Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[O:18]([C:19]1[CH:20]=[CH:21][C:22]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: O=CC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: O=C(c1ccccc1)C(O)c1ccc(Oc2ccccc2)cc1

Procedure:
Phenyglyoxal monohydrate (200 mg, 1.31 mM) and diphenylether (0.4 ml, 2.62 mM) were dissolved in dichloroethane (3 ml), titanium tetrachloride (0.07 ml, 0.66 mM) was added, and reacted at room temperature for 1 hour. Using the same procedure as in Example 1, 4'-phenoxybenzoin was obtained as crystal (331.2 mg, 80.7% yield).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[N:34]=[C:35]=[O:36].C(N(CC)CC)C.Cl>C(#N)C>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[NH:34][C:35]([NH:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2)=[O:36]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc(Cl)cc4Cl)ccc3C2=O)C(=O)N1
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.37 g, 1.0 mmol) and 2,4-dichlorophenylisocyanate (0.19 g, 1.0 mmol) in acetonitrile (10 mL), was added triethylamine (0.28 mL, 2.0 mmol) at room temperature under nitrogen. After 2 h, 1 N aq. HCl (15 mL) was added and the solids were isolated by filtration, washed with water (3×20 mL) and dried in vacuo to give 1-(2,4-dichloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.44 g, 96% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 8.99 min (96.51%); mp: 265-267° C.; 1H NMR (DMSO-d6) δ 1.89-2.06 (m, 1H, CHH), 2.29-2.47 (m, 1H, CHH), 2.54-2.70 (m, 1H, CHH), 2.78-3.06 (m, 1H, CHH), 4.32 (d, J=17.4 Hz, 1H, CHH), 4.38-4.53 (m, 3H, CHH, CH2), 5.11 (dd, J=5.0, 13.3 Hz, 1H, CH), 7.33 (dd, J=2.5, 9.1 Hz, 1H, Ar), 7.46 (d, J=7.7 Hz, 1H, Ar), 7.53 (s, 1H, Ar), 7.57 (d, J=2.5 Hz, 1H, Ar), 7.62 (t, J=5.8 Hz, 1H, NH), 7.71 (d, J=7.7 Hz, 1H, Ar), 8.20 (d, J=8.9 Hz, 1H, Ar), 8.26 (s, 1H, NH), 10.99 (br. s., 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.82, 47.13, 51.58, 121.63, 121.92, 122.02, 123.04, 125.33, 126.99, 127.50, 128.39, 130.45, 135.81, 142.48, 144.12, 154.67, 167.90, 170.99, 172.86; LCMS: MH=461/463/465; Anal Calcd for C21H18N4O4Cl2: C, 54.68; H, 3.93; N, 12.15; Cl, 15.37. Found: C, 54.37; H, 3.84; N, 12.15; Cl, 15.50.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:9][NH2:10]>C1(C)C=CC=CC=1>[CH:1](=[CH:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: CN
Reactant: O=Cc1cccnc1
Solvent: Cc1ccccc1
Product: NC=Cc1cccnc1
Reaction time: 3 h
Yield: 97.4 %

Procedure:
Nicotinaldehyde (10.7 g, 0.1 mol) was dissolved in toluene (100 ml). A 40% aqueous methylamine (23.3 g, 0.3 mol) solution was added. This mixture was subjected to azeotropic dehydration for 3 hours. The product mixture was concentrated under reduced pressure, giving N-nicotinylidenemethylamine (11.7 g, 98% yield)
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2.N1CCCCC1>C(O)C>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[CH:11][C:8]1[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=1[CH3:13]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2ccc(Cl)cc21
Yield: 87.6 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (4.5 g), 4.2 g of 5-chloro-2-oxindole, and 2.9 mL of piperidine in 50 mL of ethanol were heated to 95° C. for 5 hours. The reaction mixture was collected and concentrated. The residue was suspended in acetone and the yellow precipitate was filtered, washed with cold ethanol, 2 N aqueous hydrochloric acid and water to pH 6 then dried in a vacuum oven overnight to give 7.2 g of the title compound (88%) as a yellow solid.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH:13]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)([CH2:15][CH3:16])[CH3:14]>CN(C)C=O>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:21][C:20]1[CH:22]=[CH:23][C:17]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:18][CH:19]=1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCC(C)c1ccc(N)cc1
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Temperature: 80 °C

Procedure:
To a solution of isatoic anhydride (4.00 g, 24.0 mmol) in N,N-dimethyl formamide (80 mL) under nitrogen atmosphere was added 4-sec-butylaniline (3.66 g, 24.0 mmol). The reaction mixture was heated at 80° C. for 24 hours, then the solvent was removed under reduced pressure and the residue was diluted with ethyl acetate, washed with 1 N aqueous solution of sodium hydroxide, water, and dried over sodium sulfate. The crude oil (7 g) was purified by column chromatography (silica gel 230-400 mesh; 10/0 to 4/1 hexanes/EtOAc as eluent) to give pure 2-amino-N-(4-sec-butylphenyl)-benzamide as a brown solid. Yield: 1.8 g (27.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13](O)[N:12]2[N:16]=[C:17]([CH3:19])[N:18]=[C:11]2[CH:10]=1.P(Cl)(Cl)([Cl:22])=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:22][C:13]1[N:12]2[N:16]=[C:17]([CH3:19])[N:18]=[C:11]2[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2cc(-c3ccc(Cl)cc3Cl)nc(O)n2n1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Product: Cc1nc2cc(-c3ccc(Cl)cc3Cl)nc(Cl)n2n1

Procedure:
In analogy to Example 53A, 676 mg (49% of theory) of the product are obtained from 685 mg (2.31 mmol) of 7-(2,4-dichlorophenyl)-2-methyl[1,2,4]triazolo[1,5-c]pyrimidin-5-ol (Example 136A) by reaction in 6 ml of phosphoryl chloride and 1.59 g (6.96 mmol) of benzyltriethylammonium chloride.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([NH:8][C:9](=[O:12])[O:10][CH3:11])[CH:4]=1.ClCC1N(C)N=C(C)N=1.[CH:22]1([C:27]2([CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([CH:43]([F:45])[F:44])=[C:39]([F:46])[CH:38]=3)[O:32][C:31](=[O:33])[CH2:30][C:29](=[O:34])[CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([C:27]2([CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([CH:43]([F:45])[F:44])=[C:39]([F:46])[CH:38]=3)[O:32][C:31](=[O:33])[C:30]([CH2:2][C:3]3[O:7][N:6]=[C:5]([NH:8][C:9](=[O:12])[O:10][CH3:11])[CH:4]=3)=[C:29]([OH:34])[CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C1CC(=O)OC(CCc2ccc(C(F)F)c(F)c2)(C2CCCC2)C1
Reactant: COC(=O)Nc1cc(CBr)on1
Agent: Cc1nc(CCl)n(C)n1
Product: COC(=O)Nc1cc(CC2=C(O)CC(CCc3ccc(C(F)F)c(F)c3)(C3CCCC3)OC2=O)on1
Yield: 6 %

Procedure:
The title compound was prepared as described in Example B(53), using methyl 5-(bromomethyl)isoxazol-3-ylcarbamate (prepared as described: Sircar, J. C.; Capiris, T. U.S. Pat. No. 4,489,077, Dec. 18, 1984) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-cyclopentyl-6-{2-[4-(difluoromethyl)-3-fluorophenyl]ethyl}-dihydro-2H-pyran-2,4(3H)-dione(Example B(69), Step 3) in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 6%.
Reaction SMILES: Cl.O1CCOCC1.O.C(OC([N:16]1[C:20](=[O:21])[C:19]2([CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([O:40]C(C)(C)C)=[O:39])=[CH:34][C:33]=3[CH3:45])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:18]=[C:17]1[C:46]1[CH:51]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:49]=[C:48]([O:56][CH2:57][CH2:58][C:59]#[CH:60])[CH:47]=1)=O)(C)(C)C>>[CH2:57]([O:56][C:48]1[CH:47]=[C:46]([C:17]2[NH:16][C:20](=[O:21])[C:19]3([CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]([OH:40])=[O:39])=[CH:34][C:33]=4[CH3:45])(=[O:29])=[O:28])[CH2:23][CH2:22]3)[N:18]=2)[CH:51]=[C:50]([C:52]([F:54])([F:55])[F:53])[CH:49]=1)[CH2:58][C:59]#[CH:60]
Reactant: C#CCCOc1cc(C2=NC3(CCN(S(=O)(=O)CCc4ccc(C(=O)OC(C)(C)C)cc4C)CC3)C(=O)N2C(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: C#CCCOc1cc(C2=NC3(CCN(S(=O)(=O)CCc4ccc(C(=O)O)cc4C)CC3)C(=O)N2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4 M hydrochloric acid-dioxane (1.80 ml) and water (0.0173 ml, 0.960 mmol) were added to 8-[2-(4-tert-butoxycarbonyl-2-methyl-phenyl)-ethanesulfonyl]-2-(3-but-3-ynyloxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-3-carboxylic acid tert-butyl ester (35.9 mg, 0.048 mmol), and the mixture was stirred at room temperature for five hours. The reaction solution was concentrated under reduced pressure to give 4-{2-[2-(3-but-3-ynyloxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-3-methyl-benzoic acid as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7](Cl)([Cl:9])=[O:8]>C(Cl)Cl>[N:1]1([C:7]([Cl:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)N1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
Piperidine (0.3 g, 3.52 mmol) was added to a mixture of phosgene (4.7 ml of 20% phosgene in toluene solution, 8.81 mmol) in methylene chloride (5 ml) at 0° C. The mixture was stirred at 0° C. for 1 hour. The reaction mixture was evaporated in vacuo. The residue was suspended in ether, filtered and the eluents were condensed to obtain a yellow oil. Purification by flash column chromatography (silica gel, 0-20% ethyl acetate/hexane) gave 0.162 g of the title product. IR (film) 1738.9 cm−1.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[S:6]1(=[O:23])=[O:22].[CH3:24][NH2:25].C(=O)(O)[O-].[Na+]>CO>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:7]1[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:5]([CH2:4][CH2:3][CH2:2][NH:25][CH3:24])[S:6]1(=[O:23])=[O:22]
Reactant: CN
Reactant: O=S1(=O)N(c2ccccc2F)Cc2ccccc2N1CCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CNCCCN1c2ccccc2CN(c2ccccc2F)S1(=O)=O
Yield: 40 %

Procedure:
1-(3-bromopropyl)-3-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.15 g, 0.38 mmol) and an 33% MeNH2 in MeOH (15 mL) was stirred in a sealed tube at room temperature for 16 hours. The reaction was poured into saturated aqueous sodium bicarbonate (20 mL), extracted with ethyl acetate (20 mL), and dried over anhydrous sodium sulfate. The organics were concentrated onto silica gel. Purification via Isco (0-100% dichloromethane containing 15% ammonia in methanol/dichloromethane) followed by treatment with 1 N hydrochloric acid in ether gave 3-[3-(2-fluorophenyl)-2,2-dioxido-3,4-dihydro-1H-2,1,3-benzothiadiazin-1-yl]-N-methylpropan-1-amine (0.056 g, 40%) as an off-white amorphous solid:
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]=O)=[C:8]2Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[SH:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]>>[C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3[CH:16]=[C:26]([C:27]([O:29][CH3:30])=[O:28])[S:25][C:8]2=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CS
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc2c3ccccc3n(-c3ccccc3)c2s1
Yield: 79.6 %

Procedure:
Prepared from 1-Phenyl-2-chloroindole-3-carbaldehyde (0.90 g), K2CO3 (1.38 g) and methyl 2-mercaptoacetate (0.55 ml) yielding (51) 0.86 g (79.6%). M.p. 147°-149° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][N:6]([C:8]([NH:10][CH2:11][CH3:12])=[NH:9])[N:5]=[CH:4]1)[CH3:2].CCN(C(C)C)C(C)C.Cl[S:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=[O:30])(=[O:25])=[O:24]>C(Cl)Cl>[CH2:11]([NH:10][C:8](=[N:9][S:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=[O:30])(=[O:25])=[O:24])[N:6]1[CH2:7][CH:3]([CH2:1][CH3:2])[CH:4]=[N:5]1)[CH3:12]
Reactant: CCNC(=N)N1CC(CC)C=N1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=NS(=O)(=O)c1cccc(C(=O)O)c1)N1CC(CC)C=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.8 %

Procedure:
Under N2 atmosphere, 1.0 g 4,N-diethyl-4,5-dihydro-pyrazole-1-carboxamidine was dissolved in 15 mL dry DCM, and 1.14 mL DiPEA and 1.31 g of 3-(chlorosulfonyl)benzoic acid were added. The mixture was stirred overnight at room temperature and evaporated to dryness. The residue was purified by flash chromatography (first column with DCM/MeOH/acetic acid 84:15:1; second column with DCM/MeOH/NH4OH 84:15:1) to yield 0.08 g (4%) of an off-white powder. 1H NMR (400 MHz, CDCl3) δ 0.90 (t, J=7.4 Hz, 3H), 1.14 (t, J=7.2 Hz, 3H), 1.38-1.62 (m, 2H), 3.02-3.18 (m, 1H), 3.27-3.62 (m, 3H), 3.89-4.17 (m, 1H), 6.94 (s, 1H), 7.26 (t, J=7.8 Hz, 1H), 7.89 (d, J=7.8 Hz, 1H), 8.05 (d, J=7.8 Hz, 1H), 8.49 (s, 1H).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)(C)C.C1(C)C=CC=CC=1>[CH2:12]([CH:2]1[CH2:3][C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:1]1)[CH:13]=[CH:14][CH3:15]
Reactant: O=C1CCOc2ccccc21
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)OC
Product: CC=CCC1CC(=O)c2ccccc2O1
Yield: 38 %

Procedure:
A solution of 48 g of 4-chromanone, 67 ml of 3-buten-2-ol and 500 mg of p-toluenesulfonic acid in 67 ml of 2,2-dimethoxypropane and 500 ml of anhydrous toluene was boiled under reflux for 46 hours. The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 4:1). 24.7 g (38%) of (RS)-2-(2-buten-1-yl)-4-chromanone were obtained as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[CH2:25]([O:27][C:28]([CH:30]1[NH:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]1)=[O:29])[CH3:26].C(N(CC)CC)C>C(O)C>[CH2:25]([O:27][C:28]([CH:30]1[N:35]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[N:6]3[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:31]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1c1ncnc2c1nc(-c1ccccc1Cl)n2-c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
6-Chloro-9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purine I-(4A-7)c (103 mg, 0.27 mmol), piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (Chiu, C. K.-F. and Griffith, D. A., EP 1004583 A2; 156 mg, 0.60 mmol), and triethylamine (95 μl, 0.68 mmol) were combined in ethanol (1.5 ml) and heated at 60° C. until complete by TLC (3 days). The reaction mixture was concentrated under reduced pressure and then purified on a Biotage™ Flash 12M column using 20 to 30% ethyl acetate in hexanes as eluant to afford title compound I-(8A-1)a (78 mg, 48%): +ESI MS (M+1) 597.3; 1H NMR (400 MHz, CD3OD) δ 8.298 (br s, 1H), 7.57 (br s, 1H), 7.48–7.25 (m, 7H), 5.60 (v br s, 1H), 4.67 (d, J=13.7 Hz, 1H), 4.23–4.05 (br m, 3H), 3.43–3.00 (br m, 2H), 1.46 (s, 9H), 1.22 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:11][NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:6]2.[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>N1C=CC=CC=1.ClCCl>[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH:5]([CH2:11][NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:6]3)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(=O)NCC1Cc2cccc(N)c2C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)NCC1Cc2cccc(NS(=O)(=O)c3ccc(C(C)C)cc3)c2C1
Temperature: 5 °C
Reaction time: 3 h
Yield: 101.4 %

Procedure:
N-(4-Amino-indan-2-ylmethyl)-propionamide (0.51 g, 2.34 mmol) was dissolved in pyridine-dichloromethane (1:2, 30 mL) and cooled to 5° C. 4-Isopropylbenzenesulfonyl chloride (0.54 g, 2.47 mmol) was added and the solution stirred at 5° C. for 3 h. Solution was evaporated, partitioned between ethyl acetate and water, and the organic phase separated and dried over MgSO4. The filtered solution was concentrated to give the product as a brown oil (0.95 g, 100%).
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH2:3][CH2:4][C:5]([OH:7])=O.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17]>>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:2]([CH2:3][CH2:4][C:5]([N:14]2[CH2:21][CH2:20][CH2:19][C@H:15]2[C:16]([OH:18])=[O:17])=[O:7])=[O:1])[CH:9]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(O)CCC(=O)c1cccnc1
Product: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1cccnc1

Procedure:
As for Example 11, γ-oxo-3-pyridinebutyric acid is coupled to L-proline to give 1-[3-(3-pyridylcarbonyl)propionyl]-L-proline.
Reaction SMILES: Cl[C:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12].[N-:16]=[N+]=[N-].[Na+].O>CS(C)=O>[CH:7]12[CH2:8][CH:4]([CH2:5][CH2:6]1)[C:3]1[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:16][C:2]2=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)/C=C/C1=C(Cl)C2CCC1C2
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cc2c([nH]1)C1CCC2C1
Temperature: 105 °C
Yield: 59.8 %

Procedure:
To a solution of 334b (5.0 g, 22 mmol) in DMSO (30 mL) was added NaN3 (2.2 g, 33 mmol) and the mixture was heated at 105° C. for 6 hours. Water (13 mL) was added to reaction the mixture after cooling down to room temperature, and resulting mixture was extracted with methylene chloride (50 mL×3). The organic phase was dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography eluting with 20:1 methylene chloride/methanol to give 334c as a brown solid (2.7 g, 60%). MS: [M+H]+ 206. 1H NMR (500 MHz, CDCl3) δ 11.51 (s, 1H), 6.45 (dd, 1H), 4.14-4.19 (m, 2H,), 3.25 (d, 2H,), 1.79-1.82 (m, 2H), 1.73 (d, 1H), 1.22-1.25 (t, J=6.5, 3H), 0.89-0.91 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]1[CH2:9][O:8][C:7](=[O:10])[CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH:17][CH:18]([N:26]1[C@H:29]([SH:30])[C@H:28]([NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]1=[O:42])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CC(C)=O.C(OCC)(=O)C>[OH:17][CH:18]([N:26]1[C@H:29]([S:30][CH2:2][C:3]([CH:5]2[CH2:9][O:8][C:7](=[O:10])[CH2:6]2)=[O:4])[C@H:28]([NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:27]1=[O:42])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: O=C1CC(C(=O)CCl)CO1
Reactant: CC(C)(C)OC(=O)C(O)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)C(O)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SCC(=O)C1COC(=O)C1
Reaction time: 1 h
Yield: 67.3 %

Procedure:
(RS)-4-Chloroacetyltetrahydrofuran-2-one (2.060 g, 12.6 mmol), followed by potassium carbonate (0.690 g, 5 mmol) were added to crude t-butyl (2RS)-2-hydroxy-[(3R,4R)-4-mercapto-3-phenoxyacetamidoazetidin-2-on-1-yl]acetate (3.866 g) (prepared as described in Example 1c) in acetone (10 ml). The reaction was stirred 1 h. then diluted with ethyl acetate, washed with water (x2) and brine, dried, concentrated and flash chromatographed on silica gel eluting with 50,60,75,90% ethyl acetate in hexane to provide the title compound as a foam (3.458 g, 68%), νmax (CH2Cl2) 3380, 1780, 1680, 1235, 1150 cm-1 ; [Mass spectrum: +ve ion (thioglycerol) MH+ (509)].
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[C:5](=[O:15])[NH:4][C:3]=1[C:16]([NH2:18])=[O:17].[C:19]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(#N)C.[Fe](Cl)(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[C:5](=[O:15])[N:4]2[C:19]3([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[NH:18][C:16](=[O:17])[C:3]=12
Reactant: O=C1CCCCC1
Reactant: Cc1nc(Nc2ccncn2)c(=O)[nH]c1C(N)=O
Agent: Cl[Fe](Cl)Cl
Solvent: CC#N
Product: Cc1nc(Nc2ccncn2)c(=O)n2c1C(=O)NC21CCCCC1
Temperature: 80 °C

Procedure:
To a solution of 3-Methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyrazine-2-carboxamide (5, 100 mg, 0.41 mmol) and cyclohexanone (199 mg, 2.03 mmol) in acetonitrile in a 20 mL microwave vial was added iron(III) chloride (197 mg, 1.21 mmol). The reaction was heated at 80° C. for 16 h. On completion of the reaction, solvent was removed under vacuum and the crude was purified by silica gel (200-400 mesh) column chromatography eluting with 5% methanol in dichloromethane. Appropriate column fractions were concentrated under reduced pressure to afford 8′-methyl-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyrazine]-1′,5′-dione (Cpd. No. 216) as off white solid. Yield: 8.5 mg, 6%; MS (ESI) m/z 327.13 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 9.11 (s, 1H), 8.88 (s, 1H), 8.72 (d, J=4.0 Hz 1H), 8.47 (d, J=4.0 Hz, 1H), 2.85-2.74 (m, 2H), 2.54 (s, 3H), 1.80-1.50 (m, 7H), 1.30-120 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH:24]1([N:27]=[C:28]=[O:29])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:28]([N:13]2[CH2:14][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:10][CH:11]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:12]2)=[O:29])[CH2:26][CH2:25]1
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Reactant: O=C=NC1CC1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)NC3CC3)C2)cc1

Procedure:
62 mg (0.20 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 17 mg (0.20 mmol, 1.0 eq.) of cyclopropyl isocyanate were reacted according to General Method 4. Yield: 63 mg (80% of theory)
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:24]([CH3:25])=[CH:23][S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[N:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[C:24]([CH3:25])=[CH:23][S:22][C:12]=3[N:13]=2)=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: Cc1csc2nc(-c3ccncc3)nc(Cl)c12
Product: Cc1csc2nc(-c3ccncc3)nc(NCc3ccccc3)c12

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-4-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-benzylamino-5-methyl-thieno-[2,3-d]-pyrimidine.