Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([C:22]2[CH:30]=[CH:29][C:28]([C:31]([O:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][C:48](=[O:51])[CH:49]=[CH2:50])=[CH:36][CH:35]=3)=[O:32])=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])=[O:21])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].[N+:52]([C:55]1[CH:60]=[CH:59][C:58]([N:61]=[N:62][C:63]2[CH:81]=[CH:80][C:66]([C:67]([O:69][C:70]3[CH:79]=[CH:78][C:73]([O:74][CH:75](O)[CH3:76])=[CH:72][CH:71]=3)=[O:68])=[CH:65][CH:64]=2)=[CH:57][CH:56]=1)([O-:54])=[O:53]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([C:22]2[CH:30]=[CH:29][C:28]([C:31]([O:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:47][C:48](=[O:51])[CH:49]=[CH2:50])=[CH:38][CH:39]=3)=[O:32])=[CH:27][C:23]=2[C:24]([O:26][CH2:76][CH2:75][O:74][C:73]2[CH:78]=[CH:79][C:70]([O:69][C:67](=[O:68])[C:66]3[CH:80]=[CH:81][C:63]([N:62]=[N:61][C:58]4[CH:59]=[CH:60][C:55]([N+:52]([O-:54])=[O:53])=[CH:56][CH:57]=4)=[CH:64][CH:65]=3)=[CH:71][CH:72]=2)=[O:25])=[O:21])=[CH:17][CH:18]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: CC(O)Oc1ccc(OC(=O)c2ccc(N=Nc3ccc([N+](=O)[O-])cc3)cc2)cc1
Reactant: C=CC(=O)OCCCCCCOc1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)O)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCOc1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)OCCOc3ccc(OC(=O)c4ccc(N=Nc5ccc([N+](=O)[O-])cc5)cc4)cc3)c2)cc1

Procedure:
A solution of 0.6 g of 2,5-bis[4-(6-acryloyloxyhexyloxy)phenylcarboxy]benzoic acid, 0.4 g of (4-[4-(4-nitrophenylazo)benzoyloxy]phenoxy)ethanol and 0.04 g of 4-dimethylaminopyridine is reacted with 0.2 g of N,N'-dicyclohexyldicarbodiimide and 20 ml of dichloromethane in an analogous manner to Example 1 to give (4-[4-(4-nitrophenylazo)benzoyloxy]phenoxy)ethyl 2,5-bis[4-(6-acryloyloxyhexyloxy)phenylcarboxy]benzoate.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[NH:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=O)[O:7]C1=O.CCN(C(C)C)C(C)C>C1COCC1>[NH2:5][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:8]([NH:4][O:3][CH3:2])=[O:7]
Reactant: CON
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)c1ccccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
O-Methylhydroxylamine hydrochloride (1.253 g, 15.00 mmol) was added to 1H-3,1-benzoxazine-2,4-dione (isatoic anhydride) (1.631 g, 10 mmol) in THF (50 mL) containing DIPEA (2.79 ml, 16.00 mmol). The resulting solution was stirred at room temperature for 4 hours and then heated to reflux for 17 hours. The mixture was allowed to cool to room temperature, filtered and then evaporated. The residue was dissolved in MeOH (20 mL) and then loaded onto an SCX column. The mixture was eluted first with MeOH and then with a 7N solution of NH3 in MeOH. Fractions containing product were combined and then evaporated to afford 2-amino-N-methoxybenzamide (1.410 g, 85% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 3.67 (3H, s), 6.26 (2H, s), 6.48 (1H, m), 6.70 (1H, dd), 7.15 (1H, m), 7.31 (1H, dd), 11.36 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=167.41.
Reaction SMILES: S(=O)(O)[O-].[Na+].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[F:15])[CH:10]=[O:11].[C-:16]#[N:17].[Na+]>O.CCOCC>[Br:6][C:7]1[CH:8]=[C:9]([CH:10]([C:16]#[N:17])[OH:11])[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: [C-]#N
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: N#CC(O)c1ccc(F)c(Br)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution of sodium bisulfite (28.3 g, 271 mmol) in water at 50° C. is treated with 3-bromo-4-fluorobenzaldehyde (45.8 g, 225 mmol), stirred at 50° C. for 2 h, cooled with an ice bath, diluted with ether, treated dropwise with an aqueous solution of sodium cyanide (12.2 g, 248 mmol) over a period of 30 min and stirred at room temperature overnight. The reaction mixture is separated, and the aqueous phase is extracted with ether. The extracts are combined with the organic phase, washed with brine, dried over magnesium sulfate and concentrated to dryness to afford the title compound as a clear oil, 47.6 g (92% yield), identified by NMR analysis. 1H NMR (300 MHz, CDCl3) δ 7.75 (m, 1H), 7.47 (m, 1H), 7.23 (m, 1H), 5.54 (m, 1H), 3.19 (m, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[C:9]=1[C:26](OCC)=O.O>O1CCCC1>[CH3:26][C:9]1[C:10]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[N:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:13][C:8]=1[CH3:7]
Reactant: CCOC(=O)c1c(C)nc(-c2ccccc2)nc1-c1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2ccccc2)nc(-c2ccncc2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 1.8 %

Procedure:
To a suspension of lithium aluminum hydride (0.24 g) in dry tetrahydrofuran (40 ml) was dropwise added a solution of ethyl 6-methyl-2-phenyl-4-(4-pyridyl)-5-pyrimidinecarboxylate (2.0 g) in the same solvent (20 ml) under cooling at 7°-9° C. After the addition was completed, the mixture was stirred for 2 hours at room temperature. The excess lithium aluminum hydride was decomposed by a careful addition of water and the dried solution was concentrated in vacuo to an oil. The oil was column chromatographed on silica gel eluting with chloroform and the fractions containing a produce were collected and concentrated in vacuo. The residual crystals were recrystallized from n-hexane to give 5,6-dimethyl-2-phenyl-4-(4-pyridyl)pyrimidine (0.03 g), mp 152°-153° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=2[OH:15])=[CH:6][CH:7]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][C:9]=2[OH:15])=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Cl)nn2)c(O)c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Oc1ccc(-c2ccc(Cl)nn2)c(O)c1

Procedure:
3-Chloro-6-(2,4-dihydroxyphenyl)pyridazine (1 mole) was treated with ethyl chloroformate (1.1 mole) in pyridine to give 3-chloro-6-(4-ethoxycarbonyloxy-2-hydroxyphenyl)pyridazine.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[CH:29]=[C:28]([C:30](O)=[O:31])[NH:27][N:26]=2)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C@@H:34]([CH3:51])[CH2:35][N:36]1[CH:40]=[CH:39][C:38]([C:41]2[CH:48]=[C:47]([F:49])[C:44]([C:45]#[N:46])=[C:43]([Cl:50])[CH:42]=2)=[N:37]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:50][C:43]1[CH:42]=[C:41]([C:38]2[CH:39]=[CH:40][N:36]([CH2:35][C@@H:34]([NH:33][C:30]([C:28]3[NH:27][N:26]=[C:25]([C:23]4[N:22]=[CH:21][N:20]([C:1]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)([C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:24]=4)[CH:29]=3)=[O:31])[CH3:51])[N:37]=2)[CH:48]=[C:47]([F:49])[C:44]=1[C:45]#[N:46]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)n[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)n[nH]1

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxylic acid (0.875 mmol, 0.368 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.673 mmol, 0.250 g) using HBTU (0.067 mmol, 0.026 g) instead of HOBt. DCM (4 ml) was used as the solvent. The reaction mixture was diluted with DCM and washed with 1 M Na2CO3 and water. The separated organic phase was dried, filtered and evaporated to give 0.511 g of crude product. Another crude batch (931 mg) was combined here and purified first by trituration in ACN and then by flash chromatography to give 0.095 g of the product. 1H-NMR (400 MHz, DMSO-d6): δ 1.18 (d, 3H), 4.13-4.53 (m, 3H), 6.64 (s, 1H), 6.98 (d, 1H), 7.09-7.19 (m, 4H), 7.35-7.51 (m, 9H), 7.52-7.57 (m, 1H), 7.70-7.76 (m, 1H), 7.79-7.86 (m, 2H), 7.92 (s, 1H), 7.95 (s, 1H), 8.06-8.10 (m, 1H), 8.14-8.18 (m, 1H), 13.35 (bs, 1H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]1[O:27][CH:26]([CH3:28])[CH2:25][NH:24][CH2:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:24]3[CH2:23][CH:22]([CH3:21])[O:27][CH:26]([CH3:28])[CH2:25]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: CC1CNCC(C)O1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)CC(C)O1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 2,6-dimethylmorpholine (141-91-3) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=382.5 [MH+].
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][Cl:25])[CH:20]=2)[NH:15][C:14]=1[CH3:26])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:27]I.O>CN(C=O)C>[CH2:3]([O:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][Cl:25])[CH:20]=2)[N:15]([CH3:27])[C:14]=1[CH3:26])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1[nH]c2ccc(OCCCl)cc2c1C(=O)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)OCc2ccccc2)c2cc(OCCCl)ccc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
To a suspension of NaH (0.959 mmol, 0.038 g, 60% in mineral oil, rinsed twice with hexanes) in 5 mL of DMF at 0° C. under N2 was added a solution of 5-(2-chloro-ethoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.873 mmol, 0.300 g, Example 1, Step A) in 3.73 mL of DMF. The ice bath was removed and the solution was stirred for 2 hours at room temperature. Methyl iodide (0.959 mmol, 0.060 mL, Aldrich) was added dropwise via syringe and the solution was stirred for 20 hours. Water (10 mL) was added and the mixture was stirred for 30 minutes. The resulting precipitate was filtered off, the filtrate was extracted with ether (3×10 mL), and the extracts were washed with water (2×10 mL), brine (1×10 mL), dried over MgSO4, and concentrated. The residue was combined with the solid and purified by silica gel flash column chromatography (30% ethyl acetate/hexanes) to give a white solid (0.216 g, 69%): 1HNMR (400 MHz, DMSO-d6) δ 2.67 (s, 3H, ArCH3), 3.66 (s, 3H, NCH3), 3.87-3.89 (m, 2H, CH2Cl), 4.09-4.12 (m, 2H, CH2OAr), 5.29 (s, 2H, CO2CH2Ph), 6.80-6.83 (m, 1H, ArH), 7.21-7.50 (m, 7H, ArH); MS(APCI+): m/z 358.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]([C@@H:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][C@H:9]2[OH:15])=[C:6]([O:16][CH3:17])[CH:5]=[C:4]([O:18][CH3:19])[C:3]=1[C:20](=[O:22])[CH3:21].[Cl:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26](OC)=O.[H-].[Na+]>CN(C=O)C>[Cl:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]1[O:1][C:2]2[C:3]([C:20](=[O:22])[CH:21]=1)=[C:4]([O:18][CH3:19])[CH:5]=[C:6]([O:16][CH3:17])[C:7]=2[C@@H:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][C@H:9]1[OH:15]
Reactant: COc1cc(OC)c([C@@H]2CCN(C)C[C@H]2O)c(O)c1C(C)=O
Reactant: COC(=O)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)C[C@H]1O

Procedure:
Compound of example 105 (9 g, 29 mmol) in dry DMF (50 mL) was reacted methyl 2-chlorobenzoate (16.5 g, 96.7 mmol) in the presence of NaH (50%, 6.99 g, 145.6 mmol) as described in example 16 to obtain the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:12][NH2:13]>ClCCl.C(O)C>[S:9]1[CH:10]=[CH:11][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][NH:13][CH3:12])[C:8]1=2
Reactant: CN
Reactant: BrCc1cccc2ccsc12
Solvent: ClCCl
Solvent: CCO
Product: CNCc1cccc2ccsc12
Reaction time: 8 h

Procedure:
7-Bromomethylbenzo[b]thiophene is dissolved in dichloromethane, added to 40 ml of a 33% solution of methylamine in ethanol and allowed to stand overnight. The resulting mixture is concentrated and the residue taken up in dichloromethane and extracted with 2N HCl. The aqueous phase is made strongly basic with NaOH and shaken with dichloromethane. The organic phase is dried with potassium carbonate, concentrated by evaporation and the residue vacuum distilled to produce the title product as an oil. B.p.=103°/1.3 mbar.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]1([NH:18][CH2:19][C:20]([F:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:18]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:19][C:20]([F:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C(C)(F)CNC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.7 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (970 mg, 5 mmol) in anhydrous acetone (20 ml) at 0° C., was added dropwise a solution of ethyl 3-(cyclohexylamino)-2-fluoro-2-methylpropanoate (1.1 g, 4.76 mmol) in acetone (5 mL) over 10 min. After which, potassium carbonate (1.66 g, 12 mmol) was added and the whole was stirred at rt for 18 h. After evaporation in vacuo, the residue was partitioned between ethyl acetate (200 ml) and water (200 ml). The organic layer was washed with NaHCO3, brine and water, dried over Na2SO4 and concentrated in vacuo to give a red residue (1.9 g) which was used directly for next step. [M+H] calc'd for C16H22ClFN4O4, 389. found 389.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].Cl[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]>CN(C=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:3][C:4]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=2[CH:6]=[O:7])=[C:16]([N+:22]([O-:24])=[O:23])[CH:17]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 53.9 %

Procedure:
Sodium hydride (0.66 q) Was added in portions to a stirred solution of 3.90 g of 2-hydroxy-4-methoxybenzaldehyde in N,N'-dimethylformamide (70 mL) under nitrogen. To the resulting milky, green mixture was added 1,4-dichloro-2-nitrobenzene (4.47 g). The reaction was placed in an oil bath and stirred at 90° C. for 16 hours. The reaction was then evaporated and the residue partitioned between chloroform (75 mL) and 1 N NaOH (50 mL). The layers were separated and the aqueous layer was extracted with chloroform (75 mL). The chloroform extracts were combined and washed with water (75 mL) and brine (75 mL), dried over magnesium sulfate, and evaporated in vacuo. The orange solid was recrystallized from ethyl acetate/iso-propyl ether to yield 3.86 g (53.9%) of product as light yellow, shiny crystals. Melting Point: 130°-131° C.
Reaction SMILES: [OH:1][CH:2]([CH2:32][OH:33])[CH2:3][O:4][C:5]1[N:6]=[N:7][C:8]([NH:11][NH:12][C:13](C2C=CC=CC=2)([C:20]2C=CC=CC=2)[C:14]2C=CC=CC=2)=[CH:9][CH:10]=1.[ClH:34]>O1CCCC1>[ClH:34].[OH:1][CH:2]([CH2:32][OH:33])[CH2:3][O:4][C:5]1[N:6]=[N:7][C:8]([NH:11][N:12]=[C:13]([CH3:14])[CH3:20])=[CH:9][CH:10]=1
Reactant: OCC(O)COc1ccc(NNC(c2ccccc2)(c2ccccc2)c2ccccc2)nn1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)=NNc1ccc(OCC(O)CO)nn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (RS)-3-(2,3-dihydroxypropoxy)-6-(2-triphenylmethylhydrazino)pyridazine (3.2 g) in tetrahydrofuran (80 ml), conc. hydrochloric acid (2 ml) was added. After stirring at room temperature for 15 minutes the solution was concentrated under vacuum to small volume and diluted with acetone (50 ml). After stirring at room temperature for 30 minutes and then at 0° C. for 1 hour the precipitate was collected to yield 1.4 g of the title compound, identical to that obtained in Example 14.
Reaction SMILES: [Na].[OH:2][N:3]1[C:7](=[O:8])[CH:6]2[CH2:9][CH2:10][CH:11]=[CH:12][CH:5]2[C:4]1=[O:13].[CH2:14](Cl)[CH3:15]>>[CH2:14]([O:2][N:3]1[C:4](=[O:13])[CH:5]2[CH2:12][CH2:11][CH:10]=[CH:9][CH:6]2[C:7]1=[O:8])[CH3:15]
Reactant: O=C1C2C=CCCC2C(=O)N1O
Reactant: CCCl
Agent: [Na]
Product: CCON1C(=O)C2C=CCCC2C1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 84.1 %

Procedure:
In an autoclave 60 g of a 20 wt % solution of the sodium salt of N-hydroxytetrahydrophthalimide (0.063 mol) and 5.0 g (0.078 mol) of ethyl chloride were mixed together. The mixture was heated to 100° C. After reaching this temperature the mixture was stirred for a further 5 hours while the temperature was maintained at 100° C. After 5 hours' reaction the excess ethyl chloride was blown out and the reaction mixture was discharged. The reaction product was extracted from the mixture with toluene. Gas chromatographic analysis of the toluene extract showed that the yield was 84% of N-ethoxytetrahydrophthalimide (0.053 mol).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[Br:9]Br.C(=O)([O-])O.[Na+]>C(O)(=O)C>[Br:9][C:3]1[CH:4]=[C:5]([CH:7]=[O:8])[S:6][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1ccc(C=O)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1sc(C=O)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methylthiophene-2-carbaldehyde (2.00 g) in acetic acid (20 mL) was added dropwise bromine (0.90 mL). The reaction mixture was stirred at room temperature for 8 hr, saturated aqueous sodium hydrogen carbonate was added by small portions, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate, saturated sodium thiosulfate aqueous solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (2.11 g).
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]([C:15]3[N:23]4[C:18]([CH:19]=[N:20][C:21](O)=[N:22]4)=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH:26]=1>>[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:21]3[N:20]=[CH:19][C:18]4=[CH:17][CH:16]=[C:15]([C:11]5[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([N:1]6[CH2:5][CH2:4][CH2:3][CH2:2]6)(=[O:8])=[O:7])[CH:10]=5)[N:23]4[N:22]=3)=[CH:33][CH:32]=2)[CH:26]=1
Reactant: Nc1ccc(-c2cccnc2)cc1
Reactant: O=S(=O)(c1cccc(-c2ccc3cnc(O)nn23)c1)N1CCCC1
Product: O=S(=O)(c1cccc(-c2ccc3cnc(Nc4ccc(-c5cccnc5)cc4)nn23)c1)N1CCCC1

Procedure:
(4-Pyridin-3-yl-phenyl)-{7-[3-(pyrrolidine-1-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl}-amine was prepared from 7-[3-(pyrrolidine-1-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 4-pyridin-3-yl-phenylamine in an analogous manner to Example 1052a. Product isolated as a yellow solid (88 mg, 58%). m.p.=194-200° C.; LCMS (m/e) 497 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.87 (s, 1H), 8.78 (s, 1H), 8.56 (d, 1H, J=4.3 Hz), 8.53 (s, 1H), 8.43 (d, 1H, J=8.0 Hz), 7.91 (d, 1H, J=8.0 Hz), 7.84 (d, 1H, J=7.8 Hz), 7.74 (d, 1H, J=8.6 Hz), 7.71-7.61 (m, 3H), 7.35 (dd, 1H, J=4.9 and 7.7 Hz), 7.09 (d, 1H, J=4.8 Hz), 6.98 (s, 1H), 6.89 (d, 1H, J=4.8 Hz), 3.36-3.22 (m, 4H), 1.83-1.72 (m, 4H).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].N[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[SH:13]>C(O)C>[S:13]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:4]=[C:3]1[CH2:2][C:1]1[S:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:5]=1
Reactant: Nc1ccccc1S
Reactant: N#CCC#N
Solvent: CCO
Product: c1ccc2sc(Cc3nc4ccccc4s3)nc2c1
Reaction time: 8 h
Yield: 82 %

Procedure:
To produce the above compound, in a two-neck 100 ml round bottom flask with a condenser and a stir bar, malononitrile (2.64 g, 40 mmol) was dissolved in absolute ethanol (40 ml). 2-amino thiophenol (log, 80 mmol) was slowly added to this solution under stirring. Under a nitrogen blanket, the reaction mixture was heated and refluxed for six hours. After cooling, the flask was refrigerated overnight. Pale green crystals of bis(2-benzothiazolyl) methane that formed were recovered, following vacuum filtration, washing with hexane and drying (yield: 82%). 2.82 g (10 mmol) of the bis(2-benzothiazolyl) methane was dissolved in chloroform (50 ml) in an erlenmeyer flask. Hydrobromic acid (10 mmol) in glacial acetic acid was added dropwise with gentle stirring. A canary yellow precipitate formed within minutes, causing thickening of the reaction mixture. Stirring was continued for one hour at room temperature. A fine yellow powder was recovered, following filtration and washing with ether. The yield was quantitative and the bis(2-benzothiazolyl) methane monohydrobromide product was sufficiently pure to be used in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[NH2:20]>>[F:15][C:16]([F:28])([F:29])[C:17]1[CH:18]=[C:19]([NH:20][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:2]=2[OH:1])[CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:23]=1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C(F)(F)F)ccc1O

Procedure:
Using 2-hydroxy-5-(trifluoromethyl)benzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound. (2-Hydroxy-5-(trifluoromethyl)benzoic acid: refer to Chem. Pharm. Bull., 1996, 44, 734.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=2[N:8]=[C:7]1[C:17]1[C:18]([OH:23])=[N:19][CH:20]=[CH:21][CH:22]=1.[CH3:27][O:28][C:29](=[O:40])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=1>>[CH3:27][O:28][C:29](=[O:40])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][O:23][C:18]2[C:17]([C:7]3[N:6]([CH2:5][C:4]4[CH:24]=[CH:25][CH:26]=[C:2]([Cl:1])[CH:3]=4)[C:10]4[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=4[N:8]=3)=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:34][CH:33]=1
Reactant: Oc1ncccc1-c1nc2cc(F)c(F)cc2n1Cc1cccc(Cl)c1
Reactant: COC(=O)COc1ccc(CBr)cc1
Product: COC(=O)COc1ccc(COc2ncccc2-c2nc3cc(F)c(F)cc3n2Cc2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 3-[1-(3-chloro-benzyl)-5,6-difluoro-1H-benzoimidazol-2-yl]-pyridin-2-ol and (4-bromomethyl-phenoxy)-acetic acid methyl ester (CAS Reg. No. 104508-23-8). Colorless powder (67%). MS (Turbo Spray): m/z=550.1 (M+H).