Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[NH:8]1[CH2:14][C:12](=[O:13])[NH:11][C:9]1=[O:10]>>[C:2]1([CH:6]=[C:14]2[NH:8][C:9](=[O:10])[NH:11][C:12]2=[O:13])[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccs1
Reactant: O=C1CNC(=O)N1
Product: O=C1NC(=O)C(=Cc2cccs2)N1
Yield: 75 %

Procedure:
It known that the condensation of thiophene-2-carbaldehyde with hydantoin gives 5-(2-thenylidene) hydantoin, which can then be reduced either into 5-(2-thenyl) hydantoin, with a yield of 75% by sodium amalgam in a petroleum ether (G. BARGER and A. EASSON, J. Chem. Soc. 1938, 2100), or directly into β 2-thienyl alanine, with a yield of 72% by using ammonium sulphide (V. du VIGNEAUD et al, J. Biol. Chem., 159, 385-94, 1945).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([O:22]C)[CH:21]=1)[C:5]([N:7]([CH:16]([CH3:18])[CH3:17])[CH2:8][CH2:9][C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)=[O:6].B(Br)(Br)Br.CO>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([OH:22])[CH:21]=1)[C:5]([N:7]([CH:16]([CH3:17])[CH3:18])[CH2:8][CH2:9][C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)=[O:6]
Reactant: COc1cc(Cl)cc(C(=O)N(CCc2nnnn2C)C(C)C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(C)N(CCc1nnnn1C)C(=O)c1cc(O)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.3 %

Procedure:
To a stirred solution of 3-chloro-N-isopropyl-5-methoxy-N-[2-(1-methyl-1H-tetrazol-5-yl)-ethyl]-benzamide (0.115 g) in anhydrous dichloromethane (5.0 ml) at −78° C. was added 1M boron tribromide solution in dichloromethane (1.36 ml). The reaction mixture was stirred at this temperature for 15 min. The reaction was allowed to warm to room temperature. After 24 h, the reaction was cooled to −78° C. and methanol (1 ml) added. The reaction was allowed to rewarm to room temperature and absorbed on to silica. This was loaded on to an already prepared flash column, eluting with ethyl acetate:petroleum ether (4:1 v/v) and 25:1 dichloromethane:methanol (25:1 v/v) to give the title compound as a white solid (0.072 g).
Reaction SMILES: [C:1]([N:5]([C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[NH2:6])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:25]=1)[C:22](O)=[O:23].CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[C:1]([N:5]([C:7](=[O:15])[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)[NH:6][C:22](=[O:23])[C:21]1[CH:25]=[C:17]([Br:16])[CH:18]=[N:19][CH:20]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N(N)C(=O)c1ccc(Cl)cc1
Reactant: O=C(O)c1cncc(Br)c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)N(NC(=O)c1cncc(Br)c1)C(=O)c1ccc(Cl)cc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A solution of N'-t-butyl-N'-(4-chlorobenzoyl)hydrazine (0.5 g, 0.0022 mol) and 5-bromonicotinic acid (0.44 g, 0.0022 mol) in 10 ml of methylene chloride containing triethylamine (0.33 g) was added to a solution of methanesulfonyl chloride (0.25 g, 0.0022 mol) in 10 ml of methylene chloride at 0° C. The resulting mixture was stirred at 23° C. for 2 hours and then was allowed to stand overnight at 23° C. Aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was re-extracted with methylene chloride. The organic extracts were evaporated to give a yellow solid which was triturated with hexane/methylene chloride to afford N'-t-butyl-N-(5-bromonicotinoyl)-N'-(4-chlorobenzoyl)hydrazine as an off-white solid. m.p. 193°-197° C.
Reaction SMILES: OC[C:3]([NH:6][C:7](=[O:9])[CH3:8])([CH3:5])C.N1CC[CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1.CC#N.O.CC#N>O>[OH:17][CH2:16][CH:13]1[CH2:5][CH2:3][N:6]([C:7](=[O:9])[CH3:8])[CH2:11][CH2:12]1
Reactant: OCC1CCNCC1
Reactant: CC(=O)NC(C)(C)CO
Solvent: O
Solvent: CC#N
Product: CC(=O)N1CCC(CO)CC1

Procedure:
The title compound is prepared analogously as described for N-(2-hydroxy-1,1-dimethyl-ethyl)-acetamide from piperidin-4-yl-methanol. MS (LC-MS): [M+H]+=158.3. tR (HPLC, Waters Symmetry C18 column, 5-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 0.39 min.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][C:18]1[CH:46]=[CH:45][C:21]([CH:22]([N:30]2[C:38]3[C:33](=[CH:34][C:35](/[C:39](/[CH3:44])=[CH:40]/[C:41](O)=[O:42])=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>>[CH3:29][C:26]1[CH:25]=[CH:24][C:23]([CH:22]([N:30]2[C:38]3[C:33](=[CH:34][C:35](/[C:39](/[CH3:44])=[CH:40]/[C:41]([NH:1][C:2]4[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=4[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:42])=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)[C:21]2[CH:20]=[CH:19][C:18]([CH3:17])=[CH:46][CH:45]=2)=[CH:28][CH:27]=1
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2ccc(C)cc2)c2ccc(C)cc2)c1
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2C(c2ccc(C)cc2)c2ccc(C)cc2)c1

Procedure:
0.50 g of compound 54 was obtained in a similar manner to those described in the Examples 1 and 2 using 1.96 g of ethyl 4-(2-aminophenoxy)butyrate and 1.74 g of 3-[1-(4,4'-dimethylbenzhydryl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [C:1]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([NH:6][NH2:7])=[O:5])#[N:2].[CH3:14][CH2:15][C:16](=O)[CH2:17][C:18](=O)[CH2:19][CH3:20]>>[CH2:15]([C:16]1[CH:17]=[C:18]([CH2:19][CH3:20])[N:7]2[N:6]=[C:4]([OH:5])[C:3]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:1]2[N:2]=1)[CH3:14]
Reactant: CCC(=O)CC(=O)CC
Reactant: N#CC(C(=O)NN)c1ccccc1
Product: CCc1cc(CC)n2nc(O)c(-c3ccccc3)c2n1
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 36.1 %

Procedure:
2-Cyano-2-phenylacetohydrazide [Int-1A] (8.40 g, 43.2 mmol, 1.0 eq) and heptane-3,5-dione (5.85 mL, 43.2 mmol, 1.0 eq) were dissolved in 140 mL acidic acid and stirred for 4.5 h at 60° C. The resulting suspension was cooled to rt and the precipitate was isolated by filtration. The solid was washed with hexane and dried to give 4.17 g (29% yield) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[C@H:11]([CH3:22])[O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([O:27][C:28]1[N:29]=[CH:30][C:31]([C:34](O)=[O:35])=[N:32][CH:33]=1)[CH3:26].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:34]([C:31]3[CH:30]=[N:29][C:28]([O:27][CH2:25][CH3:26])=[CH:33][N:32]=3)=[O:35])=[CH:19][CH:20]=2)[C@H:11]([CH3:22])[O:10][C:9]1([CH3:23])[CH3:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cnc(C(=O)O)cn1
Reactant: C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CCc1ccc(N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOc1cnc(C(=O)Nc2ccc(CC[C@H]3[C@H](C)OC(C)(C)N3C(=O)OC(C)(C)C)cc2)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a stirred solution of (4S,5S)-4-[2-(4-amino-phenyl)-ethyl]-2,2,5-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (120 mg) and 5-ethoxypyrazine-2-carboxylic acid (72.4 mg) in THF (3 ml) were added N-methylmorpholine (158 μl) and TBTU (230 mg). The reaction mixture was capped and shaken at 50° C. overnight. The crude reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, gradient: 0% to 70% EtOAc in hexane) to afford (4S,5S)-4-(2-{4-[(5-ethoxy-pyrazine-2-carbonyl)-amino]-phenyl}-ethyl)-2,2,5-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester as a white solid (167 mg, 96%). MS (ISP): 507.3 ([M+Na]+), 502.3 ([M+NH4]+), 485.3 ([M+H]+), 429.3 ([M-C4H8]+).
Reaction SMILES: C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:32][CH2:33][CH2:34][C:35]([OH:37])=O)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31].[NH2:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][C:46]2[S:61][C:49]3[N:50]([CH2:57][CH:58]([CH3:60])[CH3:59])[C:51](=[O:56])[N:52]([CH3:55])[C:53](=[O:54])[C:48]=3[CH:47]=2)=[CH:41][CH:40]=1>ClCCl>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:32][CH2:33][CH2:34][C:35]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([CH2:45][C:46]3[S:61][C:49]4[N:50]([CH2:57][CH:58]([CH3:59])[CH3:60])[C:51](=[O:56])[N:52]([CH3:55])[C:53](=[O:54])[C:48]=4[CH:47]=3)=[CH:41][CH:40]=2)=[O:37])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cc(Cc3ccc(N)cc3)sc21
Reactant: COc1ccc(CCCC(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccc(CCCC(=O)Nc2ccc(Cc3cc4c(=O)n(C)c(=O)n(CC(C)C)c4s3)cc2)cc1OC
Reaction time: 8 h
Yield: 26.4 %

Procedure:
To a solution of N-ethyl-N′-[3-(dimethylamino)propyl]carbodiimide (37 mg), 1-hydroxybenzotriazole (26 mg) and 4-(3,4-dimethyloxyphenyl)butanoic acid (36 mg) in dichloromethane (6 ml) was added 6-(4-aminophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-(1H, 3H)-dione (45 mg) in dichloromethane (2 ml). The reaction mixture was stirred overnight and then washed with half saturated sodium hydrogen carbonate and extracted into ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated and the residue was purified by normal phase HPLC (isohexane:ethyl acetate 50-0:50-100) to give the title compound (19 mg) as a foam.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([F:12])=[CH:8][C:9]=2Br)[CH:4]=[CH:3]1.C([Li])(C)(C)C.[C:18](OC)(=[O:23])[C:19]([O:21][CH3:22])=[O:20]>C1COCC1>[CH3:22][O:21][C:19](=[O:20])[C:18]([C:9]1[CH:8]=[C:7]([F:12])[CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2)=[O:23]
Reactant: Cn1ccc2cc(F)cc(Br)c21
Reactant: COC(=O)C(=O)OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1cc(F)cc2ccn(C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
A solution of 1-methyl-5-fluoro-7-bromoindole (8.3 g, 36.4 mmol) in THF (250 mL) was cooled to −78° C. and a solution of tert-butyl lithium in pentanes (1.7 M, 47 mL, 80.1 mmol) added dropwise over 30 min. After 30 min at −78° C., the mixture was treated with dimethyl oxalate (10.75 g, 91 mmol) in one portion. After 15 min, the mixture was allowed to warm to room temperature and stirred 4 h. The reaction mixture was quenched with water, extracted with ethyl acetate and the extract washed with brine, dried (Na2SO4) and concentrated. Flash chromatography (EtOAc/hexanes) afforded the title compound (4.2 g, 49%). 1H NMR (400 MHz, CDCl3) 3.83(s, 3H), 4.01 (s, 3H), 6.56 (d, J=3.13 Hz, 1H), 7.15 (d, J=3.13 Hz, 1H), 7.35 (dd, J1=2.0 Hz, J2=9.4 Hz, 1H), 7.57 (dd, J1=2.34 Hz, J2=8.21 Hz, 1H); MS (ES, m/z): C12H10FNO3: 235.22 (M++1).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:50]1[C:54]2[CH:55]=[CH:56][C:57]([C:59]3[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=3)=[CH:58][C:53]=2[CH2:52][CH2:51]1>CN(C=O)C>[O:50]1[C:54]2[CH:55]=[CH:56][C:57]([C:59]3[CH:60]=[C:61]([NH:65][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:62]=[CH:63][CH:64]=3)=[CH:58][C:53]=2[CH2:52][CH2:51]1
Reactant: Nc1cccc(-c2ccc3c(c2)CCO3)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5c(c4)CCO5)c3)c(=O)oc12
Temperature: 25 °C
Yield: 95.4 %

Procedure:
DIEA (0.014 mL, 0.078 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.016 g, 0.071 mmol) and HATU (0.030 g, 0.078 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2,3-dihydro-benzofuran-5-yl)-phenylamine (0.015 g, 0.071 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.028 g of product in 94% yield: LCMS (ESI) m/z 414 (MH+).
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][CH3:20])[C:13]=3[C:12]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[Cl:37])=[N:26][C:27]=3[F:28])=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[K+].O>CO>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][NH:29][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C:12]2[C:13]3[C:18]([O:19][CH3:20])=[N:17][CH:16]=[N:15][C:14]=3[NH:10][CH:11]=2)=[C:27]([F:28])[N:26]=1
Reactant: COc1ncnc2c1c(Cc1ccc(NCc3ccccc3Cl)nc1F)cn2S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ncnc2[nH]cc(Cc3ccc(NCc4ccccc4Cl)nc3F)c12
Temperature: 45 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To [5-(7-benzenesulfonyl-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(2-chloro-benzyl)-amine (45, 0.30 g, 0.558 mmol) in 15 mL of methanol, potassium hydroxide (0.50 g, 8.9 mmol) was added. The reaction was stirred at 45° C. for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was washed with ethyl acetate to provide the desired compound (P-0090, 0.176 g). MS (ESI) [M+H+]+=397.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]2=[O:17])=[CH:5][CH:4]=1.[BrH:18].BrBr>O>[Br:18][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10](=[O:17])[NH:11][C:12](=[O:16])[NH:13][C:14]1=[O:15]
Reactant: COc1ccc(C2C(=O)NC(=O)NC2=O)cc1
Reactant: Br
Agent: BrBr
Solvent: O
Product: COc1ccc(C2(Br)C(=O)NC(=O)NC2=O)cc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-(4-Methoxyphenyl)barbituric acid (222 mg) in 3 ml of water, cooled to 0-5° C. with ice bath, are added 136 μl of 48% hydrobromic acid and 56 μl of bromine, dropwise. After 1 hour at a temperature below 10° C., the solid which separated is collected by filtration and washed on the filter with water. The solid is dried for several hours under vacuum at 50° C., to give 283 mg of the product.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]4[O:29]CCO4)=[CH:21][N:20]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:42]>C(O)(=O)C.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]3[NH:42][C:17]([C:19]4[N:20]=[CH:21][C:22]([CH:25]=[O:29])=[CH:23][CH:24]=4)=[CH:16][CH:15]=3)[CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: [NH4+]
Reactant: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ccc(C2OCCO2)cn1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 83.1 %

Procedure:
To a solution of 5-[4-(cyclopropylsulfonyl)phenyl]-1-[5-(1,3-dioxolan-2-yl)pyridin-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (4.40 g) in acetic acid (35 mL) was added ammonium acetate (10.3 g), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (3.22 g, yield 83%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 465 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=1
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1Cl
Reactant: NCc1ccc(F)cc1
Product: Cc1sc2nc(-c3cnccn3)nc(NCc3ccc(F)cc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(4-fluorobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](I)[C:8]2[CH:9]=[CH:10][N:11]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:16])[C:13]=2[C:14]=1[OH:15])=[O:4].[C:25]([Cu])#[N:26].[NH4+].[OH-].Cl>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[CH:9]=[CH:10][N:11]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:16])[C:13]=2[C:14]=1[OH:15])=[O:4]
Reactant: COC(=O)c1nc(I)c2ccn(Cc3ccccc3)c(=O)c2c1O
Reactant: N#C[Cu]
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1nc(C#N)c2ccn(Cc3ccccc3)c(=O)c2c1O
Temperature: 25 °C
Yield: 58.9 %

Procedure:
A mixture of 6-benzyl-4-hydroxy-1-iodo-5-oxo-5,6-dihydro-[2,6]naphthyridine-3-carboxylic acid methyl ester (180 mg, 0.41 mmol) and CuCN (74 mg, 0.83 mmol) in 5 mL of DMF was refluxed for 8 min. The reaction mixture was cooled to r.t. and poured into a stirring mixture of 1% NH4OH solution and CH2Cl2. 4 M HCl was then added with vigorous stirring until no more solid was present. The aqueous layer was extracted with additional CH2Cl2, and the combined organic layer was dried over MgSO4 and concentrated. The crude was chromatographed (0-15% CH2Cl2/EtOAc+1% AcOH) to give 81 mg of the title compound as a pale yellow solid. MS: (−) m/z 334.00 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C@@H:6]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][CH2:14][CH2:15][C:16]2([CH3:21])OCC[O:17]2)[C:8]1=[O:22])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][C@@H:6]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][CH2:14][CH2:15][C:16](=[O:17])[CH3:21])[C:8]1=[O:22])[CH3:2]
Reactant: CCOC(=O)C[C@@H](c1cccc(F)c1)N1CCCC(CCCC2(C)OCCO2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)C[C@@H](c1cccc(F)c1)N1CCCC(CCCC(C)=O)C1=O

Procedure:
A solution of 2-6 (500 mg, 1.10 mmol), p-TSA (10 mg) and acetone (50 mL) was heated at reflux for 4 h. The cooled reaction mixture was diluted with EtOAc and then washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated to afford 2-7 as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[N:9]1([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:16][CH:15]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CN2CCCCC2)cc1
Reaction time: 18 h
Yield: 98.9 %

Procedure:
1-(4-Nitro-benzyl)-piperidine (0.089 g, 0.404 mmol) is dissolved in MeOH (5 mL), and to this solution is added 10% Pd/C (0.009 g, 0.404 mmol). The reaction mixture is stirred under an atmosphere of H2 for 18 h. The resulting mixture is filtered through celite, and the filtered catalyst is washed with excess EtOAc. The filtrate is concentrated under high vacuum to afford the product as a solid (0.076 g, 99%); 1H NMR (DMSO-d6) δ 1.29-1.40 (m, 2H), 1.40-1.51 (m, 4H), 2.17-2.30 (m, 4H), 3.18 (s, 2H), 4.88 (s, 2H), 6.46 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H); mass spectrum [(+) ESI], m/z 191 (M+H)+
Reaction SMILES: C(OC(N1CCC(NC([N:16]2[CH2:21][CH2:20][N:19]3[C:22]([CH:30]4[CH2:35][CH2:34]OCC4)=[C:23](C#N)[C:24]([C:25](=[O:27])[NH2:26])=[C:18]3[CH2:17]2)=O)CC1)=O)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:43]CCl>>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:43][C:23]1[C:24]([C:25]([NH2:26])=[O:27])=[C:18]2[CH2:17][NH:16][CH2:21][CH2:20][N:19]2[C:22]=1[CH:30]1[CH2:35][CH2:34]1
Reactant: CC(C)OC(=O)N1CCC(NC(=O)N2CCn3c(c(C(N)=O)c(C#N)c3C3CCOCC3)C2)CC1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1c(Cl)c(C2CC2)n2c1CNCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 8-carbamoyl-7-chloro-6-cyclopropyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (100 mg, Reference Example 25) in dry dichloromethane (2 ml) was treated with trifluoroacetic acid (1 ml). After stirring at room temperature for 18 hours the reaction mixture was evaporated to afford oil, which was azeotroped with toluene and then triturated with diethyl ether to give 7-chloro-6-cyclopropyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide trifluoroacetic acid salt (42 mg) as white solid, m.p. 237–239° C. MS: 242 [MH]+, 240 [MH]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[C:4]([CH3:17])[N:3]=1.[Cl:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[C:21]([CH3:27])[CH:20]=1.CC(C)([O-])C.[K+]>C1COCC1>[Cl:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([O:26][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[C:4]([CH3:17])[N:3]=2)=[C:21]([CH3:27])[CH:20]=1
Reactant: Cc1cc(Cl)cc(C)c1O
Reactant: CCC(CC)Nc1cc(C)nc(Cl)c1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.1 %

Procedure:
To a mixture of (2-chloro-6-methyl-3-nitro-pyridin-4-yl)-(1-ethyl-propyl)-amine (850 mg, 3.30 mmol) and 4-chloro-2,6-dimethylphenol (516 mg, 3.30 mmol) in 25 ml of dry THF was added potassium tert-butoxide (370 mg, 3.30 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a yellow solid (1.31 g). The solid was purified through silica gel column chromatography using 6:4 ratio of chloroform:hexane as eluent to give 1.10 g (88%) of the title compound as yellow solid, mp 152–154° C. 1H NMR (CDCl3) δ 7.65 (d, 1H), 7.05 (s, 2H), 6.21 (s, 1H), 3.41 (m, 1H), 2.15 (s, 3H), 2.11 (s, 6H), 1.5–1.8 (m, 4H), 0.99 (t, 6H) ppm.
Reaction SMILES: O.[NH2:2][NH2:3].C1([O:10][C:11](=O)[NH:12][C:13]2[O:17][N:16]=[C:15]([CH3:18])[CH:14]=2)C=CC=CC=1>C(O)C>[CH3:18][C:15]1[CH:14]=[C:13]([NH:12][C:11]([NH:2][NH2:3])=[O:10])[O:17][N:16]=1
Reactant: NN
Reactant: Cc1cc(NC(=O)Oc2ccccc2)on1
Solvent: CCO
Solvent: O
Product: Cc1cc(NC(=O)NN)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrazine hydrate (95 μl) was added to a mixture of (3-methyl-isoxazol-5-yl)-carbamic acid phenyl ester (CA 81479-55-2) (417 mg) and ethanol (5 ml), and the resulting mixture was stirred overnight at room temperature. The precipitate was collected by filtration to obtain the title compound (100 mg).