Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:28][O:27][C:5]2=[CH:6][CH:7]=[C:8]3[C:12]([N:11]([CH2:13][C@@H:14]([NH:16]C(=O)OCC4C=CC=CC=4)[CH3:15])[N:10]=[CH:9]3)=[C:4]2[CH:3]1[O:29][CH3:30].FC(F)(F)C(O)=O>CO>[NH2:16][C@@H:14]([CH3:15])[CH2:13][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]3[O:27][CH2:28][CH:2]([OH:1])[CH:3]([O:29][CH3:30])[C:4]3=2)[CH:9]=[N:10]1
Reactant: COC1c2c(ccc3cnn(C[C@H](C)NC(=O)OCc4ccccc4)c23)OCC1O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COC1c2c(ccc3cnn(C[C@H](C)N)c23)OCC1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 130.6 %

Procedure:
To a solution of the product from Step A (0.22 g, 0.58 mmol) in methanol (5 mL) was added trifluoroacetic acid (5 mL) and the mixture was stirred at ambient temperature for 2 days. The mixture was evaporated to a residue, which was stirred with a 2 N solution of hydrogen chloride in ethanol (5 mL) and evaporated to afford a solid (0.21 g): mp 105-108° C.; LC/MS (+APCI) m/z 278 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]([O:9]C)=O)[S:5][CH:6]=1.O.[NH2:12][NH2:13]>CO>[CH3:1][C:2]1[N:3]=[C:4]([C:7]([NH:12][NH2:13])=[O:9])[S:5][CH:6]=1
Reactant: NN
Reactant: COC(=O)c1nc(C)cs1
Solvent: O
Solvent: CO
Product: Cc1csc(C(=O)NN)n1
Reaction time: 1.5 h

Procedure:
To a solution of methyl 4-methyl-2-thiazole carboxylate (step a, 2.1 g) in methanol (20 ml) was added hydrazine hydrate (3.2 ml) dropwise over 30 mins. The reaction mixture was stirred for 1.5 hours and the precipitate filtered off to yield the title compound as a white solid (1.6 g). 1H NMR (250 MHz, DMSO) δ 2.64 (3H, s), 4.82 (2H, bs), 7.79 (1H, s), 10.25 (1H, bs).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[N:5]=[C:4]([N:19]2[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]=[N:20]2)[NH:3]1.O=P(Cl)(Cl)[Cl:31]>>[Cl:31][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[N:5]=[C:4]([N:19]2[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]=[N:20]2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Oc4ccccc4)ccc3c(=O)[nH]2)c1
Product: CCOC(=O)c1cnn(-c2nc(Cl)c3ccc(Oc4ccccc4)cc3n2)c1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A mixture of the above ethyl 1-(4-oxo-7-phenoxy-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate (0.31 g, 0.82 mmol), and POCl3 (3.08 mL, 32.9 mmol), was heated to reflux for 3 h. The mixture was allowed to cool to rt and then concentrated. The residue was taken up in a minimal amount of DCM and purified by FCC (0 to 25% EtOAc/hexanes) to yield the title compound (250 mg, 77%). 1H NMR (600 MHz, DMSO-d6): 9.06 (d, J=0.7 Hz, 1H), 8.35 (d, J=9.2 Hz, 1H), 8.23 (dd, J=10.6, 6.6 Hz, 1H), 7.63-7.59 (m, 1H), 7.60-7.54 (m, 2H), 7.41-7.36 (m, 1H), 7.31-7.29 (m, 2H), 7.18 (d, J=2.4 Hz, 1H), 4.30 (q, J=7.1 Hz, 2H), 1.35-1.24 (t, J=7.2 Hz, 3H).
Reaction SMILES: C([Li])CCC.C[Si](C)(C)[C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[CH3:16].O>C(OCC)C>[C:18]1([C:15]([C:10]2[S:9][CH:8]=[N:12][CH:11]=2)([OH:17])[CH3:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[Si](C)(C)c1nccs1
Reactant: CC(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(O)(c1ccccc1)c1cncs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M solution in hexane, 7ml) in diethyl ether (30ml) was stirred at -70° C. under a nitrogen atmosphere and 2-trimethylsilylthiazole (2.5g) in diethyl ether (10 ml) was added dropwise. After 30 minutes, acetophenone (2.3g) in diethyl ether (10 ml) was added dropwise. After a further 45 minutes the mixture was allowed to warm to room temperature and was then left overnight. Water was added and the mixture was extracted with diethyl ether. The material thus obtained was purified by flash chromatography to give the title compound.
Reaction SMILES: [CH:1]([C:3]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:4]=1[O:5][CH3:6])=[CH2:2].Cl[C:13]1[NH:14][CH2:15][CH2:16][N:17]=1>>[CH:1]([C:3]1[C:4]([O:5][CH3:6])=[CH:7][CH:8]=[CH:9][C:10]=1[N:11]=[C:13]1[NH:17][CH2:16][CH2:15][NH:14]1)=[CH2:2]
Reactant: C=Cc1c(N)cccc1OC
Reactant: ClC1=NCCN1
Product: C=Cc1c(N=C2NCCN2)cccc1OC
Yield: 47 %

Procedure:
Reaction of the 2-ethenyl-m-anisidine with 2-chloro-imidazoline by the method described in Example 2 gives a 47% yield of 2-(2-ethenyl-3-methoxyphenylimino)imidazolidine, m.p. 125.5°-126° C.
Reaction SMILES: O.[Cl:2][CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=O)[C:8]2[CH:14]=[CH:15][C:16]([CH3:18])=[N:17][C:7]=2[O:6]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:28]2)=CC=1>C1(C)C=CC=CC=1>[OH2:6].[Cl:2][CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=[S:28])[C:8]2[CH:14]=[CH:15][C:16]([CH3:18])=[N:17][C:7]=2[O:6]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc2c(n1)OC(CCCl)CN(C)C2=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(n1)OC(CCCl)CN(C)C2=S
Reaction time: 1 h

Procedure:
To a suspension of 17.4 g (0.043 mole) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diposphetane-2,4-disulfide in ~300 ml of toluene was added 20 g (0.078 mole) of 2-(2-chloroethyl)-2,3-dihydro-4,8-dimethylpyrido[3,2-f][1,4]-oxazepin-5(4H)-one hydrate [1:1]. The mixture was heated to reflux for 3 hr and 4.0 g (0.01 mole) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide was added and heating was continued for 1 hr. After cooling, toluene was decanted off and washed with 3×100 ml 1N sodium hydroxide and 100 ml water. The organic layer was then extracted with 2×100 ml of 2N hydrochloric acid. The aqueous layer was made basic to litmus with conc. sodium hydroxide causing the product to precipitate out. Of the 25 g of crude collected, 2 g were recrystallized from diisopropyl ether to give pale yellow crystals, m.p. 80°-86° C.
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([NH:15]C(OC(C)(C)C)=O)=[CH:13][C:12]([S:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[C:11]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:10]=1)=O)(C)(C)C.Cl>C(Cl)Cl>[NH2:8][C:9]1[C:14]([NH2:15])=[CH:13][C:12]([S:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[C:11]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)cc2C(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Sc2cc(N)c(N)cc2C(C)(C)C)cc1

Procedure:
The title compound was prepared as described in Example VV-1 from toluene-4-thiosulfonic acid S-(4,5-bis-tert-butoxycarbonylamino-2-tert-butyl-phenyl) ester (prepared in Example UU-2; 15 g, 28 mmol), CH2Cl2 (100 mL), and HCl gas. MS(APCI): 351 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:8])[CH2:5][O:6][CH3:7].[H-].[Na+].Br.Cl[C:13]1[CH:14]=[C:15]([CH3:23])[C:16]2[N:17]([C:19]([NH2:22])=[N:20][N:21]=2)[N:18]=1.O>CN(C=O)C>[CH3:1][O:2][CH2:3][CH:4]([CH2:5][O:6][CH3:7])[O:8][C:13]1[CH:14]=[C:15]([CH3:23])[C:16]2[N:17]([C:19]([NH2:22])=[N:20][N:21]=2)[N:18]=1
Reactant: COCC(O)COC
Reactant: Cc1cc(Cl)nn2c(N)nnc12
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC(COC)Oc1cc(C)c2nnc(N)n2n1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
1,3-Dimethoxypropan-2-ol (12.96 ml) was initially charged in DMF (25 ml), admixed under argon with sodium hydride (681 mg) and stirred at 40° C. for 1 h. Subsequently, 6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.002; 1.5 g), dissolved in DMF (25 ml), was added dropwise within 20 min. After 1 h, the mixture was admixed with water and extracted by shaking four times with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated by rotary evaporation. The residue was triturated with MtB ether, filtered off with suction and dried. 764 mg of the title compound were isolated. LC-MS rt: 0.74 min [M+H]+: 268.1 (met. a)
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)(=O)=O.O[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([O:35][CH2:36][CH3:37])[C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:20]1[C:21]2[N:8]([CH2:7][CH2:6][O:5][C:23]3[CH:24]=[CH:25][C:26]([CH2:29][CH:30]([O:35][CH2:36][CH3:37])[C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:28]=3)[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:15][C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)OCCN1c2ccccc2Oc2ccccc21
Reactant: CCOC(Cc1ccc(O)cc1)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)OC
Temperature: 80 °C
Reaction time: 12 h
Yield: 390.1 %

Procedure:
A mixture of 2-(phenoxazin-10-yl)ethyl methanesulfonate (1.75 g, 5.0 mmol), methyl 3-(4-hydroxyphenyl)-2-ethoxypropanoate (1.5 g, 0.68 mmol) and potassium carbonate (3.16 g) in dry dimethylformamide (20 mL) was stirred for 12 h at 80° C. The reaction mixture was cooled to room temperature (ca. 25° C.). Water (30 mL) was added and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (50 mL), dried (Na2SO4) and evaporated. The residue was chromatographed using a mixture of ethyl acetate and pet. ether (1:9) to afford the title compound (1.15 g, 47%) as a white solid. mp 89-90° C. 1H NMR data matches with the desired product (see above).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9](=[O:17])[N:8]([CH2:18][O:19][CH3:20])[C:7]=2[CH:6]=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:4]=1>ClCCl.CO.[Pd]>[CH3:1][O:2][C:3]1[C:16]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:17])[N:8]([CH2:18][O:19][CH3:20])[C:7]=2[CH:6]=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:4]=1
Reactant: CCOC(=O)c1cc(OC)c2c3ncccc3c(=O)n(COC)c2c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1cc(OC)c2c3c(c(=O)n(COC)c2c1)CCCN3
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.2 %

Procedure:
The compound (776.5 mg, 2.27 mmol) prepared in step 6 was dissolved in dichloromethane and methanol, added with 10%-palladium (Pd) (80.0 mg). The resulting mixture was stirred at room temperature for 20 hours under hydrogen gas. After completion, 10%-palladium (Pd) was removed by celite-filter and the solvent was concentrated under reduced pressure. The residue was then purified by flash column chromatography (dichloromethane:ethyl acetate=3:1) to obtain the title compound (458 mg, yield: 58.2%, white solid).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc2ccccc2s1
Solvent: c1ccncc1
Product: O=C(Nc1nc2ccccc2s1)c1ccccc1

Procedure:
Using 2-amino-benzothiazole and benzoyl chloride in pyridine the title compound was obtained as a white solid (87% yield), MS: m/e=255.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C@H:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].[C:19]([O-])([O-])=O.[Cs+].[Cs+].CI.Cl>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C@H:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][CH3:19])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)C[C@H]1OB(O)c2cc(O)cc(C)c21
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@H]1OB(O)c2cc(OC)cc(C)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.6 %

Procedure:
To a solution of (3R)-(1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (2.0 g, 7.9 mmol) in anhydrous DMF (20 mL) were added Cs2CO3 (15.4 g, 47.4 mmol) and methyl iodide (1.43 g, 9.6 mmol) at 0° C. After stirring at room temperature for 4 hours the reaction mixture was cooled to 0° C. and acidified to pH 2 with concentrated HCl. The mixture was extracted with ethyl acetate and the organic extracts were washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (30-100% EtOAc in hexane) to give (3R)-(1-hydroxy-6-methoxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester as a yellow foam (0.7 g, 35%). 1H NMR 400 MHz (DMSO-d6) δ9.12 (s, 1H), 7.07 (d, J=2.0 Hz, 1H), 6.85 (d, J=2.0 Hz, 1H), 5.46 (dd, J=9.2, 2.4 Hz, 1H), 4.09-4.03 (m, 2H), 3.74 (s, 3H), 3.17-3.07 (m, 1H), 2.26 (s, 3H), 2.23-2.17 (m, 1H), 1.16-1.12 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7]Cl)[CH2:4][O:3]1.[N-:10]=[N+:11]=[N-:12].[Na+]>CN(C=O)C>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][N:10]=[N+:11]=[N-:12])[CH2:4][O:3]1
Reactant: CC1(C)OCC(CCl)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(CN=[N+]=[N-])O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15.05 g. of 2,2-dimethyl-4-chloromethyl-1,3-dioxolane is dissolved in 100 ml. DMF and 6.5 g. of NaN3 are added. The mixture is stirred at 50° overnight, cooled to room temperature, diluted with 300 ml. C6H6 and washed 5 times with water. The organic phase is dried and evaporated under reduced pressure to give 2,2-dimethyl-4-azidomethyl-1,3-dioxolane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][N:6]([C:13](=[O:23])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH3:21])=[C:16]([NH2:22])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=1)#[N:26].C1N=CN(C(N2C=NC=C2)=O)C=1>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][N:6]([C:13](=[O:23])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH3:21])=[C:16]([NH:22][C:35](=[O:36])[CH2:34][NH:33][C:30]2[CH:31]=[CH:32][C:27]([C:25]#[N:26])=[CH:28][CH:29]=2)[CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CNc1ccc(C(=O)N(CCC(=O)OC)c2ccccc2)cc1N
Reactant: N#Cc1ccc(NCC(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CNc1ccc(C(=O)N(CCC(=O)OC)c2ccccc2)cc1NC(=O)CNc1ccc(C#N)cc1

Procedure:
The product of 1b (23.2 mmol) and N-(4-cyano-phenyl)-glycine (23.2 mmol) were coupled with CDI (23.2 mmol) in dry THF at room temperature. After completion of the reaction the mixture was evaporated to dryness and the crude product was used without further purification.
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[NH:4].[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=O>N1C=CC=CC=1.C(OCC)C>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]1[O:1][N:2]=[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]2)[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2noc(-c3ccccc3Cl)n2)CC1

Procedure:
tert-Butyl 4-(N-hydroxyamidino)-piperazine-1-carboxylate (290 mg) prepared in Example 36 was dissolved in 2 ml of pyridine, 0.20 ml of 2-chlorobenzoyl chloride was added thereto and the mixture was heated to reflux for 1 hour. The reaction solution was diluted with diethyl ether, washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution and dried over anhydrous magnesium sulfate. The residue prepared by evaporation of the solvent was purified by a preparative thin-layer silica gel chromatography (hexane:ethyl acetate=7:3) to give 64.0 mg of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
The mixture of 702 mg of 6-chloronicotinonitrile, 954 mg of t-butylpiperazin-1-carboxylate, 1.2 g of potassium carbonate, and 10 mL of N,N-dimethylacetamide, was stirred at room temperature for 3 hours, then heated to 60° C. and stirred further for 4 hours. After cooling the reaction mixture back to room temperature, water was added thereto, and was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and 1.39 g of t-butyl-4-(5-cyanopyridin-2-yl)piperazin-1-carboxylate [140-1] was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:23][C:24]1[CH:37]=[CH:36][C:27]([C:28]([NH:30][C:31]2[S:32][CH:33]=[CH:34][N:35]=2)=[O:29])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1>>[CH3:20][S:17]([NH:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:21]=[CH:22][C:2]([C:25]2[CH:26]=[C:27]([C:28](=[O:29])[NH:30][C:31]3[S:32][CH:33]=[CH:34][N:35]=3)[CH:36]=[CH:37][C:24]=2[CH3:23])=[N:3][CH:4]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CS(=O)(=O)Nc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1ccc(C(=O)NCc2cccc(NS(C)(=O)=O)c2)cn1

Procedure:
N-(3-Methylsulphonylaminobenzyl)-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (Intermediate 11) using General Method B. LCMS: retention time 2.96 min, MH+522. NMR: δH [2H6]-DMSO 10.19, (2H, b), 9.35, (1H, t), 9.17, (1H, s), 8.38, (1H, dd), 8.22, (1H, s), 8.07, (1H, d), 7.84, (1H, d), 7.57, (1H, d), 7.52, (1H, d), 7.31-7.28, (2H, m), 7.22, (1H, s), 7.11, (2H, m), 4.52, (2H, d), 2.99, (3H, s), 2.45, (3H, s).
Reaction SMILES: C[N:2]1[CH2:11][C:10]2([CH2:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[C:20]1([O:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[O:26]([C:27]([N:2]1[CH2:11][C:10]2([CH2:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN1Cc2ccccc2C2(Cc3ccccc3O2)C1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1Cc2ccccc2C2(Cc3ccccc3O2)C1
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a previously flamed 2000 ml round-bottom flask is added N-methylspiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (32.5 g) in dichloromethane (700 ml). To this is added phenylchloroformate (20 ml). The mixture is stirred overnight. Removal of the solvent yields an oil. Trituration with n-propanol followed by recrystallization of 4.0 g of the solid so formed from ethyl acetate yields 2.6 g (69.7%) of product, mp 128°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:33])[C:15]([C:17]3[C:22]([C:23]#[C:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=4)=[CH:21][N:20]=[C:19]([NH2:32])[N:18]=3)=[CH:16][C:10]=2[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:33])[C:15]([C:17]3[C:22]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=4)=[CH:21][N:20]=[C:19]([NH2:32])[N:18]=3)=[CH:16][C:10]=2[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: Cn1c(-c2nc(N)ncc2C#Cc2cccc(O)c2)cc2c1CCN(C(=O)OC(C)(C)C)C2=O
Agent: [Pd]
Solvent: CO
Product: Cn1c(-c2nc(N)ncc2CCc2cccc(O)c2)cc2c1CCN(C(=O)OC(C)(C)C)C2=O

Procedure:
2-[2-Amino-5-(3-hydroxy-phenylethynyl)-pyrimidin-4-yl]-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (obtained as described in Example 9) (25 mg, 0.054 mmol) was dissolved in a methanol (25 mL) and the solution was submitted to continuous hydrogenation in a H-Cube apparatus equipped with a Pd/C 10% cartridge (1 atm of hydrogen, 40° C., flux: 1 mL/min). The solution was then evaporated to dryness and the crude product was purified by chromatography on silica gel (DCM/EtOH 95:5). 2-{2-Amino-5-[2-(3-hydroxy-phenyl)-ethyl]-pyrimidin-4-yl}-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]-pyridine-5-carboxylic acid tert-butyl ester were obtained as a white solid (19 mg, 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH:22]=[CH:21]1>O1CCCC1>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([NH:1][C:20]([CH:21]=[CH:22][C:23]([OH:25])=[O:24])=[O:26])=[CH:3][CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Reactant: O=C1C=CC(=O)O1
Solvent: C1CCOC1
Product: O=C(O)C=CC(=O)Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.4 %

Procedure:
To a 5° C. solution of 0.158 g of 7-amino-4-(3-bromoanilino)-quinazoline (J Med Chem, 1995:3482) in 10 mL of tetrahydrofuran was added 0.059 g of maleic anhydride. The cold solution stirred for 15 minutes, and then the ice bath was removed. The reaction warmed to room temperature where it continued stirring for 15 hours. The suspension was heated under reflux for 30 minutes and then stirred at room temperature another 15 hours. Another 0.059 g of maleic anhydride and 20 mL of tetrahydrofuran were added, and the reaction was refluxed for an additional 2 hours. After another 15 hours at room temperature, the reaction was refluxed for 15 hours. The reaction was filtered, and the light tan solid was recrystallized first from dimethyl-formamide and then a second time from methanol to afford 0.036 g of the desired product.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:35]([O:36][CH3:37])=[CH:34][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[CH:6]=1)[N:14]=[CH:13][C:12]([C:17]#[N:18])=[C:11]3[NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:27]2[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=2)=[C:22]([Cl:33])[CH:21]=1.[NH:38]1[CH:42]=[CH:41][N:40]=[N:39]1.[OH-].[Na+]>CN(C)C=O>[Cl:33][C:22]1[CH:21]=[C:20]([NH:19][C:11]2[C:10]3[C:15](=[CH:16][C:7]4[CH:6]=[C:5]([O:4][CH2:3][CH2:2][N:39]5[N:40]=[CH:41][CH:42]=[N:38]5)[C:35]([O:36][CH3:37])=[CH:34][C:8]=4[CH:9]=3)[N:14]=[CH:13][C:12]=2[C:17]#[N:18])[CH:25]=[CH:24][C:23]=1[S:26][C:27]1[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=1
Reactant: COc1cc2cc3c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c(C#N)cnc3cc2cc1OCCCl
Reactant: c1c[nH]nn1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2cc3c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c(C#N)cnc3cc2cc1OCCn1nccn1
Temperature: 80 °C
Yield: 19.3 %

Procedure:
A mixture of 0.3 g (0.55 mmol) of 8-(2-chloroethoxy)-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.32 mL (5.5 mmol) of 1H-1,2,3-triazole and 0.1 g (2.5 mmol) of sodium hydroxide powder in 5 mL of N,N-dimethyl formamide is heated at 80° C. for 4.5 hours, then cooled and poured on to ice. The solid is collected by filtration, washed with water and dried. The two isomers are separated by silica gel chromatography, utilizing a 99:1 to 85:15 gradient of ethyl acetate/methanol. The less polar material, 0.062 g of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-(2-[1,2,3]triazol-2-yl-ethoxy)benzo[g]quinoline-3-carbonitrile is obtained as yellow solid, mp 235-237° C.