Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]2[N:3]=1.Cl[C:18]([O:20][CH3:21])=[O:19].CCN(C(C)C)C(C)C>O1CCCC1>[CH:9]1([NH:8][C:6]2[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]3[N:3]=[C:2]([NH:1][C:18](=[O:19])[O:20][CH3:21])[CH:7]=2)[CH2:11][CH2:10]1
Reactant: Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Temperature: 60 °C

Procedure:
To 5-amino-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.23 mmol) in 1.0 mL tetrahydrofuran was added methyl chloroformate (35 ul, 0.46 mmol) and DIEA (39 ul). The reaction mixture was heated at 60° C. for one hour. The reaction was partitioned between ethyl acetate/water. The organic layer was collected, dried over sodium sulfate, and concentrated under high vacuum to yield methyl 7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-ylcarbamate. The crude product was taken to next step without further purification. LCMS (M+1=276)
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][C:5]([OH:7])=[O:6].[CH:8](=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11].Cl>O>[CH:8]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[O:11][CH2:4][C:5]([OH:7])=[O:6])=[O:16]
Reactant: O=C(O)CCl
Reactant: O=Cc1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1ccccc1OCC(=O)O
Temperature: 75 °C
Yield: 37 %

Procedure:
A solution of NaOH (13.3 g; 0.33 mole) in water (34.4 ml) was carefully added, with cooling, to a mixture of chloroacetic acid (15.8 g; 0.17 mole) and salicylaldehyde (20.3 g; 0.17 mole) in water (134 ml). The mixture was heated to 75° C. with magnetic stirring to facilitate dissolution. The warm solution was pumped through the CMR (15 ml/minute; 170°-2° C.; 700 kPa) and carefully acidified with conc. HCl (32 ml). After steam distillation to recover unreacted salicylaldehyde (6.0 g), the residue was cooled and the product, m.p. 130°-1° C., crystallised, filtered off and dried (7.9 g; 37% yield based on consumed salicylaldehyde). For a conventional preparation see ref.12.
Reaction SMILES: C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:33][O:34][C:35]1[CH:40]=[C:39]([CH3:41])[C:38]([S:42]([N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]2[CH2:51][O:52][CH2:53][C:54]([OH:56])=O)(=[O:44])=[O:43])=[C:37]([CH3:57])[CH:36]=1.[N:58]1([CH2:63][CH2:64][O:65][C:66]2([C:72]3[CH:77]=[CH:76][CH:75]=[C:74]([C:78]([F:81])([F:80])[F:79])[CH:73]=3)[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)[CH2:62][CH2:61][CH2:60][CH2:59]1>C(Cl)Cl>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH3:57])[C:38]([S:42]([N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]2[CH2:51][O:52][CH2:53][C:54]([N:69]2[CH2:70][CH2:71][C:66]([O:65][CH2:64][CH2:63][N:58]3[CH2:62][CH2:61][CH2:60][CH2:59]3)([C:72]3[CH:77]=[CH:76][CH:75]=[C:74]([C:78]([F:80])([F:79])[F:81])[CH:73]=3)[CH2:67][CH2:68]2)=[O:56])(=[O:43])=[O:44])=[C:39]([CH3:41])[CH:40]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)O)c(C)c1
Reactant: FC(F)(F)c1cccc(C2(OCCN3CCCC3)CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCC[C@H]2COCC(=O)N2CCC(OCCN3CCCC3)(c3cccc(C(F)(F)F)c3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
Diisopropylethylamine (4 eq.), EDCl HCl (1.2 eq.) and HOBt (1 eq.) were added to a mixture of (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid [acid D] (0.65 mmol) in methylene chloride (10 ml). A mixture of 4-(2-(pyrrolidin-1-yl)ethoxy)-4-(3-(trifluoromethyl)phenyl)piperidine [amine H] and DIPEA (2 eq.) in methylene chloride (3 ml) was added dropwise, while cooling with ice, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride, washed with saturated ammonium chloride solution, saturated sodium chloride solution, saturated sodium bicarbonate solution and with sat. sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was purified by means of column chromatography (silica gel, methanol/methylene chloride) to obtain the desired product. Yield: 78%. MS, Rt=3.9 min, m/z=696.4 [MH]+
Reaction SMILES: O.[OH-].[Li+].[O:4]1[C:8]2([CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[NH:22][C:23]3[C:24]4[C:31]([CH3:32])=[C:30]([C:33]([O:35]C)=[O:34])[S:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH2:10][CH2:9]2)[O:7][CH2:6][CH2:5]1>C1COCC1.O>[O:4]1[C:8]2([CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[NH:22][C:23]3[C:24]4[C:31]([CH3:32])=[C:30]([C:33]([OH:35])=[O:34])[S:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH2:10][CH2:9]2)[O:7][CH2:6][CH2:5]1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCC4(CC3)OCCO4)c2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCC4(CC3)OCCO4)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.065 g lithium hydroxide monohydrate was added to 2.003 g methyl 4-(2-(1,4-dioxaspiro[4.5]decan-8-yloxy)-4-fluorophenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (cpd.19.1) in 100 ml THF and 60 ml water. After stirring at rt overnight the reaction mixture was quenched by 2 M aq. HCl and concentrated in vacuo. The resulting aq. layer was filtered. The filtercake was dried and triturated with MeOH:Et2O 20:1 to give the desired compound.
Reaction SMILES: CN1CCCC1=O.Br[C:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[F:34][C:35]([F:40])([F:39])C([O-])=O.[Na+]>O>[C:22]1([N:11]2[C:12]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:13][C:14](=[O:15])[C:9]([C:35]([F:40])([F:39])[F:34])=[C:10]2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: O=c1cc(-c2ccccc2)n(-c2ccccc2)c(-c2ccccc2)c1Br
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=c1cc(-c2ccccc2)n(-c2ccccc2)c(-c2ccccc2)c1C(F)(F)F
Temperature: 160 °C
Yield: 20.4 %

Procedure:
To 40 ml of 1-methyl-2-pyrrolidinone were added 2.0 g (0.0050 mole) of 3-bromo-1,2,6-triphenyl-4(1H)-pyridinone, 2.7 g (0.020 mole) of sodium trifluoroacetate and 1.9 g (0.010 mole) of cuprous iodide. The reaction mixture was then heated at 160° C. for 5 hours in a nitrogen atmosphere. After allowing the reaction mixture to cool down, it was poured into water, followed by extraction with ethyl ether. The organic layer (the extract) was washed with 50 ml of a saturated aqueous solution of sodium hydrogen carbonate. After washing the organic layer further with water, it was dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off, and the residue was crystallized from a 1:3 mixed solvent of ethyl acetate and hexane to yield 0.4 g of 1,2,6-triphenyl-3-trifluoromethyl-4(1H)-pyridinone having a melting point of 222°-225° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][O:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]=2[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:6]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:5]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([O-])=O.O.NN>CO>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][O:11][S:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:6]=2[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:14]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1c(SOSc2ccc([N+](=O)[O-])c(-c3ccccc3)c2C(=O)OCC)ccc([N+](=O)[O-])c1-c1ccccc1
Agent: NN
Solvent: CO
Solvent: O
Product: CCOC(=O)c1c(SOSc2ccc(N)c(-c3ccccc3)c2C(=O)OCC)ccc(N)c1-c1ccccc1
Temperature: 62.5 °C
Reaction time: 0.33 h

Procedure:
To 500 parts of methanol, 115 parts of para-nitrophenyl-o-carbethoxyphenylthio ether, 10 parts of activated carbon and 1 part of ferric chloride hexahydrate were added, and the mixture was stirred at a liquid temperature of 60 to 65° C. for 20 minutes. To this reaction liquid, a mixture of 68 parts of 80% hydrazine monohydrate and 100 parts of methanol were added dropwise over 1 hour while maintaining the liquid temperature at 65° C. or less, and reaction was further carried out at the same temperature for 3 hours. The mother liquid obtained by filtration of the reaction liquid was concentrated and the precipitated solid was washed with water and dried to obtain 95.4 parts of para-aminophenyl-o-carbethoxyphenylthio ether which is the title compound.
Reaction SMILES: [CH2:1]([NH:5][CH3:6])[CH2:2][CH2:3][CH3:4].[CH2:7]=[C:8]1[O:12][C:10](=[O:11])[CH2:9]1>CO>[CH2:1]([N:5]([CH3:6])[C:10](=[O:11])[CH2:9][C:8](=[O:12])[CH3:7])[CH2:2][CH2:3][CH3:4]
Reactant: C=C1CC(=O)O1
Reactant: CCCCNC
Solvent: CO
Product: CCCCN(C)C(=O)CC(C)=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 56.5 %

Procedure:
14.1 ml (0.12 mol) N-n-butylmethylamine was added dropwise to a solution of 10.00 g (0.12 mol) diketene in 500 ml MeOH at 0° C. After stirring for 6 hours at 0° C., no starting material was detected anymore by thin-layer chromatography. The reaction mixture was spun off and the residue was purified by means of column chromatography. 11.61 g of product was obtained as a slightly yellow oil.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[Br:13][C:14]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:15]=1[CH:16]=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[Br:13][C:14]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[C:5]([C:6]#[N:7])=[CH:4][N:3]=2)=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: CCOc1cc(Cl)ncc1C#N
Reactant: O=Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(Oc2ccc(Br)c(C=O)c2)ncc1C#N
Temperature: 110 °C
Yield: 73.5 %

Procedure:
A mixture of 6-chloro-4-ethoxy-nicotinonitrile (3.80 g, 20.8 mmol), 2-bromo-5-hydroxy-benzaldehyde (4.60 g, 22.9 mmol) and K2CO3 (4.31 g, 31.2 mmol) in dimethyl formamide (30 mL) was heated to 110° C. for 5 hours. The reaction mixture was diluted with H2O (400 mL) and extracted with ethyl acetate (8×400 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (15-50% ethyl acetate/hexanes) to give the title compound as a white solid (5.31 g, 73%).
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8](=[O:18])[NH:9][C:10]2[S:11][C:12]([C:15](O)=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:19]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:9][C:10]2[S:11][C:12]([C:15]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:16])=[CH:13][N:14]=2)=[O:18])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: C1CCNC1
Reactant: O=C(O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Product: O=C(c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1)N1CCCC1

Procedure:
Prepared as described in general procedure (K) using 2-(3,3-dicyclohexyl-ureido)-thiazole-5-carboxylic acid and pyrrolidine.
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[N:14]=[C:13]([CH2:15][N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=1.C([Li])CCC.[CH3:29][CH2:30][O:31][CH:32]=[C:33]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:34]([O:36][CH2:37][CH3:38])=[O:35]>O1CCCC1>[CH2:17]([N:16]([CH2:20][CH2:21][CH3:22])[CH:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([C:2]2[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=2[CH3:23])[N:14]=1)[CH:32]([CH:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:39]([O:41][CH2:42][CH3:43])=[O:40])[O:31][CH2:30][CH3:29])[CH2:18][CH3:19]
Reactant: CCCN(CCC)Cc1cccc(-c2c(C)cc(C)cc2C)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCN(CCC)C(c1cccc(-c2c(C)cc(C)cc2C)n1)C(OCC)C(C(=O)OCC)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
N-[(6-mesitylpyridin-2-yl)methyl]-N-propylpropan-1-amine (0.71 g, 2.29 mmol), was dissolved in tetrahydrofuran (15 mL). The solution was cooled to −78° C. and n-butyllithium (2.5M, 1.0 mL, 2.51 mmol) was added drop wise. After 0.5 h, diethyl ethoxymethylene malonate (0.48 mL, 2.40 mmol) was added. The reaction was removed from the dry ice bath and allowed to warm to room temperature. The mixture was quenched with water, extracted with ether, dried over sodium sulfate, filtered and concentrated. Flash chromatography gave 0.65 g (59% yield) of an isomeric mixture of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][NH2:10].[C:11]([O:16][CH2:17][CH3:18])(=O)[C:12]([CH3:14])=[O:13].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:11]([O:16][CH2:17][CH3:18])[C:12](=[O:13])[CH3:14]
Reactant: NNc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=NNc1ccc(Cl)cc1Cl)C(C)=O
Yield: 85.1 %

Procedure:
A mixture of 2,4-dichlorophenylhydrazine (1.0 g, 4.7 mmol), ethyl pyruvate (0.53 mL, 4.7 mmol), triethylamine (0.65 mL, 4.7 mmol) and ethanol (5 mL) was heated at reflux overnight. The solvent was evaporated and the residue taken up in chloroform. The solution was washed with water and brine and dried over magnesium sulfate and concentrated, leaving an oil (1.1 g, 98%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][CH2:12][CH2:13][NH2:14].ClCC1NC2C=CC=CC=2N=1.[CH3:26][N:27]([CH3:33])[CH2:28][CH2:29][N:30]=[C:31]=[S:32]>>[CH3:26][N:27]([CH3:33])[CH2:28][CH2:29][NH:30][C:31]([NH:14][CH2:13][CH2:12][NH:11][CH2:10][C:2]1[NH:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[S:32]
Reactant: CN(C)CCN=C=S
Reactant: NCCNCc1nc2ccccc2[nH]1
Agent: ClCc1nc2ccccc2[nH]1
Product: CN(C)CCNC(=S)NCCNCc1nc2ccccc2[nH]1

Procedure:
N-(2-Benzimidazolylmethyl)ethylenediamine, prepared by reacting ethylenediamino with 2-chloromethylbenzimidazole by the procedure of Example 40, is reacted with 2-dimethylaminoethyl isothiocyanate by the procedure of Example 40 to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>C(#N)C.O>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCOC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 80 °C
Yield: 118.2 %

Procedure:
To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (10 g, 0.05 mol) in acetonitrile (150 mL) were added K2CO3(23 g, 0.16 mol) and 2-(chloromethyl) quinoline (14.2 g, 0.06 mol) under an inert atmosphere. The reaction mixture was then heated at 80° C. for 16 h, diluted with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (19 g, 95%) as an oil.
Reaction SMILES: [O-]CC.[Na+].Cl.Cl.[NH:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[NH2:8].[C:15](OCC)(=[O:23])/[CH:16]=[CH:17]\[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[O:23]=[C:15]1[NH:8][N:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16]1
Reactant: NNc1cccnc1
Reactant: CCOC(=O)/C=C\C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)C1CC(=O)NN1c1cccnc1
Temperature: 20 °C

Procedure:
A 4-neck round bottomed flask (250 mL) was charged with sodium ethoxide (21 wt % in ethanol, 56 mL, 192 mmol). 3-Hydrazinopyridine.dihydrochloride (10.0 g, 55.0 mmol) was added, causing an exotherm from 20° C. to 32° C. The reaction was allowed to cool to 20° C. and diethyl maleate (13.4 mL, 82.0 mmol) was added, and the reaction was heated at 60° C. for 3 hours. The reaction was cooled to 20° C. and quenched with acetic acid. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organics were concentrated to dryness and the residue was purified by flash column chromatography using ethyl acetate as eluent to the title compound as a blue oil (6.60 g, 51%): 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.40-8.26 (m, 1H), 8.19 (dd, J=4.4, 1.6 Hz, 1H), 7.47-7.21 (m, 2H), 4.77 (dd, J=9.8, 2.1 Hz, 1H), 4.22 (qd, J=7.1, 1.7 Hz, 2H), 3.05 (dd, J=17.0, 9.8 Hz, 1H), 1.99 (s, 1H), 1.25 (t, J=7.1 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 170.37, 146.60, 142.60, 137.28, 123.54, 121.94, 65.49, 61.32, 32.15, 20.72, 13.94; ESIMS m/z 236 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[NH:10][C:9]2[C:8](=O)[NH:7][C:6]([NH2:12])=[N:5][C:4]=2[N:3]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:26])=O>>[NH2:12][C:6]1[N:5]=[C:4]2[C:9]([NH:10][C:2]([NH2:1])=[N:3]2)=[C:8]([Cl:26])[N:7]=1
Reactant: Nc1nc2nc(N)[nH]c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: Nc1nc(Cl)c2[nH]c(N)nc2n1

Procedure:
A suspension of 8-aminoguanine (Fischer, Z. Physiol. Chem., 60, 69 (1909); Beaman et al., in Zorbach and Tipson, Synthetic Procedures in Nucleic Acid Chemistry, Vol. 1, pp 41-43, John Wiley & Sons, New York, 1968) (3.0 g, 18.1 mmol) in phosphorus oxychloride (90 mL) and N,N-diethylaniline (3 mL) was refluxed for 30 min and the excess phosphorus oxychloride was evaporated under reduced pressure. Ice (20 g) was added slowly to the resulting solution and the pH was adjusted to 6 with a concentrated aqueous sodium hydroxide solution. A yellow solid formed and was collected by filtration, washed with water, and dried to give a green solid. Crystallization from water with charcoal treatment produced 2,8-diamino-6-chloropurine as a white solid: yield, 2.11 g (63%); mp >275° C. dec.; 1H NMR d 6.09 (s, 2 H, NH2, exchange with D2O), 6.71 (s, 2 H, NH2, exchange with D2O); MS (EI) calcd. m/z for C5H5N635Cl 184.0264, found 184.0266; calcd. m/z C5H5N637Cl 186.0235, found 186.0237.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH3:16][CH2:17][CH2:18][CH:19]([NH2:23])[C:20]([OH:22])=[O:21].CC#N>O>[C:20]([CH:19]([NH:23][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:18][CH2:17][CH3:16])([OH:22])=[O:21]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: CCCC(N)C(=O)O
Solvent: CC#N
Solvent: O
Product: CCCC(Nc1nc2ccc(Cl)cc2cc1C(=O)O)C(=O)O
Yield: 15 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with DL-2-aminopentanoic acid to provide the title compound in 15% yield as yellow needles (flash chromatography on SiO2, eluent MeCN, H2O, AcOH-20, 1, 0.3).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[S:12][CH2:13][CH2:14][C:15]([OH:17])=O.C(N(CC)CC)C.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(Cl)Cl>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:11]1[C:5]2[CH:6]=[C:7]([NH:10][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:8]=[CH:9][C:4]=2[NH:3][C:15](=[O:17])[CH2:14][CH2:13][S:12]1
Reactant: Nc1ccc(N)c(C(SCCC(=O)O)c2ccccc2Cl)c1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1ccc2c(c1)C(c1ccccc1Cl)SCCC(=O)N2
Reaction time: 1.5 h

Procedure:
A solution of 138.2 g of 3-[(2,5-diaminophenyl)(2-chlorophenyl)methylthio]propionic acid dihydrochloride in 8.6 l of dry methylene chloride is treated at -5° with 94 ml of triethylamine. Subsequently, there are successively added thereto at 0° to 2° 129.1 ml of ethyl chloroformate and 188 ml of triethylamine. The cooling means is then removed and the mixture is stirred for a further 90 minutes. The mixture is evaporated and the residue is chromatographed on 1.44 kg of silica gel. Elution is carried out with chloroform in order to remove impurities and then with chloroform/ethanol (89.5:1.5). There is obtained ethyl 6-(2-chlorophenyl)-1,3,4,6-tetrahydro-2-oxo-2H-5,1-benzothiazocine-8-carbamate of melting point 229°-231°.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH2:29])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:37][C:38]([F:45])([F:44])[CH2:39][S:40](Cl)(=[O:42])=[O:41]>O1CCCC1.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH:29][S:40]([CH2:39][C:38]([F:45])([F:44])[F:37])(=[O:42])=[O:41])[C:25]([F:26])([F:27])[F:28])=[CH:4][CH:3]=1
Reactant: NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Reactant: O=S(=O)(Cl)CC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(CC(F)(F)F)NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Yield: 96.4 %

Procedure:
To a mixture of 1-[9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanamine (80.0 mg, 0.165 mmol) and triethylamine (0.0460 mL, 0.330 mmol) in tetrahydrofuran (2 mL) was added 2,2,2-trifluoroethanesulfonyl chloride (0.0219 mL, 0.198 mmol) at 0° C. The resultant mixture was stirred at room temperature for 30 min and diluted with aqueous sodium bicarbonate. The resultant mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (100 mg, 0.159 mmol, 96%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:3]=1[CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19]>FC(F)(F)C(O)=O.O>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:3]=1[CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CC(C)(C)OC(=O)CCc1c(Br)cc(Br)nc1-c1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)CCc1c(Br)cc(Br)nc1-c1ccccc1Cl
Yield: 40.8 %

Procedure:
Tert-butyl 3-[4,6-Dibromo-2-(2-chlorophenyl)-3-pyridyl]propionate (3.86 g, 8.116 mmol) was dissolved in trifluoroacetic acid-water (9:1, 25 ml) and the solution allowed to stand for 3 about hours (hereinafter “h), then evaporated in vacuo. The residue was purified by column chromatography over silica (70 g) eluting with cyclohexane-ethyl acetate (5:1)-(3:1) to give the product as an gum (1.39 g).