Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[C:9]1[Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:23]([O:26][C@H:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31]Cl)(=[O:25])[CH3:24]>CS(C)=O>[C:23]([O:26][C@H:27]([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31][N:14]1[C:15](=[O:17])[C:16]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]([Br:20])=[N:10][C:11]=2[N:12]([CH3:19])[C:13]1=[O:18])(=[O:25])[CH3:24]
Reactant: CC(=O)O[C@H](C)CCCCCl
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(Br)n2Cc2ccccc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a stirring suspension of 7-benzyl-8-bromo-3-methylxanthine (10.06 g, 30.0 mmol) in anhydrous dimethylsulfoxide was added sodium hydride (864 mg, 36.0 mmol). After stirring at room temperature for 30 min, (R)-5-acetoxy-1-chlorohexane (5.9 g, 33.0 mmol) was added. After stirring at 70-75° C. for 12 hours, the mixture was cooled to room temperature, quenched with water (600 ml) and stirred at room temperature for 4 hours. The precipitate was filtered to provide (R)-1-(5-Acetoxyhexyl)-7-benzyl-8-bromo-3-methylxanthine (12.31 g, 86% yield) as a beige powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([CH2:7][O:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[CH2:6])[CH3:2].C([O-])(O)=O.[Na+].[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C.O>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:7][O:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH2:6][S:28][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:2]
Reactant: C=C(COC1CCOCC1)C(=O)OCC
Reactant: SCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(COC1CCOCC1)CSCc1ccccc1
Yield: 36.8 %

Procedure:
A suspension of 2-(tetrahydro-pyran-4-yloxymethyl)-acrylic acid ethyl ester (2.2 g, 10.2 mmol) in ethanol (100 ml) was treated with a solution of NaHCO3 (0.86 g, 10.2 mmol) in water ml (10 ml) and benzyl mercaptan (1.21 ml, 10.2 mmol) at room temperature overnight. Ethanol evaporated off under reduced pressure, crude partitioned between ethyl acetate and water, organic layer separated and purified by mplc eluting with 1:9 to 2:8 v/v ethyl acetate-heptane mixture to give the title compound as pale yellow oil (1.27 g). MS: 339 (MH+); LCMS (Protocol B) retention time 4.3 minutes.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([N:16]3[CH2:22][CH:21]4[O:23][CH:18]([CH2:19][CH2:20]4)[CH2:17]3)[CH:13]=[C:12]([N:24]3[CH2:30][CH:29]4[O:31][CH:26]([CH2:27][CH2:28]4)[CH2:25]3)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.C(NC1C=CC=CC=1)C>C(O)C.[Pd]>[CH:29]12[O:31][CH:26]([CH2:27][CH2:28]1)[CH2:25][N:24]([C:12]1[CH:13]=[C:14]([N:16]3[CH2:22][CH:21]4[O:23][CH:18]([CH2:19][CH2:20]4)[CH2:17]3)[N:15]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=3)[N:11]=1)[CH2:30]2
Reactant: O=[N+]([O-])c1ccc(-c2nc(N3CC4CCC(C3)O4)cc(N3CC4CCC(C3)O4)n2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCNc1ccccc1
Product: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)cc(N3CC4CCC(C3)O4)n2)cc1
Reaction time: 16 h

Procedure:
In a 250 mL round-bottomed flask was placed 3,3′-(2-(4-nitrophenyl)pyrimidine-4,6-diyl)bis(8-oxa-3-azabicyclo[3.2.1]octane) (20, 65 mg, 0.15 mmol) in ethanol (3 ml). A catalytic amount of Pd on charcoal (wet) was added and the mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was filtered over Celite™, rinsed with dichloromethane and concentrated to give a quantitative yield of the title compound along with an impurity (the N-ethyl aniline product). The crude mixture was reacted in the next step.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[CH:11]=[N:10][CH:9]=[N:8][C:7]=2[NH:6][CH:5]=1.Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].O>CN(C=O)C>[C:18]([O:17][C:15](=[O:16])[CH2:14][N:6]1[C:7]2[N:8]=[CH:9][N:10]=[CH:11][C:12]=2[C:4]([Br:3])=[CH:5]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Brc1c[nH]c2ncncc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1cc(Br)c2cncnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To suspension of NaH (60% in mineral oil, 34 mg, 0.85 mmol) in DMF (1.5 mL) at 0° C. under nitrogen atmosphere was added a solution of 5-bromo-7H-pyrrolo[2,3-d]pyrimidine (140 mg, 0.71 mmol) in DMF (1.5 mL). The reaction mixture was stirred at 0° C. for 30 min and tert-butyl bromoacetate (104 μL, 0.71 mmol) was slowly added. The mixture was further stirred at RT for 30 min, then poured into water and extracted with EtOAc (×3). The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated. MS (UPLC/MS): 312.3/314.2 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:6][NH:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11].[CH3:17][C:18]1([CH3:28])[O:22][C:21](=[CH:23][C:24](Cl)=[O:25])[C:20](=[O:27])[O:19]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CCOCC>[Cl:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:6][N:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[C:24](=[O:25])[CH:23]=[C:21]1[C:20](=[O:27])[O:19][C:18]([CH3:17])([CH3:28])[O:22]1
Reactant: CC(C)CCNCc1ccc(Cl)c(Cl)c1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC(C)CCN(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To a stirred mixture of (3,4-dichloro-benzyl)-(3-methyl-butyl)-amine hydrochloride (283 mg, 1.0 mmol) and (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (206 mg, 1.08 mmol) in CH2Cl2 (10 mL) at room temperature was added diisopropylethylamine (386 μL, 2.2 mmol). After 30 min, the reaction mixture was diluted with ether (50 mL), washed with dilute aqueous HCl (1×5 mL), water (1×10 mL), and saturated aq. NaCl (1×5 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give viscous yellow oil. Purification on a Silica gel column using hexanes/ethyl acetate (20–40% EtOAc) as the eluent gave the title compound as a viscous yellow oil (400 mg, 100% yield). 1H NMR (500 MHz, CDCl3) δ: 7.42–7.26 (2H, m), 7.11 (0.67H, d, J=8.2 Hz), 7.01 (0.33H, d, J=8.2 Hz), 6.14 (0.67H, s), 6.00 (0.33H, s), 4.56 (1.34H, s), 4.52 (0.66H, s), 3.39–3.36 (0.67H, m), 3.29–3.26 (1.33H, m), 1.74 (4H, s), 1.70 (2H, s), 1.59–1.50 (1H, m), 1.47–1.42 (2H, m), 0.90–0.88 (6H, m). MS calcd for C19H24Cl2NO4 (M+H): 400.1. found: 400.07.
Reaction SMILES: [CH3:1][Si:2]([CH3:25])([CH3:24])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[N+:13]([O-:18])[C:14]([C:16]#[N:17])=[CH:15][C:10]=2[C:9]2=[CH:19][CH:20]=[CH:21][N+:22]([O-])=[C:8]12.CS([Cl:30])(=O)=O>CN(C)C=O.C(OCC)(=O)C.O>[Cl:30][C:19]1[C:9]2[C:10]3[CH:15]=[C:14]([C:16]#[N:17])[N+:13]([O-:18])=[CH:12][C:11]=3[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:25])([CH3:24])[CH3:1])[C:8]=2[N:22]=[CH:21][CH:20]=1.[Cl:30][C:21]1[CH:20]=[CH:19][C:9]2[C:10]3[CH:15]=[C:14]([C:16]#[N:17])[N+:13]([O-:18])=[CH:12][C:11]=3[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:25])([CH3:24])[CH3:1])[C:8]=2[N:22]=1
Reactant: C[Si](C)(C)CCOCn1c2c[n+]([O-])c(C#N)cc2c2ccc[n+]([O-])c21
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[Si](C)(C)CCOCn1c2c[n+]([O-])c(C#N)cc2c2c(Cl)ccnc21
Product: C[Si](C)(C)CCOCn1c2c[n+]([O-])c(C#N)cc2c2ccc(Cl)nc21
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of 9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile-1,7-dioxide (2.1 g, 5.9 mmol) in N,N-dimethylformamide (50 mL) was treated with methanesulfonyl chloride (0.78 mL, 10.0 mmol), and the reaction mixture was stirred at ambient temperature for 7 hours. The reaction mixture was then diluted with ethyl acetate (150 mL) and water (200 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 40 g, ISCO, 5-85% ethyl acetate in heptane) to afford the title compound as a 6.5:1 mixture with 2-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile-7-oxide respectively as an off-white solid (1.7 g, 77%). The mixture was triturated in ethyl acetate (10 mL) overnight and the remaining solid was collected by vacuum filtration and washed with ethyl acetate (5 mL) to afford the title compound with >98% purity. 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.39 (d, J=6.4, 1H), 8.27 (s, 1H), 7.94 (d, J=8.1, 1H), 7.32 (dd, J=7.9, 6.5, 1H), 6.55 (s, 2H), 3.73 (t, J=8.0, 2H), 0.93 (t, J=8.0, 2H), −0.04 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([SH:13])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH:14]1[C:19]([C:20]([CH2:22][Br:23])=O)=[CH:18][CH:17]=[C:16](Cl)[CH:15]=1.C(=S)([S-])N.[NH4+].Br[CH:31](C1C=CC=CC=1)[C:32]([OH:34])=[O:33].C(OC(=O)C)(=O)C>C(O)(=O)C.CC(C)=O>[Br-:23].[C:32]([O:34][C:22]1[N+:9]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:12][S:11][C:10]=2[S:13][C:20]=1[C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:33])[CH3:31]
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: Sc1nc(-c2ccc(Cl)cc2)cs1
Agent: NC(=S)[S-]
Agent: [NH4+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CC(=O)Oc1c(-c2ccccc2)sc2scc(-c3ccc(Cl)cc3)[n+]12
Product: [Br-]
Yield: 58 %

Procedure:
A mixture of 10.0 g. (0.044 m.) 4-(4-chlorophenyl)-2-mercaptothiazole (prepared by the reaction of α-bromo-4-chloroacetophenone with ammonium dithiocarbamate) and 10.0 g. (0.04 m.) α-bromophenylacetic acid in 200 ml. of acetone and 40 ml. each of glacial acetic acid and acetic anhydride is heated for 2 hours. After the solvents are removed, the residual solid is triturated with acetone and the resulting solid collected. 10 g. (58% yield) of the title product is obtained, m.p. 160°-165° C.
Reaction SMILES: [F:1][C:2]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.Cl.[OH:25][C@@H:26]([CH2:56]O)[CH2:27][N:28]1[CH:32]=[CH:31][C:30]([NH:33]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:29]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:68]=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[OH:25][C:26]([CH3:56])([CH3:68])[CH2:27][N:28]1[CH:32]=[CH:31][C:30]([NH:33][C:11](=[O:13])[C@@H:10]([N:8]2[CH2:9][C:5]([O:4][C:3]3[CH:19]=[CH:20][CH:21]=[C:22]([OH:23])[C:2]=3[F:1])=[CH:6][C:7]2=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:29]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(O)c2F)=CC1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2cccc(O)c2F)=CC1=O
Temperature: 0 °C
Yield: 67.9 %

Procedure:
To a solution of (S)-2-[4-(2-fluoro-3-hydroxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.100 g, 0.31 mmol) in dichloromethane (3 mL) was added 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 0.100 g, 0.64 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.137 g, 0.31 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.04 g, 0.31 mmol) was added. The mixture was stirred at room temperature for 4 h and the solvents were evaporated. The residue was extracted with ethyl acetate and washed with a citric acid solution. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by reverse phase HPLC (C18, 20% to 100% acetonitrile/water) which afforded (S)-2-[4-(2-fluoro-3-hydroxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (0.097 g, 57%) as an off-white solid: HR-ES-MS m/z calculated for C23H29FN4O5 [M+H]+ 461.2195, observed 461.2194, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.4 Hz, 3H), 0.94 (d, J=6.4 Hz, 3H), 1.05 (s, 3H), 1.07 (s, 3H), 1.37-1.51 (m, 1H), 1.57 (ddd, J=13.6, 9.1, 4.8 Hz, 1H), 1.68-1.84 (m, 1H), 3.90 (s, 2H), 4.20 (d, J=18.5 Hz, 1H), 4.59 (d, J=18.5 Hz, 1H), 4.67 (s, 1H), 4.85-4.92 (m, 1H), 4.88 (s, 1H), 6.45 (d, J=1.9 Hz, 1H), 6.85 (t, J=7.4 Hz, 1H), 6.91 (t, J=7.9 Hz, 1H), 6.98-7.10 (m, 1H), 7.54 (d, J=1.9 Hz, 1H), 10.36 (br. s., 1H), 10.79 (s, 1H).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:53][O:54][CH:55]([CH3:57])[CH3:56])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:9]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])([CH3:4])[CH3:3].C(O)(=O)C.C(O)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>O>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:53][O:54][CH:55]([CH3:57])[CH3:56])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:9]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])([CH3:4])[CH3:3]
Reactant: CC(C)OCc1nc(C(C)(C)O)c(C(=O)OC(C)C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)OCc1nc(C(C)(C)O)c(C(=O)OC(C)C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 95.9 %

Procedure:
A solution of 609 mg of isopropyl 4-(1-hydroxy-1-methylethyl)-2-isopropoxymethyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] in 10 ml of a 25% v/v aqueous solution of acetic acid was stirred at 60° C. for 2.5 hours. 10 ml of water were then added, after which the mixture was cooled with ice. The trityl alcohol which appeared as crystals was filtered off. The filtrate was concentrated by distillation under reduced pressure, and then acetic acid and water were distilled off as azeotropic mixtures with benzene, to give 398 mg of the title compound as an amorphous powder.
Reaction SMILES: [C:1](#N)[CH3:2].[Cl:4][C:5]1[C:6]([CH:12]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[CH:7][C:8]([NH2:11])=[N:9][CH:10]=1.Cl.CN1[CH2:38][CH2:37][N:36]([S:39](Cl)(=[O:41])=[O:40])[CH2:35][CH2:34]1.C(N(CC)CC)C>CO.O>[Cl:4][C:5]1[C:6]([CH:12]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[CH:7][C:8]([NH:11][S:39]([N:36]2[CH2:37][CH2:38][CH:1]([CH3:2])[CH2:34][CH2:35]2)(=[O:41])=[O:40])=[N:9][CH:10]=1
Reactant: Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reactant: CC#N
Reactant: CN1CCN(S(=O)(=O)Cl)CC1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC1CCN(S(=O)(=O)Nc2cc(C(c3cc(F)ccc3F)S(=O)(=O)c3ccc(Cl)cc3)c(Cl)cn2)CC1
Yield: 16 %

Procedure:
An acetonitrile (5 ml) solution of the [5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine (101 mg, 0.235 mmol) obtained in Example 196, 4-methylpiperazine-1-sulfonyl chloride hydrochloride (126 mg, 0.534 mmol) and triethylamine (150 μl, 1.07 mmol) was heated under reflux for 23 hours. To the reaction mixture were added 4-methylpiperazine-1-sulfonyl chloride hydrochloride (126 mg, 0.534 mmol) and triethylamine (150 μl, 1.07 mmol). The resulting mixture was heated under reflux for 22 hours. The reaction mixture was returned to room temperature and then, concentrated under reduced pressure. To the residue thus obtained was added water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the methanol:methylene chloride (=1:20) eluate was concentrated under reduced pressure to give the title compound (34 mg, 0.057 mmol, 16%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:14](=[O:23])[CH2:13][C:12]2=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:39]([C:41]1[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=1[NH2:43])[CH3:40]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:14](=[O:23])[CH:13]=[C:12]2[NH:43][C:42]2[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=2[CH2:39][CH3:40])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccccc1N
Reactant: O=C1CC(=O)C2(CCN(Cc3ccccc3)CC2)N1c1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCc1ccccc1NC1=CC(=O)N(c2cccc(F)c2)C12CCN(Cc1ccccc1)CC2

Procedure:
To a solution of 100 mg (0.28 mmol) 8-benzyl-1-(3-fluorophenyl)-1,8-diazaspiro[4.5]decane-2,4-dione in 0.71 mL dry toluene was added 70 mg (0.37 mmol)p-toluenesulfonic acid monohydrate and 61 μL (0.50 mmol) 2-ethylaniline. The reaction was heated to reflux for 18 h and then diluted with EtOAc, washed with 1N NaOH, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified on silica gel with 20-60% EtOAc/hexanes to afford title example 8-benzyl-4-[(2-ethylphenyl)amino]-1-(3-fluorophenyl)-1,8-diazaspiro[4.5]dec-3-en-2-one as a tan foam. 1H NMR (CD3OD, 400 MHz) δ 7.43 (q, J=7.38 Hz, 1H), 7.32 (m, 1H), 7.24 (m, 6H), 7.16 (m, 3H), 7.08 (m, 2H), 4.55 (s, 1H), 3.41 (s, 2H), 2.80 (m, 2H), 2.64 (q, J=7.51 Hz, 2H), 2.38 (m, 2H), 2.19 (m, 2H), 2.10 (dt, J=11.5 and 3.85 Hz, 2H), 1.18 (t, J=7.51 Hz, 3H); LC/MS [M+H]=456.1.
Reaction SMILES: C[O-].[Na+].[C:4](=[O:9])(OC)[O:5]C.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][CH2:23][C:24]3=O)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][C:23]([C:4]([OH:5])=[O:9])=[CH:24]3)=[CH:19][CH:18]=2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C(=O)CCC3)cc1
Reactant: COC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CC3)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of sodium methoxide (5.63 g), dimethyl carbonate (33 ml) and 7-(4-methylphenyl)-1-tetralone (4.93 g) was refluxed for 30 minutes. The reaction mixture was cooled to 0° C., and to the mixture was gradually added 3Nhydrochloricacid(80 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (30 ml), and to the mixture was added sodium boron hydride (494 mg) at 0° C. and then was dropwise added methanol (3 ml) for 30 minutes. The reaction mixture was stirred at 0° C. for 4 hours, and to the mixture was added water (500 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (20 ml), and to the mixture was added IN sodium hydroxide (20 ml). The mixture was refluxed for 4 hours, cooled, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in Diglyme (20 ml), and to the mixture was added concentrated hydrochloric acid (4 ml). The mixture was stirred at 100° C. for 2 hours, and to the mixture was added water (500 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, and concentrated under reduced pressure. The residue was dissolved in 0.5N sodium hydroxide (400 ml), and the mixture was washed with diethylether. The aqueous layer was separated and acidified with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give 7-(4-methyl-phenyl)-3,4-dihydronaphthalene-2-carboxylic acid (1.96 g) as pale brown crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([NH2:22])=[N:18][C:19]=1[O:20][CH3:21].CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[C:19]([O:20][CH3:21])[N:18]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2ncsc2n1
Reactant: COc1ccc(N)nc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Nc2nc(Cl)nc3scnc23)nc1OC
Yield: 73.3 %

Procedure:
A solution of 5,7-dichlorothiazolo[5,4-d]pyrimidine (300 mg, 1.45 mmol), 5,6-dimethoxypyridin-2-amine (269 mg, 1.74 mmol) and DIEA (281 mg, 2.17 mmol) in 5 mL of DMSO was stirred at room temperature for 24 hours. Then the mixture was poured into 30 mL of water, and the formed solid was filtered and washed with water. The obtained crude product was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with ethyl acetate) to give 5-chloro-N-(5,6-dimethoxypyridin-2-yl)thiazolo[5,4-d]pyrimidin-7-amine (344 mg, 73%) as an off-white solid. LC-MS: 324.1 [M+H]+, tR=1.69 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][CH:21]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:27]#[C:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(Cl)cc2)cc1[N+](=O)[O-]
Yield: 88.3 %

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) (728 mg, 2.0 mmol) and 4-chlorophenylacetylene (416 mg, 3.0 mmol) according to the general procedure F. Obtained as a yellow solid (658 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]2[CH:9]=[C:8]([CH2:10][OH:11])[N:7]=[C:4]2[S:5][CH:6]=1.[C:12]([Cl:17])(=[O:16])[CH2:13][CH2:14][CH3:15].N1C=CC=CC=1>C(Cl)(Cl)Cl>[ClH:17].[CH3:1][C:2]1[N:3]2[CH:9]=[C:8]([CH2:10][O:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15])[N:7]=[C:4]2[S:5][CH:6]=1
Reactant: Cc1csc2nc(CO)cn12
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCC(=O)OCc1cn2c(C)csc2n1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5 g of 3-methyl-6-hydroxymethyl-imidazo-(2,1-b)thiazole in 100 ml of dry chloroform is dropped at 35° into a solution of 15 ml of butyroyl chloride and 12 ml of pyridine in 75 ml of dry chloroform. The suspension obtained is stirred for 1 hour at room temperature and then filtered. The filtrate is concentrated by evaporation. The residue obtained is dissolved in abs.ethanol and a stream of dry hydrochloric acid is bubbled into the solution to yield 4.5 g of 3-methyl-6-butyroxymethyl-imidazo-(2,1-b)thiazole hydrochloride; m.p. 126°-128°.