Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:14]2[C:10]([S:11][CH:12]=[CH:13]2)=[N:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=O.Cl.[NH2:25]/[C:26](/[NH:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]1)=[N:27]/[H].[O-]CC.[Na+]>C(O)C>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:8]2[N:9]=[C:10]3[N:14]([C:7]=2[C:5]2[CH:4]=[CH:3][N:27]=[C:26]([NH:29][C@@H:30]4[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]4)[N:25]=2)[CH:13]=[CH:12][S:11]3)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(-c2nc3sccn3c2C(=O)C=CN(C)C)c1
Reactant: [H]/N=C(/N)N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)n2)c1
Yield: 92.9 %

Procedure:
A mixture of 3-(dimethylamino)-1-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]prop-2-en-1-one (5.0 g, 15.3 mmol) and tert-butyl (3R)-3-{[(Z)-amino(imino)methyl]amino}piperidine-1-carboxylate hydrochloride (5.28 g, 18.95 mmol) was diluted with 60 ml of absolute ethanol and treated with 1.15 eq. of a 21% w/w solution of sodium ethoxide in ethanol (6.56 ml) to form a reaction mixture. The reaction mixture was heated to reflux for 24 hours. Volatiles were removed in vacuo and the residue was taken up in 250 ml of ethyl acetate and 250 ml of water. The phases were separated and the aqueous phase was extracted with 250 ml of ethyl acetate. The combined organic extracts were washed with 250 ml each of water, and then with a saturated sodium chloride solution (250 ml). The organic phase was dried with magnesium sulfate, filtered and concentrated in vacuo, to give a yellow oil. The product was purified by flash chromatography on silica gel (ethyl acetate/hexanes, 50%) to yield 7.2 g of a pale yellow solid (93%). 300 MHz 1H NMR (DMSO-d6 at 80° C.) δ: 8.69 (d, J=3.5 Hz, 1H), 8.10 (d, J=5.3 Hz, 1H), 7.32-7.41 (m, 2H), 7.12-7.18 (m, 2H), 6.91-7.02 (m, 2H), 6.41 (d, J=5.3 Hz, 1H), 3.94 (br. d, J=7.0, 1H), 3.74-3.88 (m, 1H), 3.78 (s, 3H), 3.67 (br. d, J=13.2, 1H), 2.86-3.02 (m, 2H), 1.90-2.06 (m, 1H), 1.70-1.84 (m, 1H), 1.38-1.64 (m, 2H), 1.34 (s, 9H). LCMS: 507 [M+H].
Reaction SMILES: [CH:1]1([C:4](=[O:25])[C:5](=[CH:21]OCC)[C:6]([C:8]2[CH:18]=[CH:17][C:11]3[S:12][CH:13]=[C:14]([O:15][CH3:16])[C:10]=3[C:9]=2[O:19][CH3:20])=[O:7])[CH2:3][CH2:2]1.Cl.[NH2:27]O.C([O-])(=O)C.[Na+].O>C(O)C>[CH:1]1([C:4]2[O:25][N:27]=[CH:21][C:5]=2[C:6]([C:8]2[CH:18]=[CH:17][C:11]3[S:12][CH:13]=[C:14]([O:15][CH3:16])[C:10]=3[C:9]=2[O:19][CH3:20])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC=C(C(=O)c1ccc2scc(OC)c2c1OC)C(=O)C1CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1csc2ccc(C(=O)c3cnoc3C3CC3)c(OC)c12
Yield: 44.5 %

Procedure:
A solution containing 5-(3-cyclopropyl-2-ethoxymethylene-1,3-dioxoprop-1-yl)-3,4-dimethoxybenzo[b]thiophene (0.59 g) and hydroxylamine hydrochloride (0.137 g) was stirred for 15 minutes in ethanol. Sodium acetate (anhydrous, 0.161 g) was added and the mixture stirred for 4 hours, before evaporation of the ethanol and addition of water. The mixture was extracted with ethyl acetate, dried (anhydrous magnesium sulphate) and evaporated in vacuo. The residue was purified by column chromatography on silica, eluting with ether/cyclohexane to yield 5-cyclopropyl-4-(3,4dimethoxybenzo[b]thien-5-oyl)isoxazole (compound 3, 0.24 g) as an oil, NMR δ1.20 (2H,m), 1.35 (2H,m), 2.80 (1H,m), 3.84 (3H,s), 4.00 (3H,s), 6.39 (1H,s), 7.40 (1H, d), 7.59 (1H, d), 8.29 (1H,s).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:21]=[C:22]([NH2:24])[N:23]=3)[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:26]1[CH:27]=[C:28]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:21]=[C:22]([NH:24][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)[CH:27]=4)[N:23]=3)[CH:14]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(c2cccc(Br)c2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)cn3nc(N)nc23)cc1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cc(C(F)(F)F)cn4n3)c2)CC1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and 1-(3-bromo-phenyl)-4-methyl-piperazine in a manner analogous to Step 2d and was isolated as a yellow solid (2% yield). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.84 (s, 1H), 8.28 (d, J=8.3 Hz, 2H), 8.14 (d, J=7.2 Hz, 2H), 7.81 (s, 1H), 6.95 (m, 2H), 6.64 (d, 1H), 3.32 (bm, 4H), 3.14 (s, 3H), 2.67 (bm, 4H), 2.44 (s, 3H). MS=531.1 (MH)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C(O)=O>C(#N)C>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:2][C:3]([NH:5][C:6]2[CH:19]=[CH:18][C:9]3[O:10][C:11]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[C:8]=3[CH:7]=2)=[O:4])[CH2:23][CH2:22]1
Reactant: O=C(CCl)Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(CC(=O)Nc2ccc3oc4c(c3c2)CCCCC4)CC1
Yield: 25.4 %

Procedure:
Following the procedure of Example 40, 2-chloro-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.13 g, 0.45 mmol), N-methylpiperazine (0.062 mL, 0.56 mmol), and cesium carbonate (0.29 g, 0.90 mmol) in acetonitrile (5 mL) provided 2-(4-methylpiperazin-1-yl)-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.039 g) as its trifluroacetic acid salt after reverse-phase HPLC purification. MS (ESI) m/z 342 ([M+H]+).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[Se:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>>[C:1]1([NH:7][C:11]([C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[Se:8][S:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCS
Reactant: O=c1c2ccccc2[se]n1-c1ccccc1
Product: O=C(O)CCS[Se]c1ccccc1C(=O)Nc1ccccc1

Procedure:
Prepared similar to example 1 from 5 g (18,2 mmol) of 2-phenyl-1,2-benzisoselenazole-3(2H)-one and 2 g (18,9 mmol) of 3-mercaptopropionic acid.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:28][CH3:29])=[C:7]([CH2:19][CH2:20][C:21]2[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH:8]=[C:9]([C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[C:1]([C:5]1[C:6]([O:28][CH3:29])=[C:7]([CH2:19][CH2:20][C:21]2[N:26]=[CH:25][C:24]([NH:27][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:23][CH:22]=2)[CH:8]=[C:9]([C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ncccc1-c1cc(CCc2ccc(N)cn2)c(OC)c(C(C)(C)C)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ncccc1-c1cc(CCc2ccc(NS(C)(=O)=O)cn2)c(OC)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
step 3—To a solution of 182 (0.183 g, 0.467 mmol), pyridine (0.076 mL, 0.935 mmol) and DCM (5 mL) was added dropwise methanesulfonyl chloride (0.268 g, 2.337 mmol). The reaction was stirred overnight at RT then evaporated and taken up in EtOAc, washed with water, dried (MgSO4), filtered and evaporated. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient to afford 0.099 g of N-(6-{2-[3-tert-butyl-2-methoxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-pyridin-3-yl)-methanesulfonamide (184) along with the bis-mesylated byproduct.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([C:15]#[C:16][Si](C)(C)C)=[C:13]([O:21][C:22](=[O:24])[CH3:23])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.[F-].[K+]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([C:15]#[CH:16])=[C:13]([O:21][C:22](=[O:24])[CH3:23])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(OC(C)=O)c1C#C[Si](C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1c(CC(=O)OC)cc2ccc(F)cc2c1OC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
To a solution of (4-acetoxy-6-fluoro-3-trimethylsilanylethynyl-naphthalen-2-yl)-acetic acid methyl ester (200 mg, 0.538 mmol) in N,N-dimethylformamide and water (6 mL, v/v=150:1), was added potassium fluoride (156 mg, 2.7 mmol). The resulting mixture was stirred at room temperature for 4 hours, then poured into water (10 mL), and extracted with ethyl acetate (10 mL×3). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column (elution with 10% ethyl acetate in petroleum ether) to afford (4-acetoxy-3-ethynyl-6-fluoro-naphthalen-2-yl)-acetic acid methyl ester (153 mg, 95%) as a light yellow solid.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[C:6]([OH:25])(=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH3:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([O:25][CH2:1][CH:2]([OH:3])[CH2:4][OH:5])=[O:24]
Reactant: OCC1CO1
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO
Yield: 80.9 %

Procedure:
The experiment was carried out under the same conditions as in Example 3 but using a molar ratio of glycidol:stearic acid of 1.3:1. After 3 hours the amount of glycidol equivalent to the stearic acid had reacted and the mixture was cooled and worked up in a manner analogous to Example 1. There were obtained 116 grams of monostearin (80.9% yield) with the following properties:
Reaction SMILES: Cl.[F:2][CH2:3][C@@H:4]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:18][F:19])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[O:7]C(C)(C)[N:5]1C(OC(C)(C)C)=O>CO>[NH2:5][C@H:4]([CH2:3][F:2])[C@@H:8]([C:9]1[CH:10]=[CH:11][C:12]([S:15]([CH2:18][F:19])(=[O:17])=[O:16])=[CH:13][CH:14]=1)[OH:7]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(S(=O)(=O)CF)cc2)OC1(C)C
Agent: Cl
Solvent: CO
Product: N[C@H](CF)[C@H](O)c1ccc(S(=O)(=O)CF)cc1
Temperature: 40 °C
Yield: 96.8 %

Procedure:
A solution of 6N HCl (30 ml, 5.5 eq ) was added to a solution of 16 (12.0 g) in 200 ml of MeOH at room temperature, and the reaction mixture was warmed up to 40° C. overnight. Methanol was removed in vacuo. The reaction mixture was washed with diethyl ether (50 ml×2). The aqueous solution was neutralized with 2N NaOH and extracted with ethyl acetate (100 ml×3). The organic layer was washed with brine, dried over sodium sulfate, and concentrated to provide the pure desired product (7.6 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15](=[O:22])OCC(Cl)(Cl)Cl)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:23]1([C:29]2[N:33]=[C:32]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[S:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15]([N:37]3[CH2:38][CH2:39][N:34]([C:32]4[S:31][N:30]=[C:29]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[N:33]=4)[CH2:35][CH2:36]3)=[O:22])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(NC(=O)OCC(Cl)(Cl)Cl)cn2)CC1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CN1CCN(c2ccc(NC(=O)N3CCN(c4nc(-c5ccccc5)ns4)CC3)cn2)CC1
Yield: 10.3 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl [6-(4-methylpiperazin-1-yl)pyridin-3-yl]carbamate (271 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 1 day. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography (YMC HPLC Column eluted with 10% to 100% Liquid A; Liquid A: a 0.1% solution of trifluoroacetic acid in acetonitrile; Liquid B: an aqueous 0.1% trifluoroacetic acid solution) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 35.4 mg (10.3%) of the desired product as a solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[NH2:19][NH2:20]>>[NH:19]([C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:20]
Reactant: Clc1cc(-c2ccccc2)c2ccccc2n1
Reactant: NN
Solvent: O
Product: NNc1cc(-c2ccccc2)c2ccccc2n1

Procedure:
Refluxing a 2-chloro-4-phenylquinoline (I) with hydrazine hydrate to give a 2-hydrazino-4-phenylquinoline (II);
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:17]4[CH:18]=[C:19]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[N:20]5[C:25]=4[C:24]([NH2:26])=[N:23][CH:22]=[N:21]5)[CH:13]=[CH:14]3)=[N:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC[C:35]([N:37]([CH3:39])[CH3:38])=[O:36]>>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[CH2:28][CH2:29][N:30]([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH2:31][CH2:32]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: CN(C)C(=O)CCl
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(CC5CCCCC5)nc4c3)c12
Product: CN(C)C(=O)N1CCC(c2cc(-c3ccc4cn(CC5CCCCC5)nc4c3)c3c(N)ncnn23)CC1
Yield: 31 %

Procedure:
In a manner similar to the procedure described for Example 369 and using 5-[2-(cyclohexylmethyl)-2H-indazol-6-yl]-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and substituting dimethylcarbamyl chloride for 2-chloro-N,N-dimethylacetamide as starting materials, 21 mg (31%) of the desired product was isolated. 1H NMR (400 MHz, CD3OD) δ 8.25 (s, 1 H) 7.79-7.83 (m, 2 H) 7.65 (s, 1 H) 7.21 (d, 1 H) 6.60 (s, 1 H) 4.28 (d, 2 H) 3.83 (d, 2 H) 3.36-3.41 (m, 1 H) 2.97 (td, 2 H) 2.87 (s, 6 H) 1.99-2.16 (m, 3 H) 1.58-1.85 (m, 7 H) 1.04-1.27 (m, 5 H). LC-MS [M+H]+=501.6, RT=3.04 min.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:28][CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:10]=12)C1C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1CC1N2CCN(C)C(=O)C2=C(O)C(=O)N=1>>[OH:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)[N:11]2[CH2:28][CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:10]=12
Reactant: CN1CCn2c(CC3(c4ccccc4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: CN1CCn2c(Cc3ccccc3-c3ccccc3)nc(=O)c(O)c2C1=O
Product: CN1CCn2c(CC3(c4ccccc4)CCCC3)nc(=O)c(O)c2C1=O
Yield: 69.3 %

Procedure:
9-Hydroxy-2-methyl-6-(1-phenyl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (32-01) (164 mg, 69%) was synthesized from 9-benzyloxy-2-methyl-6-(1-phenyl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (31-01) (300 mg, 0.67 mmol) as an off-white solid following the procedure as described for 6-biphenyl-2-ylmethyl-9-hydroxy-2-methyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (12-01).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[C:7]2[C:14]([C:15](=[O:19])[C:16]([NH2:18])=[O:17])=[C:13]([CH2:20][CH3:21])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[C:8]=2[N:9]=[CH:10][N:11]=1.[OH-].[Na+]>CO>[NH2:18][C:16](=[O:17])[C:15]([C:14]1[C:7]2[C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])=[N:11][CH:10]=[N:9][C:8]=2[N:12]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C:13]=1[CH2:20][CH3:21])=[O:19]
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)ncnc2n1Cc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)ncnc2n1Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.4 %

Procedure:
A mixture of 67 mg (0.15 mmol) of [[5-(aminooxoacetyl)-6-ethyl-7-[(3-chlorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester and 2 mL of methanol were treated with 0.15 mL of 2 M sodium hydroxide and stirred at ambient temperature for 3 days. The reaction was concentrated to an oil then diluted with 5 mL of water. The product precipitated upon the addition of 0.45 mL of 1 M HCl to provide 59 mg (95%) of [[5-(aminooxoacetyl)-6-ethyl-7-[(3-chlorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid as a white solid. nmr (500 MHz, dmso-d6) δ1.01 (t, J=7.4 Hz, 3H), 2.95 (q, J=7.4 Hz, 2H), 4.92 (s, 2H), 5.60 (s, 2H), 7.03 (d, J=7.4 Hz, 1H), 7.26 (s, 1H), 7.34 (m, 2H), 7.58 (br s, 1H), 8.00 (br s, 1H), 8.46 (s, 1H), 12.9 (br s, 1H)
Reaction SMILES: [Na+:1].N1(C[CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:16]([C:19]3[S:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[C:20]=3[CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[CH:31][CH:30]=3)=[CH:15][C:11]=2[C:12]([O-:14])=[O:13])CCCC1.ClC[CH2:45][CH2:46][C:47]([O:49]C)=[O:48]>>[Na+:1].[Na+:1].[C:47]([CH2:46][CH2:45][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:16]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C:20]=2[CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:33][CH:34]=2)=[CH:15][C:11]=1[C:12]([O-:14])=[O:13])([OH:49])=[O:48].[C:47]([CH2:46][CH2:45][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:16]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C:20]=2[CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:33][CH:34]=2)=[CH:15][C:11]=1[C:12]([O-:14])=[O:13])([OH:49])=[O:48]
Reactant: O=C([O-])c1cc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)ccc1OCCN1CCCC1
Reactant: COC(=O)CCCCl
Agent: [Na+]
Product: O=C(O)CCCOc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1C(=O)[O-]
Yield: 54 %

Procedure:
The title compound was prepared in 54% yield by essentially following the procedures outlined in above in Example 1, Part A, from the phenol of Example 1, Part I, above, and methyl 4-chlorobutyrate.
Reaction SMILES: O1CCOCC1.[Cl:7][C:8]1[C:17]([C:18](=[O:25])[C:19](=[CH:21][N:22](C)C)[CH3:20])=[C:16]([Cl:26])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].Cl.NO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C.C1(C)C=CC=CC=1.O>[Cl:7][C:8]1[C:17]([C:18]2[O:25][N:22]=[CH:21][C:19]=2[CH3:20])=[C:16]([Cl:26])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc(Cl)c(C(=O)C(C)=CN(C)C)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: NO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(Cl)c(-c2oncc2C)c1Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of 30 ml dioxane and 16 ml water, was dissolved methyl 2,4-dichloro-3-(2-dimethylaminomethylidene-1-oxopropyl)benzoate in an amount of 7.57 g, and the resulting solution was then added with hydroxylamine hydrochloride in an amount of 1.70 g and further stirred for 17 hours at an ambient temperature. After distillating out the solvent in the solution under reduced pressure, the residue obtained was dissolved in ethyl acetate, and the solution was then washed with saturated saline solution and dried with anhydrous magnesium sulfate. After distillating out the solvent in the solution under reduced pressure, crude oxime-form of the product obtained was dissolved in 30 ml toluene and then stirred for 14.5 hours under reflux and heating following to the addition of p-toluenesulfonic acid in an amount of 0.5 g. The reacted-mixture was cooled, then washed with water and saturated saline solution in turn and dried with anhydrous magnesium sulfate. The solvent used for the mixture was then condensed under reduced pressure, and the residue obtained was purified by using a silica gel column chromatography to obtain an objective product, methyl 2,4-dichloro-3-(4-methylisoxazol-5-yl)benzoate in an amount of 0.83 g.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[C:8]([CH3:12])[N:9]=[C:10](Cl)[C:5]2=[N:4][CH:3]=1.Cl.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>C(O)C(C)C>[Br:1][C:2]1[N:6]2[CH:7]=[C:8]([CH3:12])[N:9]=[C:10]([NH:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([S:22]([NH2:25])(=[O:23])=[O:24])=[CH:20][CH:21]=3)[C:5]2=[N:4][CH:3]=1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1cn2c(Br)cnc2c(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)CO
Product: Cc1cn2c(Br)cnc2c(NCc2ccc(S(N)(=O)=O)cc2)n1
Temperature: 108 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
To a solution of 3-bromo-8-chloro-6-methyl-imidazo[1,2-a]pyrazine (350 mg, 1.42 mmol) in iBuOH (3 mL) is added 4-aminomethyl-benzenesulfonamide hydrochloride (334 mg, 1.42 mmol) and DIPEA (0.49 mL, 2.82 mmol). The reaction is stirred at 108° C. for 16 h. After this time the solution is allowed to cool, resulting in a thick precipitate that is filtered and washed with diethyl ether to give 4-[(3-bromo-6-methyl-imidazo[1,2-a]pyrazin-8-ylamino)-methyl]-benzenesulfonamide as a beige solid (420 mg, 75%).
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH:14]([S:16][CH2:17][CH3:18])[CH3:15])[CH2:8][C:7]1=[O:19])(=O)[CH2:2][CH2:3][CH3:4].[CH2:20]([O:22][NH2:23])[CH3:21].Cl>C(O)C>[CH2:20]([O:22][NH:23][C:1](=[C:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH:14]([S:16][CH2:17][CH3:18])[CH3:15])[CH2:8][C:7]1=[O:19])[CH2:2][CH2:3][CH3:4])[CH3:21]
Reactant: CCON
Reactant: CCCC(=O)C1C(=O)CC(CC(C)SCC)CC1=O
Agent: Cl
Solvent: CCO
Product: CCCC(NOCC)=C1C(=O)CC(CC(C)SCC)CC1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.6 %

Procedure:
5.7 g of 2-butyryl-5-(2-ethylthiopropyl)-cyclohexane-1,3-dione was dissolved in 20 ml of ethanol, 1.4 g of ethoxyamine was added thereto, and the resulting solution was stirred at room temperature for 5 hours. After pouring the reaction solution into ice-cold water and acidifing the mixture with hydrochloric acid, the mixture was extracted with chloroform. The chloroform solution was washed with water, dried over anhydrous magnesium sulfate, and the removal of chloroform by distillation under reduced pressure gave 4.5 g of the desired product as colorless oily material. nD27.5 1.5229
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O>CC(O)C>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:17]/[C:13]1[NH:12][CH:16]=[CH:15][CH:14]=1)/[C:5](=[O:11])[NH:6]2
Reactant: O=Cc1ccc[nH]1
Reactant: O=C1Cc2c(I)cccc2N1
Solvent: CC(C)O
Product: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Temperature: 23 °C

Procedure:
A mixture of 1,3-dihydro-4-iodo-2H-indol-2-one (404.1 mg, 1.56 mmol) (prepared according to T. Fukuyama et al., supra) and pyrrole-2-carboxaldehyde (163.2 mg, 1.72 mmol) (Aldrich) in 2-propanol (6.2 mL) was treated with 2 drops of piperidne (Aldrich). The reaction mixture was heated at reflux for 24 h and then allowed to cool to 23° C., at which time, the reaction mixture was filtered. The solid was washed several times with cold distilled water and then allowed to air dry to provide pure (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-indol-2-one. (Yield 341.8 mg, 65%) as a yellow solid, which was used without further purification.