Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]([OH:15])=O)[N:9]=2)=[N:3]1.[NH2:16][C@@H:17]([CH3:34])[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[C:30]([F:32])[C:27]([C:28]#[N:29])=[C:26]([Cl:33])[CH:25]=2)=[N:20]1.CN(C=O)C>O.CCOC(C)=O>[Cl:33][C:26]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][N:19]([CH2:18][C@@H:17]([NH:16][C:13]([C:10]3[N:9]=[C:8]([C:4]4[CH:5]=[C:6]([CH3:7])[N:2]([CH3:1])[N:3]=4)[O:12][N:11]=3)=[O:15])[CH3:34])[N:20]=2)[CH:31]=[C:30]([F:32])[C:27]=1[C:28]#[N:29]
Reactant: Cc1cc(-c2nc(C(=O)O)no2)nn1C
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc(C(=O)N[C@@H](C)Cn3ccc(-c4cc(F)c(C#N)c(Cl)c4)n3)no2)nn1C
Yield: 0.5 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 5-(1,5-dimethyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole-3-carboxylic acid (1.614 mmol, 0.336 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile (1.345 mmol, 0.375 g) using DMF (10 ml) as the solvent. The reaction mixture was diluted with water and EtOAc, the phases were separated and the organic phase was washed with 2 M Na2CO3, water and brine. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography and preparative HPLC, respectively. 0.003 g of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.29 (d, 3H), 2.34 (s, 3H), 4.24 (s, 3H), 4.30 (dd, 1H), 4.49 (dd, 1H), 4.61-4.72 (m, 1H), 6.65 (d, 1H), 6.88 (s, 1H), 7.53 (d, 1H), 7.61 (dd, 1H), 7.78-7.82 (m, 1H), 8.01 (d, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH:15]=[O:16])[CH2:11][CH2:10]2)=[CH:5][C:4]=1[F:17])#[N:2].[CH2:18]([CH:21]([CH2:24]O)[CH2:22][OH:23])[CH2:19][CH3:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:10][CH2:11][C@H:12]([CH:15]3[O:23][CH2:22][CH:21]([CH2:18][CH2:19][CH3:20])[CH2:24][O:16]3)[CH2:13][CH2:14]2)=[CH:5][C:4]=1[F:17])#[N:2]
Reactant: CCCC(CO)CO
Reactant: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCC1COC([C@H]2CC[C@H](c3ccc(C#N)c(F)c3)CC2)OC1
Reaction time: 3 h

Procedure:
A mixture of 2.3 g of trans-4-(4-cyano-3-fluorophenyl)-cyclohexanecarbaldehyde, 1.2 g of 2-propylpropane-1,3-diol, 0.01 g of p-toluenesulfonic acid and 15 ml of toluene is boiled for 3 hours under a water separator and is cooled. Working up in the customary manner gives 2-[trans-4-(4-cyano-3-fluorophenyl)-cyclohexyl]-5-propyl-1,3-dioxane.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[N:16][N:15]3[C:24]=2I)=[CH:8][CH:7]=1.[C:26]([Cu])#[N:27]>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[N:16][N:15]3[C:24]=2[C:26]#[N:27])=[CH:8][CH:7]=1
Reactant: CCCOc1ccc2nc(-c3ccc(OCCOC)cc3)c(I)n2n1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: CCCOc1ccc2nc(-c3ccc(OCCOC)cc3)c(C#N)n2n1

Procedure:
A mixture of 2-[4-(2-methoxyethoxy)phenyl]-3-iodo-6-propoxyimidazo[1,2-b]pyridazine (100 mg, 0.22 mmol), cuprous cyanide (22 mg, 0.24 mmol) and N,N-dimethylformamide (2 mL) was heated at 80° for 22 hours. More CuCN (10 mg) was added and the mixture heated at 100° for 29 hours. Aqueous ferric chloride solution (5%, acidified with HCl) (7 mL) was added and the resulting mixture heated at 60° for 30 minutes. The resulting suspension was filtered and the collected solid washed with saturated, aqueous sodium bicarbonate solution, water (twice) and air-dried overnight. The beige coloured solid was radially chromatographed on silica gel. Elution with 0-1% methanol in dichloromethane provided Compound 110 (50 mg, 64%) as a brilliant white solid. 1H n.m.r. (CDCl3) δ 1.06, t, J=7.4 Hz, 3H; 1.76-1.96, m, 2H; 3.47, s, 3H; 3.74-3.82, m, 2H; 4.15-4.22, m, 2H; 4.37, t, J=6.6 Hz, 2H; 6.88, d, J=9.5 Hz, 1H; 7.04, d, J=8.8 Hz, 2H; 7.82, d, J=9.5 Hz, 1H; 8.09, d, J=8.7 Hz, 2H. Mass spectrum (APCI+) m/z 353 (M+H, 100%). Further elution afforded recovered starting material (21 mg, 21%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:6]([C:11]([OH:13])=O)=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:47]1[C:55]2[C:50](=[C:51]([C:56]3[CH:57]=[C:58]([NH2:65])[C:59]4[CH:60]=[N:61][NH:62][C:63]=4[CH:64]=3)[CH:52]=[CH:53][CH:54]=2)[CH:49]=[CH:48]1>CN(C=O)C>[NH:47]1[C:55]2[C:50](=[C:51]([C:56]3[CH:64]=[C:63]4[C:59]([CH:60]=[N:61][NH:62]4)=[C:58]([NH:65][C:11]([C:6]4[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=[CH:8][N:7]=4)=[O:13])[CH:57]=3)[CH:52]=[CH:53][CH:54]=2)[CH:49]=[CH:48]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: CS(=O)(=O)c1cccnc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cccnc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.6 %

Procedure:
To 3-(methylsulfonyl)-2-pyridinecarboxylic acid (which may be prepared as described by Blank, Benjamin; DiTullio, Nicholas W.; Owings, Franklin F.; Deviney, Linda; Miao, Clara K.; Saunders, Harry L. Journal of Medicinal Chemistry (1977), 20(4), 572-576.) (89 mg, 0.44 mmol) was added O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (172 mg, 0.45 mmol), DIPEA (0.106 ml) and DMF (1 ml). The reaction was stirred for 20 mins at 25° C. 6-(1H-Indol-4-yl)-1H-indazol-4-amine (50 mg, 0.20 mmol) was added and the reaction was stirred for a further 20 h at 25° C. The solvent was dried under a stream of nitrogen to give the crude product. This sample in DMF was loaded onto an aminopropyl cartridge (5 g) and after standing for 3 h, the column was washed with 10% methanol in dichloromethane. The appropriate fractions were combined and dried under a stream of nitrogen to give the crude product which was purified by Mass Directed Automated Preparative HPLC (Method B). The solvent was dried under a stream of nitrogen to give the title compound (29 mg).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:23][C:24]1[O:25][C:26]([C:29]2[C:37]([O:38][CH3:39])=[CH:36][C:32]([C:33]([OH:35])=O)=[CH:31][C:30]=2[O:40][CH3:41])=[CH:27][N:28]=1.Cl.[NH:43]1[C:47]([C:48]2[CH:49]=[C:50]3[C:60](=[CH:61][CH:62]=2)[O:59][C:53]2([CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)[CH2:52][C:51]3=[O:63])=[N:46][N:45]=[N:44]1>O.CN(C=O)C.CCN(CC)CC>[CH3:23][C:24]1[O:25][C:26]([C:29]2[C:30]([O:40][CH3:41])=[CH:31][C:32]([C:33]([N:56]3[CH2:57][CH2:58][C:53]4([CH2:52][C:51](=[O:63])[C:50]5[C:60](=[CH:61][CH:62]=[C:48]([C:47]6[NH:46][N:45]=[N:44][N:43]=6)[CH:49]=5)[O:59]4)[CH2:54][CH2:55]3)=[O:35])=[CH:36][C:37]=2[O:38][CH3:39])=[CH:27][N:28]=1
Reactant: COc1cc(C(=O)O)cc(OC)c1-c1cnc(C)o1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)cc(OC)c1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Et3N (28 μL), HOBT (15 mg) and WSC hydrochloride (19 mg) were added to a DMF (3 mL) solution of 4-(2-methyl-1,3-oxazol-5-yl)-3,5-dimethoxybenzoic acid (22 mg) and 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (32 mg), and stirred overnight at room temperature. Water was added to the reaction liquid, the formed solid was taken out through filtration, and the solid was washed with water and ether. The solid was dried under reduced pressure to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 8.42 (1H, d, J=4.0 Hz), 8.23 (1H, dd, J=8.0, 4.0 Hz), 7.32 (1H, d, J=8.0 Hz), 7.08 (1H, s), 6.75 (2H, s), 4.32-4.18 (1H, m), 3.79 (6H, s), 3.64-3.20 (3H, m), 2.97 (2H, s), 2.41 (3H, s), 2.10-1.75 (4H, m). MS [M+H]+=531.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:25][CH3:26])[N:3]=1.[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28]1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:27](=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:25][CH3:26])[N:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(CO)cc2)nc(N)n1
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(COC(=O)CCC(=O)O)cc2)nc(N)n1
Reaction time: 16 h
Yield: 100 %

Procedure:
To a stirred suspension of the title compound of Example 44 (0.300 g, 0.809 mmol) and succinic anhydride (0.097 g, 0.971 mmol) in chloroform (10 ml) was added 4-dimethyl-amino-pyridine (0.138 g, 1.13 mmol). After stirring for 16 hours, the mixture was concentrated under reduced pressure. Water (10 ml) was added and the mixture was adjusted to pH 2 by addition of aqueous potassium hydrogen sulfate solution (0.5 M). The solid was filtered and dried under reduced pressure to provide the title compound (0.381 g, 81% yield). 1H NMR (DMSO-d6) δ1.38 (t, 3H, J=6.9 Hz, CH3), 2.48-2.50 (m, 2H, CH2), 2.50-2.52 (m, 2H, CH2), 4.13 (q, 2H, J=6.9 Hz, CH2), 5.05 (s, 2H, CH2), 6.28 (s, 2H, NH2), 6.79 (s, 1H, Ar), 7.14 (d, 1H, J=8.9 Hz, Ar), 7.29 (d, 2H, J=8.9 Hz, Ar), 7.41 (dd, 1H, J=8.9 Hz, 2.9 Hz, Ar), 7.71 (d, 2H, J=8.5 Hz, Ar), 7.93 (s, 1H, Ar), 9.22 (s, 1H, NH), 12.05 (s, 1H, COOH).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[OH:18][C:19]1[C:20]([SH:25])=[N:21][CH:22]=[CH:23][CH:24]=1>>[OH:18][C:19]1[C:20]([S:25][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: Oc1cccnc1S
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Product: O=C1CCc2cc(OCCCCSc3ncccc3O)ccc2N1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.) and 3-hydroxy-2-mercapto-pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:13][CH2:14][C:15]([OH:17])=O)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([S:13][CH2:14][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:17])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CSc1nc(-c2ccc(F)cc2)cs1
Reactant: Nc1ccccn1
Product: O=C(CSc1nc(-c2ccc(F)cc2)cs1)Nc1ccccn1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.37 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylsulfanyl]-acetic acid and 69.9 mg (0.74 mmol) of 2-amino-pyridine. Yield: 20 mg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([NH2:19])[CH:13]=[CH:12]3)[CH:2]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:29][CH3:30])=[C:25]([CH:28]=1)[CH:26]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:29][CH3:30])=[C:25]([CH:28]=1)[CH2:26][NH:19][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([NH:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:10]=2)[N:15]=1
Reactant: COc1ccc(F)cc1C=O
Reactant: Nc1ccc2cc(NCc3cccnc3)ccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(F)cc1CNc1ccc2cc(NCc3cccnc3)ccc2n1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
N6-Pyridin-3-ylmethyl-quinoline-2,6-diamine (150 mg, 0.6 mmol) was dissolved in 10 mL dichloromethane. 5-Fluoro-2-methoxybenzaldehyde (111 mg, 0.72 mmol) and acetic acid (72 mg, 1.2 mmol) were added. The reaction mixture was stirred at 40° C. for 3 h. Sodium triacetoxy borohydride (254 mg, 1.2 mmol) was added and stirring was continued at room temperature overnight. The reaction mixture was quenched by addition of 20 mL sat. sodiumbicarbonate solution. The mixture was extracted three times with dichloromethane (20 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue purified by flash chromatography on silica gel (dichloromethane/methanol 100:0->90:10 gradient). The title compound was obtained as a yellow gum (17 mg, 7%), MS: m/e=389.3 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]#[C:26][CH3:27])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:10]([C:28](=[O:31])[NH:29][OH:30])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:30][NH:29][C:28]([CH:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]#[C:26][CH3:27])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:31]
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2C(=O)NO)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CCOc1ccc(S(=O)(=O)N2CCNCC2C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.147 g (0.325 mmol) of the product of Example 58, 4-(4-but-2-ynyloxy-benzenesulfonyl)-3-hydroxycarbamoyl-piperazine-1-carboxylic acid tert-butyl ester, in 3.0 mL of dichloromethane was added 0.3 mL of trifluoroacetic acid and the reaction was stirred at room temperature for 1 h. The reaction was then concentrated in vacuo and the residue was diluted with dichloromethane. The organics were washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo to provide 0.053 g of 1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic acid hydroxyamide as a tan solid. Electrospray Mass Spec 354.2 (M+H)+
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[N:26]1[C:35]2[C:30](=[C:31]([NH:36][NH2:37])[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>>[N:26]1[C:35]2[C:30](=[C:31]([N:36]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=5)[N:8]=4)=[CH:4][CH:3]=[N:37]3)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: NNc1cccc2ncccc12
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1cccc2ncccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and quinolin-5-yl-hydrazine according to the method described for example 91. MS: M=450.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([OH:20])[C:11]([NH:14][CH2:15][C:16]([O:18]C)=[O:17])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.O1CCCC1.[OH-].[Na+].Cl>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([OH:20])[C:11]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CNc1ncc(-c2cccc(Cl)c2)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)CNc1ncc(-c2cccc(Cl)c2)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a 20 L reactor equipped with a mechanical stirrer, condenser, thermometer and nitrogen inlet was charged methyl {[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]amino}-acetate, 4, (440 g, 1.42 mol), tetrahydrofuran (3912 g, 4400 mL) and 1 M NaOH (4400 mL). The mixture was stirred for 2 hours at room temperature after which it was determined by TLC analysis using hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm to visualize the reaction components that the reaction was complete. The reaction solution was acidified to a pH of 2 with slow addition of 2M HCl (2359 g). The resulting mixture was concentrated under reduced pressure to a volume of about 7.5 L. Ware (2210 g) was added and the solution cooled to ambient temperature and agitated for 18 hours. The solid product was isolated by filtration and washed with water (6 L). the crude product was transferred back into the reactor and triturated with 2215 g o deionized water at 70° C. for 16 hours. The mixture was cooled to ambient temperature, The solid product was isolated by filtration and washed with water (500 mL) and dried under reduced pressure at 70° C. for 20 hours to afford 368 g (87% yield) of the desired product as an off-white solid. Purity by HPLC was 99.3%. 1H NMR (DMSO-d6) δ 12.84 (s, 1H), 12.39 (s, 1H), 9.39 (t, 1H), 8.56 (d, 1H), 7.94 (s, 1H), 7.81 (m, 2H), 7.55 (q, 2H), and 4.02 (d, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.[CH3:14][NH2:15].C(O)C>O>[CH3:14][NH:15][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Reactant: CN
Solvent: O
Solvent: CCO
Product: CCOC(=S)c1cnc(C)nc1NC
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (Aldrich, 20 g, 86 mmol) in 250 mL of dichworomethane at 0° C. was added slowly solution of methylamine in ethanol (33%, 35 mL 281 mmol). After stirring for 30 minutes, water (150 mL) was added and the phases were separated. The organic phase was dried (MgSO4) and filtered. The filtrate was evaporated under reduced pressure to give 19 g of the ethyl 4-methylamino-2-methylthiopyrimidine-5-carboxylate as a white solid.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[S:5])[CH3:2].[SH:6][CH2:7][C:8]([OH:10])=O.N1C=CC=CC=1>C1C=CC=CC=1>[CH2:1]([N:3]1[C:8](=[O:10])[CH2:7][S:6][C:4]1=[S:5])[CH3:2]
Reactant: CCN=C=S
Reactant: O=C(O)CS
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCN1C(=O)CSC1=S

Procedure:
Ethylisothiocyanate (10 g, 0.115 moles), 7.9 g(0.086 moles) mercaptoacetic acid and 5 mL pyridine in C6H6 was refluxed, cooled and filtered yielding 3-ethylrhodanine, which was used in the next step without any further purification. Reaction of 3-ethylrodanine with piperonal in the presence of sodium acetate was performed in CH3OH under refluxing for 1 h. The yellow precipitate obtained after cooling and filtration, was washed several times with CH3OH on the filter and crystallizated from CH3OH to give 3-ethyl-5-piperilidenerodanine. 1H-NMR(DMSO-d6, 300 MHz):7.72 (s, 1H), 7.1–7.3 (m, 3H), 6.14 (s, 2H), 3.95–4.15 (q, 2H), 1.15–1.20 (t, 3H). 13C-NMR (75.48 MHz): 12.76, 40.28, 103.07, 110.21, 110.47, 120.68, 127.89, 128.07, 134.01, 149.23, 150.74, 167.57, 193.68. (2) 3-Ethyl-5-piperilidene-rodanine (1 g, 3.4 mmoles) was added to a stirred solution of 0.16 g (6.8 mmoles) in 8 mL abs. ethanol and the mixture was refluxed for 30 min. To the solution cooled to room temperature 5 mL H2O were added and the mixture was hydrolized with 10% HCl and extracted with ether. The ether phase was separated, dried (MgSO4) and evaporated to an oil. Since the investigation by TLC of the crude reaction mixture indicated the presence of piperonal, the reaction mixture was dissolved in CH2Cl2 and the obtained solution was washed with 1M NaOH. The aqueous phase was extracted twice with CH2Cl2 and then neutralized with dilute HCl. Free thiol was extracted with ethyl ether. After concentration, the product was purified by column cromatography eluating with hexane/ethyl ether:8/2. Yield 0.4 g (62.4%). 1H-NMR(CDCl3, 300 MHz):7.69 (s, 1H), 7.7.25–7.29 (d, 1H, J 1.46), 7.1–7.18 (m, 1H), 6.85–6.9 (d, 1H, J 8.13), 6.01 (s, 2H), 4.75 (s, 1H), 4.28–4.38 (q, 2H, J 7.12), 1.35–1.42 (t, 3H, J 7.13). 13C-NMR (75.48 MHz): 14.20, 62.5, 101.41, 108.37, 109.43, 121.06, 125.45, 129.20, 134.68, 147.80, 148.05, 165.43.
Reaction SMILES: [P:1]([OH:9])([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[O:2].[CH2:10]1[O:12][CH2:11]1>>[P:1]([O:9][CH2:10][CH2:11][OH:12])([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: C1CO1
Reactant: CCOP(=O)(O)OCC
Product: CCOP(=O)(OCC)OCCO
Reaction time: 3 h

Procedure:
A 2 liter, 3-necked flask was equipped with a Dewar condenser, gas inlet and stirring bar. 875 grams (5.7 mole) of diethyl hydrogen phosphate was placed into the flask and about 400 grams of ethylene oxide were added over a 4 hour period. When the exotherm slowed, (pot temperature 50° C.) acid number=70. After the exotherm ceased and temperature dropped to 40° C., acid number=about 50. After refluxing of the ethylene oxide at 50° C. for 1 hour, acid number=about 18, after 3 hours at 50° C. acid number=about 7. All the above acid numbers were based on methyl red end point titration. The total yield was 1171 grams. Approximately half of the product was then wipe film distilled at 80° C. and 0.5 millimeter Hg. NMR data showed a compound having the formula: ##STR26## acid number=1.7 to methyl red, 6.7 to PNB HCl acid to methyl red=14.3 to phenolphthalein=16.3
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].C([N:18]([CH:21]([CH3:23])[CH3:22])CC)(C)C.C1(N)CC1>C(O)C>[CH:21]1([NH:18][C:2]2[N:10]=[C:9]([F:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]([CH3:14])[CH3:13])[CH2:23][CH2:22]1
Reactant: CC(C)n1cnc2c(Cl)nc(F)nc21
Reactant: CCN(C(C)C)C(C)C
Agent: NC1CC1
Solvent: CCO
Product: CC(C)n1cnc2c(NC3CC3)nc(F)nc21
Yield: 70.4 %

Procedure:
6-Chloro-2-fluoro-9-isopropyl-9H-purine (0.3 g, 1.4 mmol), diisopropylethylamine (0.2 g, 1.55 mmol) and cyclopropylamine (0.2 g, 2.66 mmol) were stirred together in ethanol (30 ml) at room temperature for 6 h. Volatiles were removed and the residue taken up in ethyl acetate, washed with water (50 ml), brine (50 ml), dried (MgSO4) and concentrated. The crude was purified by silica gel flash column chromatography (ethyl acetate:hexane 3:2) to give the pure product (232 mg, 70.5%) δH (CDCl3, 500 MHz) 0.63-0.55 (2 H, m, CHHCHH of Cp), 0.85-0.78 (2 H, m, CHHCHH of Cp), 1.54 (6H, d, J 7.5, CH[CH3]2), 2.97 (1 H, s, br, CH of Cp), 4.73-4.62 (1 H, m, CHMe2), 6.72 (1 H, s, br, NH) 7.7 (1 H, s, ArH); δC (CDCl3, 500 MHz) 159.29 (C), 157.63 (C), 156.8 (C), 156.64 (C), 137.69 (CH), 47.35 (CH), 22.6 (2×CH3), 21.06 (CH), 7.28 (2×CH2); m/z 236.2 (M+H)
Reaction SMILES: CN(C)[CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH:6]([OH:10])[C:5]1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:35][C:36]([NH2:38])=[NH:37])[CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]1>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:35][C:36]2[N:38]=[CH:3][C:4]3[CH2:9][CH2:8][CH2:7][CH:6]([OH:10])[C:5]=3[N:37]=2)[CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]1
Reactant: CN(C)C=C1CCCC(O)C1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(O)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 2-[1-dimethylamino-methylidene]-6-hydroxy-cyclohexanone (188 mg, 1 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (223 mg, 0.60 mmol) using in analogous manner the procedure described in example 45b). Obtained as a white solid (36 mg, 17%). MS ISP (m/e): 352.3 (100) [(M+H)+].
Reaction SMILES: [C:1]1([N:7]=[C:8]([S:11][CH:12]([CH2:18][CH3:19])[CH:13]([CH3:17])[CH2:14][CH2:15][CH3:16])[C:9]#[CH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][CH:10]=[CH:9][C:8](=[N:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:11][CH:12]([CH2:18][CH3:19])[CH:13]([CH3:17])[CH2:14][CH2:15][CH3:16])=[CH:23][CH:22]=1
Reactant: Fc1ccc(S)cc1
Reactant: C#CC(=Nc1ccccc1)SC(CC)C(C)CCC
Solvent: ClC(Cl)Cl
Product: CCCC(C)C(CC)SC(C=CSc1ccc(F)cc1)=Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.8 %

Procedure:
1-ethyl-2-methylpentyl N-phenylpropynthioimidate (0.44 g) was dissolved to chloroform (8 mL), chloroform (3 mL) solution of 4-fluorothiophenol (0.16 g) was added to the solution under ice-cooling, and then it was stirred for 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to medium pressure HPLC (hexane/ethyl acetate=98/2) to obtain 1-ethyl-2-methylpentyl 3-(4-fluorophenylthio)-N-(phenyl)thioacrylimidate (0.28 g) as pale yellow oil.