Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([NH2:18])=[O:17])[CH:10]=2)=[CH:3][CH:2]=1.[OH:20][CH:21]([C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([NH2:32])=[O:31])[CH:24]=1>C(O)C.[Pd]>[C:1]1([CH3:19])[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([NH2:18])=[O:17])[CH:10]=2)=[CH:5][CH:6]=1.[OH:20][CH:21]([C:33]1[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=1)[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]([NH2:32])=[O:31])[CH:24]=1
Reactant: Cc1ccc(/C=C/c2ccnc(NC(N)=O)c2)cc1
Agent: [Pd]
Agent: Cc1ccc(C(O)Cc2ccnc(NC(N)=O)c2)cc1
Solvent: CCO
Product: Cc1ccc(CCc2ccnc(NC(N)=O)c2)cc1
Reaction time: 3 h

Procedure:
To the solution of the mixture of [4-((E)-2-p-Tolyl-vinyl)-pyridin-2-yl]-urea and [4-(2-hydroxy-2-p-tolyl-ethyl)-pyridin-2-yl]-urea (36 mg) in ethanol (3 mL) is added 5% palladium on carbon (5 mg). The mixture is purged and back filled with hydrogen three times using a hydrogen balloon. Then the reaction is stirred for 3 hours under the hydrogen atmosphere. The palladium on carbon is filtered and the filtrate is purified by Gilson preparative HPLC to give 12 mg of [4-(2-p-tolyl-ethyl)-pyridin-2-yl]-urea and 3 mg of [4-(2-hydroxy-2-p-tolyl-ethyl)-pyridin-2-yl]-urea.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[C:17]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[C:24]([C:29]([O:31]CC)=O)[NH:23][C:22]2=[O:34])#[N:18].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:78]2[CH:82]=[N:81][C:80]([O:83][CH2:84][CH2:85][O:86][C:87]3[CH:88]=[C:89]([CH2:93][NH2:94])[CH:90]=[CH:91][CH:92]=3)=[N:79]2)C=CC=CC=1>>[C:17]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[C:24]([C:29]([NH:94][CH2:93][C:89]1[CH:90]=[CH:91][CH:92]=[C:87]([O:86][CH2:85][CH2:84][O:83][C:80]3[N:81]=[CH:82][NH:78][N:79]=3)[CH:88]=1)=[O:31])[NH:23][C:22]2=[O:34])#[N:18]
Reactant: CCOC(=O)c1nc2ccc(C#N)cc2c(=O)[nH]1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: N#Cc1ccc2nc(C(=O)NCc3cccc(OCCOc4nc[nH]n4)c3)[nH]c(=O)c2c1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 6-cyano-4-oxo-3,4-dihydroquinazoline-2-carboxylate obtained in Reference Example 51 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a yellow powder (31.7 mg, 12%).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:11][C:12]1[N:16]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:15]=[CH:14][CH:13]=1.COCCOC.C(=O)([O-])[O-].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Cu+2].C(O)(=O)C>[CH:17]1([N:16]2[C:12]([NH:11][C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]([OH:6])=[O:5])=[CH:13][CH:14]=[N:15]2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Nc1ccnn1C1CCCC1
Reactant: O=C(O)c1ccccc1I
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1Nc1ccnn1C1CCCC1
Temperature: 0 °C
Yield: 68.5 %

Procedure:
A mixture of 2-iodobenzoic acid (28 g, 0.113 mol), 5-amino-1-cyclopentylpyrazole (17 g, 0.113 mol), DME (100 ml), potassium carbonate (16 g, 0.113 mol) and Cu(OAc)2 (0.5 g) is refluxed overnight. The reaction mixture is poured into ice water, and acidified with acetic acid to a pH of 5. The gum which forms is extracted with CH2Cl2 and the CH2Cl2 layer is washed with water, dried over MgSO4, and evaporated to afford 21 g of N-(1-cyclopentyl pyrazol-5-yl) anthranilic acid.
Reaction SMILES: [ClH:1].[NH:2]1[C:10]2[C:5](=[C:6]([C:11]3([OH:24])[CH2:16][CH2:15][CH2:14][N:13](CC4C=CC=CC=4)[CH2:12]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.C>CO>[ClH:1].[NH:2]1[C:10]2[C:5](=[C:6]([C:11]3([OH:24])[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: OC1(c2cccc3[nH]ccc23)CCCN(Cc2ccccc2)C1
Agent: Cl
Solvent: CO
Product: OC1(c2cccc3[nH]ccc23)CCCNC1
Yield: 96.1 %

Procedure:
12.7 g of the hydrochloride of Step C in 500 ml of methanol were hydrogenated at 60° C. in the presence of 3.6 g of palladized active charcoal and the mixture was filtered. The filtrate was concentrated to dryness to obtain 9 g of 3-(1H-indol-4-yl)-3-piperidinol hydrochloride which was used as is for the next step.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1>>[F:32][C:28]1[CH:27]=[C:26]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:12]=3)[CH:10]=2)=[O:5])[CH:31]=[CH:30][CH:29]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Reactant: Fc1cccc(Br)c1
Product: O=C(c1cccc(F)c1)c1cn(-c2cccc(-c3cccnc3F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12i and 1-bromo-3-fluorobenzene
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)#[N:7].S(Cl)([Cl:17])(=O)=O>C1C=CC=CC=1>[Cl:17][C:13]1[C:8]([C:6]#[N:7])=[N:9][CH:10]=[CH:11][N:12]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: N#Cc1cnccn1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: N#Cc1nccnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
In 90 ml of benzene and 9.2 ml of dimethylformamide there was stirred at room temperature cyanopyrazine (12.7 g; 0.12 M) prepared in Step A above, after which there was added over 10 minutes sulfonyl chloride (64.79 g; 0.48 M). The reaction mixture was stirred for 30 minutes in an ice bath, then allowed to warm up to room temperature gradually, after which it was stirred for 5 hours. The benzene layer was decanted, and the reddish oil residue was extracted three times with ether, after which the combined benzene and ether layers were quenched with ice water and cooled in an ice bath. The combined layers were then neutralized with solid sodium bicarbonate, then separated, and the aqueous layer was extracted with ether. The combined organic layers were washed once with a small amount of water, dried with sodium sulfate, filtered, and the solvent evaporated to give the title compound (11 g).
Reaction SMILES: Cl.[CH2:2]([N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:9][N:8]=[C:7]1SC)[CH2:3][CH2:4][CH3:5].[OH-].[NH4+]>[Ni].CO>[CH2:2]([N:6]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[CH:9][N:8]=[CH:7]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCn1c(-c2ccc(OC)cc2)cnc1SC
Agent: [Ni]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CCCCn1cncc1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 11 parts of 1-butyl-5-(4-methoxyphenyl)-2-(methylthio)-1H-imidazole monohydrochloride, 20 parts of Raney-nickel catalyst, 105 parts of ammonium hydroxide and 8 parts of methanol is stirred for 2 hours at room temperature. The Raney-nickel catalyst is filtered off and another 20 parts of Raney-nickel catalyst is added. The whole is stirred for another 2 hours at room temperature. The catalyst is filtered off and the filtrate is evaporated. The residue is taken up in a small amount of water and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 8 parts of 1-butyl-5-(4-methoxyphenyl)-1H-imidazole as an oily residue.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][N:24]([CH3:33])[C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26]>>[CH3:23][N:24]([CH3:33])[C:25]([N:27]1[CH2:28][CH2:29][N:30]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:31][CH2:32]1)=[O:26]
Reactant: CN(C)C(=O)N1CCNCC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CN(C)C(=O)N1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with N,N-dimethylpiperazine-1-carboxamide (1.2 equiv) to give 196 (M+1 453.0)
Reaction SMILES: C(N(CC)CC)C.[OH:8]/[N:9]=[C:10](\[NH2:20])/[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[C:14]([CH3:19])[CH:13]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>ClCCl>[OH:8]/[N:9]=[C:10](\[NH:20][C:22](=[O:23])[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)/[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[C:14]([CH3:19])[CH:13]=1
Reactant: Cc1cc(C/C(N)=N/O)ccc1I
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C/C(=N/O)NC(=O)Oc2ccccc2)ccc1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.7 %

Procedure:
Triethylamine (0.651 mL, 4.67 mmol) was added to (Z)—N′-hydroxy-2-(4-iodo-3-methylphenyl)acetimidamide (Intermediate 29-3; 1.13 g, 3.90 mmol) in dry dichloromethane (30 mL) at 0° C. The resulting yellow solution was stirred at 0° C. for 1 hour. Phenyl chloroformate (0.598 mL, 4.67 mmol) was added and the reaction mixture stirred at 0° C. for a further 1 hour. The solution was washed sequentially with saturated Na2CO3 (50 mL) and water (50 mL×2). The organic layer was dried over MgSO4, filtered and evaporated to afford (Z)-phenyl 1-(hydroxyimino)-2-(4-iodo-3-methylphenyl)ethylcarbamate (1.675 g, 105%) as crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[C:12]=2[O:19][CH2:20][CH2:21][CH3:22])[CH:3]=1.CN.[C:25]([BH3-])#[N:26].[Na+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(O)(=O)C.CO>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:26][CH3:25])[C:12]=2[O:19][CH2:20][CH2:21][CH3:22])[CH:3]=1
Reactant: CCCOc1c(C=O)cccc1Oc1cc(Cl)ccc1C#N
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCOc1c(CNC)cccc1Oc1cc(Cl)ccc1C#N
Yield: 57.7 %

Procedure:
4-Chloro-2-(3-formyl-2-propoxyphenoxy)benzonitrile (0.68 g, 2.2 mmol), methylamine (2M in methanol, 3.2 mL, 6.4 mmol) and sodium cyanoborohydride (0.15 g, 2.4 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (70 mL) for 20 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (250 mg, 2.2 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-(3-methylaminomethyl-2-propoxyphenoxy)benzonitrile fumarate (567 mg, 59%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]2[O:36]CCO[CH2:32]2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](=[O:36])[CH3:32])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C(=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)CCCCCCC1COCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(=O)CCCCCCC=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A mixture of 1.4 g of 1-(3,4-dibenzyloxyphenyl)-9-ethylenedioxy-1-decene, 50 ml of acetone, and 50 mg of p-toluenesulfonic acid was stirred overnight at room temperature. After adding thereto 50 mg of sodium carbonate, the reaction mixture was concentrated under reduced pressure, and after adding thereto 50 ml of water, the product was extracted with toluene. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide 1.1 g of 1-(3,4-dibenzyloxyphenyl)-1-decen-9-one as an oil.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]([F:17])([F:16])[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=1.[N:18]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[F:31])=[N+:19]=[N-:20]>CO>[F:31][C:22]1[CH:23]=[C:24]([C:27]([F:29])([F:30])[F:28])[CH:25]=[CH:26][C:21]=1[N:18]1[C:14]([NH2:15])=[C:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]([F:4])([F:16])[F:17])=[CH:12][CH:11]=2)[N:20]=[N:19]1
Reactant: N#CCc1ccc(OC(F)(F)F)cc1
Reactant: [N-]=[N+]=Nc1ccc(C(F)(F)F)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1c(-c2ccc(OC(F)(F)F)cc2)nnn1-c1ccc(C(F)(F)F)cc1F
Reaction time: 8 h
Yield: 33 %

Procedure:
To a stirred and ice-cooled solution of sodium methoxide (0.296 g, 5.4848 mmol) in methanol (25 ml), commercial 4-(trifluoromethoxy)phenylacetonitrile (0.809 g, 4.0222 mmol) and 1-azido-2-fluoro-4-trifluoromethyl-benzene (0.750 g, 3.6565 mmol) are added portion wise. The reaction mixture is allowed to reach room temperature spontaneously overnight, concentrated in vacuo, added water, and extracted with ethylacetate (3×80 ml). The combined organic layers are dried over MgSO4, filtered and evaporated, to afford a brown solid residue (1.385 g, 94% mass balance). This crude material is purified by column chromatography over silica gel (230-400 mesh) eluting with 9% ethylacetate in petroleum ether, to obtain the title compound as an off-white solid (0.490 g, 33% yield). M.p. 134.2-134.9° C. LC-ESI-HRMS of [M+H]+ shows 407.0747 Da. Calc. 407.074282 Da, dev. 1 ppm.
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([Cl:13])=[CH:8][C:7]=1[OH:14].N1C2C(=CC=CC=2)C=CC=1>ClCCl>[Cl:3][C:1]([O:14][C:7]1[CH:8]=[C:9]([Cl:13])[C:10]([Cl:12])=[CH:11][C:6]=1[Cl:5])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Solvent: ClCCl
Solvent: c1ccc2ncccc2c1
Product: O=C(Cl)Oc1cc(Cl)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
About 7 g of phosgene are passed into a solution of 10.0 g of 2,4,5-trichlorophenol in 50 ml of dichloromethane at 0° C., and the mixture is stirred at 0° C. for 15 min. 7.2 ml of quinoline in 20 ml of dichloromethane are added dropwise over the course of 30 min, and the orange-colored suspension is then stirred in an ice bath for 1 h. Subsequently nitrogen is passed through the suspension for 1 h in order to blow out excess phosgene (absorber tower). The mixture is subsequently filtered, and the filtrate is washed twice with water, dried, again filtered and evaporated to dryness in vacuo. The 4.45 g of oily brownish residue are relatively pure 2,4,5-trichlorophenyl chloroformate, which crystallizes in the refrigerator and can be employed without further purification.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:6][N:7]=1)[CH3:2].C([N:23]=[C:24]=[S:25])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH2:1]([C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:24]([NH2:23])=[S:25])=[CH:10][CH:9]=2)=[CH:6][N:7]=1)[CH3:2]
Reactant: CCc1ncc(-c2ccc(N)cc2)o1
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ncc(-c2ccc(NC(N)=S)cc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To a solution of 4-(2-ethyl-oxazol-5-yl)-phenylamine (470 mg, 2.5 mmol, CAS 73286-36-9) in tetrahydrofurane (20 mL) was added benzoyl isothiocyanate (449 mg, 2.8 mmol). The reaction was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was suspended in methanol (30 mL). Potassium carbonate (1036 mg, 7.5 mmol) dissolved in water (15 mL) was added drop wise to the suspension. The reaction was stirred at room temperature over night. The resulting solution was evaporated and the residue was stirred with water. The precipitate was filtered off, washed twice with water and twice with diethyl ether. The residue was dissolved in tetrahydrofurane and the solvent was removed under reduced pressure to yield the title compound as a light yellow solid (270 mg, 44%). MS ISP (m/e): 248.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ=9.80 (s, 1H, NH), 7.61 (d, 2H), 7.52 (d, 2H), 7.46 (s, 1H), 3.80 (q, 2H), 1.28 (t, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[S:10][N:9]=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:19][S:20]([O:1][CH2:2][C:3]1[C:11]2[S:10][N:9]=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cccc2nnsc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cccc2nnsc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3.32 g of 7-hydroxymethylbenzo-1,2,3-thiadiazole, 3.1 ml of triethylamine and 0.2 g of 4-dimethylaminopyridine in 50 ml of methylene chloride there is added dropwise with cooling at -5° to 0° C. a solution of 2.23 g of methanesulfonyl chloride in 15 ml of dichloromethane, and the mixture is stirred for 2 hours at room temperature. The reaction mixture is then treated with ice-water and extracted several times using dichloromethane. The combined extracts are washed with water, dried and evaporated. Chromatographic purification on silica gel (CH2Cl2) gives the title compound as a viscous resin.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=2[N:14]=1
Reactant: NCCc1ccccc1
Reactant: CCc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: CCc1cc2c(NCCc3ccccc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-phenethylamino-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Br:16])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[C:18]1([CH2:24][C:25](=[NH:29])OCC)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[Br:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25](=[NH:29])[CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=N)Cc1ccccc1
Reactant: Nc1ncccc1OCc1ccccc1Br
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1ccccc1Br
Yield: 3.5 %

Procedure:
A mixture of 2-amino-3-(2-bromobenzyloxy)pyridine (5.58 g, 20 mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave a residue which was purified by chromatography (silica, chloroform/methanol) and recrystallisation from ethanol/ether to obtain the product (0.28 g), m.p. 158°-169° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([N:10]2[CH2:14][CH2:13][N:12]=[C:11]2SC)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:17][N:18]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[N:18]1([N:17]2[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[O:9])[N:10]3[CH2:14][CH2:13][N:12]=[C:11]23)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CSC1=NCCN1C(=O)c1cccnc1Cl
Reactant: NN1CCCCCC1
Product: O=C1c2cccnc2N(N2CCCCCC2)C2=NCCN12
Temperature: 160 °C
Yield: 66.3 %

Procedure:
A mixture of 10.0 g (39.1 mmoles) of the product of Example 12 and 12.5 g (0.109 mole) of N-aminohomopiperidine was heated at 160° C. for 1 hour. Excess N-aminohomopiperidine was removed by Kugelrohr distillation and the residue was partitioned between methylene chloride and water. The organic layer was dried (sodium sulfate) and concentrated leaving 7.40 g of 10-(hexahydro-1H-azepin-1yl)-2,10-dihydroimidazo[1,2-a]pyrido[2,3-d]pyrimidin-5(3H)-one; melting point 217°-219° C. Total yield 66%.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])=[CH:3][CH:2]=1.[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19]Br.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][N:11]([C:9]([O:8][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)=[O:10])[CH2:12][C:13]([OH:15])=[O:14]
Reactant: COC(CBr)OC
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CN(CC(=O)O)C(=O)OCc1ccccc1)OC
Temperature: 100 °C
Reaction time: 24 h
Yield: 61.2 %

Procedure:
A mixture of N-α-CBZ-glycine (2.0 g, 9.57 mmol), bromoacetaldehyde dimethyl acetal (2.25 mL, 19.13 mmol) and Cs2CO3 (2.78 g, 3.12 mmol) in 20 mL of anhydrous DMF was stirred at 100° C. for 24 h. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate (3×80 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 45-50% ethyl acetate/hexanes to give the product 37 (1.74 g, 61%). 1H NMR (400 MHz, CDCl3) δ 3.38 (s, 6H), 3.98 (d, J=5.7 Hz, 2H), 4.12 (d, J=5.3 Hz, 2H), 4.54 (t, J=5.3 Hz, 1H), 5.10 (s, 2H), 5.50 (bs, 1H), 7.32 (m, 5H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.CCN(C(C)C)C(C)C.C1C=CC(C([N:31]=[C:32]=[S:33])=O)=CC=1>ClCCl>[NH:9]1[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]=[C:5]1[CH2:4][NH:3][C:32]([NH2:31])=[S:33]
Reactant: NCc1nc2ccccc2[nH]1
Reactant: O=C(N=C=S)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=S)NCc1nc2ccccc2[nH]1
Reaction time: 0.08 h
Yield: 61.4 %

Procedure:
To a suspension of 2-(Aminomethyl)benzimidazole dihydrochloride (0.66 g, 3.0 mmol) in dichloromethane (10 mL) was added DIPEA (1.05 mL, 6.0 mmol). The reaction mixture was stirred for 5 minutes and then benzoyl isothiocyante (0.44 mL, 3.3 mmol) was added dropwise. The resulting mixture was stirred for 1 h and then evaporated in vacuo. Ammonia (saturated, in MeOH, 15 mL) was added to the residue. After 4 h the reaction mixture was evaporated. Addition of CH2Cl2 to the residue afforded a solid, which was collected by filtration, washed with dichloromethane and dried to give the title compound (0.38 g, 62%). 1H NMR (DMSO-d6) δ ppm 12.32 (1H), 8.17 (1H), 7.52-7.19 (4H), 4.83 (2H); MS (ESI) m/z 205 (M−1).