Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48]OS(C)(=O)=O)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:54]=[N+:55]=[N-:56].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][N:54]=[N+:55]=[N-:56])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOS(C)(=O)=O)CCC3)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCN=[N+]=[N-])CCC3)cc1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 86.8 %

Procedure:
A solution of 0.200 g (0.266 mmol) of crude (3R,4R)-3-[1-(3-methanesulfonyloxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester in 1.8 ml of absolute N,N-dimethylformamide was treated with 0.025 g (0.398 mmol, 1.5 equiv.) of anhydrous sodium azide, and stirred for 45 min. at 50° C. The reaction mixture was then poured into 50 ml of an ice/water mixture and extracted three times with 50 ml of ethyl acetate. The combined organic phases were washed twice with 20 ml of water, evaporated under reduced pressure and dried in a high vacuum. The thus-obtained crude product was purified by chromatography on silica gel using a 3:1 mixture of hexane and ethyl acetate as the eluent and yielded 0.162 g (0.231 mmol, 86.8% of theory) of (3R,4R)-3-[1-(3-azido-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 700 (M+H)+.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.O[CH:11]([CH3:31])[CH2:12][N:13]1[CH2:18][CH2:17][N:16]2[N:19]=[C:20]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:21]=[C:15]2[C:14]1=[O:30]>C(Cl)Cl>[F:7][CH:11]([CH3:31])[CH2:12][N:13]1[CH2:18][CH2:17][N:16]2[N:19]=[C:20]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:21]=[C:15]2[C:14]1=[O:30]
Reactant: CC(O)CN1CCn2nc(COc3ccccc3)cc2C1=O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(F)CN1CCn2nc(COc3ccccc3)cc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.4 %

Procedure:
DAST (0.02 mL, 0.15 mmol) was added dropwise to a solution of (rac)-5-(2-hydroxy-propyl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (30 mg, 0.1 mmol) in DCM (0.6 mL) at 0° C. The mixture was then allowed to warm to room temperature and stirred at 100° C. for 10 minutes under microwave irradiation. The mixture was quenched with a saturated solution of NaHCO3 and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 100/0). Desired fractions were collected and solvents evaporated in vacuo. The product was repurified by RP HPLC on (C18 XBridge 30×100 5 um). Mobile phase (Gradient from 80% 0.1% NH4CO3H/NH4OH pH 9 solution in H2O, 20% ACN to 0% 0.1% NH4CO3H/NH4OH pH 9 solution in H2O, 100% ACN) and triturated with DIPE to yield (rac)-5-(2-fluoro-propyl)-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (8.3 mg, 29% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.38 (dd, J=24.0, 6.5 Hz, 3H), 3.42 (ddd, J=20.1, 14.6, 7.6 Hz, 1H), 3.80-3.91 (m, 1H), 3.91-4.08 (m, 2H), 4.33-4.46 (m, 2H), 4.83-5.05 (m, 1H), 5.10 (s, 2H), 6.90-6.95 (m, 1H), 6.95-7.03 (m, 3H), 7.27-7.33 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[CH:11]=[CH:10][NH:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[F:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=1[N:30]=[C:31]=[O:32]>C1COCC1>[F:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=1[NH:30][C:31]([N:9]1[CH:10]=[CH:11][C:12](=[O:14])[CH2:13][CH:8]1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:32]
Reactant: COc1cc(N=C=O)c(F)cc1C
Reactant: O=C1C=CN[C@H](c2ccc(F)cc2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(NC(=O)N2C=CC(=O)CC2c2ccc(F)cc2)c(F)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.9 %

Procedure:
(S)-2-(4-Fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one (95 mg, 0.50 mmol) was dissolved in THF and cooled to −40° C. n-BuLi (1.1 eq, 0.34 ml of 2.5M solution) was added dropwise, forming a purple suspension. The mixture was allowed to stir for 30 minutes until the purple color changed to white. 1-Fluoro-2-isocyanato-4-methoxy-5-methyl-benzene (1 eq, 90 mg) was added. The mixture was allowed to stir for 1 hour at −40° C., then allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (gradient 9:1 to 1:1 hexanes/ethyl acetate) to give 2-(4-Fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid (2-fluoro-5-methoxy-4-methyl-phenyl)-amide (46 mg, 24.7%) as a foam. MS (ES+) m/z 373 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].CCC[CH2-].[Br:20]CCBr>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([Br:20])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccn1
Reactant: BrCCBr
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncccc1Br
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
2-t-Butoxycarbonylaminopyridine (10 g, 51.5 mmol) was dissolved in tetrahydrofuran (80 mL), and cooled to -78° C. N-butyllithium (120 mmol, 80 mL of 1.49M in hexanes) was added dropwise over a period of 1 h After stirring for an additional 15 min at -78° C. and then for 2.5 h at -10° C., the solution was recooled back down to -78° C. and 1,2-dibromoethane (77.2 mmol, 6.65 mL) was added dropwise over a period of 15 min via syringe. The solution was allowed to warm to room temperature. The reaction was quenched with 100 mL of saturated ammonium chloride and was extracted with ethyl acetate (3×). The organic layers were collected, dried over magnesium sulfate, filtered, and concentrated. The resulting solid was purified by flash chromatography on silica gel (25% ethyl acetate/hexanes) giving 4.5 g (32%) of the titled product as a light brown solid: mp 120°-121° C.; IR (KBr, cm-1) 3191, 2980, 1729, 1521, 1442, 1365, 1272, 1166, 1032; 1H NMR (300 MHZ, DMSO-d6) δ 9.28 (s, 1H), 8.34 (m, 1H), 8.05 (m, 1H), 7.15 (m, 1H), 1.39 (s, 9H); MS (FD) m/e 272 (M+), 274 (M+2); UV (EtOH) 280 nm (ε=4047), 230 nm (ε=9067), 204 nm (ε=16385).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([NH:11][CH2:12][C@H:13]([NH:15][S:16]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[N:24][CH:23]=[CH:22]2)(=[O:18])=[O:17])[CH3:14])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(OC([NH:36][CH2:37][C:38](O)=[O:39])=O)(C)(C)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[ClH:1].[NH2:36][CH2:37][C:38]([N:11]([CH2:12][C@H:13]([NH:15][S:16]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[N:24][CH:23]=[CH:22]2)(=[O:18])=[O:17])[CH3:14])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:39]
Reactant: C[C@H](CNCCc1ccccc1)NS(=O)(=O)c1ccc2cnccc2c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C[C@H](CN(CCc1ccccc1)C(=O)CN)NS(=O)(=O)c1ccc2cnccc2c1
Yield: 151.3 %

Procedure:
A free form (220 mg) of the compound of Example 23 and N-(tert-butoxycarbonyl)glycine (25 mg) were condensed (230 mg, 73%) using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (137 mg) in dichloromethane. Subsequently, 100 mg of the title compound was obtained as a white solid (61%) from 150 mg of a free form according to the methods described in Steps 2 and 3 of Example 1.
Reaction SMILES: B.[CH:2](=[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=O)[CH3:3].CO.Cl>C1COCC1>[CH2:2]([CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH2:5]1)[CH3:3]
Reactant: CC=C1C(=O)Nc2ccccc21
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCC1CNc2ccccc21

Procedure:
Under a nitrogen atmosphere 41 mL (41 mmol) of a 1M borane in THF solution was added dropwise to 2.2 g (14 mmol) 3-ethylidene-1,3-dihydro-indol-2-one in 50 mL THF. The reaction mixture was refluxed for 3 h and then at 0° C. mixed with 10 mL methanol followed by 15 mL semi-concentrated hydrochloric acid solution. The reaction mixture was refluxed for 3 h with stirring, cooled and washed twice with ethyl acetate. The aqueous phase was made alkaline with aqueous 4M sodium hydroxide solution and extracted three times with ethyl acetate. The organic phases were combined, dried on sodium sulphate and evaporated down.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:11]([O-])=O)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[H][H]>C(O)C.[Pd]>[NH2:11][C:3]1[C:2]([CH3:1])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(C(=O)O)c1N

Procedure:
A solution of 3-methyl-2-nitrobenzoic acid (7 g) in ethanol (250 ml) was reduced with hydrogen gas at 2 psi over 5% palladium/carbon (0.7 g) catalyst. After hydrogen uptake ceased, the mixture was filtered and solvent removed by a rotary evaporator to give a white solid. Purification was by recrystallization from ethyl ether-hexane, m.p. ca. 170°-173° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)=[O:4].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=2[N+:14]([O-:16])=[O:15])=[N:19][CH:20]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: COC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Product: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c([N+](=O)[O-])c1
Yield: 73.5 %

Procedure:
Using a similar procedure to that described in Example 1-A, 4-methoxycarbonyl-2-nitrobenzoic acid (1.87 g, 8.31 mmol) and 2-amino-5-chloropyridine (1.16 g, 9.14 mmol) afforded 2.05 g (74%) of the title compound.
Reaction SMILES: [H-].[K+].[Br:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][CH:8]=[C:7]3[CH2:13][CH:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH2:15][C:5]=1[C:6]=23.O([Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])S(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>C1COCC1>[Br:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])[CH:8]=[C:7]3[CH2:13][CH:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH2:15][C:5]=1[C:6]=23
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: CCCN(CCC)C1Cc2c[nH]c3ccc(Br)c(c23)C1
Agent: O=C([O-])O
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCN(CCC)C1Cc2cn([Si](C(C)C)(C(C)C)C(C)C)c3ccc(Br)c(c23)C1
Reaction time: 0.67 h

Procedure:
To a suspension of 1.25 g (7.50 mmol) of potassium hydride (24% dispersion in mineral oil) in 50 mL of THF at 0° C. was added a solution of 2.00 g (5.97 mmol) of 6-bromo-4-(di-n-propylamino)-1,3,4,5-tetrahydrobenz[cd]indole in 2 mL of THF. After stirring for 40 min, an addition of 1.90 mL (7.18 mmol) of triisopropylsilyl triflate was made. Stirring was continued for another hour. The mixture was then poured into cold NaHCO3 solution, and the product was extracted into CH2Cl2. This extract was washed with NaCl solution and dried over Na2SO4. Evaporation of the CH2Cl2 left a brown oil which was chromatographed over 50 g of silica gel using toluene followed by 1:3 EtOAc/toluene. The silylated product from the column was isolated as a light brown oil in quantitative yield. The product slowly crystallized upon standing.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)(=O)=O.CN(C)P(N(C)C)(N(C)C)=O.[NH2:34][C:35]1[CH:45]=[CH:44][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:37][CH:36]=1.O>C(O)C>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][NH:34][C:35]2[CH:36]=[CH:37][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:44][CH:45]=2)=[CH:10][CH:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(NCCCc2ccc(OCc3ccccc3)cc2)cc1

Procedure:
A mixture of 12.8 g. of 3-[p-(benzyloxy)phenyl]propanol O-methanesulfonate (prepared as described in Example 43), 50 ml. of hexamethylphosphoramide and 16.5 g. of ethyl p-aminobenzoate is heated at 100°-105° C. for 17.5 hours. The mixture is chilled, diluted with 15 ml. of water, 30 ml. of ethanol and chilled. In order to filter, 100 ml. of ethanol-water (1:1) is added and the solid filtered and washed with ethanol-water (1:1) and with water to give tan crystals, m.p. 98°-107° C. Recrystallization from ethanol gives light tan crystals, m.p. 114°-116° C.
Reaction SMILES: [CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:30][C@@H:29]([C:31]4[CH:42]=[CH:41][C:34]5[O:35][C:36]([CH3:40])([CH3:39])[O:37][CH2:38][C:33]=5[CH:32]=4)[O:28]C3=O)[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si](C)(C)[O-].[K+]>C1COCC1>[CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:30][C@@H:29]([C:31]3[CH:42]=[CH:41][C:34]4[O:35][C:36]([CH3:39])([CH3:40])[O:37][CH2:38][C:33]=4[CH:32]=3)[OH:28])[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCCc4cccc(S(=O)(=O)C5CCCC5)c4)C(=O)O3)ccc2O1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCCCc3cccc(S(=O)(=O)C4CCCC4)c3)ccc2O1

Procedure:
A stirred mixture of (5R)-3-(6-{4-[3-(Cyclopentylsulfonyl)phenyl]butoxy}hexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one and potassium trimethyl silanolate (240 mg) in THF (6 ml) was heated to reflux for 1.5 h. The mixture was poured into phoshate buffer solution (pH 5) and extracted into DCM. The extracts were washed with water, dried (Na2SO4) and evaporated to give the title compound (120 mg). LCMS RT=2.93 min.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH3:20])[C:14]=2Br)[CH:9]=1)(=[O:7])[CH3:6].Cl>C1(C)C=CC=CC=1>[C:5]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH3:20])[CH:14]=2)[CH:9]=1)(=[O:7])[CH3:6]
Reactant: COc1ccc2cc(C(C)=O)ccc2c1Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COc1ccc2cc(C(C)=O)ccc2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
8.2 Grams of anhydrous aluminum chloride and 59 ml of toluene are added to the solution of 2-acetyl-5-bromo-6-methoxynaphthalene obtained in example 1, keeping the temperature at -10° C. The reaction mixture is kept under stirring at room temperature for 20 hours and then it is slowly poured into a mixture made by 200 g of crushed ice and by 75 ml of a 35% (w/v) aqueous solution of hydrochloric acid.
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[C:4]([O:10][CH3:11])([O:8][CH3:9])[C:5]=1[O:6]C.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([Mg]Br)[CH:18]=[CH:19][CH:20]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C1COCC1>[CH3:1][C:2]1[C:5](=[O:6])[C:4]([O:10][CH3:11])([O:8][CH3:9])[C:3]=1[C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([O:14][CH3:13])[CH:20]=1
Reactant: COc1cccc([Mg]Br)c1
Reactant: COC1=C(C)C(=O)C1(OC)OC
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cccc(C2=C(C)C(=O)C2(OC)OC)c1
Reaction time: 0.08 h
Yield: 75 %

Procedure:
A THF solution (12 mL) of known 2-methyl-3,4,4-tris(methyloxy)-2-cyclobuten-1-one (0.500 g, 2.91 mmol, 1 equiv) was cooled to ca. −78° C. 3-Methoxyphenyl magnesium bromide (4.36 mL, 1.0 M, 1.5 equiv) was added. After 5 min, TFAA (0.657 mL, 4.66 mmol, 1.6 equiv) was added. The reaction was quenched with saturated NaHCO3 (5 mL) after an additional 5 min. Extraction with EtOAc was followed by drying (Na2SO4), filtration, and concentration to a bright yellow oil. Radial chromatography (SiO2, 4 mm plate, 80:20; hexanes/EtOAc) afforded the title compound (245) as a bright yellow oil (0.540 g, 75%). 1H NMR (CDCl3, 300 MHz) δ 7.44-7.33 (m, 3H), 7.15-7.09 (m, 1H), 3.89 (s, 3H), 3.54 (s, 6H), 2.13 (s, 3H). TLC (60:40; hexanes/EtOAc): Rf=0.45.
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].[CH3:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[CH:28]=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH3:3][C:2]1([CH3:4])[C@@H:28]([C:27]2[CH:26]=[C:25]([CH3:24])[CH:37]=[CH:36][CH:35]=2)[C@@H:29]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C=Cc1cccc(C)c1
Agent: [I-]
Product: CCOC(=O)[C@H]1[C@H](c2cccc(C)c2)C1(C)C
Yield: 75.3 %

Procedure:
Isopropyltriphenylphosphonium iodide (17.3 g, 40 mmol) and ethyl 3-methylcinnamate (7.6 g, 40 mmol) were reacted as described under General Procedure B to furnish the title compound (7.0 g, 75%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.17 (t, J=7.4 Hz, 1H), 7.03-6.95 (m, 3H), 4.18 (q, J=7.2 Hz, 2H), 2.66 (d, J=5.8 Hz, 1H), 2.33 (s, 3H), 1.93 (d, J=5.8 Hz, 1H), 1.38 (s, 3H), 1.30 (t, J=7.2 Hz, 3H), 0.93 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[OH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[K+].[K+].N1C=CC=CC=1>[O-2].[Cu+2].C(Cl)Cl>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH:12]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: Oc1cccnc1
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1cccc(Oc2cccnc2)c1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
Cu(II) oxide (2.1 g, 26 mmol, 2.5 eq) was added to a mixture of 3-bromobenzonitrile (3.8 g, 21 mmol, 2.0 eq), 3-hydroxypyridine (1.0 g, 10 mmol, 1.0 eq), K2CO3 (3.0 g, 22 mmol, 2.1 eq) and pyridine (35 mL) at 80° C. The mixture was refluxed vigorously for 20 h and cooled to rt. CH2Cl2 was added and the mixture was filtered through celite. Pyridine was removed in vacuo and the residue dissolved in EtOAc and washed with 1N HCl (1×), 1N NaOH (1×), brine (1×), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 1.5 g (73%) of the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.15 (dd, J=4.9, 1.6 Hz, 1H), 7.89 (td, J=7.6, 2.0 Hz, 1H), 7.69-7.67 (m, 2H), 7.61 (t, J=8.0 Hz, 1H), 7.51-7.49 (m, 1H), 7.17 (dd, J=7.0, 5.1 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H); ES-MS [M+1]+: 197.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[C:15]3[CH2:23][N:22](CC4C=CC=CC=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:31]([O-])=[O:32].[NH4+].CC([O:39]C)(C)C.CC(OC)(C)C.CO>CO.[OH-].[OH-].[Pd+2]>[CH3:2][C:1]([O:5][CH3:6])([CH3:4])[CH3:3].[CH3:31][OH:32].[NH4+:8].[OH-:39].[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[C:15]3[CH2:23][NH:22][CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C[O-]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ncnc3c2CN(Cc2ccccc2)CC3)C1
Agent: [Pd+2]
Agent: [NH4+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ncnc3c2CNCC3)C1
Temperature: 25 °C
Yield: 87 %

Procedure:
Pd(OH)2/C (1.2 g, 1.71 mmol) was flushed with argon, (S)-3-(6-Benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (10.95 g, 26.7 mmol) dissolved in methanol (25 mL) was added followed by the addition of ammonium formate (1.68 g, 26.7 mmol). The reaction mixture was refluxed for 1 h, cooled down to room temperature, filtered through a celite pad and concentrated under vacuum. Purification by flash chromatography on silica gel (CH2Cl2 then TBME then TBME/MeOH 100/0 to 90/10 then TBME/MeOH/NH4OH 85/15/5) gave (S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (7.39 g, 87% yield) as a yellow sticky oil. 1H NMR (400 MHz, methanol-d4, 298K) δ ppm 1.46-1.46 (m, 9 H) 2.10-2.30 (m, 2 H) 2.78-2.83 (m, 2 H) 3.11-3.14 (m, 2 H) 3.41-3.60 (m, 3 H) 3.65-3.72 (m, 1 H) 3.78 (s, 2 H) 5.68 (m, 1 H) 8.52 (s, 1 H). LCMS: [M+H]+=321.2, Rt(2)=0.87 min
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([S:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:30]=[CH:29][N:28]([CH2:31][C:32]([CH3:35])([OH:34])[CH3:33])[N:27]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([S:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:13]=[N:12]2)[C:8]([NH:25][C:26]2[CH:30]=[CH:29][N:28]([CH2:31][C:32]([OH:34])([CH3:33])[CH3:35])[N:27]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Sc2ccccc2)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Sc3ccccc3)cc2=O)n1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-(6-oxo-4-phenylsulfanyl-6H-pyridazin-1-yl)-propionic acid (Intermediate 95) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(6-oxo-4-phenylsulfanyl-6H-pyridazin-1-yl)-propionamide was obtained as an off-white solid (83.5 mg, 61%); ES+-HRMS m/e calcd for C25H31N5O3S [M+H+] 482.2221 found 482.2221. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (br. s., 3H), 1.05 (br. s., 3H), 1.19-1.78 (m, 9H), 1.78-2.00 (m, 1H), 2.10-2.32 (m, 1H), 3.88 (s, 2H), 4.67 (s, 1H), 5.42 (dd, J=10.9, 4.2 Hz, 1H), 5.95 (d, J=2.4 Hz, 1H), 6.38 (d, J=2.4 Hz, 1H), 7.52 (d, J=2.4 Hz, 1H), 7.56-7.70 (m, 5H), 7.94 (d, J=2.4 Hz, 1H), 10.79 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[N:7]=1.[C:12](OC(=O)C)(=[O:14])C.C(O)=O>O1CCCC1>[CH3:1][N:2]([C:3]1[S:4][C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[N:7]=1)[CH:12]=[O:14]
Reactant: CNc1nc(C)c(C(C)=O)s1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: C1CCOC1
Product: CC(=O)c1sc(N(C)C=O)nc1C
Reaction time: 2 h

Procedure:
To a solution of 2-methylamino-4-methyl-5-acetylthiazole (35 g) in tetrahydrofuran (700 ml) were added a mixture of acetic anhydride (94.5 ml) and formic acid (37.7 ml) at ambient temperature and the mixture was stirred for two hours. The reaction mixture was evaporated in vacuo. The residue was added to water and the resultant precipitate was collected by filtration and dried over phosphorus pentoxide to give 2-(N-methylformamido)-4-methyl-5-acetylthiazole (39.59 g).