Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17])[CH2:4][CH3:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[C:39]([O:43][C:44](=[O:51])[C@H:45]([CH2:47][CH:48]([CH3:50])[CH3:49])[NH2:46])([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C.C(Cl)CCl>[C:39]([O:43][C:44](=[O:51])[C@@H:45]([NH:46][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][C:7]([NH:6][CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])=[C:8]([N+:16]([O-:18])=[O:17])[CH:9]=1)[CH2:47][CH:48]([CH3:49])[CH3:50])([CH3:41])([CH3:40])[CH3:42]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: CCC(CC)Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)Nc1ccc(C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.2 %

Procedure:
To a solution of 6.80 g of 4-(1-ethyl-propylamino)-3-nitro-benzoic acid in 210 ml of dry DMF 1.82 g of HOBT, 7.23 g of EDC and 6.6 ml of DIPEA were added at 0° C. After 30 min 7.24 g of L-leucin-tert.-butylester-hydrochloride and 4.7 ml of DIPEA were added and the reaction was stirred at rt for 4 h. The reaction was then concentrated to about a fifth of its volume and poured into water. It was then extracted with ethyl acetate three times. The combined organic phases were washed with saturated aqueous sodium carbonate solution and brine, dried over magnesium sulphate and concentrated to yield 11.50 g (100%) of (S)-2-[4-(1-ethyl-propylamino)-3-nitro-benzoylamino]-4-methyl-pentanoic acid tert-butyl ester.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH:12]=[CH:11][CH:10]=[CH:9]1.[F:20][C:21]([F:34])([F:33])[C:22]([N:24]1[C@H:29]2[CH2:30][CH2:31][C@@H:25]1[CH2:26][C:27](=O)[CH2:28]2)=[O:23]>ClC(Cl)C>[F:34][C:21]([F:20])([F:33])[C:22]([N:24]1[CH:29]2[CH2:30][CH2:31][CH:25]1[CH2:26][C:27]1([O:19][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:8]3[CH:9]=[CH:10][CH:11]=[C:12]13)[CH2:28]2)=[O:23]
Reactant: Oc1ccccc1-n1cccc1
Reactant: O=C1C[C@H]2CC[C@@H](C1)N2C(=O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: O=C(N1C2CCC1CC1(C2)Oc2ccccc2-n2cccc21)C(F)(F)F
Temperature: 70 °C
Yield: 51.4 %

Procedure:
A solution of TFA (387 μL, 5.02 mmol) in dichloroethane (18 mL) was added to 2-pyrrol-1-ylphenol (401 mg, 2.52 mmol) and (1R,5S)-8-(2,2,2-trifluoroacetyl)-8-azabicyclo[3.2.1]octan-3-one (620 mg, 2.80 mmol). The solution was heated at 70° C. overnight. The solvent was evaporated and the crude residue was purified by column chromatography (silica gel: 0-10% EtOAc in hexanes) to afford 2,2,2-trifluoro-1-(8′-azaspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,3′-bicyclo[3.2.1]octane]-8′-yl)ethanone as a clear oil (469 mg, 46%). 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J=7.5 Hz, 1H), 7.07-6.94 (m, 4H), 6.23 (t, J=3.2 Hz, 1H), 5.87 (d, J=3.4 Hz, 1H), 4.74 (d, J=7.4 Hz, 1H), 4.42 (s, 1H), 2.50-2.34 (m, 2H), 2.34-2.16 (m, 3H), 2.16-1.89 (m, 3H). ESI-MS m/z calc. 362.4, found 363.3 (M+1)+; Retention time: 2.07 minutes (3 min run).
Reaction SMILES: [CH3:1][C:2]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:22]=2[CH3:31])=[C:5]2[N:6]=[C:7]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:8]=[C:9]([C:10]([NH2:12])=O)[N:4]2[N:3]=1.S(Cl)(Cl)=O.O>CN(C)C=O>[CH3:1][C:2]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[C:22]=2[CH3:31])=[C:5]2[N:6]=[C:7]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:8]=[C:9]([C:10]#[N:12])[N:4]2[N:3]=1
Reactant: Cc1nn2c(C(N)=O)cc(N3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C
Solvent: CN(C)C=O
Solvent: O
Solvent: O=S(Cl)Cl
Product: Cc1nn2c(C#N)cc(N3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To the solution of 2-methyl-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-5-(4-morpholinyl)pyrazolo[1,5-a]pyrimidine-7-carboxamide (200 mg, 0.461 mmol) in N,N-Dimethylformamide (DMF) (6 mL) was added thionyl chloride (0.067 mL, 0.923 mmol). The reaction mixture was stirred at rt for 2 h. Water was added in. The solid precipitated. Filtration gave the crude product. The crude was purified on silica column (20˜50% EtOAc/Hexane) to give the titled product (0.14 g, 77%). MS (ES+) m/e 416.2 [M+H]+.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9]CN)[CH2:2][CH2:3][CH3:4].C(=O)([O-])O.[Na+].[CH2:31](I)[CH2:32][CH2:33][CH3:34].[CH3:36][N:37](C)P(=O)(N(C)C)N(C)C>O>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][N:37]([CH2:31][CH2:32][CH2:33][CH3:34])[CH3:36])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(CCN)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: CCCCI
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCCNc1cc(CN(C)CCCC)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred mixture of (3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)methylamine (3.6 g; prepared as described in Example 115), sodium hydrogen carbonate (0.9 g) and hexamethylphosphoric triamide (15 ml) a solution of n-butyl iodide (1.85 g) in hexamethylphosphoric triamide (5 ml) is dropwise added during about one hour. After additional stirring for 30 minutes, the mixture is diluted with water to precipitate crude (3-n-butylamino-4-phenoxy-5-sulfamylbenzyl)-n-butylmethylamine. After filtration and recrystallization twice from ethanol it is obtained with a melting point of 103°-104° C. The material (IR, analysis) is identical with the material prepared as in Example 128.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[SH:15].[C:16]1([N:22]=[C:23]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:24]=[CH:25]S(C2C=CC=CC=2)(=O)=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)(=O)C.O>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][CH:25]=[CH:24][C:23](=[N:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Sc1ccccc1Br
Reactant: O=S(=O)(C=CC(=Nc1ccccc1)Oc1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccccc1SC=CC(=Nc1ccccc1)Oc1ccccc1
Reaction time: 1 h
Yield: 87.5 %

Procedure:
Sodium hydride (60% in oil: 0.026 g) was suspended to DMF (2 ml), and 2-bromothiophenol (0.10 g) was added thereto under ice-cooling. Furthermore, phenyl N-phenyl-3-(phenylsulfonyl)acrylimidate (0.20 g) was added thereto, and stirred for one hour under ice-cooling. After the reaction, water and ethyl acetate were added to the reaction mixture, and extracted. The organic layer was washed with aqueous saturated sodium chloride solution, dried, and distilled off the solvent. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain phenyl 3-(2-bromophenylthio)-N-phenylacrylimidate (0.19 g).
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH3:5][Mg]Br.[C:8]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:21])[C:16](=[O:22])[N:15]([CH:23]1[CH2:28][CH2:27][N:26]([C:29]3[C:38]4[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=4)[N:32]=[CH:31][N:30]=3)[CH2:25][CH2:24]1)[C:14]2=[O:43])(=[O:10])[CH3:9].[Cl-].[NH4+]>C1COCC1>[CH3:40][O:39][C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][C:35]=1[O:41][CH3:42])[N:32]=[CH:31][N:30]=[C:29]2[N:26]1[CH2:27][CH2:28][CH:23]([N:15]2[C:14](=[O:43])[C:13]3[C:18](=[CH:19][CH:20]=[C:11]([C:8]([OH:10])([CH3:5])[CH3:9])[CH:12]=3)[N:17]([CH3:21])[C:16]2=[O:22])[CH2:24][CH2:25]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)c5cc(C(C)=O)ccc5n(C)c4=O)CC3)c2cc1OC
Reactant: C[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc(C(C)(C)O)ccc5n(C)c4=O)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
In 3 ml of THF was suspended 246.5 mg (1.0 mmol) of thoroughly dried cerium chloride, and 1 ml of a 1M solution of methylmagnesium bromide in THF was added thereto under an argon gas atmosphere, followed by stirring at room temperature for 1 hour. To the reaction mixture was dropwise added a solution of 245.0 mg (0.50 mmol) of Compound 63 obtained in Example 50 in 5 ml of THF, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of ammonium chloride was added thereto in excess to stop the reaction, followed by extraction with chloroform. The organic layer was washed and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=100/1) and recrystallized from ether to give 78.8 mg (yield: 31%) of Compound 61 as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]([CH3:22])[C:20](=[O:23])[N:19]([CH3:24])[C:18](=[O:25])[CH:17]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1>O1CCCC1.ClCCl.CN=C=O>[CH3:22][N:21]1[C:16]([N:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH2:7][O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][C:18]([NH:19][CH3:20])=[O:25])=[CH:3][CH:4]=3)[CH2:15][CH2:14]2)=[CH:17][C:18](=[O:25])[N:19]([CH3:24])[C:20]1=[O:23]
Reactant: Cn1c(N2CCN(CCCOc3ccc(N)cc3)CC2)cc(=O)n(C)c1=O
Agent: CN=C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(OCCCN2CCN(c3cc(=O)n(C)c(=O)n3C)CC2)cc1
Reaction time: 20 h
Yield: 179.3 %

Procedure:
1.5 g of 6-[4-(3-[4-aminophenoxy]propyl)piperazin-1-yl]-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione obtained in Example 6 was dissolved in a mixed solvent of tetrahydorfuran/dichloromethane (15 ml/10 ml), and 0.26 ml of methyl isocyanate was added to the solution at room temperature, followed by stirring for 20 hours. The precipitated crystals were collected by filtration, and then washed with a small amount of cooled dichloromethane, thereby obtaining 1.55 g (yield: 90%) of 1,3-dimethyl-6-[4-(3-[4-(N'-methylureido)phenoxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[C:23](=[O:25])=[O:24]>O1CCCC1>[CH:9]1([O:8][C:5]2[CH:6]=[CH:7][C:2]([C:23]([OH:25])=[O:24])=[CH:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: Brc1ccc(OC2CC2)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OC2CC2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 46.7 %

Procedure:
To a −78° C. solution of 1-bromo-4-(cyclopropoxy)benzene (33 g, 154.9 mmol) in tetrahydrofuran (500 mL) add 1.6 M butyl lithium in hexane (96.8 mL, 154.9 mmol) while maintaining a temperature below −70° C. Stir the mixture at −78° C. for 20 minutes after the addition. Add dry ice (464.6 mmol) in 3 portions 5 minutes apart. Stir the mixture at −78° C. for 30 minutes. Remove the cooling bath and quench the mixture with 10% sodium hydrogen sulfate (NaHSO4) (200 mL). Warm the mixture to ambient temperature and extract 3× with EtOAc (300 mL). Combine the organics and wash once with brine, dry over sodium sulfate, filter, and concentrate under reduced pressure. Suspend the residue in diethyl ether and filter. Dry the solid in a vacuum oven to give the title compound (12.9 g, 47%): MS (m/z): 179 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]4)[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.ClC1C=C2C(C3N=C(N[C@H]4CCCNC4)C(F)=CN=3)=CNC2=NC=1.[CH2:49]([N:52]=[C:53]=[O:54])[CH2:50][CH3:51]>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][N:20]([C:53]([NH:52][CH2:49][CH2:50][CH3:51])=[O:54])[CH2:19]4)[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCCN=C=O
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1NC1CCCNC1
Agent: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1N[C@H]1CCCNC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCNC(=O)N1CCCC(Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-amine, 5b, (0.020 g, 0.058 mmol) in 1:1 mixture of CH2Cl2/pyridine (2 mL) was added propylisocyanate (0.005 mL, 0.058 mmol). The reaction mixture was stirred at room temperature for 12 hours. The resulting residue was purified by preparatory HPLC (0.1% TFA-H2O/acetonitrile) to afford the desired product, 196.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[C:12]([O-:15])(=[O:14])[CH3:13].[Na+]>CN(C)C=O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][O:15][C:12](=[O:14])[CH3:13])=[CH:6][CH:7]=1
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 10 h
Yield: 78.4 %

Procedure:
To a 3 liter flask were added 400 grams (2.32 mol) 2-chloro-1-(4-fluorophenyl)ethanone, 1 liter of N,N-dimethylformamide and 265 grams (3.23 mol) anhydrous sodium acetate. The mixture was stirred and heated to 90° C., and the reaction lasted 10 hours. After the reaction was completed, the heating was stopped. The reaction solution was cooled down to room temperature, and extracted with ethyl acetate (600 ml×6). The organic phases were combined, washed three times with brine, dried over anhydrous sodium sulfate and concentrated until dry. The residue was crystallized from the mixed toluene/petroleum ether solution and dried to obtain 357 grams (1.82 mol) compound A-1 with yield of 78.5%. 1H NMR (400 MHz, CDCl3): δ 2.23 (s, 3H, CH3), 5.30 (s, 2H, —CH2—), 7.14-7.19 (m, 2H, Cpr-H), 7.93-7.97 (m, 2H, Cpr-H); MS (m/z): 197 [M+H].
Reaction SMILES: B(O)(O)O.O.[B:6]([O:9][B:10]([OH:12])[OH:11])([OH:8])[O-:7].[NH4+:13].Br([O-])(=O)=O.Br([O-])(=O)=O.[NH4+].[NH4+]>>[B:6]([O:9][B:10]([OH:12])[OH:11])([O-:8])[O-:7].[NH4+:13].[NH4+:13]
Reactant: [O-]B(O)OB(O)O
Agent: OB(O)O
Agent: [NH4+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: O
Product: [O-]B([O-])OB(O)O

Procedure:
100 gms of boric acid are heated to 160° C. to 200° C. until three mols of water is removed per molecule thereby producing boron oxide (B2O3). The powdered boric oxide is slowly added to 100 gms of aqueous ammonia containing 25% ammonia while agitating and keeping the temperature below the temperature wherein the ammonia evaporates from the water. Increase pressure may also be used to prevent the loss of ammonia from the water and the ammonia may be added to the water in a gaseous form, The mixture is allowed to react for 1-4 hours thereby producing a mixture of monoammonium diborate, diammonium dibromate, polyammonium dibromate and ammonium salt of boric acid. The mixture is dried and the ammonium salt of boric acid condensates to form diammonium diborate. The mixture is pulverized into a fine powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].CN.ClC1C=[C:20]([NH:22]C)C([N+]([O-])=O)=C(NC)C=1>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH:22][CH3:20])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: CNc1cc(Cl)cc(NC)c1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Agent: CN
Solvent: CCO
Product: CNc1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 23 h

Procedure:
0.150 mole (34 g) of 2,4,6-trichloronitrobenzene is added portionwise, at ambient temperature, to 300 ml of a 30% strength solution of methylamine in absolute ethanol. After stirring for 23 hours at ambient temperature, a precipitate, consisting essentially of 4-chloro-2-methylamino-6-methylaminonitrobenzene, is removed by filtration. The filtrate is evaported to dryness under reduced pressure. 800 ml of concentrated hydrochloric acid are added to the dry extract obtained in this manner. The insoluble fraction is removed by filtration. After dilution of the filtrate with 650 ml of water, the expected product precipitates. It is washed with water and is then dried under vacuum in the presence of phosphorus pentoxide. After recrystallization from isopropanol and then from absolute ethanol, it melts at 120° C.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][CH2:5][NH:6][CH:7]=[O:8].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][Cl:17])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21]>C(O)(C)C>[Cl-:17].[CH3:1][N+:2]([CH3:9])([CH2:16][C:15]1[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[C:13]([N+:20]([O-:22])=[O:21])[CH:14]=1)[CH2:3][CH2:4][CH2:5][NH:6][CH:7]=[O:8]
Reactant: COc1ccc(CCl)cc1[N+](=O)[O-]
Reactant: CN(C)CCCNC=O
Solvent: CC(C)O
Product: COc1ccc(C[N+](C)(C)CCCNC=O)cc1[N+](=O)[O-]
Product: [Cl-]
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a refluxing solution of 35.4 parts of N-(3-dimethylaminopropyl)formamide in 40 parts of isopropyl alcohol there was added over a two hour period 50.4 parts of 4-methoxy-3-nitrobenzyl chloride. Refluxing was continued for four hours after which the reaction mixture was diluted with 100 parts of isopropyl alcohol and cooled to 20° C. The solid that separated was collected and washed with a small amount of fresh isopropyl alcohol and then dried in a vacuum oven to yield 71.1 parts of N,N-dimethyl-N-(3-nitro-4-methoxybenzyl)-N-3-formamidopropyl-ammonium chloride, as a cream colored solid which melted at 180°-183° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1.[NH2:21][CH2:22][CH2:23][OH:24]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14](/[CH:13]=[CH:12]/[C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[C:7]([NH:21][CH2:22][CH2:23][OH:24])=[O:9])=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(Br)cc1
Reactant: NCCO
Product: COc1ccc(C(=O)NCCO)cc1/C=C/c1ccc(Br)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-bromophenyl)vinyl]benzoic acid obtained in step B of Example 2-2-43 and 2-aminoethanol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:16][O:17][C:18]([C:20]1[C:21]([C:27]([F:30])([F:29])[F:28])=[N:22][C:23](Cl)=[N:24][CH:25]=1)=[O:19].C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:16][O:17][C:18]([C:20]1[C:21]([C:27]([F:30])([F:28])[F:29])=[N:22][C:23]([N:13]2[CH2:14][CH2:15][N:10]([C:5]3[N:4]=[N:3][C:2]([Cl:1])=[C:7]([CH3:8])[C:6]=3[CH3:9])[CH2:11][CH2:12]2)=[N:24][CH:25]=1)=[O:19]
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: Cc1c(Cl)nnc(N2CCNCC2)c1C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cl)c(C)c3C)CC2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.1 %

Procedure:
To a roundbottom flask is added 3-chloro-4,5-dimethyl-6-piperazin-1-yl-pyridazine (1 g, 4.41 mmol), 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid methyl ester (2.12 g, 8.82 mmol) and diisopropylethylamine (2.3 mL, 13.23 mmol) in a dioxane (9 mL) solution and stirred for 18 h at room temperature. Filter the reaction mixture and rinse with water and ethylacetate to give 1.35 g of 2-[4-(6-chloro-4,5-dimethyl-pyridazin-3-yl)-piperazin-1-yl]-4-trifluoromethyl-pyrimidine-5-carboxylic acid methyl ester (71%).
Reaction SMILES: [CH2:1]=O.[CH2:3]([CH:5]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:6][NH:7][CH2:8][CH:9]([CH2:14][CH3:15])[CH2:10][CH2:11][CH2:12][CH3:13])[CH3:4].[PH:20](=[O:39])([O:30][CH2:31][CH:32]([CH2:37][CH3:38])[CH2:33][CH2:34][CH2:35][CH3:36])[O:21][CH2:22][CH:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:28]([CH:23]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:22][O:21][P:20]([CH2:1][N:7]([CH2:6][CH:5]([CH2:3][CH3:4])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:8][CH:9]([CH2:14][CH3:15])[CH2:10][CH2:11][CH2:12][CH3:13])(=[O:39])[O:30][CH2:31][CH:32]([CH2:37][CH3:38])[CH2:33][CH2:34][CH2:35][CH3:36])[CH3:29]
Reactant: C=O
Reactant: CCCCC(CC)CO[PH](=O)OCC(CC)CCCC
Reactant: CCCCC(CC)CNCC(CC)CCCC
Product: CCCCC(CC)COP(=O)(CN(CC(CC)CCCC)CC(CC)CCCC)OCC(CC)CCCC
Temperature: -15 °C

Procedure:
Into a reaction vessel, which was heated to 100° C., with a reflux condenser (-15° C.), were simultaneously added aqueous formaldehyde (12.17 g of 37% solution) and a mixture of di(2-ethylhexyl)amine (36.22 g) and di(2-ethylhexyl) phosphonate (45.96 g). The mixture was heated for 1 hour with stirring and then cooled to 20° C. The water was removed by distillation under reduced pressure to give di(2-ethylhexyl){[di(2-ethylhexyl)amino]methyl}phosphonate, as a colourless liquid (nD20 =1.4563).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:32]=[CH:31][C:18]3/[C:19](=[CH:28]/[C:29]#[N:30])/[C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[CH2:22][CH2:23][C:17]=3[CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].N[OH:34].C1N=C[N:37]([C:40](N2C=NC=C2)=[S:41])C=1.C1CCN2C(=NCCC2)CC1>C(O)C.C(OCC)(=O)C>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:32]=[CH:31][C:18]3/[C:19](=[CH:28]/[C:29]4[NH:37][C:40](=[S:41])[O:34][N:30]=4)/[C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[CH2:22][CH2:23][C:17]=3[CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Reactant: NO
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\c1noc(=S)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.6 %

Procedure:
(E)-[2-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (JP-B-2526005; 220 mg, 0.53 mmol) was dissolved in ethanol (5 mL), hydroxylamine (50% aqueous solution, 0.48 mL, 7.63 mmol) was added, and the mixture was heated under reflux for 16 hr, and concentrated under reduced pressure. The obtained residue was dissolved in acetonitrile (5 mL), N,N′-thiocarbonyldiimidazole (141 mg, 0.79 mmol) and DBU (315 μL, 2.11 mmol) were added, and the mixture was stirred at room temperature for 2 hr. Ethyl acetate was added to the mixture, and the organic layer was washed with 5% aqueous citric acid solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=95/5) to give the title compound (compound 8) (67 mg, 26%).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[C:11]([F:25])[CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH2:39][CH2:38][CH2:37][C:36](=[O:40])[CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.O.CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[C:2]([C:34]3[CH2:39][CH2:38][CH2:37][C:36](=[O:40])[CH:35]=3)=[N:7][CH:6]=[CH:5][N:4]=2)=[CH:10][C:11]=1[F:25]
Reactant: Fc1cc(Oc2nccnc2Cl)ccc1Nc1nc2ccccc2s1
Reactant: CC1(C)OB(C2=CC(=O)CCC2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: O=C1C=C(c2nccnc2Oc2ccc(Nc3nc4ccccc4s3)c(F)c2)CCC1
Temperature: 140 °C

Procedure:
A mixture of N-(4-(3-chloropyrazin-2-yloxy)-2-fluorophenyl)benzo[d]thiazol-2-amine (2098 mg, 5.63 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-enone (1000 mg, 4.50 mmol), dichlorobis(triphenylphosphine)palladium(ii) (316 mg, 0.450 mmol), and sodium carbonate (1432 mg, 13.51 mmol) in DME/H2O/EtOH (7:3:2, 36 ml) was heated to 140° C. for 3 h. Water (100 ml) was added and the reaction mixture was extracted with EtAOc (3×100 ml). The combined organic layers were washed with brine and dried over sodium sulfate. Filtration and concentration under reduced pressure afforded 3-(3-(4-(benzo[d]thiazol-2-ylamino)-3-fluorophenoxy)pyrazin-2-yl)cyclohex-2-enone. MS (ESI, pos. ion) m/z: 433.0 (M+1). IC50 (uM) +++++.