Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]=2[C:4](=[S:11])[NH:3][CH:2]=1.[CH2:12](N(CC)CC)C.IC>CS(C)=O>[CH3:12][S:11][C:4]1[C:5]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: CCN(CC)CC
Reactant: S=c1[nH]cnc2ccncc12
Solvent: CS(C)=O
Solvent: CI
Product: CSc1ncnc2ccncc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 156.7 %

Procedure:
A mixture of 3H-pyrido[4,3-d]pyrimidin-4-thione (676 mg, 4.14 mmol), triethylamine (1.4 mL, 10.31 mmol), DMSO (4 mL), and iodomethane (0.48 mL, 7.72 mmol) is stirred for 12 h under N2 at 25° C. The mixture is poured onto water and extracted with EtOAc. The organic extracts are dried (MgSO4), and the solvent is removed under reduced pressure to yield 4-methylthiopyrido[4,3-d]pyrimidine (1.15 g, quant.) as a brown solid. 1H NMR (DMSO) δ 9.52 (1H, s), 9.16 (1H, s), 8.95 (1H, d, J=6 Hz), 7.86 (1H, d, J=8 Hz), 2.75 (1H, s).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15](OC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[CH2:12][CH:11]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[OH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:36]3[CH2:37][CH2:38][CH:33]([OH:32])[CH2:34][CH2:35]3)=[O:16])[CH2:12][CH:11]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: OC1CCNCC1
Reactant: CCOC(=O)C1CC(c2ccc(CC)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC(c2ccc(CC)cc2)CN(C(=O)N2CCC(O)CC2)C1
Temperature: 150 °C

Procedure:
370 mg (0.81 mmol) of 3-ethyl 1-(4-nitrophenyl) 5-(4-ethylphenyl)piperidine-1,3-dicarboxylate, 245 mg (2.42 mmol) of 4-hydroxypiperidine and 112 mg (0.81 mmol) of potassium carbonate were added to 9 ml of DMF and heated in a single-mode microwave (Emrys Optimizer) at 150° C. for 15 min. For work-up, water was added and the reaction solution was extracted with ethyl acetate. The organic phase was dried with sodium sulphate and concentrated under reduced pressure. The residue was purified by preparative HPLC. Yield: 208 mg (66% of theory)
Reaction SMILES: [OH:1][CH:2]1[CH:6]2[O:7][C:8](=[O:15])[CH:9]3[CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH:3]1[CH2:4][CH:5]23.[Cl:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:16][CH2:17][CH2:18][CH2:19][C:20]([O:1][CH:2]1[CH:6]2[O:7][C:8](=[O:15])[CH:9]3[CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH:3]1[CH2:4][CH:5]23)=[O:21]
Reactant: COC(=O)C1C2CC3C(OC(=O)C31)C2O
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)C1C2CC3C(OC(=O)C31)C2OC(=O)CCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
In 180 ml of tetrahydrofuran were dissolved 21.2 g of methyl 6-hydroxy-2-oxohexahydro-3,5-methano-2H-cyclopenta-[b]furan-7-carboxylate and 16.9 g of 4-chlorobutyric acid chloride. To the solution below 20° C., 9.10 g of pyridine was added dropwise. The solution was stirred at room temperature for 1 hour and combined with 40 g of a 5% aqueous solution of sodium hydrogen carbonate, followed by ordinary work-up. There was obtained 30.4 g of a crude product (crude yield 96%).
Reaction SMILES: [CH2:1]([NH:8][CH:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH2:16]([O+](CC)CC)[CH3:17]>C(Cl)Cl>[CH2:1]([N:8]=[CH:9][O:10][CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[O+](CC)CC
Reactant: O=CNCc1ccccc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC=NCc1ccccc1

Procedure:
A solution of 690 mg (5.1 mmoles) of N-benzylformamide in 5 ml of methylene chloride is cooled in an ice-water bath and put under an argon blanket. The solution is stirred while 4.9 ml (4.9 mmoles) of 1 M triethyloxonium fluoroborate in methylene chloride is added dropwise. After a 45 minute reaction time, the mixture is concentrated to dryness under reduced pressure at room temperature, and the residue is dried under reduced pressure over P2O5. The nuclear magnetic resonance spectrum of the product in deuterochloroform is fully in accord with the product being a fluoroborate etherate complex of ethyl N-benzylformimidate.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[C:6]([F:13])[CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[CH:33]([Sn](CCCC)(CCCC)CCCC)=[CH2:34]>C1(C)C=CC=CC=1>[F:13][C:6]1[CH:7]=[C:8]([C:11]#[N:12])[CH:9]=[C:10]2[C:5]=1[N:4]([C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[N:3]=[C:2]2[CH:33]=[CH2:34]
Reactant: N#Cc1cc(F)c2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2c(F)cc(C#N)cc12
Temperature: 100 °C
Reaction time: 1.58 h

Procedure:
Under nitrogen atmosphere, 3.32 g of 3-bromo-7-fluoro-1-trityl-1H-indazole-5-carbonitrile was dissolved in 100 mL of toluene, added with 398 mg of tetrakis(triphenylphosphilne)palladium(0) and 2.50 mL of vinyltributyltin, and stirred at 100° C. for 95 minutes. After cooling to room temperature, 10 g of silica gel was added, the solvent was evaporated, followed by purification by silica gel column chromatography, to afford 2.59 g of the title compound as white crystals.
Reaction SMILES: [I-].[CH3:2][N+:3]12[CH2:18][CH2:17][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:6][CH2:5][CH2:4]2.[Li].COCC(O)C.N>C1C=CC=CC=1.CCCCCC>[CH3:2][N:3]1[CH2:4][CH2:5][CH2:6][CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]2[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]=2[CH2:17][CH2:18]1
Reactant: C[N+]12CCCC1(c1ccccc1)c1[nH]c3ccccc3c1CC2
Agent: N
Agent: [I-]
Agent: [Li]
Solvent: COCC(C)O
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CN1CCCC(c2ccccc2)c2[nH]c3ccccc3c2CC1

Procedure:
Then 2,3,5,6,11,11b-hexahydro-4-methyl-11b-phenyl-1H-indolizino[8,7-b]indolium iodide (8.09 g.), 286 mg. lithium, 2.03 g. 1-methoxy-2-propanol and 2 liters liquid ammonia are reacted according to the method of Example I-(a). The white foam isolated from the 1:9 and 1:4 benzene-hexane elutes is crystallized from hexane to provide 4.38 g. base. A 300 mg. portion is crystallized (twice) from hexane thereby yielding 200 mg. of title compound, m.p. 117°-119°C., NMR (CDCl3): δ 2.45 (singlet, 3-methyl), 5.70 (triplet, J 8 cps., 7-hydrogen) ppm.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].NOCCN(C)C[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2C)[C@H](O)[C@@H]1O.C(OC(=[N:36][O:37][CH2:38][CH2:39][N:40]([CH3:65])[CH2:41][C@H:42]1[O:46][C@@H:45]([N:47]2[C:56]3[N:55]=[CH:54][N:53]=[C:51]([NH2:52])[C:50]=3[N:49]=[C:48]2[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C@H:44]([OH:63])[C@@H:43]1[OH:64])C)C>>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[NH2:36][O:37][CH2:38][CH2:39][N:40]([CH3:65])[CH2:41][C@H:42]1[O:46][C@@H:45]([N:47]2[C:56]3[N:55]=[CH:54][N:53]=[C:51]([NH2:52])[C:50]=3[N:49]=[C:48]2[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C@H:44]([OH:63])[C@@H:43]1[OH:64]
Reactant: CCOC(C)=NOCCN(C)C[C@H]1O[C@@H](n2c(-c3ccccc3)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Agent: Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CN(C)CCON)[C@@H](O)[C@H]1O
Agent: O=S(=O)(O)O
Product: CN(CCON)C[C@H]1O[C@@H](n2c(-c3ccccc3)nc3c(N)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 7c was prepared by the same procedure as described for the preparation of 7a using 6c (99 mg, 0.20 mmol): yield 57 mg (42%), MS: m/z 416 (M+H)+; 1HNMR (D2O) δ 8.37 (s, 1H, H-2), 7.73-7.76 (m, 2H, 8-phenyl o-H's), 7.60-7.70 (m, 3H, 8-phenyl m- and p-H's), 6.02 (d, 1H, H-1′, J1′,2′=5.7 Hz), 5.25 (t, 1H, H-2′, J2′,3′=4.9 Hz), 4.46-4.54 (bm, 2H, H-3′, 4′), 4.03 (t, 2H, NH2O—CH2), 3.87-4.0 (m, 1H, 5′-CH2), 3.61-3.67 (m, 1H, 5′-CH2), 3.50-3.55 (m, 2H, N(CH3)—CH2), 3.0 (s, 3H, N—CH3); UV λmax, nm, pH 1, 275 (∈ 21,600), pH 7, 275 (∈ 17,100), pH 13, 274.4 (∈ 16,800). Anal. (C19H25N7O4.2.0H2SO4.3H2O) C, H, N, S.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5](I)=[CH:4][N:3]=1.[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)CO.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.C(O)(C)C>[Cl:1][C:2]1[C:7]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)ncc1I
Reactant: Sc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Nc1ccnc(Cl)c1Sc1ccccc1
Reaction time: 24 h
Yield: 97 %

Procedure:
To a 250 mL round flask was added 2-chloro-5-iodo-4-aminopyridine (5.0 g, 19.6 mmol), thiophenol (2.16 g, 19.6 mmol), CuI (0.187 g, 0.98 mmol), ethylene glycol (2.5 g, 39 mmol), potassium carbonate (5.4 g, 39 mmol), and 150 mL of isopropanol. The reaction was heated to reflux and stirred under a nitrogen atmosphere for 24 h. After cooling, the mixture was purified by a silica gel column. Yield (97%) of 2-chloro-3-phenylthio-4-aminopyridine was 4.5 g.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([CH3:8])[CH3:7])C.Cl.[OH-].[K+].[Br:15][C:16]1[CH:17]=[C:18]([NH:23][C:24]2[C:25]3[CH:33]=[C:32]([NH:34][C:35](=[O:45])[CH2:36]P(=O)(OCC)OCC)[N:31]=[CH:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH:19]=[CH:20][C:21]=1[Br:22].[Li+].[Cl-]>O.C(Cl)Cl.CO.CC(N(C)C)=O.C1COCC1>[Br:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[Br:22])[NH:23][C:24]1[C:25]2[CH:33]=[C:32]([NH:34][C:35](=[O:45])/[CH:36]=[CH:4]/[CH2:5][N:6]([CH3:7])[CH3:8])[N:31]=[CH:30][C:26]=2[N:27]=[CH:28][N:29]=1
Reactant: CCOC(CN(C)C)OCC
Reactant: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc(Br)c(Br)c3)ncnc2cn1)OCC
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CN(C)C/C=C/C(=O)Nc1cc2c(Nc3ccc(Br)c(Br)c3)ncnc2cn1
Temperature: 45 °C
Reaction time: 23 h
Yield: 97.4 %

Procedure:
To a stirred mixture of 2,2-diethoxy-N,N-dimethylethanamine (2.25 g, 14.0 mmol) and water (2.4 mL) at room temperature and under a nitrogen atmosphere was added an aq. 37% HCl (2.35 mL, 28.0 mmol). After addition the mixture was stirred at 45° C. (bath) for 23 h. It was cooled to 0° C. (bath). This is called solution A. KOH (4.02 g, 71.7 mmol) was dissolved in water (12 mL) at room temperature under a nitrogen atmosphere. It was cooled to 0° C. (bath). This is called solution B. To a stirred heterogeneous mixture of compound 234 (3.21 g, 5.60 mmol) and THF (12 mL) at room temperature and under a nitrogen atmosphere was added minimum amount of DMA (6 mL) to give a homogeneous solution. LiCl (237 mg, 5.60 mmol) was added and stirred at 0° C. (bath) for 15 min. The cold solution B was added and stirred at 0° C. for 2 min. Then the cold solution A was added and the final reaction mixture was continued to stir at 0° C. under a nitrogen atmosphere. The reaction was monitored by TLC(DCM-MeOH=25:1). After 1 h it was poured into water (200 mL). Petroleum ether (200 mL) was added and stirred at room temperature for 30 min. Petroleum ether layer was decanted. More petroleum ether (200 mL) was added and stirred for 15 min. The solid was collected by suction filtration; washed with water (5×20 mL); dried under reduced pressure over silica gel/KOH to give (2E)-N-[4-(3,4-dibromoanilino)pyrido[3,4-d]pyrimidin-6-yl]-4-(dimethylamino)-2-butenamide (7) (2.76 g, 98%) as a beige solid, mp 176-179° C.; HPLC: 97.2% pure; 1H NMR δ [(CD3)2SO] 10.95 (s, 1H), 10.35 (s, 1H), 9.03 (s, 1H), 9.00 (s, 1H), 8.67 (br s, 1 H), 8.37 (br s, 1 H), 7.89 (br d, J=7.8 Hz, 1H), 7.77 (d, J=8.8, 1H), 6.87 (dt, J=15.4, 6.0 Hz, 1H), 6.52 (br d, J=15.4 Hz, 1H), 3.08 (br d, J=5.3 Hz, 2H), 2.19 (s, 6H). Anal. Calcd for C19H8Br2N6O.0.5H2O: C, 44.30; H, 3.72; N, 16.31. Found C, 44.24; H, 3.81; N, 15.98.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:15]([O:19]C)(=[O:18])[CH:16]=[CH2:17]>CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][CH2:17][CH2:16][C:15]([OH:19])=[O:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC(OCCC(=O)O)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (350 mg, 2.0 mmol) and NaH (6 mg of a 60% dispersion in mineral oil, 0.15 mmol) was warmed until effervescence had ceased. The mixture was stirred at ambient temperature for 15 min, then methyl acrylate (940 μL, 10.5 mmol) was added. After 3 h, the reaction was diluted with Et2O (50 mL), before being washed with H2O (10 mL) and brine (10 mL) then dried (MgSO4). The Et2O solution was filtered and evaporated, then EtOAc (15 mL) was added. The solvents were removed, then more EtOAc (15 mL) was added, before being evaporated off again to ensure that no methyl acrylate remained. The residue was dissolved in MeOH (3 mL), before being treated with 2 M NaOH (2.0 mL). After 1 h, the MeOH was removed, then H2O (12 mL) and Et2O (10 mL) were added. The Et2O layer was extracted further with H2O (8 mL), then the combined aqueous extracts were acidified to pH 2 with 2 M HCl and the resulting mixture extracted with EtOAc (50+40 mL). The combined organic extracts were washed with brine and dried (MgSO4). Filtration, solvent evaporation and column chromatography (IH-EtOAc, 1:1) gave the title compound: δC (CDCl3): 28.1, 34.8, 56.3, 63.9, 68.0, 79.9, 156.4, 176.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:22][O:23][C:24](=[O:42])[C:25]([CH3:41])([N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1)[CH3:26]>>[CH3:22][O:23][C:24](=[O:42])[C:25]([N:27]1[CH:31]=[C:30]([C:2]2[CH:3]=[C:4]3[C:10]([CH:11]([C:13]4[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=4[Cl:21])[CH3:12])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:29]=[N:28]1)([CH3:41])[CH3:26]
Reactant: COC(=O)C(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
Product: COC(=O)C(C)(C)n1cc(-c2cnc3[nH]cc(C(C)c4c(Cl)ccc(F)c4Cl)c3c2)cn1

Procedure:
Prepared from 5-bromo-3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]-pyridine and 2-methyl-2-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)pyrazol-1-yl]-propionic acid methyl ester according to the Suzuki coupling procedure described in Example 1. Purification by flash column chromatography using 0→70% EtOAc in hexanes afforded the title compound as a light yellow solid. MS (ES+): m/z 475.06/477.04 (100/68) [MH+]. HPLC: tR=2.51 min (ZQ3, polar—5 min).
Reaction SMILES: O1CCCC1.Cl[C:7]1[CH:12]=[C:11]([NH:13][C:14]2[N:19]=[CH:18][N:17]=[C:16](NC(C3CC3)=O)[CH:15]=2)[C:10](=[O:26])[N:9]2[C:27]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34](F)C=3)(C)[NH:28][C:29](=O)[C:8]=12.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:40]>CO.ClCCl>[N:17]1[CH:16]=[CH:15][C:14]([NH:13][C:11]2[C:10](=[O:26])[N:9]3[C:27]4([CH2:32][CH2:37][CH2:36][CH2:35][CH2:34]4)[NH:28][C:29](=[S:40])[C:8]3=[CH:7][CH:12]=2)=[N:19][CH:18]=1
Reactant: CC1(c2cccc(F)c2)NC(=O)c2c(Cl)cc(Nc3cc(NC(=O)C4CC4)ncn3)c(=O)n21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: O=c1c(Nc2ccncn2)ccc2n1C1(CCCCC1)NC2=S
Temperature: 50 °C

Procedure:
A vial containing tetrahydrofuran (10 mL) was charged with 6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione (1, 0.6 g, 1.93 mmol) and phosphorus pentasulfide (857 mg, 3.85 mmol). Seal the vial and heat the reaction mixture at 50° C. for 16 h. After completion, the reaction mass was diluted with 5% methanol in dichloromethane (100 mL), washed with water (2×100 mL) and brine solution (100 mL), dried over anhydrous sodium sulfate, concentrated under vacuum. Crude material was purified by flash chromatography in silica gel in 3-4% methanol in dichloromethane, fraction were combined concentrated under reduced pressure. The product was triturated with methanol, filtered washed with methanol (3 mL), ether (5 mL), dried under high vacuum to obtain the desired product 6′-(pyrimidin-4-ylamino)-1′-thioxo-1′,2′-dihydro-5′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-5′-one (Cpd. No. 131) as light yellow solid. Yield: 0.050 g, 8%; MS (ESI) m/z 328.41 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 9.46 (s, 1H), 8.80-8.77 (d, 2H), 8.39-8.38 (d, 1H), 7.39-7.38 (d, 1H), 7.07-7.06 (d, 1H), 2.97 (t, 2H), 1.78-1.72 (m, 5H), 1.59-1.56 (d, 1H), 1.26 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]([NH:13][CH3:14])=[O:12].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=CC=1.O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]2[C:3]=1[CH2:9][CH2:10][C:11](=[O:12])[N:13]2[CH3:14]
Reactant: CNC(=O)CCc1c(Cl)cccc1Br
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CN1C(=O)CCc2c(Cl)cccc21
Temperature: 25 °C

Procedure:
3-(2-Bromo-6-chlorophenyl)-N-methylpropanamide (Example 1g), 2.98 g, 10.8 mmol), palladium acetate (0.12 g, 0.54 mmol), Pd2(dba)3 (0.020 g, 0.02 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.671 g, 1.08 mmol) and cesium carbonate (4.92 g, 15.1 mmol) in toluene (30 mL) and 1,4-dioxane (45 mL) were heated to +95° C. under argon for 6 h. The mixture was allowed to cool to rt. 100 mL of ethyl acetate was added and the mixture was filtered through a pad of Celite. The filtrate was collected and the solvent was removed by rotary evaporation. The crude product was added to a silica gel column and was eluted with 0-2% methanol in dichloromethane. The collected fractions were combined and the solvent was removed by rotary evaporation to give the title compound. Yield: 1.50 g, 71%. 1H NMR (500 MHz, CDCl3) δ ppm 2.66 (dd, 2H) 3.02-3.09 (m, 2H) 3.36 (s, 3H) 6.91 (d, 1H) 7.08-7.12 (m, 1H) 7.17-7.22 (m, 1H). MS m/z 196.6 [M+H]+
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@@H:13]1[CH2:17][CH2:16][C@:15]([CH3:21])([C:18]([OH:20])=O)[C:14]1([CH3:23])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH3:29][NH2:30]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:26])([CH3:25])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C@@H:13]1[CH2:17][CH2:16][C@:15]([CH3:21])([C:18]([NH:30][CH3:29])=[O:20])[C:14]1([CH3:23])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@@H]1CC[C@](C)(C(=O)O)C1(C)C
Reactant: CN
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@@H]1CC[C@](C)(C(=O)NC)C1(C)C

Procedure:
The product from Example 205 and methylamine hydrochloride (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.48 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.13 (s, 3H), 1.23 (s, 3H), 1.26-1.42 (m, 3H), 1.57 (s, 9H), 1.57-1.66 (m, 2H), 1.72-1.82 (m, 1H), 2.24-2.45 (m, 2H), 2.54-2.56 (m, 3H), 2.61-2.67 (m, 2H), 2.96-3.02 (m, 1H), 7.24-7.28 (m, 1H), 8.50 (s, 1H). (ESI+) m/z 408 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[CH3:7][C:8]1[CH:17]=[C:11]2[N:12]=[CH:13][CH:14]=[C:15]([NH2:16])[N:10]2[N:9]=1.[N+:18]([O-])([OH:20])=[O:19].N>>[CH3:7][C:8]1[C:17]([N+:18]([O-:20])=[O:19])=[C:11]2[N:12]=[CH:13][CH:14]=[C:15]([NH2:16])[N:10]2[N:9]=1
Reactant: Cc1cc2nccc(N)n2n1
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: N
Agent: O=S(=O)(O)O
Product: Cc1nn2c(N)ccnc2c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 66 %

Procedure:
27 cc of 98% sulphuric acid were introduced into a 100 cc three-necked flask equipped with a magnetic stirrer, a thermometer and a condenser, after which 5.5 g of 2-methylpyrazolo[1,5-a]pyrimidin-7-ylamine hydrochloride were dissolved portionwise at 5° C. A mixture of 1.98 g of fuming nitric acid and 5 cc of 98% sulphuric acid was then added dropwise over 30 minutes. After reaction for 2 h 30', the medium was poured onto 200 cc of ice-cold water and neutralized with 122 g of 20% aqueous ammonia. The green precipitate which formed was filtered off. After drying under vacuum over phosphorus pentoxide, 3.8 g of 2-methyl-3-nitropyrazolo[1,5-a]pyrimidin-7-ylamine were obtained in the form of a green powder. (Crude yield=66%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:25]=1[CH2:26]Cl>CN(C=O)C>[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:25]=1[CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1
Reactant: COC(=O)C1=Cc2cc(O)ccc2CCC1
Reactant: Fc1cccc(F)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1=Cc2cc(OCc3c(F)cccc3F)ccc2CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
To methyl 2-hydroxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (327 mg, 1.50 mmol) dissolved in DMF (6 ml) were added potassium carbonate (415 mg, 3.00 mmol) and 2,6-difluorobenzyl chloride (268 mg, 1.65 mmol), and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (40 ml) was added to the residue and the resulting mixture was washed with water (5 ml×2) and an aqueous saturated solution of sodium chloride (5 ml). The organic layer was dried with anhydrous magnesium sulfate and was then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel: 15 g, ethyl acetate/hexane=1/25). The objective fractions were concentrated under reduced pressure to obtain methyl 2-(2,6-difluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (507 mg, 1.47 mmol, 98%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[CH3:10][O:11][C:12](=[O:30])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=2[Cl:28])[CH:14]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:10][O:11][C:12](=[O:30])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:2]3[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=3[F:9])=[CH:23][C:22]=2[Cl:28])[CH:14]=1
Reactant: COC(=O)c1ccc(Cl)c(C(=O)c2ccc(N)cc2Cl)c1
Reactant: Fc1ccc(Br)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cl)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
1-Bromo-2,4-difluorobenzene (87 μL, 0.77 mmol) was dissolved in 2.5 mL dry toluene under an argon atmosphere. Compound 462 (250 mg, 0.77 mmol) was added and dissolved in the solvent. 4,5-bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene (13 mg, 0.023 mmol), Pd(OAc)2 (3.5 mg, 0.015 mmol) and Cs2CO3 (352 mg, 1.08 mmol) were added, and the reaction mixture was stirred under an argon atmosphere at 120° C. for 24 h. The reaction mixture was filtered and then purified by flash chromatography using EtOAc/petroleum ether 1:2 as the eluent to afford the title compound as a solid.