Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][CH:12]=[N:11][C:10]=2[CH:9]1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[CH:24]2.C1CCN2C(=NCCC2)CC1>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([O:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][CH:25]=[CH:24]4)=[N:13][CH:12]=[N:11][C:10]=2[CH:9]1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1c2ncnc(Cl)c2CCN1C(=O)OC(C)(C)C
Reactant: Oc1ccc2[nH]ccc2c1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1c2ncnc(Oc3ccc4[nH]ccc4c3)c2CCN1C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To a solution of 4-chloro-8-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (228 mg, 0.80 mmol), 5-hydroxyindole (139 mg, 1.05 mmol) and MeCN (5 mL) is added DBU (0.15 mL, 1.05 mmol). The resulting mixture is heated at 80° C. for 4 h. The reaction is then concentrated in vacuo and the residue separated via FCC (5-60% EtOAc/heptane). MS (ESI) m/z 381.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=O.[C:22]([O:29][CH3:30])(=[O:28])[CH2:23][CH2:24][C:25]([CH3:27])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:27][C:25]1[N:1]=[C:2]2[S:3][CH:4]=[C:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]2=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:24]=1[CH2:23][C:22]([O:29][CH3:30])=[O:28]
Reactant: Cc1ccc(C(=O)c2c(-c3ccccc3)csc2N)cc1
Reactant: COC(=O)CCC(C)=O
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2scc(-c3ccccc3)c2c1-c1ccc(C)cc1
Yield: 85.2 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4-phenylthiophen-3-yl)(p-tolyl)methanone (0.264 g; 0.9 mmol), methyl levulinate (0.127 mL; 0.99 mmol), chlorotrimethylsilane (0.460 mL; 3.6 mmol) in DMF (3.6 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-40%) in heptane furnished 0.297 g (85%) of the title compound as a yellow solid.
Reaction SMILES: [Li].C(N)C(N)C.[CH2:7]([OH:38])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:7]([OH:38])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]#[CH:37]
Reactant: CCCCCCCCCCCCCCCCCCCCC#CCCCCCCCCCO
Agent: CC(N)CN
Agent: [Li]
Product: C#CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.0 g (0.1448 mol) of lithium wire was added in small pieces to 75 ml of propylenediamine under an argon atmosphere at room temperature. The mixture was stirred for 15 min at room temperature and then heated at 70° C. until the blue coloration had disappeared. It was cooled to room temperature, 10 g (0.0891 mol) of potassium t-butylate were added, the mixture was stirred for 15 min at room temperature and 10 g (0.0223 mol) of hentriacont-10-yn-1-ol of Example 9 were added as a solid. The mixture was left to stand overnight at room temperature, poured into ice-water and stirred for 30 min at room temperature. The product was filtered off with suction and dried under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([C:14]1[O:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:17][CH:18]=1)=[O:13].Br[C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([CH2:10][CH2:11][C:12](=[O:13])[C:14]2[O:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH:4]=[CH:5][C:6]=1[O:9][C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: O=C(CCc1ccc(O)c(Cl)c1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)o1
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)o2)c(Cl)c1Cl

Procedure:
Tert-butyl 2-(2,3-dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)fur-2-yl)propyl)phenoxy)-2-methylpropanoate is prepared from 3-(2,3-dichloro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)fur-2-yl)propan-1-one and tert-butyl bromoisobutyrate according to general procedure D.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.O[CH2:21]N1C2C=CC=CC=2N=N1.[BH4-].[Na+]>CCO.CN(C=O)C>[CH3:21][NH:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2
Reactant: OCn1nnc2ccccc21
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CNc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 70 °C

Procedure:
A mixture of (−)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (154 mg, 0.613 mmol, described in Intermediate 3) and 1-(hydroxymethyl)benzotriazole (93 mg, 0.625 mmol) in EtOH (2 mL) and DMF (0.2 mL) was heated at reflux for 4 h, then concentrated to dryness under reduced pressure. The residue was resuspended in THF (3 mL) and sodium borohydride (40 mg, 1.05 mmol) was added. The resulting mixture was heated to 70° C. for 6 h then quenched with H2O (50 mL) and extracted with EtOAc (50 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 80:20, to give the title compound, which was of sufficient purity for use in the next step. MS: m/z=266 (M+1).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([O-])=O.[CH:9]1([CH:12]=O)C[CH2:10]1.C([O-])(=O)C.[NH4+]>C1C=CC=CC=1.N1C=CC=CC=1>[CH:9]1([C:2](=[CH2:3])[C:1]([O:7][CH3:8])=[O:6])[CH2:12][CH2:10]1
Reactant: O=CC1CC1
Reactant: COC(=O)CC(=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: C=C(C(=O)OC)C1CC1
Yield: 88 %

Procedure:
To a solution of monomethyl malonate (14.16 g, 1.2 eq based on the cyclopropanecarboxaldehyde) and ammonium acetate (0.3 g) in benzene (20 ml) was added dropwise a solution of cyclopropanecarboxaldehyde (7.1 g, 101.3 mmol) in pyridine (11 ml) at 0±5° C. After addition, the solution was refluxed to remove water outside. To the reaction mixture was added 1N hydrochloric acid to acidify. After separation, the aqueous layer was extracted with diisopropyl ether (70 ml) twice. The combined organic layer was concentrated under reduced pressure to give methyl cyclopropylacrylate (11.1 g, yield 88%).
Reaction SMILES: C[O-].[Na+].Br[CH2:5][CH2:6][OH:7].[N:8]1[CH:13]=[CH:12][C:11]([CH2:14][SH:15])=[CH:10][CH:9]=1>C(O)C>[OH:7][CH2:6][CH2:5][S:15][CH2:14][C:11]1[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=1
Reactant: SCc1ccncc1
Reactant: OCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: OCCSCc1ccncc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 18.1 %

Procedure:
Sodium methoxide (361 mg., 6.7 mmoles) was dissolved in 15 ml. of ethanol and cooled in an ice-water bath. 2-Bromoethanol (760 mg., 6.08 mmoles) was added dropwise over 5 minutes, followed by the dropwise addition of 4-picolyl mercaptan (760 mg., 6.08 mmoles) in 5 ml. of ethanol. The reaction mixture was warmed to room temperature and stirred for 20 hours. Precipitated salts were removed by filtration and the filtrate evaporated to crude product, which was chromatographed on 20 g. of silica gel with chloroform and then 1% methanol in chloroform as eluant. The column was monitored by tlc (9:1 chloroform:ethanol, Rf 0.25). Clean product fractions were combined and evaporated to yield clear title product as an oil (186 mg.), having m/e 269 and pnmr/CDCl3 /TMS/delta: 8.63-8.42 (m, 2H), 7.38-7.18 (m, 2H), 3.73 (t, 2H), 3.72 (s, 2H), 2.89 (s, broad, 1 H) and 2.63 (t, 2H) ppm.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH3:11])=[CH:9][N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:6]=2[N:7]=1.C(OC([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[N:33][C:34]([NH2:37])=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=O)(C)(C)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C(OCC)(=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].O1CCOCC1>[CH3:11][C:10]1[C:5]2[CH:4]=[N:3][C:2]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([N:28]4[CH2:27][CH2:26][NH:25][CH2:30][CH2:29]4)=[CH:32][N:33]=3)=[N:7][C:6]=2[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: Cc1cn(-c2ccccn2)c2nc(Cl)ncc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cn(-c2ccccn2)c2nc(Nc3ccc(N4CCNCC4)cn3)ncc12
Temperature: 100 °C

Procedure:
A mixture of 2-Chloro-5-methyl-7-pyridin-2-yl-7H-pyrrolo[2,3-d]pyrimidine (15 mg, 0.06 mmol), 4-(6-Amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (20.5 mg, 0.075 mmol), Pd2(dba)3 (2.8 mg, 0.0031 mmol), BINAP (3.82 mg, 0.0061 mmol), sodium tert-butoxide (8.84 mg, 0.092 mmol), and 1,4-dioxane (4 mL) under nitrogen is heated in a sealed tube apparatus at 100° C. for 2.5 h. After cooling to room temperature the reaction mixture is diluted with ethyl acetate and washed with brine. The organic phase is dried (anhydrous Na2SO4) and the solvent is evaporated. The crude product is dissolved in DCM (2 mL) and TFA (0.5 ml was added). The solution is stirred at room temperature. The reaction mixture is diluted with ethyl acetate and washed with brine. The organic phase is dried (anhydrous Na2SO4) and the solvent is evaporated. The crude product is purified by hplc to afford (5-Methyl-7-pyridin-2-yl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-(5-piperazin-1-yl-pyridin-2-yl)-amine as a pale yellow solid (27%, two steps). 1H NMR (400 MHz, DMSO-d6) 8.80-8.81 (m, 2H), 8.51 (s, 1H), 8.12 (d, J=5.0 Hz, 1H), 8.0-8.11 (m, 1H), 8.0 (d, J=2.9 Hz, 1H), 7.90 (s, 1H), 7.49 (d, J=2.4 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 3.04-3.06 (m, 4H), (2.86-2.89 (m, 4H), 2.32 (s, 3H). MS (ESI) m/z 387.09 [M+H]+.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[CH:29])[CH:23]=1.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>CN(C=O)C>[ClH:2].[ClH:1].[C:28]([C:24]1[CH:23]=[C:22]([NH:21][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([O:5][CH2:4][CH2:3][N:30]4[CH:34]=[CH:33][N:32]=[CH:31]4)[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:27]=[CH:26][CH:25]=1)#[CH:29]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCCl)cc23)c1
Reactant: c1c[nH]cn1
Agent: Cl
Solvent: CN(C)C=O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCn4ccnc4)cc23)c1
Yield: 67.7 %

Procedure:
The title product of Example 30 (110 mg, 0.253 mmol) in DMF (2 mL) was treated with imidazole (172 mg, 2.53 mmol) at 110° C. for 48 hours. The reaction mixture was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product (125 mg) was chromatographed on silica using 10% methanol/CH2Cl2 to provide 86 mg of pure title product as its free base. This white solid was dissolved in a minimum volume of CHCl3, and titrated with 2 equivalents of 1M HCl in ether to precipitate the title product as a white solid dihydrochloride salt (95 mg; 78%; M.P. 85°-100° C. (dec); LC-MS: 430 (MH+); anal. RP18-HPLC RT: 4.13 min.).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CS(C)=O>[C:32]([O:31][C:30]([N:29]([C:23]1[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:22]=1[F:21])[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[N:3]=1)=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)Nc1c(F)cccc1F
Reactant: CCOC(=O)c1ccc(Cl)nc1-c1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N(C(=O)OC(C)(C)C)c2c(F)cccc2F)nc1-c1ccc(F)cc1F
Temperature: 57.5 °C
Reaction time: 48 h

Procedure:
A mixture of Compound 5 (100.82 g, 0.33 mol, 1.0 equiv.), Compound 7 (101.05 g, 0.44 mol, 1.30 eq), and cesium carbonate (177.12 g, 0.54 mol, 1.60 eq) was suspended in DMSO (250 mL, 2.5 volumes) and stirred vigorously at 55-60° C. for 48 hours (completeness of reaction determined by HPLC). The mixture was cooled to 20-30° C. and the base was quenched by careful and slow addition of a 1 N HCl (aq) solution (540 mL, 1.60 eq), keeping the internal temperature of the reaction mixture below 30° C. Upon cooling, a precipitate formed and was filtered and washed with water (2×250 mL, 2×2.5 volumes). The precipitate was then suspended in absolute ethanol (1000 mL, 10 volumes) and heated to reflux. The reflux was maintained for 30-60 minutes, and water (200 mL, 2 volumes) was added to the mixture. The resulting mixture was then heated again to reflux, and reflux was maintained for 30 minutes, at which point the suspension was cooled to 10° C. The resulting solids were then filtered and washed with water (2×250 mL, 2×2.5 volumes), followed by absolute ethanol (250 mL, 2.5 volumes), and then transferred to a vacuum oven and dried at 50-60° C. The title Compound, 8, was obtained as a white crystalline solid. (1H NMR, 500 MHz; CDCl3) δ 8.28 (d, 1H), 8.12 (d, 1H), 7.19 (q, 1H), 6.96 (t, 2H), 6.81 (t, 1H), 6.74 (t, 1H), 4.25 (q, 2H), 1.50 (s, 9H), 1.20 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1[C:14]1[CH2:15][O:16][C@:17]2([CH2:23][CH2:22][CH2:21][NH:20][C@H:19]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]=1.C(O)(=O)C>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:11])[F:12])=[CH:5][C:4]=1[C@@H:14]1[CH2:18][C@@:17]2([CH2:23][CH2:22][CH2:21][NH:20][C@H:19]2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:16][CH2:15]1
Reactant: COc1ccc(OC(F)(F)F)cc1C1=C[C@@]2(CCCN[C@H]2c2ccccc2)OC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(OC(F)(F)F)cc1[C@H]1CO[C@]2(CCCN[C@H]2c2ccccc2)C1
Reaction time: 16 h

Procedure:
A mixture of (5R,6S)-3-(2-methoxy-5-trifluoromethoxyphenyl)-6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-ene (Example 2; 1.4 g), 10% palladium hydroxide/carbon (0.25 g) in methanol (90 ml) containing acetic acid (9 ml) was hydrogenated at 50 psi for 16 h. The solution was filtered, evaporated and the residue was crystallized twice from hexane to give the title compound. m.p. 91-104° C. 1H NMR (250 MHz, CDCl3) δ 7.50-7.54 (2H, m), 7.33-7.36 (3H, m),), 6.90 (1H, dd, J 8.9, 2.07 Hz), 6.68 (1H, d, J 8.9 Hz), 6.17 (1H, d, J 2.7 Hz), 4.08 (1H, t, J 7.8 Hz), 3.75 (1H, m), 3.69 (4H, s+d), 3.24 (1H, bd), 3.12 (1H, dd, J 10.3, 8.03 Hz), 2.82 (1H, td, J 12.4, 2.6 Hz), 2.16-1.80 (6H, m), and 1.55-1.64 (2H, m). m/z (ES+) 408 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:28])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23](I)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.[Cl:30][C:31]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:32]=1[OH:39]>>[CH3:1][C:2]1([CH3:29])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:28])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([O:39][C:32]4[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:31]=4[Cl:30])[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1
Reactant: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(I)cc1=O
Reactant: COc1cccc(O)c1Cl
Product: COc1cccc(Oc2cnn(C(CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)c(=O)c2)c1Cl

Procedure:
Using the method described in Example 126, Step 1,2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (Intermediate 94) and 2-chloro-3-methoxy-phenol afforded 2-[4-(2-chloro-3-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide as a white solid as a mixture of diastereomers (42 mg, 77%); ES+-HRMS m/e calcd for C26H32N5O6Cl [M+H+] 546.2114 found 546.2114. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.78-0.97 (m, 6H), 1.24 (s, 3H), 1.30 (2×s, 3H), 1.45 (br. s., 1H), 1.69-1.87 (m, 1H), 2.05-2.25 (m, 1H), 3.73 (dd, J=8.5, 5.7 Hz, 1H), 3.92 (s, 3H), 4.00 (dd, J=8.5, 6.3 Hz, 1H), 4.04-4.19 (m, 2H), 4.35 (quin, J=5.8 Hz, 1H), 5.51 (dd, J=11.0, 4.1 Hz, 1H), 5.71 (d, J=2.7 Hz, 1H), 6.38 (d, J=2.4 Hz, 1H), 7.06 (d, J=8.2 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.45 (t, J=8.2 Hz, 1H), 7.59 (s, 1H), 8.19 (d, J=2.7 Hz, 1H), 10.84 (s, 1H).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[F:18])[N:11]2[CH:19]=[N:20][C:21]([C:22]3[N:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[O:24][N:23]=3)=[C:10]2[CH2:9]1)=O)(C)(C)C>CO>[CH:27]1([C:25]2[O:24][N:23]=[C:22]([C:21]3[N:20]=[CH:19][N:11]4[C:12]5[C:17](=[C:16]([F:18])[CH:15]=[CH:14][CH:13]=5)[NH:8][CH2:9][C:10]=34)[N:26]=2)[CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1Cc2c(-c3noc(C4CC4)n3)ncn2-c2cccc(F)c21
Solvent: CO
Product: Fc1cccc2c1NCc1c(-c3noc(C4CC4)n3)ncn1-2
Reaction time: 8 h

Procedure:
A mixture of 5-(tert-butyloxycarbonyl)-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-6-fluoro-4,5-dihydroimidazo[1,5-a]quinoxaline (I, EXAMPLE 51, 3.39 g) and 50 ml of methanol saturated with HCI(g) is stirred at 20°-25° overnight. The solvent is then removed under reduced pressure and the residue is partitioned between dichloromethane and aqueous sodium bicarbonate. The organic phase is separated and dried over sodium sulfate and taken to dryness to give the title compound, NMR (CDCl3) 1.23, 1.35, 2.26, 4.32, 4.86, 6.80, 6.95, 7.22 and 8.06 δ.
Reaction SMILES: CO[C:3](=[O:16])[CH2:4][NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19].[H-].[Na+]>C1(C)C=CC=CC=1>[O:16]=[C:3]1[CH2:4][N:5]([C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:19][CH:18]1[C:17]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CNC(=O)OCc1ccccc1
Reactant: C=CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
A solution of carbobenzyloxyglycine methyl ester (10 g, 44.8 mmol) and methyl acrylate (4.03 mL, 44.8 mmol) in toluene (100 mL) at 0° C. was added 60% NaH in mineral oil (1.971 g, 49.3 mmol) which was stirred for 10 minutes, and then it was warmed up to RT and stirred for 20 minutes. The reaction mixture was heated to 50° C. for 3 hrs. The reaction mixture was quenched with 10% citric acid solution until pH about 3, and then it was extracted with 100 mL×3 of EtOAc. The combined organic phases were washed with 100 mL of brine and dried over Na2SO4. Filtration and concentration to yield the product (12 g, 96% yield). MS(ES+) m/z: 278.2 (M+H); HPLC retention time: 2.44 min (analytical HPLC Method B).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([Cl:15])[N:7]=[C:6]2[NH:16][NH2:17].[C:18]1(C)C=CC(S(O)(=O)=O)=CC=1.COC(OC)OC>>[Cl:15][C:8]1[N:7]2[CH:18]=[N:17][N:16]=[C:6]2[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:12]([O:13][CH3:14])=[CH:11][C:10]=2[N:9]=1
Reactant: COc1cc2nc(Cl)nc(NN)c2cc1OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Product: COc1cc2nc(Cl)n3cnnc3c2cc1OC
Reaction time: 19 h

Procedure:
A mixture of 10.0 g. of 6,7-dimethoxy-2-chloro-4-hydrazinoquinazoline, 1.0 g. of p-toluenesulfonic acid and 150 ml. of trimethoxy methane is refluxed with stirring for 19 hours and then stirred for 24 hours at room temperature. The resulting mixture is evaporated in vacuo to dryness and the residue dissolved in 1500 ml. of methylene chloride. This solution is extracted twice with sodium carbonate solution, washed neutral with water, dried and evaporated in vacuo to dryness. The residue is twice crystallized from methylene chloride/ diethyl ether and then from ethanol to obtain 5-chloro-8,9-dimethoxy-1,2,4-triazolo[4,3-c]quinazoline, m.p. 269°-271° C.
Reaction SMILES: C([O:3][C:4](=[O:13])[CH:5]([C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1)[NH2:6])C.[OH-].[Na+].Cl.[C:17]([O:21][C:22](ON=C(C1C=CC=CC=1)C#N)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CO.C(N(CC)CC)C.O>[C:17]([O:21][C:22]([NH:6][CH:5]([C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1)[C:4]([OH:3])=[O:13])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CCOC(=O)C(N)c1csc(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C(=O)O)c1csc(N)n1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
A mixture of 2-(2-aminothiazol-4-yl)glycine ethyl ester (24.2 g) and 2 N aqueous solution of sodium hydroxide (7.2 g) in methanol (240 ml) was stirred at ambient temperature for an hour. After adjusting to pH 7 with conc. hydrochloric acid, water (250 ml), and then 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (29.5 g) and triethylamine (18.2 g) were added thereto. After stirring at ambient temperature for an hour, the reaction mixture was evaporated. The resultant aqueous solution was washed twice with ethyl acetate, followed by adding ethyl acetate and adjusting to pH 7 with 10% hydrochloric acid. After removal of the insoluble substance by filtration, the aqueous layer was separated out, adjusted to pH 4 with 10% hydrochloric acid and treated with activated charcoal. To the filtrate was added sodium chloride, followed by stirring under ice-cooling. The precipitated solid was collected by filtration and dried to give N-tert-butoxycarbonyl-2-(2-aminothiazol-4-yl)glycine (10.2 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Na+].O.C(OCC)C>O1CCCC1>[CH2:2]([C:14]1[CH2:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCBr
Reactant: c1cc[cH-]c1
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCC1=CC=CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
Under a high purity nitrogen atmosphere, 5.8 ml (30 mmol) of 1-bromooctane was introduced into a Schlenck flask and 50 ml of tetrahydrofuran (THF) was added thereto. To the resulting mixture, 18 ml of 2N sodium cyclopentadienide in THF was added at 0° C. The resultant was stirred for 5 hours at room temperature, 100 ml of water and 100 ml of diethyl ether were added thereto, followed by agitation. The diethyl ether layer was dried over anhydrous magnesium sulfate. After filtering magnesium sulfate, the organic solvent was distilled off under a reduced pressure and the residue was subjected to silica gel column chromatography (eluent:hexane) to obtain 4.21 g of n-octylcyclopentadiene (yield: 79%).