Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([O:7][C:8]1[CH:13]=[C:12]([NH:14][S:15]([N:18]2[CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[N:11]=[C:10]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=2[F:31])[N:9]=1)[CH3:6])C.[BH4-].[Li+]>C1COCC1>[F:31][C:25]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][S:22][C:10]1[N:11]=[C:12]([NH:14][S:15]([N:18]2[CH2:21][CH2:20][CH2:19]2)(=[O:16])=[O:17])[CH:13]=[C:8]([O:7][C@H:5]([CH3:6])[CH2:4][OH:3])[N:9]=1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CO)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 2-[[6-[(1-azetidinylsulfonyl)amino]-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester, (the product of example 23) (0.40 g) in THF (10 mL) was added 2M lithium borohydride in THF (0.82 mL) dropwise and the mixture was stirred at ambient temperature for 20 h. The reaction mixture was cooled to 0° C. and quenched with 1M aqueous hydrochloric acid. The resulting mixture was extracted with EtOAc (×2). The combined organic layers were washed with 1M aqueous hydrochloric acid then brine and was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using EtOAc/isohexane (1:1) as eluent. The resulting oil was triturated with DCM to give the title compound as a white solid. Yield: 0.25 g
Reaction SMILES: [CH:1]([OH:3])=[O:2].OO.[Cl:6][C:7]1[CH:17]=[C:16](C=O)[C:10]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[CH:9][N:8]=1>>[Cl:6][C:7]1[CH:17]=[C:16]([C:10]([C:11](=[O:12])[N:13]([CH3:14])[CH3:15])=[CH:9][N:8]=1)[C:1]([OH:3])=[O:2]
Reactant: CN(C)C(=O)c1cnc(Cl)cc1C=O
Reactant: O=CO
Agent: OO
Product: CN(C)C(=O)c1cnc(Cl)cc1C(=O)O
Reaction time: 96 h
Yield: 37.1 %

Procedure:
Formic acid (0.628 mL, 16.5 mmoles) and 30% hydrogen per oxide (1.87 mL, 16.5 mmoles) were added to 6-chloro-4-formyl-N,N-dimethyl-nicotinamide (Intermediate 67, 0.7 g. 3.3 mmoles), and the solution was kept at 4° C. for 4 days. The precipitate was filtered and washed with cold water. The solid was heated to reflux in toluene then collected by filtration (2×25 mL) to afford 0.28 g (35.89%) of the title compound as pale yellow solid. MS (APCI): 229 (M+H+) for C9H9ClN2O3; NMR: 2.76 (s, 3H), δ 2.97 (s, 3H), δ 7.84 (s, 1H), δ 8.47 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([CH:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])=[N:16][N:15]=[CH:14]2.CN(C(ON1N=NC2[CH:38]=[CH:39][CH:40]=[N:41]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1>CN(C)C=O>[CH:40]1([NH:41][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([CH:21]([CH3:26])[C:22]([F:23])([F:24])[F:25])=[N:16][N:15]=[CH:14]4)[CH:4]=2)[CH2:38][CH2:39]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(C(C)C(F)(F)F)nncc2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C(C)C(F)(F)F)nncc2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 4-methyl-3-(1-(1,1,1-trifluoropropan-2-yl)phthalazin-6-yl)benzoic acid (86 mg, 239 μmol) in N,N-dimethylformamide (1000 μl) were added HATU (136 mg, 358 μmol) and cyclopropylamine (8 μl, 2387 μmol). The resulting mixture was stirred at RT for 20 h, during which LC-MS indicated conversion to the desired product. The reaction was diluted with EtOAc and washed with water and brine. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Preparative HPLC purification (Shimadzu) afforded the title compound as a white amorphous solid. MS (ES+): 400.4 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:12]2[CH:16]=[CH:15][N:14]([CH2:17][C@@H:18]([NH:20][C:21]([C:23]3[N:24]=[CH:25][N:26]([CH2:28][CH2:29][C:30](=[O:32])[CH3:31])[CH:27]=3)=[O:22])[CH3:19])[N:13]=2)[CH:7]=[CH:8][C:9]=1[C:10]#[N:11].O>C(O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:12]2[CH:16]=[CH:15][N:14]([CH2:17][C@@H:18]([NH:20][C:21]([C:23]3[N:24]=[CH:25][N:26]([CH2:28][CH2:29][CH:30]([OH:32])[CH3:31])[CH:27]=3)=[O:22])[CH3:19])[N:13]=2)[CH:7]=[CH:8][C:9]=1[C:10]#[N:11]
Reactant: CC(=O)CCn1cnc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(O)CCn1cnc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium borohydride (9.8 mg, 0.26 mmol) was added to a solution of (S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-(3-oxobutyl)-1H-imidazole-4-carboxamide (100 mg, 0.24 mmol) in ethanol (3 ml) at RT. Thereafter the reaction mixture was stirred at RT for 3 h. Then water was added and the product was extracted into ethyl acetate. The combined organic layers were washed with water and dried. The solvent was evaporated to obtain the title compound. 1H NMR (400 MHz, CDCl3): 1.21 (31-1, d), 1.22 (3H, d), 1.89 (2H, m), 2.31 (1H, broad s), 3.73 (1H, m), 4.15 (2H, m), 4.28 (1H, distorted dd), 4.40 (1H, distorted dd), 4.56 (1H, m), 6.61 (1H, d), 7.51 (2H, m), 7.60 (1H, d), 7.66 (1H, distorted d), 7.79 (1H, m), 7.95 (1H, d), 8.18 (1H, d).
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[C:4]([C:12]2[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=2)=[CH:3]1.Cl>C1COCC1>[F:18][C:2]1([F:1])[CH2:11][CH2:10][C:5](=[O:6])[C:4]([C:12]2[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=2)=[CH:3]1
Reactant: Cn1nccc1C1=CC(F)(F)CCC12OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: Cn1nccc1C1=CC(F)(F)CCC1=O
Yield: 27.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 67c by using the 5-(8,8-difluoro-1,4-dioxaspiro[4.5]dec-6-en-6-yl)-1-methyl-1H-pyrazole (758 mg, 2.96 mmol) prepared in Example 88e, 5 M hydrochloric acid (10 mL) and THF (10 mL), to yield the title compound (170 mg, 14%, 3 steps) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[CH3:19][C:20]1[O:21][C:22]([C:28]([F:31])([F:30])[F:29])=[C:23]([C:25](O)=[O:26])[N:24]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]([F:31])([F:29])[F:30])=[O:26])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: Cc1nc(C(=O)O)c(C(F)(F)F)o1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: Cc1nc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OCC3(F)F)c2)c(C(F)(F)F)o1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 2-methyl-5-trifluoromethyl-oxazole-4-carboxylic acid following procedure I yielded the title compound as a colorless foam. MS (ISP): m/z=437.1 [M+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[C:24]([CH3:25])=[CH:23][N:22]=[C:21](Cl)[N:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:25][C:24]1[C:19]([NH:18][CH2:17][CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[N:20][CH:21]=[N:22][CH:23]=1
Reactant: Cc1cnc(Cl)nc1NCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: Cc1cncnc1NCC1CCNCC1

Procedure:
A mixture of 4-[(2-chloro-5-methyl-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester (EXAMPLE 59, 2.00 g, 5.34 mmol), Pd/C (10%, 0.20 g) in absolute ethanol (15 mL) was vigorously stirred under 1 atm H2. Filtered and concentrated, the reaction gave 4-[(5-methyl-pyrimidin-4-ylamino)-methyl]-piperidine. M.S. (M+1): 207.29
Reaction SMILES: [CH3:1][N:2]([CH3:59])[C@H:3]1[CH2:56][C@@H:55]([CH3:57])[O:54][CH:5]([O:6][C@@H:7]2[C@@H:23]([CH3:24])[C:22](=[O:25])[C@@H:21]([CH3:26])[C:20](=[O:27])[O:19][C@H:18]([CH2:28][CH3:29])[C@:17]3([CH2:30][OH:31])[C@H:13]([N:14]([CH2:33][CH2:34][CH2:35][CH2:36][N:37]4[CH:41]=[C:40]([C:42]5[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=5)[N:39]=[CH:38]4)[C:15](=[O:32])[O:16]3)[C@@H:12]([CH3:48])[C:11](=[O:49])[C@H:10]([CH3:50])[CH2:9][C@:8]2([O:52][CH3:53])[CH3:51])[C@@H:4]1[OH:58].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(OCC)(=O)C>[CH3:59][N:2]([CH3:1])[C@H:3]1[CH2:56][C@@H:55]([CH3:57])[O:54][CH:5]([O:6][C@@H:7]2[C@@H:23]([CH3:24])[C:22](=[O:25])[C@@H:21]([CH3:26])[C:20](=[O:27])[O:19][C@H:18]([CH2:28][CH3:29])[C@:17]3([CH:30]=[O:31])[C@H:13]([N:14]([CH2:33][CH2:34][CH2:35][CH2:36][N:37]4[CH:41]=[C:40]([C:42]5[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=5)[N:39]=[CH:38]4)[C:15](=[O:32])[O:16]3)[C@@H:12]([CH3:48])[C:11](=[O:49])[C@H:10]([CH3:50])[CH2:9][C@:8]2([O:52][CH3:53])[CH3:51])[C@@H:4]1[OH:58]
Reactant: CC[C@H]1OC(=O)[C@H](C)C(=O)[C@H](C)[C@@H](OC2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@H]2N(CCCCn3cnc(-c4cccnc4)c3)C(=O)O[C@]12CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC[C@H]1OC(=O)[C@H](C)C(=O)[C@H](C)[C@@H](OC2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@H]2N(CCCCn3cnc(-c4cccnc4)c3)C(=O)O[C@]12C=O
Reaction time: 3 h
Yield: 19 %

Procedure:
To (3aR,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyl-3a-(hydroxymethyl)-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (1 eq) in dichloromethane was added Dess-Martin Periodinane (1.1 eq). After stirring for 3 hours, more Dess-Martin Periodinane (1 eq) was added. After stirring for an additional 15 hours, the solution was diluted with ethyl acetate and was washed with 1:1 10% Na2S2O3/NaHCO3(sat), with NaCl(sat.), dried over MgSO4, filtered and concentrated. Purification by RP HPLC yielded (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyl-3a-formyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (19% yield) as a white solid. MH+(826.5).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[C:22]#[N:23].[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].C(OCC)(=O)C.[OH-].[Na+]>N1C=CC=CC=1>[C:22]([C:3]1[C:2]([NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:7][C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([N:13]([CH3:14])[CH3:15])[CH2:9]2)=[C:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:4]=1)#[N:23]
Reactant: CN(C)[C@H]1CCN(c2cc(N)c(C#N)cc2-c2ccccc2)C1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CN(C)[C@H]1CCN(c2cc(NC(=O)C(C)(C)C)c(C#N)cc2-c2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.1 %

Procedure:
4-Amino-6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]biphenyl-3-carbonitrile (I-243) (300 mg, 0.98 mmol) was dissolved in pyridine (3 ml), and under nitrogen atmosphere at room temperature, pivaloyl chloride (181 μl, 1.47 mmol) was added. After stirring at room temperature for 3 days, the reaction liquid was fractionated with ethyl acetate and aqueous 1 M sodium hydroxide solution. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, then the solvent was evaporated away and the resulting residue was purified by middle-pressure liquid chromatography (eluent, chloroform:methanol=98:2) to obtain the entitled compound (364 mg, 95%) as a pale yellow gel.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[C:6]([NH2:18])[CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH2:18][C:6]1[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[CH:8][C:7]=1[S:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(Sc2ccc(O)cc2)c(N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(CO)ccc1Sc1ccc(O)cc1
Temperature: 70 °C
Yield: 65.5 %

Procedure:
To the product from Example 65B (500 mg, 1.82 mmol) in tetrahydrofuran (50 mL) was added a solution of lithium aluminum hydride (1.0M in THF, 1.8 mL, 1.82 mmol) dropwise at room temperature followed by heating the mixture to 70° C. for 4 hours. Water (25 mL) was then carefully added to the solution and the organic layer separated, dried and concentrated under vacuum to provide the title compound (295 mg, 66%).
Reaction SMILES: [O:1]=O.[C:3]([C:6]12[CH2:15][C:10]3([C:16]([OH:18])=[O:17])[CH2:11][CH:12]([CH2:14][C:8]([C:19]([OH:21])=[O:20])([CH2:9]3)[CH2:7]1)[CH2:13]2)([OH:5])=[O:4]>C(O)(=O)C>[C:16]([C:10]12[CH2:15][C:6]3([C:3]([OH:5])=[O:4])[CH2:13][C:12]([OH:1])([CH2:14][C:8]([C:19]([OH:21])=[O:20])([CH2:7]3)[CH2:9]1)[CH2:11]2)([OH:18])=[O:17]
Reactant: O=O
Reactant: O=C(O)C12CC3CC(C(=O)O)(C1)CC(C(=O)O)(C3)C2
Solvent: CC(=O)O
Product: O=C(O)C12CC3(O)CC(C(=O)O)(C1)CC(C(=O)O)(C3)C2
Temperature: 75 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
In an atmosphere of oxygen, to 25 mL of acetic acid was added 10 mmole of the 1,3,5-tricarboxyadamantane, 1 mmole of NHPI and 0.005 mmole of Co(AA)2 and the mixture was stirred for 6 hours at 75° C. As a result, the conversion was 76% and 1,3,5-tricarboxy-7-adamantanol was obtained in a 70% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[N:21]=[N:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28]>>[OH:28][CH2:27][C:26]([NH:25][C:22]([C:19]1[N:20]=[N:21][C:16]([O:15][CH2:14][C:9]2[N:10]([CH3:13])[N:11]=[N:12][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:17][CH:18]=1)=[O:23])([CH3:30])[CH3:29]
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)nn1
Reactant: CC(C)(N)CO
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC(C)(C)CO)nn1
Yield: 40 %

Procedure:
As described for example 42b, 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (67 mg, 0.20 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of 4-aminotetrahydropyran, to the title compound (37 mg, 40%) which was obtained as a white solid. MS: m/e=401.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH:13]([C:17]([NH2:19])=[O:18])[C:14]([NH2:16])=[O:15].C(N(CC)CC)C>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][CH:13]([C:17]([NH2:19])=[O:18])[C:14]([NH2:16])=[O:15])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: NC(=O)C(Br)C(N)=O
Reactant: NCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=O)C(NCc1ccc([N+](=O)[O-])cc1)C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a solution of 41.60 g of p-nitrobenzylamine in 660 ml of dry ethanol was added 49.34 g of α-bromomalonamide and 38.2 ml of triethylamine. After being stirred for two hours under refluxing, the reaction mixture was cooled to room temperature. And then separated crystals were filtered off, washed with ethanol and isopropyl ether, and dried to give 53.36 g of α-(4-nitrobenzyl)aminomalonamide. And a mixture of 50.45 g of α-(4-nitrobenzyl)aminomalonamide, 177.8 g of triethyl orthoformate and 0.76 g of p-toluenesulfonic acid monohydrate in 1.3 liters of dry ethanol was stirred for three hours under refluxing in an argon atmosphere. The reaction mixture was cooled on an ice-bath and separated crystals were filtered off, washed with ethanol and isopropyl ether, and dried to give 50.78 g of 5-carbamoyl-1-(4-nitrobenzyl)imidazolium-4-olate.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].C([O-])([O-])=O.[K+].[K+].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.O>CN(C=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4])=[CH:16][CH:15]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)(O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)COc1ccc(Br)cc1
Temperature: 140 °C
Reaction time: 48 h

Procedure:
To a solution of 1-chloro-2-methylpropan-2-ol (434.4 mg, 4 mmol) in DMF (10 mL) was added K2CO3 (552 mg, 4 mmol) and 4-bromophenol (346 mg, 2 mmol), the reaction was stirred at 140° C. for 48 hours. About of 10% 4-bromophenol was remained and the reaction was poured into 30 mL of water, extracted with EA (20 mL×3), washed with 30 mL of water and brine, concentrated and purified on TLC (EA:PE=1:3) to give yellow solid. MS (m/z): 196 (M−50)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH2:22][C:23]3[C:24]([NH:36][CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[C:25]4[CH:33]=[N:32][N:31]([CH2:34][CH3:35])[C:26]4=[N:27][C:28]=3[CH2:29][CH3:30])=[O:20])[CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:43]([C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1)=[O:44].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:8][C:6]1[CH:5]=[C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH2:22][C:23]3[C:24]([NH:36][CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[C:25]4[CH:33]=[N:32][N:31]([CH2:34][CH3:35])[C:26]4=[N:27][C:28]=3[CH2:29][CH3:30])=[O:20])[CH:14]=2)=[O:12])[CH:3]=[C:2]([C:49]2[CH:48]=[CH:47][CH:46]=[C:45]([CH:43]=[O:44])[CH:50]=2)[CH:7]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Cl)cc(Br)c2)c1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Cl)cc(-c3cccc(C=O)c3)c2)c1

Procedure:
N-[(3-Bromo-5-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (300 mg, 0.459 mmol), (3-formylphenyl)boronic acid (68.8 mg, 0.459 mmol), potassium carbonate (190 mg, 1.376 mmol), and tetrakis(triphenylphosphine)palladium(0) (26.5 mg, 0.023 mmol) were placed in a 2-5 mL Biotage microwave vial along with a stir bar. Then 1,4-dioxane (3 mL) and water (1 mL) were added. The vial was capped and microwaved for 15 min at normal power in the SmithCreator microwave at 100° C. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (10 mL). The organic phase was washed 3× with water (10 mL), 1× with brine (10 mL), and dried over anhydrous Na2SO4. The crude product was taken up in dichloromethane and absorbed on Isolute® Sorbent and purified using CombiFlash on a 40 g silica column eluted with 0-10% DCM/MeOH to afford the title compound as a pale yellow solid. LC-MS m/z 679.0 (M+H)+, 2.21 min (ret time); mp 123-127° C.; analytical HPLC shows 96.2% purity, (ret time 14.171 min).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].CS([C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2/[C:35](=[CH:40]\[O:41][CH3:42])/[C:36]([O:38][CH3:39])=[O:37])[CH:23]=1)(=O)=O.O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:22]2[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3/[C:35](=[CH:40]\[O:41][CH3:42])/[C:36]([O:38][CH3:39])=[O:37])[CH:23]=2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(S(C)(=O)=O)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(OCc2ccc([N+](=O)[O-])cc2)ncn1
Temperature: 60 °C
Yield: 44.3 %

Procedure:
To a solution of 4-nitrobenzyl alcohol (666 mg) in DMF (8 ml) was added potassium carbonate (800 mg) followed by a solution of (E)-methyl 2-[2-(6-methanesulphonylpyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (1.0 g, prepared as described in Example 1) in DMF (3 ml). The reaction mixture was heated to 60° C. under an atmosphere of nitrogen for 5½ hours, cooled and then poured into water (40 ml). The resulting mixture was extracted with ether (×3) and the combined ether layers were dried and evaporated to yield an orange oil. Chromatography (eluent ether-hexane, 7:3) gave (E)-methyl 2-[2-(6-(4-nitrobenzyloxy)pyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (532 mg) as a glass which solidified on standing; m.p. 96-98° C.; 1H NMR: δ 3.55 (3H, s), 3.75 (3H, s), 5.50 (2H, s), 6.15 (1H, s), 7.15 (1H, d), 7.3 (3H, m), 7.45 (1H, s), 7.58 (2H, d), 8.22 (2H, d), 8.42 (1H, s) ppm; IR maxima: 1700, 1620, 1560, 1340 cm−1; mass spectrum m/e 437 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH2:12]([O:11][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(Br)c1OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 5.22 g (23.9 mmol) of 2-bromo-6-nitrophenol, 3.0 ml (25.1 mmol) of benzyl bromide and 3.64 g (26.3 mmol) of potassium carbonate in 50 ml of acetonitrile was heated under reflux for 2 h. After cooling to RT, the solid was filtered off and the filtrate was freed from the solvent on a rotary evaporator. The residue obtained was dissolved in ethyl acetate and washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate, the mixture was filtered and the filtrate was concentrated on a rotary evaporator. The residue that remained was dried under high vacuum. This gave 7.53 g (99% of theory) of the title compound.
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]1[N:17]2[C:18]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:19]=3[N:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21](=[O:23])[CH2:22][C:16]2=[N:15][N:14]=1)=O)C1C=CC=CC=1.Br>C(O)(=O)C>[NH2:11][CH2:12][C:13]1[N:17]2[C:18]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:19]=3[N:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21](=[O:23])[CH2:22][C:16]2=[N:15][N:14]=1
Reactant: O=C(NCc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: NCc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2

Procedure:
4.5 g of 1-[[(benzyloxycarbonyl)amino]-methyl]-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in 60 ml acetic acid saturated with hydrogen bromide is stirred at 20° for 1 hour. The reaction mixture is concentrated to one-half its original volume in vacuo and diluted with ether. The precipitate is filtered off, suspended in methylene chloride and shaken with excess 2N aqueous sodium bicarbonate. The organic phase is separated, washed with water, dried and evaporated to give the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:5]2[S:10][C:9]3[N:11]=[C:12]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=4)[CH:13]=[C:14]([CH3:15])[C:8]=3[C:6]=2[N:7]=1.[CH3:32][CH2:33][O-:34].[K+]>O1CCOCC1>[CH2:33]([O:34][C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:5]2[S:10][C:9]3[N:11]=[C:12]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=4)[CH:13]=[C:14]([CH3:15])[C:8]=3[C:6]=2[N:7]=1)[CH3:32]
Reactant: CC[O-]
Reactant: COc1ccc(-c2cc(C)c3c(n2)sc2c(N4CCNCC4)nc(Cl)nc23)cc1OC
Agent: [K+]
Solvent: C1COCCO1
Product: CCOc1nc(N2CCNCC2)c2sc3nc(-c4ccc(OC)c(OC)c4)cc(C)c3c2n1

Procedure:
0.1 g (0.22 mmol) 2-chloro-7-(3,4-dimethoxyphenyl)-9-methyl-4-piperazin-1-yl-pyrido-[3′,2′:4,5]thieno[3,2-d]pyrimidine and 0.22 ml (0.44 mmol) potassium ethylate (2M THF) are refluxed in 10 ml absolute dioxane for 3 h. Then, the solvent is removed and the residue is suspended in some water. The aqueous suspension is extracted with dichloromethane, the organic phase is dried on sodium sulfate and the solvent is removed. 50 mg (49%) of the title substance is obtained.