Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(O)(C)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1.[H-].[Na+].O>C1(C)C=CC=CC=1>[CH2:11]([C:8]1[CH:7]=[CH:6][C:5]([C:4]#[CH:3])=[CH:10][CH:9]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1ccc(C#CC(C)(C)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C#Cc1ccc(CCCC)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 86.1 %

Procedure:
3-Methyl-1-(4'-butylphenyl)-1-butyne-3-ol (100 g) was dissolved in toluene (900 ml) under nitrogen atmosphere, and then sodium hydride (60% in paraffin liquid; 5.7 g) was added thereto, followed by stirring at 60° C. for 6 hours. The reaction solution was poured into water (500 ml), and then extracted with chloroform, followed by washing with water 3 times. After distilling off toluene and chloroform, the resultant was distilled under reduced pressure (b.p. 62° to 65° C./3 mmHg) to give 4-butylphenylacetylene (63 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:15](=[O:17])[N:14](COC(=O)C(C)(C)C)[C:13](=[O:26])[N:12]([CH3:27])[C:11]=2[N:10]=[CH:9]1.[H-].[Na+]>CO.O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:26])[N:12]([CH3:27])[C:11]=2[N:10]=[CH:9]1
Reactant: Cn1c(=O)n(COC(=O)C(C)(C)C)c(=O)c2c1ncn2-c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
2,2-Dimethyl-propionic acid 7-(2-chlorophenyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydropurin-1-ylmethyl ester (144 mg) was dissolved in methanol (2 ml) and tetrahydrofuran (1 ml), and sodium hydride (20 mg) was added thereto. The reaction solution was stirred at room temperature overnight, diluted with ethyl acetate, and washed with 1 N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with ethyl acetate-diethyl ether to give 72 mg of 7-(2-chlorophenyl)-3-methyl-3,7-dihydropurine-2,6-dione. This was dissolved in N,N-dimethylformamide (1 ml), and N-chlorosuccinimide (35 mg) was added thereto. The reaction solution was stirred at room temperature overnight, diluted with ethyl acetate, and washed with 1 N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 58 mg of the title compound.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:20]2[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[N:17][C:16]([CH:67]=[C:68]=[O:69])([NH:33][C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]3[N:47](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:46]=[N:45][N:44]=3)[CH:38]=2)=[O:35])[C:15]1=[O:70])=[O:5])C.[OH-].[Na+].Cl.O>COCCOC.C(OCC)(=O)C>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:18]1[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=2[N:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:4]([OH:5])=[O:3])[C:15](=[O:70])[C:16]([CH:67]=[C:68]=[O:69])([NH:33][C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]3[NH:47][N:46]=[N:45][N:44]=3)[CH:38]=2)=[O:35])[N:17]=1
Reactant: CCOC(=O)COc1ccccc1N1C(=O)C(C=C=O)(NC(=O)Nc2cccc(-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)N=C(c2ccccc2F)c2cccc(C)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Cc1cccc2c1N(c1ccccc1OCC(=O)O)C(=O)C(C=C=O)(NC(=O)Nc1cccc(-c3nnn[nH]3)c1)N=C2c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
A mixture of N-[(3RS)-1-(2-ethoxycabonylmethoxyphenyl)-carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-{3-[1-(triphenylmethyl)tetrazol-5-yl]phenyl}urea (196 mg) and 1N NaOH in 1,2-dimethoxyethane (2 ml) was stirred at room temperature overnight. 4N-HCl in ethyl acetate (2 ml) was added to the reaction mixture and stirred at room temperature for three days. Ethyl acetate and water were added to the reaction mixture. The separated organic layer was washed with water and brine successively, and dried over magnesium sulfate. Removal of the solvent in vacuo afforded N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-1-(2-carboxymethoxyphenyl)-carbonylmethyl-9-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-[3-(tetrazol-5-yl)phenyl]urea (66.0 mg, 47.4%).
Reaction SMILES: [Na+].[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([O-:17])=O)=[CH:13][CH:12]=2)=[N:9][CH:10]=1)(=[O:4])[CH3:3].CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[NH:38]1[CH2:42][CH2:41][CH2:40][C@H:39]1[CH2:43][N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1>ClCCl>[N:44]1([CH2:43][C@@H:39]2[CH2:40][CH2:41][CH2:42][N:38]2[C:15]([C:14]2[CH:13]=[CH:12][C:11]([C:8]3[N:9]=[CH:10][C:5]([C:2](=[O:4])[CH3:3])=[CH:6][CH:7]=3)=[CH:19][CH:18]=2)=[O:17])[CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: CC(=O)c1ccc(-c2ccc(C(=O)[O-])cc2)nc1
Agent: COc1nc(Cl)nc(OC)n1
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)nc1
Reaction time: 0.75 h

Procedure:
Procedure W′: To a stirring solution of 4-(5-acetyl-pyridin-2-yl)-benzoic acid sodium salt (1.0 mmol) and n-methyl morpholine (1.0 mmol) in dichloromethane (0.10M) in a 0° C. ice bath, add 2-chloro-4,6-dimethoxy-1,3,5-triazine (1.0 mmol). Remove the ice bath and stir for 45 minutes. After this time, add (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (1.0 mmol) and stir at room temperature for three hours. After this time, wash the reaction with saturated aqueous sodium bicarbonate while extracting with 10% isopropanol/dichloromethane (3×). Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Purify the title compound via chromatography eluting with 2M ammonia in methanol and dichloromethane. MS (m/e): 378.3 (M+1)
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([Cl:7])[C:4]([NH:8][C:9]2[NH:13][CH2:12][CH2:11][N:10]=2)=[C:3]([Cl:14])[CH:2]=1.Br[CH2:16][CH2:17][C:18]([CH3:20])=[CH2:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:14][C:3]1[CH:2]=[CH:1][CH:6]=[C:5]([Cl:7])[C:4]=1[N:8]([C:9]1[NH:10][CH2:11][CH2:12][N:13]=1)[CH2:16][CH2:17][C:18]([CH3:20])=[CH2:19]
Reactant: C=C(C)CCBr
Reactant: Clc1cccc(Cl)c1NC1=NCCN1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=C(C)CCN(C1=NCCN1)c1c(Cl)cccc1Cl
Temperature: 120 °C

Procedure:
A mixture of 6.9 gm (0.03 mol) of clonidine, 5.6 gm of 4-bromo-2-methyl-1-butene, and 5 ml of triethylamine in 25 ml of toluene was heated for 24 hours at 120° C. After cooling, the solvent was decanted, and the residue remaining was dissolved in 1 N hydrochloric acid. After extraction with ether several times (the ethereal extracts were abandoned), the solution was extracted with ether in fractions at stepwisely rising pH values (alkalizing with 2 N sodium hydroxide solution). The thin-layer chromatographically uniform ether extracts were united and dried over MgSO4, and the ether was evaporated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:29])[CH2:18][CH2:17][CH:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([CH:16]1[CH2:17][CH2:18][C:13]([F:29])([F:12])[CH2:14][CH2:15]1)[C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: Cc1ncc(C(CN)C2CCC(F)(F)CC2)cn1
Product: Cc1ncc(C(CNC(=O)c2cccc(F)c2Cl)C2CCC(F)(F)CC2)cn1

Procedure:
From 2-chloro-3-fluorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-methylpyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=412.1, tR (minutes, Method F)=2.18
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH2:5].C(O)(C(F)(F)F)=O.[CH2:13]([O:20][C:21](ON1C(=O)CCC1=O)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1OCCOCCOCCOCCOCCOC1.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>>[CH3:1][NH:2][CH2:3][CH2:4][NH:5][C:21](=[O:22])[O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNCCN
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: O=C(O)C(F)(F)F
Product: CNCCNC(=O)OCc1ccccc1
Yield: 355.7 %

Procedure:
To a solution of N-methyl ethylene diamine (10 g, 135 mmol) in CHCL3 (100 mL) was added TFA (11.43 mL, 148.4 mmol) and the solution was stirred for several minutes. The reaction was then treated successively with 1-{[(benzyloxy)carbonyl]oxy}pyrrolidine-2,5-dione (Aldrich, 43.7 g, 175.3 mmol) and 18-crown-6 (71.3 g, 269.8 mmol). The reaction became slightly green. After stirring for 1 hour at room temperature, TLC (ninhydrin stain) showed no remaining starting amine. The reaction was transferred to a separatory funnel and washed with KOH solution. The aqueous layer was back-extracted several times. The organic layers were combined, dried over Na2SO4, filtered and concentrated to give 100 g of a yellow oil. The oil was dissolved in 300 ml CHCl3 and half of this volume was chromatographed on silica (150 mm×7 inches, 1 Kg silica gel, packed in CHCl3) eluting with CHCl3 saturated NH3. The pure fractions were collected and the remaining half of the crude chromatographed in the same way. Product fractions contaminated with some bis-CBZ protected material were dissolved in CHCl3 and washed with acid water. The aqueous was then basified and extracted with CHCl3. The organic layer was dried over Na2SO4, filtered and concentrated with the other pure fractions to give the product as a clear, colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27](B(O)O)[CH:26]=1>>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:27]2[CH:26]=[N:25][C:34]4[C:29]([CH:28]=2)=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)=[CH:20][CH:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Product: CC(C)(C)c1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2cnc3ccccc3c2)cc1

Procedure:
The title compound was prepared in accordance with Example 8(c) from 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester (see Example 1(a)) and quinoline-3-boronic acid , followed by ester hydrolysis in accordance with the procedure described in Example 35, Method 3, step (b).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[NH:4][N:3]=1.[NH:25]1[CH:29]=[C:28](B(O)O)[CH:27]=[N:26]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C(OCC)(=O)C>[N:19]1([C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:8]3[CH:9]=[C:10]4[C:2]([C:28]5[CH:29]=[N:25][NH:26][CH:27]=5)=[N:3][NH:4][C:5]4=[N:6][CH:7]=3)[CH:12]=2)=[O:18])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: OB(O)c1cn[nH]c1
Reactant: O=C(c1cccc(-c2cnc3[nH]nc(I)c3c2)c1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(c1cccc(-c2cnc3[nH]nc(-c4cn[nH]c4)c3c2)c1)N1CCOCC1
Yield: 28.6 %

Procedure:
A mixture of [3-(3-iodo-1H-pyrazolo[3,4-b]pyridin-5-yl)-phenyl]-morpholin-4-yl-methanone (25 mg, 58 μmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichlormethane adduct (5 mg, 6 μmol) and 1H-pyrazol-4-ylboronic acid (11 mg, 98 μmol) in acetonitrile (2 mL) and 2 M solution of sodium carbonate (1 mL) was irradiated in a Personal Chemistry Optimizer at 175° C. for 30 min. The crude reaction mixture was diluted with water (1 mL) and ethyl acetate (3 mL) and the organic phase separated, filtered and concentrated. The resulting crude mixture was then purified by mass-triggered reverse phase HPLC using a gradient of acetonitrile in water containing 0.1% of formic acid to afford morpholin-4-yl-{3-[3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-methanone (6.2 mg, 29% yield) of as a colorless powder. 1H-NMR (500 MHz, d6-DMSO) δ 13.59 (s, 1H), 13.17 (s, 1H), 8.87 (d, 1H), 8.73 (d, 1H), 8.60 (s, br, 1H), 8.17 (s, br, 1H), 7.95 (ddd, 1H), 7.89 (t, 1H), (t, 1H), 7.59 (t, 1H), 7.43 (ddd, 1H), 3.80-3.35 (m, 8H). MS: m/z 397 [MNa+], 375 [MH+].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[Br:8][C:9]1[CH:14]=[C:13]([Br:15])[N:12]=[C:11]([Cl:16])[C:10]=1[OH:17].Cl[C:19]([F:29])([F:28])C(C1C=CC=CC=1)=O>CC#N>[Br:8][C:9]1[CH:14]=[C:13]([Br:15])[N:12]=[C:11]([Cl:16])[C:10]=1[O:17][CH:19]([F:29])[F:28]
Reactant: O=C(c1ccccc1)C(F)(F)Cl
Reactant: Oc1c(Br)cc(Br)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: FC(F)Oc1c(Br)cc(Br)nc1Cl
Temperature: 100 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
Potassium carbonate (K2CO3; 5.01 g, 36.3 mmol) and H2O (4 mL) were added to a microwave reaction vessel. 4,6-Dibromo-2-chloropyridin-3-ol (0.359 g, 1.25 mmol) was dissolved in CH3CN (4 mL) and added to the microwave reaction vessel. 2-Chloro-2,2-difluoro-1-phenylethanone (0.953 g, 5.00 mmol) was then added, and the microwave reaction vessel was sealed. The reaction mixture was heated with vigorous stirring with a large stir bar in a Biotage microwave reactor at 100° C. for 4 h. (The reaction mixture is biphasic, and the reaction will not proceed to completion without vigorous stirring.) The reaction mixture was then partitioned between EtOAc and H2O. The organic phase was washed once more with H2O, dried and concentrated. The product was redissolved in CH2Cl2 and filtered through short plug of silica gel utilizing CH2Cl2 as the eluting solvent. The eluent was concentrated to provide the title compound as a light yellow low-melting solid (0.325 g, 0.963 mmol, 77%): 1H NMR (300 MHz, CDCl3) δ 7.73 (s, 1H), 6.63 (t, J=73.1, 1H); EIMS m/z 337.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[C:10]([O:14][C:15]([N:17]1[CH2:22][C@H:21]2[C@H:19]([CH2:20]2)[C@H:18]1[CH2:23][NH2:24])=[O:16])([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:22][C@H:21]2[C@H:19]([CH2:20]2)[C@H:18]1[CH2:23][NH:24][C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CN
Reactant: CCOC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
At 0° C. ethyl trifluoroacetate (41.9 mmol, 1.3 eq) is added to a solution of (1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (32.0 mmol, 1.00 eq) in THF (80 mL). The mixture is stirred at RT for 90 min and the solvents are removed in vacuo to give the desired product which is used without further purification in the next step. LC-MS: tR=0.94 min; [M+H]+=309.1.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]([C:14]([NH2:17])([CH3:16])[CH3:15])[CH:11]=[CH:12][CH:13]=2)=[CH:6][C:5]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:4]1)[CH3:2].CCN(CC)CC.[F:34][C:35]([F:43])([F:42])[CH2:36][NH:37][S:38](Cl)(=[O:40])=[O:39]>>[CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]([C:14]([NH:17][S:38]([NH:37][CH2:36][C:35]([F:43])([F:42])[F:34])(=[O:40])=[O:39])([CH3:16])[CH3:15])[CH:11]=[CH:12][CH:13]=2)=[CH:6][C:5]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[N:4]1)[CH3:2]
Reactant: O=S(=O)(Cl)NCC(F)(F)F
Reactant: CCn1nc(CCc2ccc(F)cc2)cc1-c1cccc(C(C)(C)N)c1
Solvent: CCN(CC)CC
Product: CCn1nc(CCc2ccc(F)cc2)cc1-c1cccc(C(C)(C)NS(=O)(=O)NCC(F)(F)F)c1

Procedure:
Prepared by the procedure of Example 1 Step 3. The amine from Step 3 (67 mg, 0.19 mmol), Et3N (80 □L, 0.57 mmol) and 2,2,2-trifluoroethylsulfamoyl chloride (75 mg, 0.38 mmol) were reacted to yield after purification by column chromatography on silica using 80% Et2O/iso-hexanes the title sulfamide (25 mg, 26%). 1H NMR (CDCl3, 500 MHz) δ 7.57-7.49 (2H, m), 7.45 (1H, t, J=7.8 Hz), 7.30 (1H, d, J=7.8 Hz), 7.19 (2H, dd, J=8.7, 5.6 Hz), 6.97 (2H, t J=8.7 Hz), 6.03 (1H, s), 4.69 (1H, s), 4.39 (1H, t, J=5.4 Hz), 4.10 (2H, q, J=7.2 Hz), 3.57 (2H, quintet, J=5.4 Hz), 3.03-2.90 (4H, m), 1.78 (6H, s), 1.39 (3H, t, J=7.2 Hz). MS (ES+) C24H28F4N4O2S requires: 512, found: 513 (M+H+, 100%).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH2:44][CH2:45][F:46])[C:36]=1[F:47])=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[F:47][C:36]1[C:37]([O:43][CH2:44][CH2:45][F:46])=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:35]=1[CH:21]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1)[C:20]1[NH:19][C:18](=[O:17])[N:1]([C:3]2[N:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCF)c1F
Reactant: NNc1ncccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(OCCF)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
After adding 1.09 g of 2-hydrazinopyrimidine [CAS No. 7504-94-1] and 1.37 ml of triethylamine to a solution of 5.0 g of {2-[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 50 ml of DMF, the mixture was stirred at 85° C. for 20 hours and 30 minutes under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 30 ml of methanol, 10 ml of THF and 3 ml of acetic acid. Next, 2.0 g of sodium cyanotrihydroborate was added to the solution, and after stirring at room temperature for 3 hours, 1.0 g of sodium cyanotrihydroborate was further added and stirring was continued for 2 hours and 30 minutes at room temperature. Water and ethyl acetate were added to the reaction mixture, and the insoluble portion was filtered off to give the title compound as a white solid. The filtrate was extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (total: 4.88 g) as a white solid.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)([CH3:21])[C:8]([CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11](OCC)=[O:12])=[O:9]>CCOC(C)=O>[OH:12][C:11]1[C:23]2[C:22](=[CH:27][CH:26]=[C:25]([CH3:28])[CH:24]=2)[C:7]([CH3:6])([CH3:21])[C:8](=[O:9])[C:10]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccc(C)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(O)c2cc(C)ccc2C(C)(C)C1=O
Reaction time: 1.5 h
Yield: 51.5 %

Procedure:
Concentrated H2SO4 (11.5 mL, 216 mmol) was added dropwise via addition funnel to stirred diethyl 2-(2-methyl-2-p-tolylpropanoyl)malonate (6.92 g, 21.6 mmol) at 0° C. The reaction mixture was stirred for 1.5 hours and then poured into a flask of ice, diluted with 200 mL of EtOAc, added to a separatory funnel, partitioned with water, washed 2 times with 75 mL of water, separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (3.05 g) as a brown oil which was used without further purification. MS (m/z)=275 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[NH:15][N:16]=2)[N:13]=1.[F:25][C:26]([F:32])([F:31])[CH2:27][CH2:28][CH2:29]I.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[N:15]([CH2:29][CH2:28][CH2:27][C:26]([F:32])([F:31])[F:25])[N:16]=2)[N:13]=1
Reactant: FC(F)(F)CCCI
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: O=c1n(CCCC(F)(F)F)nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 80 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
A suspension of 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (20 mg, 0.056 mmol), 1,1,1-trifluoro-4-iodobutane (20 mg, 0.084 mmol) and solid K2CO3 (12 mg, 0.084 mmol) in anhydrous DMF (0.6 mL) was stirred at 80° C. for 1 h. Analysis by HPLC/MS indicated the reaction was not complete. Additional 1,1,1-trifluoro-4-iodobutane (12 mg, 0.084 mmol) was added, the reaction was allowed to continue at 80° C. for 30 min. After cooling to room temperature, the reaction mixture was diluted with water, and extracted with EtOAc (20 mL×2). The combined EtOAc extracts were washed with water, saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluting with a gradient of EtOAc (0-60%) in hexanes to yield a yellow oily product, which was lyophilized in acetonitrile to afford 19 mg (73%) of the title compound as a yellow powder. HPLC (method B): retention time=7.70 min. 1H NMR (CDCl3, 400 MHz): δ 7.45 (m, 2H), 7.35 (m, 2H), 7.25 (m, 1H), 7.20 (d,J=8.8 Hz, 2H), 7.04 (d,j=8.8 Hz, 2H), 4.17 (t,J=6.1 Hz, 2H), 2.17-2.25 (m, 4H).
Reaction SMILES: C1C=CC=CC=1.[F:7][C:8]1[CH:23]=[CH:22][C:11]2[O:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15](=O)[CH2:16][C:10]=2[CH:9]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(=O)(O)[O-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.O>[F:7][C:8]1[CH:23]=[CH:22][C:11]2[O:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)=[CH:16][C:10]=2[CH:9]=1
Reactant: CN1CCNCC1
Reactant: O=C1Cc2cc(F)ccc2Oc2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CN1CCN(C2=Cc3cc(F)ccc3Oc3ccccc32)CC1
Reaction time: 4 h

Procedure:
A solution of 6.44 g. of titanium (IV) chloride in 25 ml. of benzene is added dropwise over a period of 15 minutes with cooling to a solution of 9.12 g. of 2-fluoro-10,11-dihydro-dibenz[b,f]oxepin-10-one and 18 g. of 1-methyl-piperazine in 100 ml. of benzene in such a manner that the temperature does not exceed 25° C. The mixture is subsequently stirred for 4 hours at reflux. The resulting mixture is cooled and poured into a solution of 10 g. of sodium bicarbonate in 100 ml. of water. The precipitated titanium dioxide is removed by filtration and washed carefully with benzene and chloroform. The benzene solution and the chloroform solution are washed four times with water, combined, dried over sodium sulfate, evaporated in vacuo, and there is obtained crude, crystalline 1-[2-fluoro-dibenz[b,f]oxepin-10-yl]-4-methyl-piperazine.