Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)=S)([CH3:4])([CH3:3])[CH3:2].[N:17]#[C:18][NH2:19].C1CCC(N=C=NC2CCCCC2)CC1.C(N(C(C)C)CC)(C)C>C1COCC1>[C:1]([NH:5][C:6]([NH:19][C:18]#[N:17])=[N:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=S)Nc1cc(F)cc(F)c1
Reactant: N#CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=Nc1cc(F)cc(F)c1)NC#N
Yield: 32.3 %

Procedure:
To a solution of 1.5 g of N-t-butyl-N'-(3,5-difluorophenyl)thiourea produced in Example A-8 in 27 ml of THF were added 0.46 g of cyanamide, 2.2 g of DCC and 0.14 ml of diisopropylethylamine. The mixture was refluxed for 24 hours and evaporated in vacuo. The residue was mixed with 100 ml of benzene and the resulting crystals were filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using a 9:1 mixture of benzene-ethyl acetate as a solvent to give 0.8 g of crude product. Recrystallization from benzene-cyclohexane mixture gave 0.5 g of the title compound as colorless needles melting at 170.0°-172.0° C.
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[O:32][CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:10][N:9]=1.[OH-].[Na+:48]>C(O)C>[Na+:48].[F:46][C:2]([F:1])([F:45])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:40]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[O:32][CH:33]([CH2:34][CH3:35])[CH2:36][CH3:37])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O-:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCC(CC)Oc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(CC)Oc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)[O-])cn1

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(1-ethylpropoxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (190 mg) is dissolved in ethanol (5 ml), and thereto is added a 1N-aqueous sodium hydroxide solution (1 ml) and the mixture is stirred at room temperature for 3 hours and 30 minutes. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→93:7) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(1-ethylpropoxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (158 mg). The resulting 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(1-ethylpropoxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (158 mg) is dissolved in ethanol (1 ml), and thereto is added 1N-aqueous sodium hydroxide solution (237 μl) and concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(1-ethyl-propoxy)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid sodium salt (149 mg). MS (m/z): 666 [M−Na]−
Reaction SMILES: C(O[C:4](=O)[NH:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[CH2:8][CH2:7]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:15][C:13]([OH:16])([CH3:14])[CH2:12][N:9]1[CH2:10][CH2:11][CH:6]([NH:5][CH3:4])[CH2:7][CH2:8]1
Reactant: CCOC(=O)NC1CCN(CC(C)(C)O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CNC1CCN(CC(C)(C)O)CC1
Temperature: 0 °C
Yield: 96.6 %

Procedure:
A mixture of the above described [1-(2-hydroxy-2-methyl-propyl)-piperidin-4-yl]-carbamic acid ethyl ester (2.35 g, 10 mmol) in tetrahydrofuran (40 mL) with lithium aluminum hydride (913 mg, 24 mmol) was refluxed for 16 h. Cooled to 0° C., added water (0.913 mL), then at 23° C. 15% NaOH solution (2.739 mL), then again water (0.913 mL), stirred at 23° C. for 30 min, filtered the solid off, washed with tetrahydrofuran, the filtrate was evaporated to give the title compound as a colorless oil (1.80 g, 100%); MS: m/e=187.2 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]23[CH2:17][CH2:16][C:15](=[O:18])[CH:7]2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[CH2:14]3)[N:3]=[CH:2]1.[BH4-].[Na+].O>C(O)C>[NH:1]1[CH:5]=[C:4]([C:6]23[CH2:17][CH2:16][CH:15]([OH:18])[CH:7]2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[CH2:14]3)[N:3]=[CH:2]1
Reactant: O=C1CCC2(c3c[nH]cn3)Cc3ccccc3C12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC1CCC2(c3c[nH]cn3)Cc3ccccc3C12
Temperature: 37.5 °C
Reaction time: 4 h

Procedure:
To a solution of 8a-(1H-imidazol-4-yl)-1,3a,8,8a-tetrahydro-2H-cyclopenta[a]inden-3-one (1 g) in 40 ml of ethanol was added 0.16 g of sodium borohydride under a nitrogen atmosphere. The reaction mixture was stirred at 35-40° C. for 4 hours and then poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The combined organic layers were dried over sodium sulfate and the solvent removed under reduced pressure. The crude product was purified by flash chromatography using methylene chloride/methanol (95:5) as eluent. The yield was 0.6 g, m.p. 183-186° C.
Reaction SMILES: [OH:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=[CH:5][CH:4]=[N:3]1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>>[CH3:14][N:13]([CH3:15])[C:10]1[CH:9]=[CH:8][C:7]([C:6]2[N:2]([O:1][C:18](=[O:19])[N:17]([CH3:16])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:3]=[CH:4][CH:5]=2)=[CH:12][CH:11]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CN(C)c1ccc(-c2ccnn2O)cc1
Product: CN(C)c1ccc(-c2ccnn2OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title compound was prepared from 1-hydroxy-5-(4-dimethylaminophenyl)-pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (27%, crystals).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[N:16][NH:17][C:11]=3[C:10]3[N:18]=[CH:19][CH:20]=[CH:21][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH3:34])=[C:29]([CH:33]=1)[C:30](Cl)=[O:31]>>[NH:17]1[C:11]2[C:10]3[N:18]=[CH:19][CH:20]=[CH:21][C:9]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:33]=[C:25]([F:24])[CH:26]=[CH:27][C:28]=4[CH3:34])=[CH:3][CH:4]=3)=[O:7])[CH2:14][CH2:13][C:12]=2[CH:15]=[N:16]1
Reactant: Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3ncccc32)cc1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3ncccc32)cc1

Procedure:
As described for Example 2, 2 mmol of 6-(4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]pyrido-[3,2-b]azepine is reacted with 2.2 mmol of 5-fluoro-2-methylbenzoyl chloride to give the product as a solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].[NH2:10][CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[CH:24]=[C:23]([CH2:25][CH3:26])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:14][C@@H:13]1[OH:27].[OH-].[Na+]>O>[CH2:25]([C:23]1[C:21](=[O:22])[NH:20][C:18](=[O:19])[N:17]([CH:24]=1)[C@@H:15]1[O:16][C@H:12]([CH2:11][NH:10][C:7](=[O:8])[CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C@@H:13]([OH:27])[CH2:14]1)[CH3:26]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)Cc3cccs3)O2)c(=O)[nH]c1=O
Reaction time: 0.17 h
Yield: 52.8 %

Procedure:
0.18 g of 2-thiopheneacetylchloride was added to a solution of 0.255 g of 5'-amino-2',5'-dideoxy-5-ethyluridine in 5 ml of water containing 1.2 ml of 1M sodium hydroxide solution and the resulting mixture was shaken vigorously for 10 minutes. The resulting white solid was collected by filtration, washed with water, dried at 50° C. in vacuo over phosphorus pentoxide and recrystallized from ethanol to give 0.2 g of 2',5'-dideoxy-5-ethyl-5'-[2-(2-thienyl)acetamido]uridine of melting point 215°-217° C.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH:5]([C:7]1[CH2:8][N:9]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=2[N:13]=1)[NH2:6]>O1CCCC1>[CH3:1][NH:2][C:3](=[O:4])[NH:6][NH:5][C:7]1[CH2:8][N:9]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=2[N:13]=1
Reactant: CCc1cc2c(s1)N=C(NN)CN=C2c1ccccc1Cl
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CCc1cc2c(s1)N=C(NNC(=O)NC)CN=C2c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.1 ml of methyl isocyanate is added to a suspension of 5 g of 2-hydrazino-5-o-chlorophenyl-7-ethyl-3H-thieno[ 2,3-e] [1,4] diazepine in 100 ml of tetrahydrofuran, and the resulting mixture is stirred at room temperature for 2 hours. Then the reaction mixture is poured into ice water, and the precipitated crystals are collected by filtration, washed with water, dried, and recrystallized from a mixture of chloroform and ligroin to give 2-(4-methylsemicarbazido)-5-o-chlorophenyl-7-ethyl-3H-thieno[ 2,3-e][1,4]diazepine, melting at 213°-215° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=[C:13]2[N:12]=[C:11]([CH3:24])[C:10]=1[C:25]([O-:27])=[O:26]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=[C:13]2[N:12]=[C:11]([CH3:24])[C:10]=1[C:25]([OH:27])=[O:26]
Reactant: Cc1nc2cc(-c3ccccc3)nn2c(-c2ccc(Cl)cc2Cl)c1C(=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2cc(-c3ccccc3)nn2c(-c2ccc(Cl)cc2Cl)c1C(=O)O
Reaction time: 5 h

Procedure:
To a stirred solution of 7-(2,4-dichlorophenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine-6-carboxylate (27.5 mg, 0.07 mmol) in THF (2 mL) and H2O (0.5 mL) was added LiOHH2O (4.2 mg, 0.1 mmol). After 5 h at 50° C., the reaction was concentrated under reduced pressure and diluted with EtOAc (10 mL). The organic layer was extracted with 1N HCl (6 mL), saturated NH4Cl (10 mL) and brine, dried (MgSO4), filtered and concentrated. The crude reaction product, 7-(2,4-dichlorophenyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid, was moved onto next step without further purification (purity ˜90%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([S:17][CH3:18])[N:3]=1.N.COCCOCC[N:27](CCOCCOC)CCOCCOC>[Cu].CCO>[NH2:1][C:2]1[N:7]=[C:6]([NH2:27])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([S:17][CH3:18])[N:3]=1
Reactant: CSc1nc(N)nc(Cl)c1-c1ccc(Cl)cc1Cl
Reactant: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [Cu]
Agent: N
Solvent: CCO
Product: CSc1nc(N)nc(N)c1-c1ccc(Cl)cc1Cl
Temperature: 180 °C
Yield: 1181.2 %

Procedure:
A mixture of 2-amino-4-chloro-5-(2,4-dichlorophenyl)-6-methylthio pyrimidine (0.5 g) (Example 32) EtOH saturated with ammonia (20 ml), copper powder (0.05 g) and tris[2-(2-methoxyethoxy)ethyl]amine (0.01 g) was heated in an autoclave at 180° C. for 18 hours. The cooled reaction mixture was filtered, evaporated and the residue purified by flash column chromatography to give the title compound (0.11 g, 23.5%), mp. 191°-192° C. Microanalysis:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:14](Br)[CH:15]=[CH2:16]>C(#N)C>[CH2:16]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH2:14]
Reactant: Oc1ccccc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1ccccc1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 81.8 %

Procedure:
To a round-bottomed flask containing a solution of phenol (30 g, 319 mmol) in acetonitrile (150 ml) at room temperature was added potassium carbonate (66 g, 478 mmol) and allyl bromide (49.8 g, 412 mmol). The mixture was heated to 50° C. and stirred for 3.5 hours. The solids were filtered out and the filtrate was concentrated to a minimum volume. The crude material was diluted with water (200 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (2×100 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated to afford crude allyloxybenzene as brown oil (35 g); 1H NMR (300 MHz, CDCl3): δ 7.20-7.30 (m, 2H), 6.89-6.96 (m, 3H), 5.99-6.12 (m, 1H), 5.41 (d, J=17.1 Hz, 1H), 5.28 (d, J=10.5 Hz, 1H), 4.52 (d, J=5.1 Hz, 2H).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[N:9]=1)[C:5](=O)[CH3:6].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:37][C:38]([NH2:40])=[NH:39])[CH:28]=[CH:29][C:30]=1[N:31]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]1>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:37][C:38]2[N:40]=[C:5]([CH3:6])[C:4]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[N:9]=3)=[CH:3][N:39]=2)[CH:28]=[CH:29][C:30]=1[N:31]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CC(=O)C(=CN(C)C)c1nc(C)no1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc(-c3nc(C)no3)c(C)n2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from crude 4-dimethylamino-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-but-3-en-2-one (313 mg, 1.6 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (297 mg, 0.8 mmol) using in analogous manner the procedure described in example 39b). Obtained as a pale-yellow solid (142 mg, 47%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[O-]S([O-])(=O)=O.[Mg+2]>CCOC(C)=O>[NH2:12][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9]([C:10]=1[NH:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][P:27](=[O:34])([O:28][CH2:29][CH3:30])[O:31][CH2:32][CH3:33])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CCOP(=O)(CCOCCOCCOCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12)OCC
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: CCOP(=O)(CCOCCOCCOCCNc1c(N)c(Cl)nc2ccccc12)OCC
Reaction time: 7 h
Yield: 97 %

Procedure:
To a solution of diethyl (2-(2-(2-(2-((2-chloro-3-nitroquinolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethyl)phosphonate (1 equiv.) in EtOAc (0.10 M) was added 10% PUC (5% equiv. by weight) and MgSO4 (2 equiv.) in a Paar Shaker Flask. The reaction mixture was placed in a Paar Shaker at 40 psi for 7 h. At this point the reaction mixture was passed through a pad of Celite, washing with a 2:1 mixture of CHCl3:MeOH. The combined organic layers were dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system using a gradient of 0-10% MeOH/DCM to provide the title compound (97%) as a solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43](OC)=[O:44])=[N:8]1.O.[OH-].[Li+].[N:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][NH2:60])[CH:54]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O1CCCC1.O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([C:43]([NH:60][CH2:59][C:55]3[CH:54]=[N:53][CH:58]=[CH:57][CH:56]=3)=[O:44])[CH:47]=[CH:48][CH:49]=2)=[N:8]1
Reactant: NCc1cccnc1
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1cccnc1)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 60 °C
Reaction time: 67 h
Yield: 50.3 %

Procedure:
To a stirred solution of methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl) (1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.431 g, 0.667 mmol) in a tetrahydrofuran/water mixture (2.70 mL/1.62 mL) was added lithium hydroxide monohydrate (0.0840 g, 2.00 mmol) and the mixture heated at 60° C. for 21 h. To this mixture was added tetrahydrofuran (2.00 mL), 3-pyridylmethylamine (0.189 mL, 1.86 mmol), 1-hydroxybenzotriazole hydrate (0.251 g, 1.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.356 g, 1.86 mmol). This reaction mixture was stirred for 67 h at ambient temperature. The mixture was extracted with ethyl acetate (2×). The combined organic extracts were washed with an aqueous saturated solution of sodium bicarbonate, followed by brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography with 5% methanol/ethyl acetate gave the title compound (0.242 g, 50% yield). ES-MS (m/z) 480 [M+1(−Tr)]+
Reaction SMILES: [CH3:1][CH:2]([N:11]=[C:12]([CH3:23])[C:13]([C:15]1[S:19][CH:18]=[C:17]([C:20]([NH2:22])=[O:21])[CH:16]=1)=[O:14])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[BH4-].[Na+].[ClH:26].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[ClH:26].[OH:14][CH:13]([C:15]1[S:19][CH:18]=[C:17]([C:20]([NH2:22])=[O:21])[CH:16]=1)[CH:12]([NH:11][CH:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:23]
Reactant: CC(=NC(C)CCc1ccccc1)C(=O)c1cc(C(N)=O)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(CCc1ccccc1)NC(C)C(O)c1cc(C(N)=O)cs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
An ice-cold solution of 5-[2-[(1-methyl-3-phenylpropyl)imino]-1-oxopropyl]thiophene-3-carboxamide (0.7 g) in methanol (50 ml) was treated portionwise with sodium borohydride (0.76 g), stirred at 0° for 1 h, poured onto ice, acidified with dilute hydrochloric acid (2 N), neutralised with aqueous sodium bicarbonate (8%), and extracted with ethyl acetate (2×300 ml). The extract was washed with brine (50 ml) and evaporated to a small volume (ca. 20 ml) to deposit a fine white solid (0.47 g) which was partitioned between ethyl acetate (2×300 ml) and aqueous sodium bicarbonate (1 M; 100 ml). The organic solution (MgSO4) was dried and evaporated to give an off-white foam which was dissolved in ethyl acetate (ca. 100 ml) and treated with ethereal hydrogen chloride to precipitate the title compound (0.42 g) m.p. 125°-130°. TLC SiO2 (3% Et3N/20% i-PrOH/EtOAc) Rf 0.22 and 0.27.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.BrCCBr.CN([CH:18]=[O:19])C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1)[CH:18]=[O:19]
Reactant: COc1cccc(Cl)c1Cl
Reactant: CN(C)C=O
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COc1cc(Cl)cc(C=O)c1
Temperature: -10 °C
Yield: 44.9 %

Procedure:
To a mixture of dichloroanisole (60 mmol, 10.62 g), Mg (66 mmol, 1.60 g) and THF (30 ml) was added 1,2-dibromoethane (6 mmol, 1.13 g). The mixture was stirred until bubbles of gas started to evolve (2-3 min), and then heated to reflux for 2.5 h. The resulting dark brown mixture was cooled to −10° C. on an acetone-ice bath and DMF (90 mmol, 7 ml) was added slowly. After 20 min the ice-bath was removed, the mixture was stirred for 3 h and subsequently quenched with NHrCl (10% w/w in water, 100 ml). The product mixture was extracted with DCM (4×50 ml), the organic phase washed with water, then brine and dried (MgSO4). Filtration and evaporation under reduced pressure gave a red liquid residue, which was purified by means of flash chromatography (silica, pentane/ether gradient. 5-30%) to provide the title compound (4.60 g, 45%) as a clear liquid. 1H NMR (DMSO, 300 MHz) δ 3.84 (s, 3H), 7.16 (s, 1H), 7.25 (s, 1H), 7.43 (s, 1H) and 9.92 (s, 1H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[CH:3]=1.C1C(=O)N([Cl:28])C(=O)C1>CN(C=O)C>[Cl:28][C:3]1[N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH2:11])[C:10]=2[C:2]=1[I:1]
Reactant: Nc1ncnc2c1c(I)cn2-c1cccc([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)c(Cl)n2-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a suspension of 5-iodo-7-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (17) (1.6 g, 4.2 mmol) in DMF (30 mL) was added NCS (840 mg, 6.3 mmol). The resulting mixture was stirred at r.t. overnight. Another portion of NCS (560 mg, 4.2 mmol) was introduced. After the stifling was continued for 8 hrs, the reaction was quenched with water (100 mL). The resulting white precipitates was collected by filtration to afford 6-chloro-5-iodo-7-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (18) (1.7 g, 91% yield) as a yellow solid. LC-MS (ESI): m/z (M/M+2) 414.6/416.6.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12](I)=[CH:13][C:8]=2[C:7](=[O:15])[N:6]([CH3:16])[C:5]2[CH:17]=[CH:18][CH:19]=[N:20][C:4]1=2)[CH3:2].[C:21]([C:25]1[CH:30]=[C:29](C)[CH:28]=[C:27](C(C)(C)C)[C:26]=1O)(C)(C)C.C([Sn](CCCC)(CCCC)CCCC)C1C=CC=CC=1.[F-].[K+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:21]([C:12]1[CH:11]=[N:10][C:9]2[N:3]([CH2:1][CH3:2])[C:4]3[N:20]=[CH:19][CH:18]=[CH:17][C:5]=3[N:6]([CH3:16])[C:7](=[O:15])[C:8]=2[CH:13]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCN1c2ncc(I)cc2C(=O)N(C)c2cccnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](CCCC)(CCCC)Cc1ccccc1
Agent: [F-]
Solvent: CN(C)C=O
Product: CCN1c2ncc(Cc3ccccc3)cc2C(=O)N(C)c2cccnc21
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of 5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.3 g, 0.79 mmol), bis(triphenylphosphine)palladium(II) chloride (18 mg, 0.03 mmol), and 2,6-di-tert-butyl-4-methylphenol (1 crystal) in 5 mL of N,N-dimethylformamide was added benzyltributylstannane (0.36 g, 0.94 mmol). The resultant reaction mixture was heated at 100° C. under argon for 5 hours. An aqueous solution of potassium fluoride was added and the mixture was stirred for 5 hours. The product was extracted with dichloromethane and purified by flash chromatography, eluting with ethyl acetate/dichloromethane, to give 20 mg of the title compound as an oil.