Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].Cl[C:23]1[CH:24]=[C:25]2[N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[C:8]([C:7]1[CH:10]=[C:3]([CH:4]=[CH:5][C:6]=1[O:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:17]=1)[CH2:2][O:1][C:23]1[CH:24]=[C:25]2[N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1cncc(C(F)(F)F)c1
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3cncc(C(F)(F)F)c3)c(C#N)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 5-(hydroxymethyl)-2-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15].C(N(CC)CC)C>ClCCl>[CH3:18][C:13]([CH3:19])([CH:12]=[O:11])[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)C(C)(C)CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)C(C)(C)C=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
DMSO (22.0 mL, 303 mmol, 4.00 equiv) was added to a pre-cooled solution of oxalyl chloride (13.7 mL, 151 mmol, 2.00 equiv) in dichloromethane (40 mL) at −78° C., and the resulting mixture was stirred for 15 minutes before a solution of methyl 3-hydroxy-2,2-dimethylpropanoate (10.0 g, 75.7 mmol, 1 equiv) in dichloromethane (100 mL) was added. The reaction mixture was stirred for 1 hour, then triethylamine (52.7 mL, 378 mmol, 5.00 equiv) was added. The mixture was warmed to 0° C. and held for 30 minutes, then concentrated to a volume of ca 50 mL. The residue was partitioned between aqueous saturated sodium bicarbonate solution (200 mL) and ethyl acetate (200 mL). The organic layer was dried over sodium sulfate and concentrated on a rotorary evaporator without using heat (product is volatile) to provide methyl 2,2-dimethyl-3-oxopropanoate (29-1) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 9.66 (s, 1H), 3.76 (s, 3M), 1.36 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([C:52]#[N:53])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[C:52]([C:49]1[CH:50]=[CH:51][C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:19][CH:18]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:47][CH:48]=1)#[N:53]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: N#Cc1ccc(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
Solvent: O
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(C#N)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (400 mg) was added toluene/ethanol/water (20/5/2, 21.6 ml) and then were added 4-cyanophenyl borate (147 mg) and potassium carbonate (147 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (46 mg), and the mixture was refluxed for 6 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-(4-cyanophenyl)-N-(4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 92) (90 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:29]#[N:30])[CH:23]=2)=[O:21])=[CH:5][CH:4]=1.[Cl:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C([O-])([O-])=O.[Cs+].[Cs+]>>[ClH:31].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[C:24]([C:29]#[N:30])[CH:23]=2)=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)c(C#N)c2)cc1
Reactant: ClCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)c(C#N)c2)cc1
Product: Cl
Yield: 81.4 %

Procedure:
1.6 g of the title compound was prepared from 1.45 g (3.49 mmol) of [2-(4-methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][3-cyano-4-hydroxyphenyl]methanone, 1.3 g(7 mmol) of 1-(2-chloroethyl)piperidine, and 4.9 g (15 mmol) of Cs2CO3 in a manner similar to that in Preparation 2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.N1CCC[CH2:13]1>CN(C=O)C.C(OCC)C.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:8]=[CH:13][NH:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: C1CCNC1
Agent: [Zn]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Brc1ccc2cc[nH]c2c1
Temperature: 110 °C

Procedure:
To a solution of 4-bromo-2-nitrotoluene (4.3 g., 20 mmol.) in DMF (40 mL.) was added DMF dimethylacetal (7.15 g., 60 mmol.) and pyrrolidine (1.4 g., 20 mmol.). The solution was heated to 110° C. for 4 hr. then cooled to rt. and diluted with ethyl ether. The mixture was washed 3×with water, dried with Na2SO4, filtered and the solvent evaporated. The residue was dissolved in 80% aqueous acetic acid (125 mL.) and heated to 75° C. Zinc dust (9.75 g., 150 mmol.) was added gradually over 20 min. The reaction mixture was heated to 85° C. for 2 hr. then cooled to ~35° C. and filtered to remove unreacted zinc. The filtrate was diluted with ethyl ether, washed 3×with water then with saturated aqueous NaHCO3. The solution was dried with Na2SO4, filtered and concentrated in vacuo to ~30 mL. then diluted with hexanes and filtered. The filtrate was concentrated to an off-white solid which was dissolved in hexane, filtered, and concentrated to give 1.65 g. of the title compound as a light green solid.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9]>C(#N)C.CCOCC.N1C2C(=CC=CC=2)C=CC=1>[Cl:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](=[O:9])[C:1]#[N:2]
Reactant: [C-]#N
Reactant: O=C(Cl)c1ccccc1CCl
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Solvent: c1ccc2ncccc2c1
Product: N#CC(=O)c1ccccc1CCl
Temperature: 60 °C
Yield: 97.5 %

Procedure:
A mixture of acetonitrile (100 ml), 95% sodium cyanide (6.19 g), 95% cuprous iodide (2.00 g) and quinoline (0.13 g) was stirred at 60° C. A solution of 2-chloromethylbenzoyl chloride (19.0 g) in acetonitrile (100 ml) was added dropwise to the reaction mixture over 3 hours. After completion of the addition, the mixture was stirred at 60° C. for 5 hours. After the reaction mixture was cooled by allowing it to stand, the reaction mixture was diluted with ether, and washed successively with water, a saturated aqueous solution of sodium bicarbonate and water. The ether layer thus obtained was dried over anhydrous sodium sulfate and at the same time decolorized with Norit SX-3. Evaporation of the solvent under reduced pressure gave the crude title compound (17.6 g, purity: about 72% determined by 1H-NMR analysis).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:37]=3)[CH2:12][CH2:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][C:15]=3[NH:23][C:24]([NH:26][CH2:27][CH2:28][NH:29]C(=O)OC(C)(C)C)=[O:25].[ClH:38].O1CCOCC1>C(Cl)Cl.CCOCC>[ClH:1].[ClH:38].[NH2:29][CH2:28][CH2:27][NH:26][C:24]([NH:23][C:15]1[CH:16]=[CH:17][C:18]2[NH:19][C:20]3[N:21]=[C:5]([NH:6][C:7]4[CH:8]=[CH:9][CH:10]=[C:11]([CH:37]=4)[CH2:12][CH2:13][C:14]=1[CH:22]=2)[N:4]=[CH:3][C:2]=3[Cl:1])=[O:25]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: NCCNC(=O)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of tert-butyl {2-[({[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)amino]ethyl}carbamate (326 mg, 0.622 mmol) in DCM (12 mL) was added 4.0 M of hydrogen chloride in 1,4-dioxane (0.544 mL, 2.18 mmol). After stirring overnight, the reaction solution was diluted with ether. The resulting precipitate was filtered and dried under vacuum to give the desired product (245 mg, 79%). LCMS calculated for C21H23ClN7O (M+H)+: m/z=424.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:26](OCC)=[O:27])=[N:4][C:5]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][OH:25])=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].C(OC(C1C([N+]([O-])=O)=C(NC2C=CC=CC=2OC)N=C(NC2C=CC=CC=2CO)[N:37]=1)=O)C.[CH2:63]([OH:65])C>[Pd]>[OH:25][CH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][C:5]1[N:6]=[C:7]2[C:2]([NH:1][C:63](=[O:65])[N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:3]([C:26]([NH2:37])=[O:27])[N:4]=1
Reactant: CCOC(=O)c1nc(Nc2ccccc2CO)nc(Nc2ccccc2OC)c1N
Reactant: CCOC(=O)c1nc(Nc2ccccc2CO)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: CCO
Agent: [Pd]
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(Nc3ccccc3CO)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
Ethyl 5-amino-2-(2-(hydroxymethyl)phenylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate. Ethyl-5-nitro-2-(2-(hydroxymethyl)phenylamino)-6-(2-methoxy-phenylamino)pyrimidine-4-carboxylate (0.325 g, 0.740 mmol) was dissolved in ethanol (20 mL) and 10% palladium on carbon (0.081 g) were added to the flask and flushed with fresh hydrogen gas and allowed to stir at room temperature. After 16 h, the reaction was filtered through celite and the filtrate condensed under reduced pressure. The crude oil was purified using biotage chromatography (50-100% ethyl acetate in hexanes) to afford the title compound (0.270 g., 89%). MS (ESI) m/z 410.5 [M+1]+.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[C:6](=O)([O:15]N1C(=O)CCC1=O)[O:7][N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]1=[O:14].C(N(CC)CC)C>C(#N)C>[C:6](=[O:15])([O:7][N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]1=[O:14])[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(OCC1CC1)ON1C(=O)CCC1=O
Reaction time: 8 h

Procedure:
To a stirred solution of cyclopropylmethanol (1.0 g, 13.8 mmol) in acetonitrile (15 mL) was added bis(2,5-dioxopyrrolidin-1-yl) carbonate (7.1 g, 27.7 mmol) and triethylamine (5.8 mL, 41.6 mmol). The reaction was stirred overnight then quenched with saturated NaHCO3 (aq.) and extracted with ethyl acetate (3×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as an amber oil: 1H NMR (300 MHz, CDCl3) δ 4.16 (d, J=7.5 Hz, 2H), 2.84 (s, 4H), 1.26 (m, 1H), 0.70-0.64 (m, 2H), 0.40-0.35 (m, 2H).
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([CH:28]=[CH:29][C:30]#[N:31])=[N:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[C:30]([NH2:31])[N:12]3[N:13]=[C:14]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:11]3[CH:10]=2)=[N:26][CH:27]=1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Reactant: N#CC=Cc1ccc(Cl)cn1
Product: Nc1cc(-c2ccc(Cl)cn2)cc2nc(-c3ccco3)nn12

Procedure:
The title compound, MS m/e (%): 312 (M+H+, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and 3-(5-chloro-pyridin-2-yl)-acrylonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[C:13](Cl)(=[O:16])[CH2:14][CH3:15].[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([NH:1][C:13](=[O:16])[CH2:14][CH3:15])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(C(=O)O)cc1N
Product: CCC(=O)Nc1cc(C(=O)Nc2ccc(Cl)cc2)ccc1OC

Procedure:
Compound 2613 is synthesized following a similar method as in Example 1 and using 3-amino-4-methoxybenzoic acid, propionyl chloride and 4-chloroaniline as materials. Total yield of the two steps: 30%.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.O[CH:13]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)[CH:14]1[CH2:16][CH:15]1[C:17]#[N:18].[CH3:29][S:30]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:42]=1[NH:41][CH:40]=[CH:39]2)(=[O:32])=[O:31]>ClCCCl.ClCCl>[CH3:29][S:30]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:42]=1[NH:41][CH:40]=[C:39]2[CH:13]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)[CH:14]1[CH2:16][CH:15]1[C:17]#[N:18])(=[O:32])=[O:31]
Reactant: N#CC1CC1C(O)c1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClCCCl
Product: CS(=O)(=O)Cc1cccc2c(C(c3ccc(C(F)(F)F)cc3)C3CC3C#N)c[nH]c12

Procedure:
1.05 g (4.75 mmol) of indium(III) chloride and 0.55 ml (7.12 mmol) of trifluoroacetic acid were added to 954 mg (3.96 mmol) of the compound from Example 160A and 1.02 g (4.75 mmol) of the compound from Example 86A in 60 ml of 1,2-dichloroethane, and the mixture was heated under reflux overnight. It was diluted with dichloromethane and washed with water and saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 197 mg (12% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH2:15][N:14]([C:16](=[C:33]([CH3:37])[CH2:34][O:35][CH3:36])[C:17]([O:19]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:18])[C:13]1=[O:38])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH2:15][N:14]([C:16](=[C:33]([CH3:37])[CH2:34][O:35][CH3:36])[C:17]([OH:19])=[O:18])[C:13]1=[O:38])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Solvent: COc1ccccc1
Product: COCC(C)=C(C(=O)O)N1CC(NC(=O)COc2ccccc2)C1=O
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
Benzhydryl 2-(3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methyl-4-methoxy-2-butenoate (200 mg) was dissolved in 1 ml of 1:1 mixture of anisole and trifluoracetic acid at 0°. After 30 min. at 0°, 50 ml of hexane was added and the solvents were removed under reduced pressure. The residue thereby obtained was washed thoroughly with ether and dried. A total of 53 mg of the title product was isolated: nmr (CDCl3) δ 2.07 (s, 3, CH3), 3.33 (s, 3, --OCH3), 4.33 (s, 2, --CH2OCH3), 3.77 (m, 2, C4 --H), 5.00 (m, 1, C3 --H), 4.52 (s, 2, side chain CH2) and 7.2 (b, ArH).
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)=[O:6])=[N+]=[N-].[H][H]>[Ni].O1CCOCC1.C(O)C>[NH2:1][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)(=[O:16])=[O:15])=[CH:12][CH:13]=1)=[O:6]
Reactant: [N-]=[N+]=NCC(=O)Nc1ccc(S(=O)(=O)c2cccc(Cl)c2)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: C1COCCO1
Product: NCC(=O)Nc1ccc(S(=O)(=O)c2cccc(Cl)c2)cc1
Yield: 55.8 %

Procedure:
A mixture of 12 g of 2-azido-4'-(m-chlorophenylsulfonyl)acetanilide and 8 ml of Raney nickel in 150 ml of p-dioxane and 50 ml of ethanol was hydrogenated in a Parr shaker with an initial pressure of 30 psi of hydrogen for 2 hours. The mixture was filtered through a celite pad and the volatiles removed from the filtrate. The residue was crystallized from p-dioxane, giving 6.2 g of the desired product, mp 195°-196° C.
Reaction SMILES: Cl.Cl.C[N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17](=[O:31])/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=O)=[CH:22][CH:21]=2)C[CH2:5]1.C1C=CC2[N:40]([OH:41])N=NC=2C=1.[CH2:42](Cl)[CH2:43]Cl.NOC1CCCCO1>CN(C=O)C>[OH:41][NH:40][C:28](=[O:30])/[CH:27]=[CH:26]/[C:23]1[CH:24]=[CH:25][C:20](/[CH:19]=[CH:18]/[C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][N:7]2[CH2:43][CH2:42][N:4]([CH3:5])[CH2:9][CH2:8]2)=[O:31])=[CH:21][CH:22]=1
Reactant: On1nnc2ccccc21
Reactant: ClCCCl
Reactant: CN1CCN(Cc2ccccc2C(=O)/C=C/c2ccc(/C=C/C(=O)O)cc2)CC1
Agent: Cl
Agent: NOC1CCCCO1
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccccc2C(=O)/C=C/c2ccc(/C=C/C(=O)NO)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
A mixture of (E)-3-(4-{(E)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid bis-hydrochloride (350 mg, 0.756 mmol), HOBT (204 mg, 1.51 mmol), EDC (288 mg, 1.51 mmol), TEA (0.210 ml, 1.51 mmol) and NH2OTHP (106 mg, 0.907 mmol) in DMF (8 ml) was stirred overnight at room temperature and then partitioned between water and AcOEt. The phases were separated and the aqueous layer was brought to basic conditions with NH4OH and extracted with DCM. The collected organic extracts were dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by silica gel chromatography (eluent: DCM/MeOH/NH4OH 95:5:0.2) and the resulting product was dissolved in DCM and treated with HCl/Et2O for 1 h. The hygroscopic precipitate was filtered and freeze dried to give 229 mg of (E)-N-Hydroxy-3-(4-{(E)-3-[2-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylamide as its bis-hydrochloride salt.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:17]=[CH:16][S:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C(O)(C)C.Cl.O1CCOCC1>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([NH:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[C:3]2[CH:17]=[CH:16][S:15][C:4]=2[N:5]=1
Reactant: Nc1ccncc1
Reactant: Fc1ccccc1-c1nc(Cl)c2ccsc2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Fc1ccccc1-c1nc(Nc2ccncc2)c2ccsc2n1
Temperature: 80 °C
Yield: 87.8 %

Procedure:
4-Chloro-2-(2-fluoro-phenyl)-thieno[2,3-d]pyrimidine (110 mg, 0.41 mmole) and 4-aminopyridine (78 mg, 0.830 mmole) were combined in isopropanol (3 ml), then 4 drops of 4 M HCl/dioxane were added and the reaction mixture was heated to 80° C. for 7 hours. The reaction mixture was cooled and the product was isolated by filtration, washed with minimum cold methanol and dried under vacuum to give 116 mg of product (yield: 86%).
Reaction SMILES: Br[C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.C([Li])CCC.[CH2:18]([C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#N)=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)[CH2:19][CH2:20][CH2:21][CH3:22].Cl.C1C[O:41]CC1>CCCCCC>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:12])([F:11])[C:33]([C:32]2[CH:35]=[CH:36][C:29]([C@H:26]3[CH2:27][CH2:28][C@H:23]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25]3)=[CH:30][CH:31]=2)=[O:41])=[CH:4][CH:5]=1)#[N:10]
Reactant: N#Cc1ccc(C(F)(F)Br)cc1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCCCC[C@H]1CC[C@H](c2ccc(C(=O)C(F)(F)c3ccc(C#N)cc3)cc2)CC1
Reaction time: 0.25 h

Procedure:
0.08 mol of bromodifluoro(4-cyanophenyl)methane [prepared by the method of A. Haas, M. Spitzer, M. Lieb, Chem. Ber. 121 (1988)] are dissolved in 50 ml of THF; at -78°, 50 ml of a 1.6 molar solution of butyllithium in hexane are added dropwise. The mixture is stirred for 15 minutes, and then a solution of 0.08 mol of 4-(trans-4-pentylcyclohexyl)benzonitrile in 60 ml of THF is added dropwise. The mixture is allowed to warm to 0° and then poured into a mixture of ice and dilute hydrochloric acid. The organic phase is separated off, and the aqueous phase is extracted with ether (50 ml) and dichloromethane (2×25 ml). The organic phases are combined, the solvents are removed by distillation, and the residue is chromatographed on a silica gel column using petroleum ether/ether as the eluent. After the eluate has been evaporated, the residue is recrystallized from ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:15]O>>[CH3:15][O:9][C:8](=[O:10])[CH:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:13][CH:12]=1)[CH3:11]
Reactant: CO
Reactant: CC(Oc1ccc(N)cc1)C(=O)O
Agent: Cl
Product: COC(=O)C(C)Oc1ccc(N)cc1
Yield: 37.2 %

Procedure:
Method-A Through a mixture of 2-(4-aminophenoxy)-propionic acid 9 (240 g, 1.103 mmol) in methanol (4.8 liters) was passed dry HCl gas at 10° C. for 1 hour followed by reflux for 48 hours. Methanol (2.5 liter) was distilled off, ice water (1 liter) was added and the pH was adjusted to 7.5 with K2CO3. Crude 10 was extracted into chloroform, washed with 5% NaHCO3 solution, water, dried over Na2SO4 and distilled to give 10 (80 g, 37.2%) as a brown syrup. Method-B 2-(4-Nitrophenoxy)-propionic acid methyl ester 14 (20 g, 88.88 mmol) was dissolved in dimethyl formamide (100 ml) in a pressure vessel, Raney nickel (20 grams) was added and the mixture stirred under an atmosphere of hydrogen (4 kg) for 6 hours. The catalyst was removed by filtration and the dimethyl formamide distilled off under vacuum. Crude 10 was purified by column chromatography on silica gel using chloroform as eluant to get pure 10 (15 g, 86.55%) as a brown syrup.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:24](OC(=O)C)(=[O:26])[CH3:25]>O.O1CCCC1>[ClH:1].[CH3:25][C:24]([NH:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1)=[O:26]
Reactant: N=C(Nc1cccc(N)c1)N1CCCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cccc(NC(=N)N2CCCC2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of the product of step (b), 1.38 g, 0.0050 moles, was dissolved in 20 ml of water. The solution was gradually treated with sodium carbonate, 0.84 g, 0.0100 moles, and cooled to 0° C. Next a solution of 0.5 ml of acetic anhydride in 10 ml of tetrahydrofuran was added. This was stirred overnight under nitrogen. The mixture was diluted with enough water to bring the volume to 100 ml, and washed with 20 ml of chloroform. The aqueous layer was made basic with 50% sodium hydroxide and extracted with 20 ml of chloroform (twice). The chloroform was dried with potassium carbonate, filtered and evaporated. The oil was dissolved in 20 ml of isopropanol and treated with 1 ml of concentrated hydrochloric acid. This mix was then diluted to 250 ml with ether. The solids were filtered and washed with 10 ml of ether (twice). The sample was allowed to dry overnight to yield N-(3-((methylcarbonyl)amino)phenyl)-1-pyrrolidinecarboximidamide monohydrochloride.