Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH3:11])=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[S-:12][C:13]#[N:14].[K+]>C(O)C>[Cl:2][C:3]1[C:4]([CH3:11])=[C:5]([NH:9][NH:10][C:13]([NH2:14])=[S:12])[CH:6]=[CH:7][CH:8]=1
Reactant: N#C[S-]
Reactant: Cc1c(Cl)cccc1NN
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1c(Cl)cccc1NNC(N)=S

Procedure:
19.3 g (0.1 mole) of 3-chloro-2-methylphenylhydrazinehydrochloride were dissolved in 200 ml of absolute ethanol. 11.64 g (0.12 mole) of potassium thiocyanate were added to the solution, and the mixture was heated during reflux for 16 hours. The mixture was then cooled, whereby the product was partially precipitated, and the mixture was subsequently evaporated to dryness by means of a rotating evaporator. The product was recrystallized from 200 ml water and 250 ml methanol, separated by filtration and washed thoroughly with water.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12]>C(O)C>[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:12][CH2:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCC
Reactant: C=CCN1CCNCC1
Solvent: CCO
Product: C=CCN1CCN(CCC(=O)OCC)CC1
Yield: 80 %

Procedure:
A mixture of 1-(2-propenyl)piperazine (6.6 g) and ethyl 2-propenoate (11.3 ml) in ethanol (100 ml) was stirred and refluxed for 1 hour 30 minutes. The solvent was evaporated, yielding 9.6 g (80%) of ethyl 4-(2-propenyl)- 1-piperazine-propanoate (interm. 1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:18](=[O:19])[O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ccc(CNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
To a solution of 4-aminobenzenemethanamine (1.5 g, 12.3 mmol) in 20 mL CH2Cl2 was added benzylchloroformate (1.57 mL, 11 mmol), followed by triethylamine (Et3N) (1.5 mL, 11 mmol) at room temperature. White percipitates was observed immediately. The reaction was stirred at room temperature for 10 minutes and removed Et3N salt by filtration. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and H2O. The EtOAc layer was washed with a sat. solution of KHSO4, a sat. solution of NaHCO3, concentrated in vacuo and subjected to a silica-gel column using CHCl3 /CH3 OH=25/1 ratio as an eluting solvent to give title compound (43% yield).
Reaction SMILES: [O-]CC.[Na+].[CH2:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15].C1(C)C=CC(S([N:25]=[N+:26]=[N-])(=O)=O)=CC=1.O>C(O)C>[N+:25](=[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15])=[N-:26]
Reactant: O=C1CCc2ccccc2C1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=C1C(=O)CCc2ccccc21
Yield: 39.3 %

Procedure:
To a solution of sodium ethoxide (4.68 g) in ethanol (150 ml), a solution of 2-tetralone (5.0 g, 34 mmole) in ethanol (10 ml) was added dropwise at 0° C., followed by the dropwise addition of p-toluenesulfonylazide (6.9 g, 35 mmole) obtained in Synthesis Example 7, (1), at -15° C. The resultant mixture was poured into cold H2O (350 ml), extracted with methylene chloride (250 ml×2), and the organic layer was washed with H2O (200 ml), dried over anhydrous MgSO4 and evaporated in vacuo. The resultant purplish-red crystals (5.2 g) were chromatographed on silica gel (Wakogel C-200) with n-hexane/methylene chloride [7/1→5/1→3/1 (v/v)] as eluent to give 2.3 g of the desired product as orange crystals having a melting point of 41.5°-43.5° C.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)=[C:2]=[S:3].[CH3:14][C:15]1[N:16]=[CH:17][N:18]([CH2:20][CH2:21][CH2:22][NH2:23])[CH:19]=1>>[CH3:14][C:15]1[N:16]=[CH:17][N:18]([CH2:20][CH2:21][CH2:22][N:23]2[C:6](=[O:8])[C:5]3[C:4](=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:1][C:2]2=[S:3])[CH:19]=1
Reactant: Cc1cn(CCCN)cn1
Reactant: COC(=O)c1ccccc1N=C=S
Product: Cc1cn(CCCn2c(=S)[nH]c3ccccc3c2=O)cn1

Procedure:
The compound was synthesized starting from methyl 2-isothiocyanatobenzoate (0.093 g. 0.48 mmol) and 3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (9) (0.067 g, 0.48 mmol) as described above.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>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>[Cl:11][C:12]1[CH:17]=[C:16]([C:2]2[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[CH:3]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cc(F)cc(Br)c1
Reactant: OB(O)c1cccc(Cl)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+]
Product: COc1cc(F)cc(-c2cccc(Cl)c2)c1
Temperature: 25 °C
Yield: 101.8 %

Procedure:
A RBF was charged with 1-bromo-3-fluoro-5-methoxybenzene (2.104 g, 10.26 mmol), (3-chlorophenyl)boronic acid (1.765 g, 11.29 mmol), potassium carbonate (4.25 g, 30.8 mmol), and Pd(Ph3P)4 (0.593 g, 0.513 mmol). The flask was flushed with Ar (g), then 1,4-dioxane (25.7 ml) and water (8.55 ml) were added. A reflux condenser was attached, and the flask was lowered into a 90° C. heating bath for 45 min. The mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (50-g SNAP Ultra column, 25-g silica gel column, 0-5% EtOAc/Heptane) to give 3′-chloro-3-fluoro-5-methoxy-1,1′-biphenyl (2.47 g, 10.44 mmol, 102% yield) as a clear oil containing about 10 wt % impurities.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([NH:7][NH2:8])=[O:6].[CH3:13][C:14]([CH3:16])=O.FC(F)(F)C(O)=O>CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([NH:7][N:8]=[C:14]([CH3:16])[CH3:13])=[O:6]
Reactant: Cc1ccc(C(=O)NN)cc1Br
Reactant: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: CC(C)=NNC(=O)c1ccc(C)c(Br)c1
Temperature: 25 °C
Yield: 89.5 %

Procedure:
To a mixture of 3-bromo-4-methylbenzohydrazide (2.0 g, 8.72 mmol, 1.0 eq) and acetone (10 mL, 172 mmol, 21 eq) in hexane (10 mL), was added molecular sieves (500 mg) followed by trifluoroacetic acid (2 mL) and the resulting mixture was refluxed for 3 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum and the residue was taken in ethyl acetae (100 mL), washed with water (50 mL), aqueous saturated sodium bicarbonate solution (50 mL), brine (50 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure to afford the 2.10 g of the 3-bromo-4-methyl-N′-(propan-2-ylidene)benzohydrazide. 1HNMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H, D2O exchangeable), 8.02 (s, 1H), 7.75 (dd, J=1.0, 8.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 2.40 (s, 3H), 2.01 (s, 3H), 1.94 (s, 3H); ESI-MS (m/z) 269, 271 [(MH)+, Br79,81].
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[NH:12][N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31])(=[O:23])=[O:22]>N1C=CC=CC=1>[C:1]1([NH:7][C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][S:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[S:21]([CH3:20])(=[O:23])=[O:22])(=[O:32])=[O:31])[CH:17]=3)[NH:12][N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc2[nH]nc(C(=O)Nc3ccccc3)c2c1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(C(=O)Nc3ccccc3)c2c1
Yield: 67.7 %

Procedure:
N-Phenyl-5-(2-methylsulfonylbenzenesulfonylamino)-1H-indazole-3-carboxamide can be obtained as described in Example 2 from 40 mg of N-phenyl-5-amino-1H-indazole-3-carboxamide, 4 ml of pyridine and 40 mg of 2-methylsulfonylbenzenesulfonyl chloride. 50 mg of N-phenyl-5-(2-methylsulfonylbenzenesulfonylamino)-1H-indazole-3-carboxamide are thus obtained in the form of a pale yellow solid melting at 258° C. (analysis C21H18N4O5S2.0.48H2O, % calculated C, 53.61; H, 3.86; N, 11.91; O, 17.00; S, 13.63. % found C, 53.17; H, 3.48; N, 11.58; S, 14.08).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH2:26]([O:28][CH2:29][CH2:30][C:31](O)=[O:32])[CH3:27]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:31](=[O:32])[CH2:30][CH2:29][O:28][CH2:26][CH3:27])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: CCOCCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CCOCCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (23 mg, 68.2%), MS (ISP) m/z=431.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0744 mmol) and 3-ethoxypropanoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([NH:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]2)=[O:20])[C:5]([NH:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: CNc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Product: CNc1nc(C)c(C)cc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 52 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methylaminopyridin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH2:9][OH:10])[C:3]=1[CH3:11].[CH3:12][O-:13].[Na+]>CN(C)C=O.CO>[OH:10][CH2:9][C:4]1[C:3]([CH3:11])=[C:2]([O:13][CH3:12])[C:7]([CH3:8])=[CH:6][N:5]=1
Reactant: C[O-]
Reactant: Cc1cnc(CO)c(C)c1Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1c(C)cnc(CO)c1C
Yield: 55 %

Procedure:
In a round bottom flask equipped with a stirrer, a condenser and a nitrogen bubbler, 4-Chloro-2-hydroxymethyl-3,5-Lutidine (1 eq.) was dissolved in Dimethylformamide (3-9 volumes) and Methanol (1.5-4.5 volumes). Sodium methoxide (4 eq.) was added and the temperature was raised to (95-100ℑ C.). At the end of the reaction the solvent was distilled under vacuum. Water (2 volumes) was added to the residue and the product was extracted with dichloromethane (2×4 volumes). The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The crude product, 2-hydroxymethyl-4-Methoxy-3,5-lutidine, was obtained in 55% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1)=[O:36])[CH3:39]
Reactant: CCOC(=O)Cl
Reactant: O=C(NCC1CCCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: CCOC(=O)N1CCCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (piperidin-3-ylmethyl)-amide (example A145) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:27]2[CH2:28][CH2:29][CH:24]([C:20]3[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=3)[CH2:25][CH2:26]2)=[CH:4][CH:3]=1
Reactant: ClCCCOc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCOc3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-chloro-4-(3-chloropropoxy)benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDCl3) δ 7.71 (dd, 1H, J=3.2, 5.7 Hz), 7.53 (dd, 1H, J=3.2, 5.7 Hz), 7.50 (m, 1H), 7.31 (m, 1H), 7.24–7.20 (m, 2H) 6.94 (d, 1H, J=7.9 Hz), 6.85–6.82 (m, 2H), 4.00 (t, 2H, J=6.1 Hz), 3.07 (d, 2H, J=10.9 Hz), 2.55 (m, 3H), 2.50 (sept, 1H, J=6.2 Hz), 2.08 (dt, 2H, J=3.1, 10.9 Hz), 2.00 (m, 2H), 1.83 (m, 3H), 1.69 (qt, 1H, J=6.2 Hz), 1.24 (d, 6H, J=6.8 Hz); Anal. Calcd for C24H31ClN2O2+HCl: C, 63.8; H, 7.09; N, 6.21. Found: C, 63.3; H, 7.04; N, 6.27; ESMS m/e: 415.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]([CH2:19]Br)=[C:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])=[O:10])[O:8][C:4]=2[CH:3]=1.[CH3:23][O-:24].[Na+]>CO>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]([CH2:19][O:24][CH3:23])=[C:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])=[O:10])[O:8][C:4]=2[CH:3]=1
Reactant: C[O-]
Reactant: O=C(c1ccc(Cl)cc1Cl)c1oc2cc(Br)ccc2c1CBr
Agent: [Na+]
Solvent: CO
Product: COCc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(Br)ccc12
Reaction time: 3 h
Yield: 23.8 %

Procedure:
To a solution of (6-bromo-3-bromomethyl-benzofuran-2-yl) -(2,4-dichloro-phenyl)-methanone (1.1 g, 2.3 mmol) in methanol (4 mL) was added 0.5 M sodium methoxide (252 mg, 4.7 mmol). The reaction was stirred at 50 C for 3 h. The solvent was removed at reduced pressure and the mixture was triturated with methanol, providing (227 mg, 23%) a cream colored solid. 1H-NMR (CDCl3) δ 7.87-7.37 (m, 6H), 5.00 (s, 2H), 3.47 (s, 3H)
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br.[H-].[Na+].O>CN(C)C=O>[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCCCBr)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 59.2 %

Procedure:
2.05 g (5.26mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one obtained in Example 66 was dissolved in 50 mL of dimethylformamide under argon atmosphere, 3.6 mL (26.3 mmol) of 1,5-dibromopentane and 631 mg (15.8 mmol) of sodium hydride (60% oil dispersion) were added and the mixture was stirred at room temperature for 1.2 hours. The reaction solution was cooled on ice, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:ethyl acetate=60:l) to give 1.68 g of 5-(5-bromopentylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one (yield: 59%).
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16](Cl)[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].CS(C)=O.[Cl-].[NH2:25][C:26]([NH2:28])=[NH2+:27].[OH-].[Na+]>O>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([N:25]=[C:26]([NH2:28])[NH2:27])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC(N)=[NH2+]
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(Cl)nn12
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N=C(N)N)nn12
Yield: 32.2 %

Procedure:
3.36 g 3-(5-nitro-1-methyl-2-imidazolyl)-6-chloro-s-triazolo[ 4,3-b] pyridazine were dissolved in 30 ml. dimethyl sulfoxide and mixed at 70°C., while stirring, with 3.4 g guanidinium chloride. 5 ml. water were then added thereto, followed by the dropwise addition of 2.4 ml. 1ON aqueous sodium hydroxide solution, whereafter the reaction mixture was further stirred for an hour at 70°C. After cooling and diluting with water, the precipitated crystals were filtered off with suction, washed with water and dried in a vacuum. 2.5 g of crude product were thus obtained which, after recrystallization from 25 ml. dimethyl formamide, with the addition of active charcoal, gave 1.17 g 3-(5-nitro-1-methyl-2-imidazolyl)-6-(diaminomethylene-amino)-s-triazolo [4,3-b] pyridazine in the form of a yellow material which melted, with decomposition, at 278° - 280°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](Cl)=[C:11]3[C:10]([CH3:18])=[N:9]2)=[CH:5][CH:4]=1.[F:21][C:22]1[CH:23]=[C:24]([C:29]2[C:30](=[O:43])[N:31]([CH3:42])[C:32]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:33][CH:34]=2)[CH:25]=[CH:26][C:27]=1[OH:28].C(=O)([O-])[O-].[K+].[K+].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[F:21][C:22]1[CH:23]=[C:24]([C:29]2[C:30](=[O:43])[N:31]([CH3:42])[C:32]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:33][CH:34]=2)[CH:25]=[CH:26][C:27]=1[O:28][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]=[C:10]([CH3:18])[C:11]=12
Reactant: COc1ccc(Cn2nc(C)c3c(Cl)ccnc32)cc1
Reactant: Cn1c(Nc2ccccc2)ncc(-c2ccc(O)c(F)c2)c1=O
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(-c5cnc(Nc6ccccc6)n(C)c5=O)cc4F)ccnc32)cc1
Temperature: 110 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
To a 10 mL round bottom flask was added 1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine (18.7 mg, 0.065 mmol; prepared according to the procedure of Example 43, Step E), 5-(3-fluoro-4-hydroxyphenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (13.5 mg, 0.043 mmol) and the solids were dissolved in DMF (0.5 mL). Potassium carbonate (9.0 mg, 0.065 mmol) was added followed by a 1M solution of potassium t-butoxide in THF (0.065 mL, 0.065 mmol), and the mixture was stirred at 110° C. for 18 hours. The reaction mixture was cooled to room temperature and then partitioned between water (5 mL) and ethyl acetate (10 mL). The organic layer washed with water, brine, dried over Na2SO3 and concentrated to afford 24.3 mg of crude oil. The crude product was triturated with ether to afford the desired product (16 mg, 65%) as a tan solid. LRMS (APCI pos) m/e 563.3 (M+1).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[CH:4]=[N:3][CH:2]=1.[I:10]N1C(=O)CCC1=O>C(#N)C>[I:10][C:9]1[C:5]2[CH:4]=[N:3][CH:2]=[N:1][C:6]=2[NH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ncc2cc[nH]c2n1
Solvent: CC#N
Product: Ic1c[nH]c2ncncc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
A mixture of 7H-pyrrolo[2,3-d]pyrimidine (Preparation 202, 28.0 g, 235 mmol) and N-iodosuccinimide (55.4 g, 246 mmol) in acetonitrile (470 mL) was stirred at room temperature for 16 hours. The solids were filtered, rinsed with acetonitrile (150 mL) and dried in vacuo. The solid was dissolved in 1.5 L of 1N aqueous sodium hydroxide solution and to it was added 2N aqueous hydrogen chloride solution until ˜pH 9. The resulting precipitate was filtered, rinsed with water (300 mL), and dried in vacuo for 16 hours at 70° C., ˜10 mbar, to afford the title compound in 81% yield, 46.84 g.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[I:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([OH:36])=O>C(Cl)Cl>[I:30][C:31]1[CH:32]=[C:33]([C:34]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:36])[CH:37]=[CH:38][CH:39]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cccc(I)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN1CCN(C(=O)c2cccc(I)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.2 %

Procedure:
1-Methylpiperazine (0.58 mL, 5.2 mmol), HOBt (0.70 g, 5.2 mmol) and EDCl (1.0 g, 5.2 mmol) were added to a solution of 3-iodobenzoic acid (1.0 g, 4.0 mmol) in dry DCM (40 mL). The mixture was stirred at room temperature for 16 h, washed with saturated aqueous sodium bicarbonate (30 mL), water (15 mL), brine, dried over sodium sulphate, and evaporated to afford the title compound (1.27 g, 96%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1([C:11]([O-:13])=[O:12])[CH2:10][CH2:9][CH2:8][O:7]1.S(=O)(=O)(O)O.[CH3:22]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1([C:11]([O:13][CH3:22])=[O:12])[CH2:10][CH2:9][CH2:8][O:7]1
Reactant: O=C([O-])C1(Cc2cccc(O)c2)CCCO1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1(Cc2cccc(O)c2)CCCO1

Procedure:
To a solution of 2.20 g of 2-(3-hydroxybenzyl)-tetrahydro-2-furancarboxylate in 50 ml of methanol was added 0.5 ml of sulfuric acid, and the mixture was heated under reflux for 18 hours. The solvent was evaporated, and the residue was dissolved in 200 ml of ethyl acetate. The organic layer washed twice with 50 ml of water, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography, to give 2.20 g of the title compound from the 7:3 hexane-ethyl acetate fraction.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Li]CCCC.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>C1COCC1>[CH2:24]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH3:23])[C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[CH2:25][CH2:26][CH3:27]
Reactant: c1ccc2scnc2c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
20 ml of freshly distilled THF was flushed for 30 min with a stream of nitrogen after which benzothiazole (1.0 g, 7.4 mmol) was added. After being flushed for another 30 min, the solution was cooled to −78° C. and placed under inert nitrogen atmosphere. 0.9 equivalents of n-BuLi (2 M solution in hexane, 2.66 ml, 6.66 mmol) was added dropwise over a period of 30 min, during which the solution turned to deep red. The solution was kept at −78° C. for 1 h and then tri-n-butyltin chloride (2.0 mi, 7.4 mmol) was added dropwise over a period of 1 h. During this addition, the solution shifted from deep red to brownish yellow, then to greenish blue and finally to light brown. After yet another hour at −78° C., the solution was allowed to reach room temperature. The THF was removed on a rotary evaporator and the product, a yellow oil, was isolated by distillation in vacuo. Yield: 2.47 g, 79%. 1H NMR (CDCl3): δ 0.90 (t, J═S, 9H, Bu3Sn), 1.29 (in, 6H, Bu3Sn), 1.35 (m, 6H, Bu3Sn), 1.63 (t, J=8, 6H, Bu3Sn), 7.37 (t, J=8, 1H, ArH), 7.46 (t, J=8, 1H, ArH, 7.96 (d, J=8, 1H, ArH), 8.17 (D, J=8, 1H, ArH).