Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH3:25])=[N:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OC(C)C)(C)C>CN(C)C=O.O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:15][C:16]2[CH:21]=[N:20][C:19]([O:22][CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: CCCOc1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Solvent: O
Product: CCCOc1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a solution of 2.2 g of 2-t-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 1.9 g of 5-chloromethyl-2-propyloxypyridine in 20 ml of N,N-dimethylformamide was added under stirring 1.5 g of potassium carbonate at room temperature. After additional stirring for 8 hours at room temperature, the mixture was poured into 50 ml of water and then extracted twice with 50 ml of benzene. The organic layer was washed with water, dried over anhydrous sodium sulfate and then freed of solvent by distillation under reduced pressure to obtain 3.7 g of a crude product. The crude product was added with isopropyl ether and recrystallized therefrom to give 3.0 g of 2-t-butyl-4-chloro-5{-(6-propyloxy-3-pyridyl)-methylthio}-3(2H)-pyridazinone, m.p. 92.0°~93.5° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([F:8])[CH2:5][N:4]1[C:9]([NH:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]([NH2:23])=[O:22])[CH:13]=1)=[O:10].[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C.O>C(Cl)Cl>[F:8][C@H:6]1[CH2:5][N:4]([C:9]([NH:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]([NH2:23])=[O:22])[CH:13]=2)=[O:10])[C@H:3]([CH2:2][NH:1][S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[F:24])(=[O:33])=[O:32])[CH2:7]1
Reactant: NC[C@@H]1C[C@@H](F)CN1C(=O)Nc1cn(C(N)=O)c2ccccc12
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=O)n1cc(NC(=O)N2C[C@H](F)C[C@H]2CNS(=O)(=O)c2ccccc2F)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-[((2S,4R)-2-aminomethyl-4-fluoro-pyrrolidine-1-carbonyl)-amino]-indole-1-carboxylic acid amide (52 mg, 0.163 mmol) (prepared as described Scheme B11) and 2-fluorobenzenesulfonyl chloride (24 μL, 0.179 mmol) in CH2Cl2 (0.5 mL), was added triethylamine (25 μL, 0.179 mmol) and the resulting suspension was stirred at RT under nitrogen overnight. The mixture was poured into water and extracted twice with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 19×50 mm, eluent: 20% to 100% CH3CN in H2O in 15 min, CH3CN and H2O containing 0.1% HCOOH, flow: 20 mL/min) to give after lyophilization of the purified fractions the desired material. Rf, TLC (EtOAc)=0.55; MS (LC-MS): 478.1 [M+H]+, 500 [M+Na]+, 516 [M+K]+, 977.2 [2M+Na]+, 476 [M−H]−; tR (HPLC conditions f): 1.73 min.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[CH2:15]([N:17]([CH2:41][CH3:42])[CH:18]1[CH:23]([CH3:24])[CH2:22][CH:21]([C:25]2[C:30]3[C:31](S)=[N:32][C:33]4=[CH:34][CH:35]=[CH:36][C:28]([C:29]=34)=[CH:27][CH:26]=2)[CH:20]([CH:38]([CH3:40])[CH3:39])[CH2:19]1)[CH3:16].[N:43]1([CH2:48][CH2:49][CH2:50][NH2:51])[CH:47]=[CH:46][N:45]=[CH:44]1>C(O)C>[CH2:15]([N:17]([CH2:41][CH3:42])[CH:18]1[CH:23]([CH3:24])[CH2:22][CH:21]([C:25]2[C:30]3[C:31]([NH:51][CH2:50][CH2:49][CH2:48][N:43]4[CH:47]=[CH:46][N:45]=[CH:44]4)=[N:32][C:33]4=[CH:34][CH:35]=[CH:36][C:28]([C:29]=34)=[CH:27][CH:26]=2)[CH:20]([CH:38]([CH3:40])[CH3:39])[CH2:19]1)[CH3:16]
Reactant: NCCCn1ccnc1
Reactant: CCN(CC)C1CC(C(C)C)C(c2ccc3cccc4c3c2C(S)=N4)CC1C
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CCO
Product: CCN(CC)C1CC(C(C)C)C(c2ccc3cccc4c3c2C(NCCCn2ccnc2)=N4)CC1C

Procedure:
6-Bromobenz(cd)indol-2-(1H)-one is treated with ethyl chloroformate in alkaline solution to yield the N-carbethoxy derivative. Successive reactions with magnesium, formaldehyde, and 48% hydrobromic acid leads to 6-bromomethylbenz(cd)indol-2(1H)-one, which on treatment with diethylamine yields the 6-diethylaminomethyl derivative. Treatment with P2S5 in refluxing pyridine leads to 6-diethylaminomenthylbenz(cd)indol-2-thiol, which on reaction with molar equivalents of 3-(1H-imidazol-1yl)propanamine and mercuric acetate in refluxing ethanol, under the conditions of Example 55, leads to the preparation of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7]C=O)[CH:4]=[C:3]1[C:10]([Cl:12])=[O:11].C(N(C(C)C)CC)(C)C.[NH2:22][CH2:23][CH2:24][C:25]#[N:26].Cl>O1CCCC1.CO>[ClH:12].[CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[C:3]1[C:10]([NH:26][CH2:25][CH2:24][C:23]#[N:22])=[O:11]
Reactant: N#CCCN
Reactant: Cn1cc(NC=O)cc1C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cn1cc(N)cc1C(=O)NCCC#N
Reaction time: 1 h

Procedure:
To 1-methyl-4-formylamino-2-pyrrolecarbonyl chloride (II) (16.0 mmol) dissolved in 80 mL of tetrahydrofuran are added diisopropylethylamine (18 mmol) and 3-aminopropionitrile (18 mmol) with continuous stirring for 1 hour. The reaction mixture is evaporated under vacuum and the resulting crude product is washed with water several times and dried to yield crude 3-(1-methyl-4-formylamino-2-carboxamido)propionitrile. This is N-deformylated by treatment with 30 mL of a solution of hydrogen chloride in methanol for 1 hour, the methanol is evaporated and the resulting crude product is crystallized from isopropanol/ethyl acetate to furnish 3-(1-methyl-4-amino-2-pyrrolecarboxamido)propionitrile hydrochloride, whose analytical data are in agreement with the above mentioned literature. This compound is acylated with 1-methyl-4-formylamino-2-pyrrolecarbonyl chloride (II) as above and subjected to the Pinner reaction to yield the hydrochloride of 3-(1-methyl-4-(1-methyl-4-aminopyrrole-2-aminocarbonyl)pyrrole-2-carboxamido)propionamidine (Ib, n=0)) from which Distamycin is obtained as described in Example 4.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[O:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[C:24]([Cl:32])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[ClH:32].[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([NH:9][C:10]([C:12]1[O:13][C:14]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21][CH:22]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: Nc1ccc(-c2ccc(C(=O)NC3CN4CCC3CC4)o2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: Cl
Product: O=C(Nc1ccc(-c2ccc(C(=O)NC3CN4CCC3CC4)o2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5-(4-amino-phenyl)-furan-2-carboxylic acid(1-aza-bicyclo[2.2.2]oct-3-yl)-amide (0.155 g, 0.5 mmol), dichloromethane (25 ml) and benzoyl chloride (0.117 ml, 1.0 mmol) was stirred for 3 hours at room temperature. The crude mixture was filtered. The product was precipitated from the filtrate by adding diethyl ether (5 ml) as hydrochloric acid salt. Yield 56 mg (25%). M.p. 215° C.
Reaction SMILES: COC(=O)C([N:8]1[C@H:11]([S:12]([CH3:15])(=[O:14])=[O:13])[C@@H:10]([C:16]([CH3:24])([CH3:23])[O:17][SiH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]1=[O:25])=C(C)C.O=[O+][O-].O=O.CSC>C(Cl)Cl>[C:19]([SiH2:18][O:17][C:16]([CH3:24])([CH3:23])[C@@H:10]1[C@@H:11]([S:12]([CH3:15])(=[O:14])=[O:13])[NH:8][C:9]1=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H](C(C)(C)O[SiH2]C(C)(C)C)[C@H]1S(C)(=O)=O
Agent: O=O
Agent: O=[O+][O-]
Solvent: ClCCl
Solvent: CSC
Product: CC(C)(C)[SiH2]OC(C)(C)[C@H]1C(=O)N[C@@H]1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 25 g (61.7 mmol) of 2-[(3S,4R)-3-(tert.-butyl-dimethyl-silyloxymethyl)-4-methylsulphonyl-2-oxoazetidin-1-yl]-3-methyl-2-butenoic acid methyl ester in 400 ml of methylene chloride is treated at -10° with an ozone/oxygen mixture. The disappearance of the starting material is monitored by thin layer chromatography. When the reaction is complete, 30 ml of dimethyl sulphide are added and the mixture is stirred for a further 3 hours at room temperature. The solution is concentrated and the residue is taken up in a mixture of 160 ml of methanol, 24 ml of ethyl acetate and 3 ml of water and heated for 40 minutes at 70° C. The solvent is then removed and the residue is evaporated twice in the presence of toluene. The crystallising oil is taken up in methylene chloride and the crystals, consisting of (3S,4R)-3-hydroxymethyl-4-methylsulphonylazetidin-2-one, are isolated by filtration. The filtrate is concentrated and (3S,4R)- 3-(tert.-butyl-dimethyl-silyloxymethyl)-4-methylsulphonylazetidin-2-one is obtained in pure form by chromatography over silica gel with toluene/ethyl acetate (3:1):
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:12]2=[N:13][C:14]([O:17][CH3:18])=[CH:15][N:16]=[C:11]2[CH:10]=[CH:9][C:8]1=[O:19].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:18][O:17][C:14]1[N:13]=[C:12]2[N:7]([CH2:6][CH:2]=[O:1])[C:8](=[O:19])[CH:9]=[CH:10][C:11]2=[N:16][CH:15]=1
Reactant: COc1cnc2ccc(=O)n(CC3OCCO3)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc2ccc(=O)n(CC=O)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 120.1 %

Procedure:
To 0.12 g of 5-(1,3-dioxolan-2-ylmethyl)-3-methoxypyrido(2,3-b)pyrazin-6(5H)-one, 5 mL of a 90% aqueous trifluoroacetic acid solution was added, and the mixture was stirred at room temperature for 3 hours 30 minutes. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction mixture, the organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.12 g of (3-methoxy-6-oxopyrido(2,3-b)pyrazin-5(6H)-yl)acetaldehyde as a light yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH:2]=[CH2:3].[H-].[Na+].[CH3:23]I>CN(C=O)C.O>[CH2:1]([C:4]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH3:23])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCc1c(OCc2ccccc2)ccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCc1c(OCc2ccccc2)ccc2c1ccn2C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
4-Allyl-5-(benzyloxy)-1H-indole (368.7 mg, 1.40 mmol) (Example 58) was dissolved in anhydrous DMF (12 mL) under an inert atmosphere, and the reaction mixture was cooled in an ice-water bath. Sodium hydride (60% in mineral oil) (181 mg, 1.68 mmol) was added, and the reaction mixture was stirred for an additional 30 min. Methyl iodide (278 mg, 1.96 mmol) was added and stirring at rt was continued for 30 min. The reaction mixture was heated to 40° C. for 12 h, cooled to rt, and water (10 drops) was added. The reaction mixture was concentrated under reduced pressure, after which water was added, and the aqueous phase was extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/hexane (v/v)=1:15) gave 259 mg (67%) of the title compound as an oil. 1H NMR (400 MHz, CDCl3): δ 3.72 (m, 5H), 4.98 (d, 1H), 5.07 (d, 1H), 5.12 (s, 2H), 6.06 (m, 1H), 6.47 (s, 1H), 7.00 (d, 1H), 7.03 (s, 1H), 7.12 (d, 1H), 7.31 (m, 1H), 7.39 (m, 2H), 7.48 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:4]2[C:5]([O:7]C(=O)[NH:9][C:3]=12)=O.[ClH:15].[CH3:16][O:17][C:18](=[O:28])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:20]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:16][O:17][C:18](=[O:28])[CH:19]([NH:20][C:5](=[O:7])[C:4]1[CH:11]=[C:12]([Cl:15])[C:13]([Cl:14])=[CH:2][C:3]=1[NH2:9])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=c1[nH]c2c(Cl)c(Cl)ccc2c(=O)o1
Reactant: Cl
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccccc1)NC(=O)c1cc(Cl)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
3,4-Dichloroisatoic anhydride (147 mg, 0.634 mmol) was dissolved in DMF (2 mL). (L)-Phenylalanine methyl ester hydrochloride (150 mg, 0.697 mmol) and DMAP (85 mg, 0.697 mmol) were added and the mixture was stirred overnight at rt. The mixture was quenched with water and extracted with EtOAc (3×). The combined organic layers were washed with water, dried (MgSO4), filtered and concentrated to provide the crude product. The crude solid was purified by flash chromatography (hexanes/EtOAc) to provide the desired product as a white solid (150 mg, 68%). 1H NMR (400 MHz, CDCl3): 7.27-7.21 (m, 5H), 7.07-7.05 (m, 2H), 6.30 (d, J=7.2, 1H), 5.44 (br s, 2H), 4.95-4.90 (m, 1H), 3.71 (s, 3H), 3.22-3.09 (m, 2H).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[O-][CH2:17]C.[Na+].[C:20]([C:24]1[CH:25]=[CH:26][C:27]([O:33][CH2:34][CH3:35])=[C:28]([CH:32]=1)[C:29]([NH2:31])=[NH:30])([O:22][CH3:23])=[O:21].C(O)(=O)C>C(O)C>[O:13]=[C:11]1[NH:31][C:29]([C:28]2[CH:32]=[C:24]([C:20]([O:22][CH2:23][CH3:17])=[O:21])[CH:25]=[CH:26][C:27]=2[O:33][CH2:34][CH3:35])=[N:30][CH:4]=[C:5]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOc1ccc(C(=O)OC)cc1C(=N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(OCC)c(-c2ncc(C(=O)OCC)c(=O)[nH]2)c1
Yield: 75.9 %

Procedure:
Diethyl ethoxymethylenemalonate (1.18 g., 5.45 mmoles) was added to a cold, stirred mixture of sodium ethoxide (0.37 g., 5.45 mmoles) and 5-carbomethoxy-2-ethoxy-benzamidine (1.21 g., 5.45 mmoles) in ethanol (15 ml.). The mixture was poured onto ice-water and acidified with acetic acid. The precipitate was recrystallized from ethanol to give the title compound (1.49 g., 76%) as colorless crystals, m.p. 180°-181.5°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][P:13]([OH:16])(=[O:15])[OH:14])[C:7](=[O:17])[C:6](=[O:18])[NH:5]2.C(=O)([O-])[O-].[Na+].[Na+].[C:25](OC(=O)C)(=[O:27])[CH3:26]>O>[C:25]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][P:13]([OH:16])(=[O:14])[OH:15])[C:7](=[O:17])[C:6](=[O:18])[NH:5]2)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)[nH]c(=O)c(=O)n2CP(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)[nH]c(=O)c(=O)n2CP(=O)(O)O
Reaction time: 1 h

Procedure:
100 mg of 1-(6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-l-yl)methanephosphonic acid is adjusted in 20 ml of water to a pH of 9.5 with a saturated sodium carbonate solution and combined with 0.2 ml of acetic anhydride. After one hour of stirring, the mixture is concentrated, dissolved in a minimum amount of water, introduced into an ion exchanger (IR 120, strongly acidic), and eluted with water: The corresponding fractions are combined, concentrated, and dried, thus obtaining 110 mg of 1-(6-acetylamino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)methanephosphonic acid, mp: 120° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.O>[Cl:6][C:7]1[C:8]([CH2:9][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=[CH:13][C:14]=1[OH:15]
Reactant: O=Cc1cccc(O)c1Cl
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1cccc(CN2CCCC2)c1Cl
Yield: 54.6 %

Procedure:
Pyrrolidine (71.3 mL, 855 mmol) was added to a solution of intermediate 12, 2-chloro-3-hydroxybenzaldehyde (103 g, 658 mmol) in dichloromethane (1 L). The reaction mixture was cooled on ice bath, and sodium triacetoxyborohydride (209.3 g, 987 mmol) was added in portions under stirring. The reaction mixture was stirred for 12 h at room temperature. Water (500 mL) and concentrated HCl were added to attain pH˜2. The organic layer was separated. The aqueous one was extracted with CH2Cl2 (2×400 mL), then with EtOAc (400 mL). The organic layers were discarded. The aqueous fraction was alkalized with K2CO3 to pH˜10, and the product was extracted with CHCl3 (3×500 mL). The organic layer was dried with Na2SO4 and evaporated in vacuo. The obtained crystals were separated by filtration from Et2O/hexane mixture (1:1) and coevaporated with dioxane to give the title compound (76 g, 55%, 359 mmol). LCMS data: 214 and 212 (M+H)+ (calculated for C11H14ClNO 211.7); 1H NMR data (DMSO-d6): 9.96 (br.s, 1H, OH); 7.08 (t, 1H, J=7.8 Hz, Ar—H); 6.91 (dd, 1H, J1=1.7 Hz, J2=7.3 Hz, Ar—H); 6.86 (dd, 1H, J1=1.7 Hz, J2=8.0 Hz, Ar—H); 3.64 (s, 2H, CH2Ar); 2.43-2.52 (m, 4H+DMSO); 1.65-1.74 (m, 4H).
Reaction SMILES: C(S([C:6]1[N:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH:9]=[C:8]([O:23][C:24]2[CH:25]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:28][CH:29]=2)[N:7]=1)(=O)=O)C.C1COCC1.Cl.[CH3:40][NH:41][CH3:42].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:40][N:41]([CH3:42])[C:6]1[N:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)[CH:9]=[C:8]([O:23][C:24]2[CH:25]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:28][CH:29]=2)[N:7]=1
Reactant: CCS(=O)(=O)c1nc(Cc2cccc(C(F)(F)F)c2)cc(Oc2cccc(C(F)(F)F)c2)n1
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)c1nc(Cc2cccc(C(F)(F)F)c2)cc(Oc2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 432 h
Yield: 110.5 %

Procedure:
2-(Ethylsulfonyl)-4-[m-(trifluoromethyl)benzyl]-6-[(α,α,α-trifluoro-m-tolyl)oxy]pyrimidine (0.40 g, 0.82 mmol) is added to THF (20 ml). Dimethylamine hydrochloride (0.11 g, 13.4 mmol) and triethylamine (0.17 g, 16.8 mmol) is added and the reaction stirred at room temperature for 18 days. Ethyl acetate is added to the reaction and the organic phase is washed with water, brine and dried over magnesium sulfate. The solvent is removed under vacuum and the residue is chromatographed to afford 0.40 g 2-(Dimethylamino)-4-[m-(trifluoromethyl)-benzyl]-6-[(α,α,α-trifluoro-m-tolyl)oxy]pyrimidine as a yellow oil. 1H NMR CDCl3 3.02 (6H, b) 3.92 (2H, s) 5.87 (1H, s) 7.3-7.65 (8H, m).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[C:17]2[N:16]([CH3:18])[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=O)=[C:27]([CH3:36])[CH:26]=3)=[O:24])[CH2:12][C:11]=2[CH:10]=[N:9]1.Cl.Cl.[CH3:39][C:40]([CH3:50])([CH3:49])[CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[CH3:39][C:40]([CH3:50])([CH3:49])[CH2:41][CH2:42][N:43]1[CH2:44][CH2:45][N:46]([C:33](=[O:35])[CH2:32][CH2:31][C:28]2[CH:29]=[CH:30][C:25]([C:23]([N:13]3[CH2:12][C:11]4[CH:10]=[N:9][N:8]([CH3:7])[C:17]=4[N:16]([CH3:18])[C:15]4[CH:19]=[CH:20][CH:21]=[CH:22][C:14]3=4)=[O:24])=[CH:26][C:27]=2[CH3:36])[CH2:47][CH2:48]1
Reactant: CC(C)(C)CCN1CCNCC1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3N(C)c3ccccc32)ccc1CCC(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3N(C)c3ccccc32)ccc1CCC(=O)N1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Oxalyl chloride (0.018 ml, 0.20 mmol) was added to a solution of 3-[4-(3,4-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-phenyl]-propionic acid from Example E80.2 (40 mg, 0.10 mmol) in dichloromethane (5 ml) and a few drops of DMF. The mixture was stirred for 1 h at room temperature, concentrated in vacuo and azeotroped with toluene. The residue was dissolved in dichloromethane (5 ml) and 1-(3,3-dimethyl-butyl)-piperazine dihydrochloride from Example E4 (30 mg, 0.12 mmol) and DIEA (0.052 ml, 0.30 mmol) were added. The mixture was stirred for 20 h at room temperature, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (36 mg, 65%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:12]=[N:11][C:10]([NH:13][C:14](=[O:27])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)=[CH:9][CH:8]=1)#[N:2].N[NH:29][C:30]([NH2:32])=[S:31].C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[NH2:32][C:30]1[S:31][C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[N:12]=[N:11][C:10]([NH:13][C:14](=[O:27])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:24])([F:25])[F:26])[CH:17]=3)=[CH:9][CH:8]=2)=[N:2][N:29]=1
Reactant: NNC(N)=S
Reactant: N#CCCCCc1ccc(NC(=O)Cc2cccc(OC(F)(F)F)c2)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Nc1nnc(CCCCc2ccc(NC(=O)Cc3cccc(OC(F)(F)F)c3)nn2)s1
Temperature: 65 °C
Reaction time: 5 h

Procedure:
1118 (1.0 equiv., 0.154 mol, 58.2 g) was charged into a 500 mL round bottom flask along with thiosemicarbazide (1.2 equiv., 0.184 mol, 16.8 g). TFA (5 vol., 291 mL) slowly added to reaction vessel while stirring. The reaction slurry was heated in a 65° C. bath with an open top reflux condenser. The reaction usually goes to completion after 5 hours (determined by LC/MS). Toluene (10 vol., 582 mL) added to deep red solution, azeotroped by rotary evaporation (bath≦30° C.) to a red oil. Slowly transferred oil to a well stirred 6000 mL Erlenmeyer flask containing 7.5% sodium bicarbonate solution (69 vol., 4.0 L) cooled in a 0° C. bath. The crystals were filtered through a Büchner funnel and rinsed twice with diethyl ether (5 vol., 2×250 mL). Dried under high vacuum to a constant weight to afford N-(6-(4-(5-amino-1,3,4-thiadiazol-2-yl)butyl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide 657; yield of 55.7 g (80%). 1H NMR (300 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.21 (d, J=9.2 Hz, 1H), 7.58 (d, J=9.2 Hz, 1H), 7.51-7.26 (m, 4H), 6.99 (s, 2H), 3.88 (s, 2H), 2.87 (m, 4H), 1.71 (m, 4H).
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([NH2:30])[CH:24]=1.FC(F)(F)C(O)=O>O1CCCC1>[NH2:30][C:25]1[CH:24]=[C:23]([F:22])[CH:28]=[CH:27][C:26]=1[NH:29][C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([CH2:12][NH:11][C:1](=[O:10])[CH:2]=[CH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(F)cc1N
Reactant: O=C(C=Cc1ccccc1)NCc1ccc(C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Nc1cc(F)ccc1NC(=O)c1ccc(CNC(=O)C=Cc2ccccc2)cc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a suspension of 0.29 g (1.78 mmol) of N,N′-carbonyldiimidazole in tetrahydrofuran (15 ml) is added 0.50 g (1.78 mmol) of 4-[N-cinnamoylaminomethyl]benzoic acid, followed by stirring at 45° C. for 1 hour. After cooling, the reaction mixture is added to a separately prepared tetrahydrofuran (10 ml) solution including 0.28 g (2.22 mmol) of 4-fluoro-1,2-phenylenediamine and 0.20 g (1.78 mmol) of trifluoroacetic acid at room temperature. After reaction at room temperature for 16 hours, the deposited white solid is collected by filtration, washed with tetrahydrofuran, and then dried to give the title compound (0.45 g, 65%). 1H NMR (300 MHz, DMSO-d6): δppm: 4.42 (2H, d), 4.92 (2H, br.s), 6.62 (1H, t), 6.78 (2H, m), 7.01 (1H, t), 7.32 (5H, m), 7.54 (5H, m), 8.76 (1H, br.t), 9.58 (1H, br.s). IR (KBr) cm−1: 3306, 1618, 1517, 1308, 745. HRMS calcd for C23H20N3O2F: 389.4292. Found: 389.4294. MA calcd for C23H20N3O2F: C, 70.94%; H, 5.18%; N, 10.79%. Found: C, 70.72%; H, 5.18%; N, 10.88%.