Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:30][CH2:31][O:32][CH2:33][CH3:34])[CH2:28][CH3:29])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:33]([O:32][CH2:31][CH2:30][N:27]([C:24]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:26][CH:25]=1)[CH2:28][CH3:29])[CH3:34]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C=O)CC1
Reactant: CCOCCN(CC)c1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOCCN(CC)c1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
A mixture of methyl 7-bromo-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2 g), 4-[N-(2-ethoxyethyl)-N-ethylamino]phenyl borate (0.46 g), 1M potassium carbonate solution (3.2 ml), ethanol (3.2 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.03 g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-[N-(2-ethoxyethyl)-N-ethylamino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.23 g) as green amorphous.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH2:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23]>>[C:22]([C:21]1[CH:20]=[C:19]([CH2:18][N:3]2[C:4]3[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[CH:26]=[CH:25][CH:24]=1)#[N:23]
Reactant: N#Cc1cccc(CBr)c1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cccc(C#N)c1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(bromomethyl)benzonitrile: 1H NMR (400 MHz, CDCl3) δ 7.56 (m, 1H), 7.45 (m, 2H), 7.33 (d, J=8.5 Hz, 1H), 7.21 (s, 1H), 7.12 (d, J=8.1 Hz, 1H), 6.69 (s, 1H), 5.40 (s, 2H), 2.43 (s, 3H); MS (ES) m/z 340 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1
Reactant: COc1ccccc1B(O)O
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: COc1ccccc1-c1cncc(N2CC3CC4CC2CN(C4)C3)c1

Procedure:
The title compound was prepared from the product of Example 65A and 2-methoxyphenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 336.0 (M+H)+, retention time 1.30 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]([CH3:11])=[CH:8][C:7](=[O:12])[NH:6][C:5]=2[N:4]([CH3:13])[N:3]=1.CCN(C(C)C)C(C)C.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[Cl:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:12][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:8][C:9]=2[CH3:11])[N:4]([CH3:13])[N:3]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(=O)[nH]c2c1c(Cl)nn2C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C)c2c(Cl)nn(C)c2n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
3-chloro-1,4-dimethyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (720 mg, 3.64 mmol) was dissolved in DMF (5 ml) at rt. Then, DIPEA (1.04 g, 8.0 mmol) and ethyl 2-bromoacetate (0.60 ml, 5.5 mmol) were added and the mixture heated at 90° C. After 1 h, the mixture was cooled to rt, the solvent removed under reduced pressure and the residue purified by column chromatography (eluent 70% hexane in EtOAc) to yield 664 mg (64%) of the title compound. [1H-NMR (DMSO-d6, 400 MHz) δ 6.67 (s, 1H), 4.98 (s, 2H) 4.17 (q, 2H), 3.84 (s, 3H), 2.62 (s, 3H), 1.19 (t, 3H); HPLC-MS RtJ=1.13 min; [M+H]+=284.0, 286.0
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3](=O)[CH:4]=[CH:5]OC.Cl.O.[NH2:13][NH2:14].[OH-].[Na+]>O.C(O)C>[F:1][C:2]([F:10])([F:9])[C:3]1[CH:4]=[CH:5][NH:14][N:13]=1
Reactant: NN
Reactant: COC=CC(=O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1cc[nH]n1
Yield: 92 %

Procedure:
2.71 kg of 1,1,1-trifluoro-4-methoxy-but-3-en-2-on, 2.44 kg of ethanol and 3.10 kg of water were charged into a reaction vessel. 20 ml of concentrated hydrochloric acid and 0.80 kg of hydrazine hydrate were successively added and the mixture was heated to reflux for 4 h. The mixtures was allowed to cool and neutralized by addition of 10% aqueous NaOH to about pH 4-5. Then the mixture was evaporated. Toluene was added and the mixture was again evaporated to yield 2 kg of raw 3-trifluoromethylpyrazole with a purity of >85%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[C:11](=[O:25])[N:10]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([O:35][CH3:36])=[O:34])[CH:28]=3)[CH2:9]2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[C:11](=[O:25])[N:10]([CH2:26][C:27]3[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=3)[C:33]([O:35][CH3:36])=[O:34])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCNCC3)C2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 1-(4-fluorophenyl)-3-(3-(methoxycarbonyl)benzyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.42 g, 0.84 mmol) was added 4M solution of HCl in dioxane (5 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated in vacuo to obtain methyl 3-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as a hydrochloride salt.
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16]([NH2:19])[C:17]#[CH:18].[F-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH2:16]([NH:19][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[O:7])=[CH:4][CH:3]=1)[C:17]#[CH:18]
Reactant: O=C(Nc1nnn[nH]1)c1ccc(F)cc1
Reactant: C#CCN
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C#CCNc1ccc(C(=O)Nc2nnn[nH]2)cc1

Procedure:
A mixture of 20 g (0.097 mol) of 4-fluoro-N-1H-tetrazol-5-ylbenzamide, 12.8 ml (0.193 mol) of propargylamine, 5.6 g of anhydrous potassium fluoride, and 13 g of potassium carbonate, in 320 ml of dimethylsulfoxide is heated at 50°-70° C. for six to twenty hours. The reaction is poured into water and the precipitate is collected, washed with water, and dried in vacuo to give the title compound.
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:10][CH2:9][CH2:8][CH2:7][S:6]1)([O-:3])=[O:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>C(Cl)(Cl)Cl>[S:6]1[CH2:7][CH2:8][CH2:9][N:10]=[C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:13][N:14]([CH3:16])[CH3:15]
Reactant: COC(OC)N(C)C
Reactant: O=[N+]([O-])C=C1NCCCS1
Solvent: ClC(Cl)Cl
Product: CN(C)C=C(C1=NCCCS1)[N+](=O)[O-]

Procedure:
8.0 G OF TETRAHYDRO-2-(NITROMETHYLENE)-2H-1,3-thiazine, prepared as described in Example 2 of Ser. No. 554,361, 5.95 g of N,N-dimethylformamide dimethyl acetal and 25 ml of chloroform were mixed and the mixture was refluxed for about 16 hours. The solvent then was evaporated under reduced pressure to leave a dark orange solid. Recrystallization from ethyl acetate and methanol gave (1), as a light orange solid, m.p.: 168.5°-170°.
Reaction SMILES: C([O:5][C:6](=[O:36])[C@@H:7]([NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19]([NH:21][C:22]([NH2:24])=[NH:23])=[O:20])=[CH:15][CH:16]=1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:29]([O:28][C:26]([NH:25][C@@H:7]([CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19]([NH:21][C:22]([NH2:24])=[NH:23])=[O:20])=[CH:15][CH:16]=1)=[O:11])[C:6]([OH:36])=[O:5])=[O:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC(=N)N)s1)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)NC(=O)CCc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)O)s1
Temperature: 25 °C
Yield: 23.6 %

Procedure:
30 mg of the product obtained in step d) were dissolved in 3 ml of dichloromethane. 0.3 ml of trifluoroacetic acid were added, and the mixture was stirred at room temperature. After 3.5 hours the solution was evaporated, the residue was dissolved in 2 ml of glacial acetic acid and again evaporated in vacuo. This procedure was repeated twice. Then the residue was triturated with diethyl ether to give a suspension which, after filtration, gave 6.3 mg of the title compound as a colourless amorphous solid.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.[NH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH2:14][CH2:13]1.C(Cl)Cl>CCOCC>[NH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][N:12]([NH:11][C:8]([NH:7][C:4]3[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=3)=[O:9])[CH2:13][CH2:14]2)=[CH:21]1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: NN1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)NN2CCN(CCc3c[nH]c4ccccc34)CC2)cc1
Reaction time: 3 h

Procedure:
4.0 g of p-tolylisocyanate are added dropwise to a stirred solution of 6.13 g of 3-[2-(4-aminopiperazin-1-yl)-ethyl]indole in 100 ml. of dry methylene chloride while maintaining the reaction temperature below 35° C. After three hours at ambient temperature, ether is added to promote precipitation. The precipitate is filtered, washed with ether, and dried. The resulting solid is recrystallized twice from a methanol and water mixture to give 1-[1-(indol-3-ylethyl)piperazin-4-yl]-3-p-tolylurea, m.p. 201°-203° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12](=[O:17])[N:11]([CH2:18][C:19]([O:21]C(C)C)=[O:20])[C:10]1=[O:25].[N+:26]([O-])([OH:28])=[O:27]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:26]([O-:28])=[O:27])=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12](=[O:17])[N:11]([CH2:18][C:19]([OH:21])=[O:20])[C:10]1=[O:25]
Reactant: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2ccc(F)cc2Cl)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1c(=O)n(CC(=O)O)c(=O)n(-c2cc([N+](=O)[O-])c(F)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of isopropyl 3-(2-chloro-4-fluorophenyl)-tetrahydro-5-methyl-2,4,6-trioxo-s-triazine-1(2H)-acetate (48.7 g, 0.0508 mol) in concentrated sulfuric acid is cooled to 0° C., treated with 90% nitric acid (2.6 mL), stirred at room temperature overnight, treated with 90% nitric acid (1.0 mL), stirred for 4 hours, treated with 90% nitric acid (2.0 mL), stirred at room temperature overnight, treated with 90% nitric acid (1.0 mL), stirred for 1 hour and poured onto ice. The resultant aqueous solution is filtered to obtain a solid. A solution of the solid in ether is dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as a yellow foam which is identified by NMR spectral analyses.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[C:18]([CH3:20])[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([OH:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl.Cl[CH2:26][C:27]1[CH:28]=[C:29]([CH:42]=[CH:43][CH:44]=1)[O:30][CH2:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:21][CH2:26][C:27]2[CH:44]=[CH:43][CH:42]=[C:29]([O:30][CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]=3)[CH:28]=2)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:18]([CH3:20])[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: CCOC(=O)c1c(C)cc(OCc2ccccc2)cc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)cc(OCc2ccccc2)cc1OCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 4-benzyloxy-2-hydroxy-6-methyl-benzoate (5.1 g, 16 mmol, example 63) in DMF (100 mL), with 25° C. water bath cooling, is added 60% sodium hydride emulsion (1.3 g, 32 mmol) over 2 minutes. This mixture is stirred 30 minutes with the cooling bath removed. A solution of 3-(quinolin-2-ylmethoxy)-benzyl chloride hydrochloride (5.1 g, 16 mmol, example 49), in DMF (55 mL) is added and the reaction heated at 60° C. for 6 hours. The solvent is removed in vacuo and the residue purified by flash chromatography (silica, 0.5 to 2% methanol in dichloromethane) to give the title compound. MS (ESI) 534 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[Br:12][CH2:13]Br.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Br:12][CH2:13][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: BrCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC(C#N)(CBr)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.5 %

Procedure:
3.2 g of 2-(3,3,3-trifluoropropyl)malononitrile, 7.0 g of dibromomethane and 5.5 g of potassium carbonate were added to 40 ml of dimethyl sulfoxide, and the mixture was stirred at room temperature for 18 hours. Thereafter, the reaction mixture was poured to water and then extracted with diethyl ether. The organic layer was washed successively with water and aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.4 g of 2-bromomethyl-2-(3,3,3-trifluoropropyl)malononitrile (hereinafter, referred to as the present compound (52)).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[CH2:6]([O:9][C:10]([N:12]1[C@H:16]([CH:17]=[CH:18][C:19]2[S:23][C:22]3=[CH:24][N:25]=[CH:26][N:21]3[CH:20]=2)[CH2:15][C@@H:14](OS(C)(=O)=O)[CH2:13]1)=[O:11])[CH:7]=[CH2:8].C(OCC)(=O)C>CN(C=O)C>[C:1]([S:3][C@H:14]1[CH2:15][C@@H:16]([CH:17]=[CH:18][C:19]2[S:23][C:22]3=[CH:24][N:25]=[CH:26][N:21]3[CH:20]=2)[N:12]([C:10]([O:9][CH2:6][CH:7]=[CH2:8])=[O:11])[CH2:13]1)(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C=Cc1cn2cncc2s1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C=Cc1cn2cncc2s1
Temperature: 70 °C
Reaction time: 4 h
Yield: 57.8 %

Procedure:
Potassium thioacetate (0.22 g) is added to a solution of 1.07 g of (3R,5S)-1-allyloxycarbonyl-3-methane sulfonyloxy-5-[2-(imidazo[5,1-b]thiazol-2-yl)vinyl]pyrrolidine (a mixture of geometrical isomers) in 5 ml of DMF, and the mixture is stirred at 70° C. for 4 hr. Ethyl acetate is added to the reaction mixture, and the mixture is successively washed with water and a saturated aqueous sodium hydrogencarbonate solution, and saturated saline and dried over magnesium sulfate. The solvent is removed by evaporation. The residue is purified by column chromatography on silica gel to give 0.42 g of the title compound.
Reaction SMILES: [C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1>>[C:1]1([C:7](=[N:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]2)[C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)c1cc2ccncc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCC(ON)C1
Product: CC(C)(C)OC(=O)N1CCCC(ON=C(c2ccccc2)c2cc3ccncc3[nH]2)C1

Procedure:
tert-Butyl 3-[[[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]piperidine-1-carboxylate was prepared from phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 35) and tert-butyl 3-(aminooxy)piperidine-1-carboxylate (Reference Example 11) following the procedure described for Example 104 (geometry of the oxime double bond undefined).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:33]=[C:32]([NH:34][CH2:35][CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[C:31]3[C:26](=[CH:27][C:28]([Cl:43])=[CH:29][CH:30]=3)[N:25]=2)=[CH:20][CH:19]=1>CN(C=O)C.[Pd]>[Cl:43][C:28]1[CH:27]=[C:26]2[C:31]([C:32]([NH:34][CH2:35][CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])=[N:33][C:24]([C:21]3[CH:22]=[CH:23][C:18]([C:11]4[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=4)=[CH:19][CH:20]=3)=[N:25]2)=[CH:30][CH:29]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCN(CC)CCCNc1nc(-c2ccc(Br)cc2)nc2cc(Cl)ccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2ccc(-c3ccc(Cl)cc3)cc2)nc2cc(Cl)ccc12

Procedure:
1,2 Equivalents of K2CO3, 1,2 equivalents of 4-chlorophenylboronic acid and 10 mol % of Pd((PPh3)4 are added to a solution of N′-[2-(4-bromo-phenyl)-7-chloro-quinazolin4-yl]-N,N-diethyl-propane-1,3-diamine (16,5 mmol) in 80 ml of DMF and it is heated at 80° until conversion is complete. After filtering off the catalyst and customary working up for solution reactions, N′-[7-chloro-2-(4′-chloro-biphenyl-4-yl)-quinazolin-4-yl]-N,N-diethyl-propane-1,3-diamine is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.[H][H]>C(O)(=O)C.[Pt].[C]>[Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH3:13])[NH:7]2
Reactant: [H][H]
Reactant: Cc1ccc2c(Cl)c(Cl)ccc2n1
Agent: [Pt]
Solvent: CC(=O)O
Product: CC1CCc2c(ccc(Cl)c2Cl)N1
Yield: 78.5 %

Procedure:
5,6-Dichloroquinaldine (5.5 g) was dissolved in 50 ml of acetic acid and 0.1 g of 5% platinum-carbon was added to the solution, which was then subjected to Parr's hydrogenation method to reduce the compound catalytically at a hydrogen gas pressure of 4 kg/cm2. After theoretical amount of hydrogen was absorbed the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. After rendering it alkaline with 50 ml of water and 20% sodium hydroxide, the residue was extracted with 100 ml of chloroform. The extract was dried by the addition of anhydrous potassium carbonate and concentrated to give 4.4 g of 5,6-dichloro-1,2,3,4-tetrahydroquinaldine as oily product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:14]4[O:15][CH2:16][CH2:17][O:18][C:13]=4[CH:12]=3)[O:10][C:3]=12.[CH3:21][C:22]1[C:30]([NH2:31])=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>>[O:15]1[C:14]2[CH:19]=[CH:20][C:11]([C:9]3[O:10][C:3]4[C:4](=[N:5][CH:6]=[CH:7][C:2]=4[NH:31][C:30]4[C:22]([CH3:21])=[C:23]5[C:27](=[CH:28][CH:29]=4)[NH:26][CH:25]=[CH:24]5)[CH:8]=3)=[CH:12][C:13]=2[O:18][CH2:17][CH2:16]1
Reactant: Cc1c(N)ccc2[nH]ccc12
Reactant: Clc1ccnc2cc(-c3ccc4c(c3)OCCO4)oc12
Product: Cc1c(Nc2ccnc3cc(-c4ccc5c(c4)OCCO5)oc23)ccc2[nH]ccc12

Procedure:
The title compound was prepared by procedure E using 7-chloro-2-(2,3-dihydro-1,4-benzodioxin-6-yl)furo[3,2-b]pyridine (28.50 mg; 0.10 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (15.21 mg; 0.10 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one, and was obtained as a beige solid (22 mg, 55%). (HPLC (method F): 96%, RT: 3.96 min); 1H NMR (500 MHz, DMSO-d6) δ [ppm] 11.15 (s, 1H), 8.52 (s, 1H), 7.92 (d, J=5.5, 1H), 7.54 (d, J=1.8, 1H), 7.46 (d, J=8.5, 1H), 7.41-7.34 (m, 1H), 7.34-7.26 (m, 2H), 6.98 (dd, J=14.6, 8.5, 2H), 6.51 (s, 1H), 6.05 (d, J=5.4, 1H), 4.31 (s, 4H), 2.36 (s, 3H); MS (m/z) 398 [M+H]+, RT: 3.9 min.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10](Cl)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.Cl>O>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CNCCN1
Agent: Cl
Solvent: O
Product: O=C(O)c1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Yield: 99.5 %

Procedure:
To the suspension of 50 g 2-nitro-5-chlorobenzoic acid in 750 ml water, 86 g of piperazine is added and the reaction mixture is heated at reflux temperature for 20 hours. The mixture is then neutralized with conc. hydrochloric acid and the precipitated crystalline material is filtered off and dried to obtain 62 g title compound (MH+: 252)
Reaction SMILES: CC([O:4][CH2:5][C@H:6]1[O:11][C@@H:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:9]([O:19]C(C)=O)[C@@H:8]([O:23]C(C)=O)[C@@H:7]1[O:27]C(C)=O)=O.CO.C[O-].[Na+]>C(O)(=O)C>[CH:16]1[CH:15]=[CH:14][C:13]([O:12][C@@H:10]2[O:11][C@H:6]([CH2:5][OH:4])[C@@H:7]([OH:27])[C@H:8]([OH:23])[C@H:9]2[OH:19])=[CH:18][CH:17]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: OC[C@H]1O[C@@H](Oc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 5 h
Yield: 78.1 %

Procedure:
To phenyl-2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (21.2 g) were added methanol (120 ml) and 28% sodium methylate (0.28 ml) and the mixture was refluxed with stirring for 5 hours. After the reaction solution was cooled, acetic acid (0.1 ml) was added and the mixture was stirred for 30 minutes. Concentration of the reaction solution and crystallization with ethanol (180 ml) gave 10.0 g (yield 78%) of phenyl-β-D-glucopyranoside. Melting point: 177.0° C.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH:15]=[O:16]>O1CCCC1>[F:11][C:12]1[CH:13]=[C:14]([CH:15]([OH:16])[CH2:4][N+:1]([O-:3])=[O:2])[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])CC(O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add nitromethane (200 mL) to a suspension of potassium carbonate (30 g) and 3,5-difluorobenzaldehyde (200 g) in tetrahydrofuran (600 mL) at room temperature. Stir at room temperature overnight, filter, wash with ethyl acetate and concentrate to give the desired compound as a crude oil (330 g) which is used in the next step without further purification.