Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@H:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12][N:6]2[C:5](=[O:20])[CH2:4][CH2:3]1.O=[C:22]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)C.[Pd]>[CH2:26]([O:25][C:23]([C@H:22]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@H:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:11][CH2:12][N:6]2[C:5](=[O:20])[CH2:4][CH2:3]1)[CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:24])[CH3:27].[CH2:26]([O:25][C:23]([C@@H:22]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@H:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:11][CH2:12][N:6]2[C:5](=[O:20])[CH2:4][CH2:3]1)[CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCN2C(=O)CC[C@H](N)C(=O)N12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@H](CCc1ccccc1)N[C@H]1CCC(=O)N2CC[C@@H](C(=O)OC(C)(C)C)N2C1=O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CCC(=O)N2CC[C@@H](C(=O)OC(C)(C)C)N2C1=O

Procedure:
A solution of 1.15 g of tert.butyl 8(S)-amino-2,3,6,7,8,9-hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1(S)-carboxylate and 3.10 g of ethyl 2-oxo-4-phenylbutanoate in 50 ml of ethanol was hydrogenated over 1.0 g of 10% palladium-on-carbon in the presence of molecular sieve at 4 atmospheres for 48 hours. The catalyst was removed by filtration and the filtrate was evaporated. The residue was chromatographed on silica gel to give 0.18 g of tert.butyl 8(S)-[1(R)-ethoxycarbonyl-3-phenylpropylamino]-2,3,6,7,8,9-hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1(S)-carboxylate in the form of a pale yellow oil and subsequently 0.19 g of tert.butyl 8(S)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-2,3,6,7,8,9-hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1(S)-carboxylate in the form of a pale yellow oil.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[OH:12]O>CCOCC>[O:12]1[C:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[O:1][C:2]1=2
Reactant: OO
Reactant: O=c1ccoc2ccccc12
Solvent: CCOCC
Product: O=c1c2c(oc3ccccc13)O2
Temperature: 0 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
Chromone (3 g) was dissolved in ether (200 ml) and the solution was cooled to 0° C. in ice water. Then, 30% hydrogen peroxide (15 ml) and Triton B (10 ml) solution were added portionwise. The whole was stirred at 0° C. for 4 hours. After adding ice water, the reaction liquor was extracted with dichloromethane. The organic layer was washed with sodium thiosulfate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was fractionatedby silica gel column chromatography (diethyl ether/hexane =1:8) to give the titled compound (2.34 g; yield =75%). Melting point: 66°-67° C. Mass spectrum (M+): 162. 1H-NMR(CDCl3, δ ppm): 3.69 (d, 1H, H3), 5.67 (d, 1H, H2), 7.05 (d, 1H, H8), 7.14 (t, 1H, H6), 7.54 (t, 1H, H7), 7.79 (dd, 1H, H5).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:16])([CH3:15])[C:7](=[O:14])[N:8]2[CH:11]2[CH2:13][CH2:12]2)=[CH:4][C:3]=1[F:17].[OH-].[NH4+:19].ClCCl>CN1C(=O)CCC1.[Cu-]=O>[NH2:19][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:16])([CH3:15])[C:7](=[O:14])[N:8]2[CH:11]2[CH2:13][CH2:12]2)=[CH:4][C:3]=1[F:17]
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(Br)c(F)cc21
Reactant: [NH4+]
Agent: O=[Cu-]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)N(C2CC2)c2cc(N)c(F)cc21
Temperature: 110 °C

Procedure:
To a solution of 6-bromo-1-cyclopropyl-5-fluoro-3,3-dimethylindolin-2-one (example 36b, 400 mg, 1.34 mmol) in NMP (7 ml) were added ammonium hydroxide (6.3 g, 7 ml, 44.9 mmol) and copper(I) oxide (38.4 mg, 268 μmol). The reaction mixture was heated in a sealed tube to 110° C. for 24 hours and then poured into dichloromethane (20 ml). The organic phase was washed with 1 M aqueous sodium bicarbonate solution and with water, dried over sodium sulfate and concentrated in vacuo. The NMP was removed by kugelrohr distillation. The residue was purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as off-white crystals (257 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:19])=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:44][C@H:45]1[CH2:47][C@H:46]1[C:48](O)=[O:49].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[F:44][C@H:45]1[CH2:47][C@H:46]1[C:48]([NH:18][C:13]1[N:14]=[CH:15][C:16]2[C:11]([CH:12]=1)=[CH:10][N:9]=[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([F:1])[C:3]=1[CH3:19])[CH:17]=2)=[O:49]
Reactant: O=C(O)[C@@H]1C[C@@H]1F
Reactant: Cc1c(F)cncc1-c1cc2cnc(N)cc2cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(F)cncc1-c1cc2cnc(NC(=O)[C@@H]3C[C@@H]3F)cc2cn1
Temperature: 70 °C
Yield: 42 %

Procedure:
A mixture of 7-(5-fluoro-4-methyl-3-pyridyl)-2,6-naphthyridin-3-amine (35 mg, 0.14 mmol), HATU (113 mg, 0.29 mmol), (1S,2S)-2-fluorocyclopropanecarboxylic acid (29 mg, 0.28 mmol), and N,N-diisopropylethylamine (0.10 mL, 0.55 mmol) in DMF (1 mL) was heated at 70° C. for 8 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (25 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by reverse phase HPLC purification (5-85% ACN in water w/0.1% NH4OH, 14 min). Desired fractions were combined and evaporated in vacuo to afford the title compound as an off-white solid (20 mg, 43%). 1H NMR (400 MHz, DMSO) δ 11.22 (s, 1H), 9.35 (s, 1H), 8.70 (s, 1H), 8.59 (sz, 1H), 8.58 (s, 1H), 8.24 (s, 1H), 4.98 (m, 1H), 2.37 (d, J=1.9 Hz, 3H), 2.31 (m, 1H), 1.72 (m, 1H), 1.23 (m, 1H). LCMS (Method E): RT=3.978 min, M+H+=341.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH2:16])=[C:10]([CH3:17])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:19](O)(=[O:22])[C:20]#[CH:21].CCN(C(C)C)C(C)C.CCCP(=O)=O.CN(C=O)C>C(Cl)Cl>[CH3:14][C:12]1[C:11]([CH2:15][NH:16][C:19](=[O:22])[C:20]#[CH:21])=[C:10]([CH3:17])[N:9]=[C:8]([NH:7][C:6](=[O:18])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Reactant: C#CC(=O)O
Agent: CCCP(=O)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CC(=O)NCc1c(C)cc(NC(=O)OC(C)(C)C)nc1C
Temperature: 23 °C
Reaction time: 24 h

Procedure:
To a solution of (5-aminomethyl-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (4.50 g, 17.90 mmol), propiolic acid (0.918 ml, 14.92 mmol), DIPEA (7.82 ml, 44.8 mmol) in DCM (140 ml) at 23° C. was added dropwise over 5 min 50% propylphosphonic anhydride in DMF (12.5 ml, 21.41 mmol). The reaction was stirred at 23° C. for 1 day. The reaction was quenched by addition of brine, and the phases were separated. The aqueous phase was further extracted with DCM, and the combined organic phase was dried over Na2SO4, filtered, and evaporated to provide the crude product, which was purified by flash column chromatography (silica gel 0.040-0.063 mm, 160 g, flow rate 60 ml/min, detection at 220 nm, MeOH in DCM 0->1% over 10 min, then 1->5% over 20 min) to yield the title compound. HPLC (Method G) Rt=1.333 min; MS (Method F) [M+H]+=304.31.
Reaction SMILES: [BH4-].[Na+].[C:3](O)(=O)[CH3:4].[H][H].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[O:24][N:23]=[C:22]([CH3:25])[C:21]=2[CH3:26])(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH2:3]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[O:24][N:23]=[C:22]([CH3:25])[C:21]=2[CH3:26])(=[O:18])=[O:17])=[CH:12][CH:11]=1)[CH3:4]
Reactant: Cc1noc(NS(=O)(=O)c2ccc(N)cc2)c1C
Reactant: [H][H]
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCNc1ccc(S(=O)(=O)Nc2onc(C)c2C)cc1
Yield: 18.6 %

Procedure:
Sodium borohydride (71 mg, 3.74 mmol) was added to a solution of acetic acid (740 mg, 12 mmol) in dry benzene (5 ml) with the temperature being kept at 20° C. When the evolution of hydrogen gas had ceased (ca. 5 min), 4-amino-N-(3,4-dimethyl-5-isoxazolyl)benzenesulfonamide (0.5 g, 1.87 mmol) was added in one lot and the reaction mixture was refluxed for 3 h. The reaction was cooled and shaken with saturated sodium bicarbonate solution. The organic layer was then washed with brine (2×20 ml), dried over magnesium sulfate and evaporated. the crude product was purified by column chromatography on silica gel using 1% methanol in chloroform as eluent to give 103 mg (19%) of a colorless oil. Further purification by HPLC gave a white solid, m.p. 123° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH2:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH3:32][C:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH:24][C:39]([C:33]2([CH3:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCN(C[C@H](N)Cc2ccccn2)CC1
Reactant: CC1(C(=O)Cl)CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C[C@@H](Cc2ccccn2)NC(=O)C2(C)CCCCC2)CC1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
To a solution of (1R)-2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-1-pyridin-2-ylmethyl-ethylamine (1.06.; 3.2 mmol, from Example 13) in dichloromethane (40 mL) at 0° C. was added triethylamine (0.90 mL; 6.5 mmol) and a solution of 1-methyl-1-cyclohexanecarbonyl chloride (520 mg.; 3.2 mmol) in dichloromethane (6 mL). The reaction mixture was stirred while allowing to warm to ambient temperature over 1 hour, washed sequentially with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and the solvent removed in vacuo. The crude residue was purified by flash chromatography on silica gel (2% methanol/chloroform) to yield the free base of the title compound as a clear oil (1.0 g.; 70%). Treatment with an equimolar amount of fumaric acid in ethanol afforded the fumarate salt as a white amorphous solid, m.p. 135–139° C.; MS (+) FAB [M+H]+ @ m/z 451; 1H NMR, 400 MHz, DMSO-d6. Analysis for C27H38N4O2.C4H4O4 Calculated: C, 65.70; H, 7.47; N, 9.89 Found: C, 65.29; H, 7.69; N, 9.77
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:16])[C:7]=1[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1.[Li]CCCC.[CH3:22][O:23][C:24](=O)[CH2:25][O:26]C.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:16][C:6]1[C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[C:2]([C:25](=[O:26])[CH2:24][O:23][CH3:22])[CH:3]=[N:4][CH:5]=1
Reactant: Clc1cncc(Br)c1COC1CCCCO1
Reactant: COCC(=O)OC
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(=O)c1cncc(Cl)c1COC1CCCCO1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
3-Bromo-5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridine (0.30 g, 0.98 mmol) was dissolved in anhydrous THF (15 mL) under Ar and the solution was cooled to −78° C. n-BuLi (0.62 mL, 1.6 M in hexanes, 0.98 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for 0.5 h. Then methoxy-acetic acid methyl ester (0.97 mL, 9.8 mmol) dissolved in anhydrous THF (10 mL) was added dropwise and stirring was continued at −78° C. for 2 h. At completion of the reaction, monitored by TLC, saturated NaHCO3 was added with vigorous stirring. The quenched mixture was extracted with EA (2×20 mL) and the combined organic extracts were washed with saturated NaHCO3 (20 mL) and dried over Na2SO4. The residue was purified by flash chromatography on silica gel with EA/hexane to provide the title compound as a colorless oil. MS (m/z): 300.5 [M+H+].
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>O1CCCC1>[F:23][C:24]1[CH:25]=[C:26]([CH2:27][CH2:13][C:14]2[N:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])[CH:29]=[CH:30][CH:31]=1
Reactant: Fc1cccc(CBr)c1
Reactant: Cc1ncccc1C(=O)O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cccnc1CCc1cccc(F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Dissolve diisopropylamine (3.8 mL, 27.3 mmol) in dry tetrahydrofuran (75 mL). Chill the resulting mixture to −78° C. and add butyl lithium (1.6M solution in hexanes, 17.1 mL, 27.3 mmol). Warm the reaction mixture to 0° C. and add a fine slurry of 2-methyl-nicotinic acid (1.5 g, 10.9 mmol) in THF (25 mL) portionwise during 10 min. Stir the resulting slurry for 1 h, then add 3-fluorobenzyl bromide (2.0 mL, 16.4 mmol) and stir 5 min. Quench the reaction with water (100 mL). Extract the reaction mixture with diethyl ether (100 mL). Adjust the pH of the aqueous layer to 3.1 with concentrated aqueous hydrochloric acid solution. Treat the resulting slurry with ethyl acetate and stir to dissolve all solids. Separate the layers and extract the aqueous layer with ethyl acetate. Concentrate the combined extracts to dryness. LCMS (APCI-pos): 244.1 (M+H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:18])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[C:6]=1[CH:7]=[O:8].N1C=CN=C1.[H][H]>[Pd]>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:5]2[C:6]([CH:7]=[O:8])=[CH:2][N:3]=[C:4]2[CH3:18])=[CH:11][CH:12]=1)#[N:17]
Reactant: [H][H]
Reactant: Cc1nc(Br)c(C=O)n1Cc1ccc(C#N)cc1
Agent: [Pd]
Agent: c1c[nH]cn1
Product: Cc1ncc(C=O)n1Cc1ccc(C#N)cc1
Reaction time: 2 h

Procedure:
A solution of 4-bromo-1-(4-cyanobenzyl)-2-methylimidazole-5-carboxaldehyde (1.33 g, 4.37 mmol) (Step B) and imidazole (0.600 g, 8.74 mmol) in 1:1 ethyl acetate-alcohol (150 mL) was stirred with 10% palladium on carbon (0.020 g) under 1 atm hydrogen. After 2 h, the reaction was filtered through celite and concentrated to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1.[OH-].[K+].Cl>CO.C1COCC1>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(OCc2ccccc2F)cc1
Reaction time: 36 h

Procedure:
Methyl 4-(2-fluorobenzyloxy)benzoate (P1, 10.0 g, 26.9 mmol) was dissolved in methanol (60 mL) and THF (90 mL). A 45 wt % potassium hydroxide solution (20 mL) was then added and the resulting exotherm was controlled by a water bath. After 1.5 days at 20-25° C. the solution became a thick suspension. Using a water bath to control the exotherm, 20 mL of concentrated HCl was added. The mixture was then concentrated to remove the THF and methanol and 150 mL water was added. The solid was isolated by filtration and washed with 50 mL water. After drying under vacuum, the title compound was isolated as a white crystalline solid (9.4 g, 99% yield).
Reaction SMILES: [CH2:1]([N:5]([CH2:29][CH2:30][CH2:31][CH3:32])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16](=[CH:22][CH:23]=O)[C:15]=2[O:25][CH3:26])=[C:8]([O:27][CH3:28])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:33]([C:35]1[C:36](=[C:43]([C:46]#[N:47])[C:44]#[N:45])[O:37][C:38]([CH3:42])([CH3:41])[C:39]=1[CH3:40])#[N:34].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:29]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16](=[CH:22][CH:23]=[CH:40][C:39]3[C:38]([CH3:41])([CH3:42])[O:37][C:36](=[C:43]([C:44]#[N:45])[C:46]#[N:47])[C:35]=3[C:33]#[N:34])[C:15]=2[O:25][CH3:26])=[C:8]([O:27][CH3:28])[CH:7]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCN(CCCC)c1ccc(C=CC2=C(OC)C(=CC=O)CC(C)(C)C2)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=CC2=C(OC)C(=CC=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)CC(C)(C)C2)c(OC)c1
Temperature: 50 °C
Yield: 83.2 %

Procedure:
In 6 ml of ethanol and 2 ml of tetrahydrofuran were dissolved 239 mg (0.54 mmol) of [3-[2-(4-dibutylamino-2-methoxyphenyl) vinyl]-2-methoxy-5,5-dimethyl-2-cyclohexenylidene]acetaldehyde and 120 mg (0.60 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene)propanedinitrile. To this mixture was added 42 mg of ammonium acetate, and the mixture was stirred with heating at 50° C. for 2.5 hours. The solvent was evaporated off and the residue was purified by silica gel column chromatography to give 279 mg of a dark brown crystal (yield: 82.7%; mp: 244-246° C.).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH:9]2[CH2:11][CH2:10]2)=[CH:7][CH:6]=[CH:5][C:4]=1[N:12]1[C:16](=[O:17])[N:15]([CH3:18])[N:14]=[N:13]1.[CH3:19][C:20]1[CH:25]=[C:24]([N:26]2[C:30]([CH3:31])=[C:29]([CH3:32])[C:28]([CH3:33])=[N:27]2)[CH:23]=[CH:22][C:21]=1[OH:34].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:9]1([C:8]2[C:3]([CH2:2][O:34][C:21]3[CH:22]=[CH:23][C:24]([N:26]4[C:30]([CH3:31])=[C:29]([CH3:32])[C:28]([CH3:33])=[N:27]4)=[CH:25][C:20]=3[CH3:19])=[C:4]([N:12]3[C:16](=[O:17])[N:15]([CH3:18])[N:14]=[N:13]3)[CH:5]=[CH:6][CH:7]=2)[CH2:11][CH2:10]1
Reactant: Cn1nnn(-c2cccc(C3CC3)c2CBr)c1=O
Reactant: Cc1cc(-n2nc(C)c(C)c2C)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(-n2nc(C)c(C)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Temperature: 25 °C

Procedure:
A mixture of 1-(2-bromomethyl-3-cyclopropylphenyl)-4-methyl-1,4-dihydrotetrazole-5-one (described in Reference Preparation example 2) δ0 g, 2-methyl-4-(3,4,5-trimethyl-pyrazol-1-yl)-phenol (described in Reference Preparation example 20) 0.36 g, potassium carbonate 0.29 g and acetonitrile 15 ml was stirred with heating under reflux for seven hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was then concentrated. The resulting residue was subjected to a silica gel column chromatography to give 1-{3-cyclopropyl-2-[2-methyl-4-(3,4,5-trimethyl-pyrazol-1-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (hereinafter, referred to as “Present compound 2”) δ1 g.
Reaction SMILES: [CH2:1]=O.[CH2:3]1[CH2:9][O:8][CH2:7][CH2:6][NH:5][CH2:4]1.Cl.[CH3:11][C:12]1[CH:13]=[C:14]2[N:19]([CH:20]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH2:21]>CC(O)=O>[CH3:11][C:12]1[CH:13]=[C:14]2[N:19]([C:20]=1[CH2:1][N:5]1[CH2:4][CH2:3][CH2:9][O:8][CH2:7][CH2:6]1)[N:18]=[CH:17][N:16]=[C:15]2[NH2:21]
Reactant: C=O
Reactant: Cc1cc2c(N)ncnn2c1
Reactant: C1CNCCOC1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc2c(N)ncnn2c1CN1CCCOCC1
Yield: 77.7 %

Procedure:
A solution of formaldehyde (0.61 mL, 8.10 mmol, 37% in H2O) and homomorpholine hydrochloride (1.11 g, 8.10 mmol) in AcOH (5 mL) was added to a stirring solution of 6-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (1.00 g, 6.75 mmol) in AcOH (5 mL) at 60° C. The reaction was allowed to stir until all starting material had been consumed as shown by HPLC (1 hr). The reaction mixture was worked up by diluting with EtOAc and washing 3× with saturated sodium carbonate solution. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was triturated with Et2O to obtain 1.37 g (78%) of a light brown powder. 1H-NMR (DMSO-d6) δ 7.76 (s, 1H), 7.47 (br s, 2H), 6.65 (s, 1H), 3.85 (s, 2H), 3.62 (t, J=5.7 Hz, 2H), 3.55-3.51 (m, 2H), 2.61-2.55 (m, 4H), 2.21 (s, 3H), 1.77-1.74 (m, 2H); MS [M+H]+=262.0; LCMS RT=1.02.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][C:14](=[O:16])[CH3:15])=[C:7]([CH3:17])[C:6]=1[CH2:18][CH2:19][C:20]([O:24][C:25]([C:27]1[C:28]([C:33]([OH:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:26])([C:22]#[CH:23])[CH3:21])(=[O:3])[CH3:2].[CH3:36][C@H:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(O)C.C(OCC)C>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][C:14](=[O:16])[CH3:15])=[C:7]([CH3:17])[C:6]=1[CH2:18][CH2:19][C@:20]([O:24][C:25]([C:27]1[C:28]([C:33]([OH:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:26])([C:22]#[CH:23])[CH3:21])(=[O:3])[CH3:2].[CH3:36][C@@H:37]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH2:44]
Reactant: C#CC(C)(CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O)OC(=O)c1ccccc1C(=O)O
Agent: C[C@H](N)c1ccccc1
Solvent: CCOCC
Solvent: CCO
Product: C#C[C@](C)(CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O)OC(=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 27.00 g (0.056 mol) of rac-1,2-benzenedicarboxylic acid [3-[2,5-bis(acetyloxy)-3,4,6-trimethylphenyl]-1-ethynyl-1-methylpropyl]ester in 50 mL of 95% ethanol was added, with stirring 7.02 (0.058 mol) of (S)-(-)-α-methylbenzylamine in 250 mL of diethylether. The resulting solution was stirred at 25° C. for 0.5 h, then cooled in an ice bath until crystallization occured. It was further stirred at 0° C. for 0.5 h and the crystals were collected and air dried to give 16 g of white solid. This white solid was dissolved in 50 mL of ethanol (95%) and 150 mL of diethylether. The solution was kept at 25° C. for approximately 1.0 h and crystallization occurred. It was further stored at 0° C. for 1.0 h and the crystals were collected, dried at 25° C./0.5 mm for 24 h to yield 10.1 g of (S)-1,2-benzenedicarboxylic acid[3-[2,5-bis(acetyloxy)3,4,6-trimethylphenyl]-1-ethynyl-1-methylpropyl]ester(S)-α-methyl benzenemethanamine (1:1) (salt) as a white solid (30% yield from racemic starting materials), m.p. 162°-165° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].[H][H].[Br:11][C:12]1[C:13](Cl)=[N:14][C:15]([Cl:18])=[N:16][CH:17]=1>C1COCC1>[Br:11][C:12]1[C:13]([O:1][C@@H:2]2[CH2:6][CH2:5][O:4][CH2:3]2)=[N:14][C:15]([Cl:18])=[N:16][CH:17]=1
Reactant: [H][H]
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: O[C@@H]1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ncc(Br)c(O[C@@H]2CCOC2)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 40.8 %

Procedure:
To a solution of (R)-(−)-3-hydroxytetrahydrofuran (0.9 g, 10.2 mmol) in 1.2 mL anhydrous THF at 0° C. was added NaH (60% in mineral oil, 100 mg, 2.5 mmol). The mixture was stirred at 0° C. for 5 min and then r.t. for 2 h until there was no hydrogen bubbles generated. This mixture was added slowly to a solution of 5-bromo-2,4-dichloropyrimidine (570 mg, 2.5 mmol) and (R)-(−)-3-hydroxytetrahydrofuran (0.1 g, 1.1 mmol) in 0.8 mL THF at −10° C., and then the reaction mixture was stirred at the same temperature for 30 min. The reaction was quenched with water and extracted with EtOAc. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The residue was purified using ISCO chromatography (40 g silica gel, 1-20% EtOAc in hexanes in 40 min) to give the title compound (285 mg, 41%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.45 (s, 1H), 5.69-5.66 (m, 1H), 4.11-3.91 (m, 4H), 2.36-2.21 (m, 2H).