20]([NH2:21])=[O:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1C=Cc2cc(Cl)ccc2N1C(=O)c1ccccc1
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: NC(=O)C1C=Cc2cc(Cl)ccc2N1C(=O)c1ccccc1
Reaction time: 4 h
Yield: 17.7 %

Procedure:
A solution of 1-(Benzoyl)-6-chloro-1,2-dihydro-quinoline-2-carbonitrile (8.0 g), sodium bicarbonate (4.0 g), and 0.1N aqueous sodium hydroxide (20 mL) in acetone (125 mL) was treated with slow addition of 30% hydrogen peroxide (120 mL). The pH of the reaction was kept near 8 by the addition of 0.1N sodium hydroxide. After 4 hours, the mixture was diluted with ethyl acetate and washed with an aqueous solution of sodium thiosulfate. The organic phase was subsequently washed with water and brine. The organic phase was dried over magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel using ethyl acetate/hexane (2:8) followed by ethyl acetate/methylene chloride/hexane (3:1:6) and finally 100% ethyl acetate to yield 1.5 g of the desired compound as a white solid, m.p. 230-234° C.
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:11][NH:12][C:13](=[S:16])[NH:14][NH2:15].[OH-].[K+]>O1CCCC1>[CH2:2]([C:1]1[N:12]([CH3:11])[C:13]([SH:16])=[N:14][N:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)Cl
Reactant: CNC(=S)NN
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCc1nnc(S)n1C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
5 g (30.74 mmol, 1 eq) of octanoyl chloride and 3.58 g (33.81 mmol, 1.1 eq) of 4-methyl-3-thiosemicarbazide in solution in 350 ml of tetrahydrofuran are stirred for 3 hours at room temperature. The solution is concentrated to dryness. The solid obtained is taken up in 350 ml of a 10% aqueous potassium hydroxide solution 35 g (0.82 mmol, 20 eq). The reaction mixture is stirred overnight under reflux. In the cold state, the reaction medium is acidified. The precipitate obtained is filtered, washed with a minimum of water and then dried. 5.94 g (90%) of the expected compound are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([O:19][CH2:20][CH2:21][NH:22]C(OCC1C=CC=CC=1)=O)[C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[NH:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.O1CCCC1.[Pd]>[C:1]([O:5][C:6]([N:8]([O:19][CH2:20][CH2:21][NH2:22])[C:9]([NH:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])=[NH:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(=N)N(OCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(=N)N(OCCN)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
A mixture of [N,N′-di(tert-butoxycarbonyl)] 2-(benzyloxycarbonylamino)-ethoxyguanidine (730 mg, 1.5 mmol), as prepared in the preceding step, and 10% Pd/C (70 mg) in ethanol (20 mL) and tetrahydrofuran (20 mL) was hydrogenated under hydrogen (balloon) for 30 min. The catalyst was removed by filtration through Celite and the filtrate was concentrated in vacuo. The residue was purified by Waters Sep-Pak (10 g, 95:5 methylene chloride:methanol saturated with ammonia) to give the title compound as a colorless oil (290 mg, 61%). 1H-NMR (300 MHz, CDCl3) δ9.08 (br s, 1H), 4.08 (t, J=5.2 Hz, 2H), 2.99 (q, J=5.1 Hz, 2H), 1.50 (s, 9H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([O:19]C(=O)C(C)(C)C)[CH:13]=[CH:12][C:11]=3[CH2:10]2)=[C:5]([NH:26][C:27](=O)[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:31][CH:30]=2)[CH:4]=1.[H-].[Na+].[C:47](OCCBr)(=[O:49])[CH3:48].[Cl-].[NH4+]>O1CCCC1>[OH:49][CH2:47][CH2:48][N:26]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][N:38]2[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)=[CH:31][CH:30]=1)[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[CH:9]1[CH2:10][CH2:11][C:16]2[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12][C:17]=2[CH2:18]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NC(=O)Cc2ccc(OCCN3CCCCC3)cc2)c1
Reactant: CC(=O)OCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(CCO)CCc2ccc(OCCN3CCCCC3)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of pivalic acid 6-{4-methoxy-2-{2-[4-(2-piperidin-1-ylethoxy)phenyl]acetylamino}phenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) in tetrahydrofuran (1 ml) was added 60% sodium hydride (2.2 mg), the solution was stirred for 30 minutes at room temperature, then bromoethyl acetate (6.1 μl) was added thereto followed by stirring for 1 hour. To the reaction solution was added a saturated aqueous solution of ammonium chloride, the solution was extracted with chloroform, and concentrated in vacuo. The residue was subjected to the synthetic method of Example 337 described above to provide the title compound (14 mg).
Reaction SMILES: FC1C=C(F)C=CC=1N[S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=O)=O.[Cl:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[CH2:32]S>>[Cl:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[CH2:32][S:10][CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1
Reactant: Fc1ccc(CS)c(Cl)c1
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Product: CCOC(=O)C1=CCCCC1SCc1ccc(F)cc1Cl
Yield: 78.6 %

Procedure:
In the same manner as in Reference Example 1, ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (835 mg) and (2-chloro-4-fluorophenyl)-methanethiol (853 mg) were reacted to give ethyl 6-[(2-chloro-4-fluorobenzyl)sulfanyl]-1-cyclohexene-1-carboxylate (625 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]([NH2:24])=O)=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]([NH2:24])=[S:39])=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)C1=C(COCC(N)=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CC#N
Product: CCOC(=O)C1=C(COCC(N)=S)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
A mixture of 2-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}-acetamide (6.8 g) and Lawesson's reagent (6.4 g) in acetonitrile (300 ml) was stirred at room temperature for 2.5 hours, filtered and evaporated. The residue was purified by chromatography on silica (80 g) using dichloromethane plus 0-10% v/v ethyl acetate as eluant. Appropriate fractions were combined and evaporated and the residual oil triturated with diethyl ether. The resulting solid was collected, washed with diethyl ether and dried to give the title compound (5.9 g), m.p. 149°-150° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[NH:7][C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[C:10]([NH:12][CH2:13][C:14]#[CH:15])=[O:11])([O-:3])=[O:2].[O:23]1CCC[CH2:24]1.[H-].[Na+].ClC(Cl)(Cl)C(N1C=CN=C1)=O>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[C:8]3[C:9](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:10](=[O:11])[N:12]([CH2:13][C:14]#[CH:15])[C:24]2=[O:23])[CH:20]=[CH:21][CH:22]=1)([O-:3])=[O:2]
Reactant: C#CCNC(=O)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Reactant: C1CCOC1
Agent: O=C(n1ccnc1)C(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C#CCn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.0 g of 2-(m-nitroanilino)-N-propargylbenzamide and 25 ml of dry tetrahydrofuran was added 1.0 g of approximately 55 % sodium hydride, and the solution was stirred for 30 minutes at room temperature. To this was added dropwise 2.1 g of 1-trichloroacetylimidazole and the mixture was refluxed for one hour. After the reaction was complete, the solvent was distilled off from the resulting mixture under reduced pressure. To the residue thus obtained was added water to yield a crude product. This product was recrystallized from methanol to yield 2.8 g of 1-(m-nitrophenyl) -3-propargylquinazoline-2,4(1H, 3H)-dione as colorless needles, melting at 222°-223° C.
Reaction SMILES: [S:1]([N:11]1[C:15]([CH2:16][OH:17])=[CH:14][N:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)(Cl)Cl>[C:25]([O:17][CH2:16][C:15]1[N:11]([S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])[CH:12]=[N:13][CH:14]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)n2cncc2CO)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)OCc1cncn1S(=O)(=O)c1ccc(C)cc1
Reaction time: 5 h

Procedure:
To a solution of 10 mmole of 1-tosylimidazol-5-ylmethanol in 10 ml of chloroform is added dropwise 20 mmole of triethylamine followed by the addition of 13 mmole of acetic anhydride over a period of 2 hours. Stirring is continued for 5 hours at 25° C. after which the solvent is removed under reduced pressure. The residue is partitioned between ethyl acetate and water. The organic phase is washed with sodium bicarbonate, dried over magnesium sulfate and evaporated under vacuo. Recrystallization of the residue from ethyl acetate yields 5-acetoxymethyl-1-tosylimidazole.
Reaction SMILES: [CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]1[C:13]([OH:15])=O)[CH3:2].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[Cl:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=1[CH2:43][NH2:44].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[Cl:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=1[CH2:43][NH:44][C:13]([CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11](=[O:12])[N:3]1[CH2:1][CH3:2])=[O:15]
Reactant: CCN1C(=O)c2ccccc2C1C(=O)O
Reactant: NCc1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1C(=O)c2ccccc2C1C(=O)NCc1ccc(Cl)cc1Cl
Reaction time: 3 h
Yield: 51.4 %

Procedure:
2-Ethyl-3-oxo-2,3-dihydro-1H-isoindole-1-carboxylic acid (0.061 g, 0.3 mmol, prepared as described below) was dissolved in anhydrous dimethylformamide (5 ml) and to this was added 1-hydroxybenzotriazole (0.045 g, 0.3 mmol), diisopropylethylamine (0.105 ml, 0.6 mmol), [(2,4-dichlorophenyl)methyl]amine (0.054 g, 0.3 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.114 g, 0.3 mmol). The mixture was stirred for 3 hrs and then left to stand overnight. The mixture was diluted with water (50 ml) and a little saturated aqueous sodium chloride solution and extracted with ethyl acetate (3×20 ml). The organic fractions were combined and washed with 10% aqueous sodium carbonate (50 ml) and then with saturated aqueous sodium chloride solution (50 ml), dried over magnesium sulphate and evaporated to give a gum. The gum was purified by mass-directed automated HPLC to give N-[(2,4-dichlorophenyl)methyl]-2-ethyl-3-oxo-2,3-dihydro-1H-isoindole-1-carboxamide (0.056 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22]([OH:24])=O)[NH:17]4)=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[ClH:25].Cl.Cl.[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1>>[ClH:1].[ClH:25].[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH:45][C:22]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[C:13]([O:12][CH2:11][C:8]3[C:7]5[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=5[O:10][CH:9]=3)[CH:21]=[CH:20][CH:19]=4)=[O:24])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1
Reactant: O=C(O)c1cc2c(OCc3coc4cccc(Cl)c34)cccc2[nH]1
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Agent: Cl
Product: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cccc(Cl)c34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(4-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (118) (preparation see below) and amine 61 analogously to the method described in example 1.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[NH:7][C:6]([CH3:9])([CH3:8])[CH2:5][N:4]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]#[N:16])[C:3]1=[O:17]>CO.[Ni]>[CH3:1][C:2]1([CH3:18])[NH:7][C:6]([CH3:8])([CH3:9])[CH2:5][N:4]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][NH2:16])[C:3]1=[O:17]
Reactant: CC1(C)CN(CCOCCC#N)C(=O)C(C)(C)N1
Agent: [Ni]
Solvent: CO
Product: CC1(C)CN(CCOCCCN)C(=O)C(C)(C)N1

Procedure:
215.9 g (0.85 moles) of 3-[2-(3,3,5,5-tetramethyl-2-oxo-piperazin-1-yl)-ethoxy]-propionitrile are dissolved in 900 m of methanol and hydrogenated at 120° C. and at 50 bars in the presence of 100 g of Ni Raney as catalyst. The mixture is then filtered and the organic phase is evaporated under vacuum (40° C./1 0 mbar). The residue is distilled giving a white oil b.p. 130-136OC./0.8 mbar.
Reaction SMILES: [CH:1]1([CH2:5][C:6]2([CH3:23])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8](C(OCC)=O)[C:7]2=[O:22])[CH2:4][CH2:3][CH2:2]1>O1CCOCC1.Cl.O>[CH:1]1([CH2:5][C:6]2([CH3:23])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[CH:8][C:7]2=[O:22])[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)C1=C(O)c2ccccc2C(C)(CC2CCC2)C1=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC1(CC2CCC2)C(=O)C=C(O)c2ccccc21
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution of Example 55E (0.055 g, 0.174 mmol) in 4 mL of dioxane and 4 mL of 1N HCl was refluxed for 3 hours. The solution was cooled to room temperature, diluted with water and extracted with 3× ethyl acetate. The combined organic layers were dried over MgSO4, and concentrated in vacuo to yield the title compound (0.035 g, 83% yield) as an oil that solidifies on standing. 1H NMR (300 MHz, DMSO-d6): δ ppm 1.16 (m, 3H) 1.48 (s, 3H) 1.70 (m, 3H) 2.04 (m, 2H) 2.21 (m, 1H) 5.76 (m, 1H) 7.30 (m, 1H) 7.44 (m, 1H) 7.63 (m, 1H) 8.00 (d, J=8.09 Hz, 1H). MS (ESI+) m/z=243 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12]1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:14](=[O:16])[CH2:13][CH2:12]1
Reactant: Fc1ccc(CBr)cc1
Reactant: COc1cccc(OC)c1C1CCC(=O)N1
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1ccc(F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 5-(2,6-dimethoxyphenyl)pyrrolidin-2-one with commercially available 1-(bromomethyl)-4-fluorobenzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.71 min.; [M+H]+: 330.24 g/mol.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:8]([CH3:17])=[CH:7][C:6]=1[NH:18][C:19]1[N:24]=[C:23]2[NH:25][N:26]=[C:27]([CH3:28])[C:22]2=[C:21]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[N:20]=1)([CH3:3])[CH3:2].[CH3:42]C(O)=O.C=O.[NH4+].[Cl-]>CO.C1COCC1>[CH:1]([O:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:42])[CH2:13][CH2:12]2)[C:8]([CH3:17])=[CH:7][C:6]=1[NH:18][C:19]1[N:24]=[C:23]2[NH:25][N:26]=[C:27]([CH3:28])[C:22]2=[C:21]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[N:20]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)n[nH]c3n2)c(OC(C)C)cc1C1CCNCC1
Reactant: CC(=O)O
Agent: C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)n[nH]c3n2)c(OC(C)C)cc1C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N6-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (39 mg, 0.067 mmol) in 5.0 mL of MeOH and 5.0 mL of THF was added drops of AcOH and HCHO [1N in MeOH and THF (v/v: 1/1), 0.12 mmol, 120 μL] sequentially. The reaction mixture was stirred at room temperature for 30 min, then NaB(CN)H3 (6.6 mg, 0.12 mmol) was added and the reaction mixture was stirred for another 1 h. Saturated aqueous NH4Cl was added to the reaction and the reaction mixture was concentrated in vacuo. The crude was partitioned between EtOAc and brine. The organic extracts were concentrated and purified by RP-HPLC to afford N6-(2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine. MS (ES+): 592.3 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:19]3[C:14]([CH:15]=[N:16][C:17]([S:20][CH3:21])=[N:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CO.O1CCCC1.[Br:29]N1C(=O)CCC1=O>>[Br:29][C:13]1[CH:12]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=2)[N:19]2[C:14]=1[CH:15]=[N:16][C:17]([S:20][CH3:21])=[N:18]2
Reactant: CSc1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: C1CCOC1
Product: CSc1ncc2c(Br)cc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
Into a 30 mL vial, 7-(4-Methanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.205 g, 0.000642 mol), Methanol (4 mL, 0.1 mol) and Tetrahydrofuran (9 mL, 0.1 mol) were added. N-Bromosuccinimide (0.137 g, 0.000770 mol) was added portion wise over 5 minutes. The reaction was stirred at room temperature over night. The solvent was removed under vacuum. The solid was partitioned with water and filtered to give a yellow solid. The solid was washed with cold methanol to give 5-Bromo-7-(4-methanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid (140 mg, 55%). NMR 1H (DSMO-d6)-9.01 (s, 1H), 8.48 (d, 2H, J=8.48 Hz), 8.07 (d, 2H, J=8.53 Hz), 7.79 (s, 1H), 3.28 (s, 3H), 2.62 (s, 3H)
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[N:18]4)=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:27]>CC(O)C>[C:21]1([C:17]2[CH:16]=[CH:15][C:14]3[C:19](=[CH:20][C:11]([C:10]4[C:3]5[C:2]([NH2:27])=[N:7][CH:6]=[N:5][C:4]=5[S:8][CH:9]=4)=[CH:12][CH:13]=3)[N:18]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Clc1ncnc2scc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Reactant: N
Solvent: CC(C)O
Product: Nc1ncnc2scc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Temperature: -78 °C

Procedure:
From 7-(4-chlorothieno[2,3-d]pyrimidin-5-yl)-2-phenylquinoline: Gaseous NH3 was bubbled into a iPrOH (1 ml) solution of 7-(4-chlorothieno[2,3-d]pyrimidin-5-yl)-2-phenylquinoline (56 mg, max. 0.084 mmol) in a sealable tube, cooled to −78° C. in a dry ice/acetone bath, for 15 min. The sealed tube was equipped with a Teflon washer, sealed and heated at 110° C. for 8 h. After that time, the excess NH3 and the solvent were evaporated. The remaining material was purified by HPLC to give the title compound as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([F:12])[CH:10]=2)[CH:5]=[C:4]([NH:15][C:16]2[CH:20]=[C:19]([CH:21]3[CH2:23][CH2:22]3)[NH:18][N:17]=2)[N:3]=1>C(O)(C)C>[CH:21]1([C:19]2[NH:18][N:17]=[C:16]([NH:15][C:4]3[N:3]=[C:2]([O:13][CH:8]([CH3:9])[CH3:7])[C:11]4[C:6]([CH:5]=3)=[CH:7][C:8]([O:13][CH3:14])=[C:9]([F:12])[CH:10]=4)[CH:20]=2)[CH2:23][CH2:22]1
Reactant: COc1cc2cc(Nc3cc(C4CC4)[nH]n3)nc(Cl)c2cc1F
Solvent: CC(C)O
Product: COc1cc2cc(Nc3cc(C4CC4)[nH]n3)nc(OC(C)C)c2cc1F

Procedure:
Similar procedure as described in example 376 was used, starting from isopropanol, (1-Chloro-7-fluoro-6-methoxy-isoquinolin-3-yl)-(5-cyclopropyl-1H-pyrazol-3-yl)-amine to give (5-Cyclopropyl-1H-pyrazol-3-yl)-(7-fluoro-1-isopropoxy-6-methoxy-isoquinolin-3-yl)-amine. LC-MS: m/e 357(MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=O)[CH2:11][S:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C(=O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:41][NH:42][O:43][CH3:44].CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[CH3:44][O:43][N:42]([CH3:41])[C:13]([C@@H:12]1[CH2:11][S:10][CH2:9][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CON(C)C(=O)[C@@H]1CSCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To a solution in DMF (10 mL) of N-tert-butoxycarbonyl-(R)-(−)thiazolidine-4-carboxylic acid (777 mg, 3.33 mmol), prepared as in Example 164A, 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (602 mg, 3.69 mmol), and ethyl dimethylaminopropyl carbodiimide hydrochloride (709 mg, 3.70 mmol) was added N,O-dimethylhydroxylamine hydrochloride (357 mg, 3.66 mmol) and 4-methylmorpholine (0.44 mL, 4.01 mmol) and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and extracted with aqueous 1M H3PO4 (2×), saturated aqueous NaHCO3 (2×), and brine. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on silica gel (2:1 hexane-ethyl acetate) gave N-tert-butoxycarbonyl-(R)-(−)thiazolidine-4-carboxylic acid-N-methoxy-N-methyl amide (605 mg) as a thick yellow oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[S:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1>>[CH3:20][C:18]1[CH:17]=[CH:16][C:15]([S:21][C:22]2[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2cccc(O)c2)c(N)c1
Product: Cc1ccc(Sc2cccc(O)c2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (277 mg, 1.56 mmol) was reacted with the product from Example 52b (245 mg, 1.56 mmol) for 5 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (399 mg, 52%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.38 (s, 3H) 2.75 (s, 3H) 6.30 (d, J=6.99 Hz, 1H) 6.53-6.58 (m, 2H) 6.61 (d, J=8.09 Hz, 1H) 6.90-7.08 (m, 1H) 7.27-7.47 (m, 3H) 7.77 (d, J=8.46 Hz, 1H) 8.39 (d, J=6.99 Hz, 1H) 8.94 (d, J=8.82 Hz, 1H) 9.58 (s, 1H) 10.96 (s, 1H) 14.34 (s, 1H); MS (ESI+) m/z 374 (M+H)+.