Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(-c2ncc(Br)cc2[N+](=O)[O-])cn1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ncc(Br)cc2N)cn1
Temperature: 70 °C
Reaction time: 19 h

Procedure:
To a stirred mixture of 5-bromo-6′-methoxy-3-nitro-2,3′-bipyridine (0.34 g, 1.10 mmol) in EtOAc (10 mL) was added tin(II) chloride dihydrate (1.26 g, 5.57 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 70° C. After 19 h, the reaction was cooled to rt and diluted with EtOAc, then washed with 1M NaOH, water, and brine. After drying over anhydrous sodium sulfate, filtration, and concentration, the residue was identified as mostly 5-bromo-6′-methoxy-2,3′-bipyridin-3-amine. 1H NMR (500 MHz, CDCl3) δ ppm 8.50 (1H, d, J=2.4 Hz), 8.18 (1H, d, J=2.0 Hz), 7.90 (1H, dd, J=8.6, 2.4 Hz), 7.26 (1H, m), 6.88 (1H, d, J=8.6 Hz), 4.07 (5H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@H:13]([C:15]3[O:22][NH:29][C:17](=[O:18])[CH:16]=3)[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(F)c(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 52.6 %

Procedure:
Trans-methyl 2-(3,4-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (502 mg, 1.36 mmol) (from example 23, step 1) was dissolved in MeOH (5 mL) and cooled to −40° C. Sodium hydroxide (0.358 mL, 1.36 mmol) dissolved in water (0.500 mL) was added and the reaction stirred at −40° C. for 20 min. Hydroxylamine (0.083 mL, 1.36 mmol) was added and stirring continued for 3.5 h at −40° C. The reaction mixture was then added to a prewarmed 80° C. solution of hydrogen chloride (7.02 mL, 42.13 mmol) and stirred for 20 min. The solvent was evaporated in vacuo. DCM (50 mL) and water (50 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (50 mL). The combined organic phase were dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 20-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Trans-methyl 2-(3,4-difluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (242 mg, 52.6%) was isolated as a white solid. 1H NMR (600 MHz, CDCl3) δ 1.60-1.72 (m, 1H), 1.94 (d, 1H), 1.98-2.07 (m, 1H), 2.60 (d, 1H), 2.78-2.94 (m, 2H), 3.77 (s, 3H), 4.25 (s, 1H), 5.51-5.71 (m, 2H), 6.94-6.99 (m, 1H), 7.02-7.09 (m, 1H), 7.17 (dd, 1H). MS m/z 337 (M−H)−.
Reaction SMILES: [CH:1]1([N:6]([CH3:27])[C:7]2[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.O>[CH:1]1([N:6]([CH3:27])[C:7]2[C:8]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N(C)C3CCCC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1)C1CCCC1

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(cyclopentyl(methyl)amino)-2-phenylquinoxaline-6-carboxylate (200 mg, 0.55 mmol, 1.00 equiv) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (110.8 mg, 2.77 mmol, 5.00 equiv) in water (3 mL) dropwise with stirring. The resulting solution was stirred for 3 hs at 50° C. in an oil bath. The pH value of the aqueous solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting solids were collected by filtration and washed with ether. This resulted in 56 mg (29%) of 3-(cyclopentyl(methyl)amino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:5]=[C:6](O)[C:7]2[S:13][CH2:12][CH2:11][CH2:10][C:8]=2[N:9]=1)#[N:2].P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:6]1[C:7]2[S:13][CH2:12][CH2:11][CH2:10][C:8]=2[N:9]=[C:4]([CH2:3][C:1]#[N:2])[N:5]=1
Reactant: N#CCc1nc(O)c2c(n1)CCCS2
Reactant: O=P(Cl)(Cl)Cl
Product: N#CCc1nc(Cl)c2c(n1)CCCS2

Procedure:
The title compound was prepared following substantially the same procedure described in Example 1, Step B using the product from Step A and phosphorus oxychloride. This procedure gave 1.2 g of product as a brown granular solid which was used in the next step.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:33])=[C:5]([CH2:7][O:8][C:9]2[CH:32]=[CH:31][C:12]([CH2:13][N:14]3[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])[C:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:15]3)=[CH:11][CH:10]=2)[N:6]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[CH3:1][C:2]1[O:3][C:4]([CH3:33])=[C:5]([CH2:7][O:8][C:9]2[CH:32]=[CH:31][C:12]([CH2:13][N:14]3[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:16]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[N:15]3)=[CH:11][CH:10]=2)[N:6]=1
Reactant: COC(=O)CCc1cn(Cc2ccc(OCc3nc(C)oc3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(COc2ccc(Cn3cc(CCC(=O)O)c(-c4ccccc4)n3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
A mixture of methyl 3-[1-[4-(2,5-dimethyl-4-oxazolylmethoxy)benzyl]3-phenyl-1H-pyrazol-4-yl]propionate (254 mg), lithium hydroxide monohydrate (69.9 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours, and 1N hydrochloric acid (1.7 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated to yield 3-[1-[4-(2,5-dimethyl-4-oxazolylmethoxy)benzyl]3-phenyl-1H-pyrazol-4-yl]propionic acid (243 mg, yield: 99%) as an amorphous substance.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:63])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C@H:24]([O:57][CH3:58])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:55][CH3:56])[C@@H:34]([CH3:54])[C:35]([NH:37][C@@H:38]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:39]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].[O:64]=[C:65]1[CH:69]=[CH:68][C:67](=[O:70])[N:66]1[CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][C:76]([NH:78][NH2:79])=[O:77]>>[O:70]=[C:67]1[CH:68]=[CH:69][C:65](=[O:64])[N:66]1[CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][C:76]([NH:78][NH:79][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:63])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C@H:24]([O:57][CH3:58])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:55][CH3:56])[C@@H:34]([CH3:54])[C:35]([NH:37][C@@H:38]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:39]([N:41]1[CH2:42][CH2:43][O:44][CH2:45][CH2:46]1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:77]
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCOCC1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCOCC1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
This compound was prepared in analogy to the synthesis described in Intermediate 157 from N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(2S)-1-(morpholin-4-yl)-1-oxo-3-phenylpropan-2-yl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide and commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][CH:43]([OH:59])[CH2:44][N:45]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH2:52]([N:45]([CH2:44][CH:43]([OH:59])[CH2:42][NH:41][C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NCC(O)CN(Cc1ccccc1)c1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCC(O)CN(Cc1ccccc1)c1ccccc1

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (85 mg, 0.15 mmol) and 1-amino-3-(N-benzylanilino)-2-propanol (47 mg, 0.18 mmol) according to Method C with HPLC purification to the title compound (23 mg) as a diasteromeric mixture. IR (KBr) 3414, 1654 cm−1; HRMS m/z 768.3382 (calc. of monoisotopic mass for C42H48N4O10 gives 768.3370).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:11]2)[CH2:6][CH2:5]1.C([O-])([O-])=O.[K+].[K+].Cl[C:34]([O:36][CH3:37])=[O:35]>ClCCl>[CH3:37][O:36][C:34]([NH:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][CH:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[C:12]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[CH:11]2)[CH2:8][CH2:9]1)=[O:35]
Reactant: Cc1ccc2c(c1)c(-c1ccc(F)cc1)cn2C1CCN(CCN)CC1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)NCCN1CCC(n2cc(-c3ccc(F)cc3)c3cc(C)ccc32)CC1

Procedure:
A mixture of 1-[1-(2-aminoethyl)-4-piperidyl]-3-(4-fluorophenyl)-5-methyl-1H-indole 12a (8.9 g), K2CO3 (4.2 g) and dichloromethane (80 ml) was cooled to 0°-5° C. and a solution of methyl chloroformate (2.9 g)in dichloromethane (50 ml) was added during 15 min. After reaction for further 2 h at room temperature the reaction mixture was washed with water (2×50 ml), dried (MgSO4) and the solvents were evaporated in vacuo. This afforded the 1-[1-(N-methoxycarbonyl-2-aminoethyl)-4piperidyl]-3-(4-fluorophenyl)-5-methyl-1H-indole, as an oil, which was used without further purification. Yield: 8.8 g.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[F:14][C:15]1[CH:16]=[C:17]([C:21]2([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)[CH:29]3[CH:25]([CH2:26][NH:27][CH2:28]3)[C:24](=[O:30])[CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>ClCCl>[F:37][C:33]1[CH:32]=[C:31]([C:21]2([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=3)[CH:29]3[CH:25]([CH2:26][N:27]([C:10](=[O:12])[CH2:9][C:4]4[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:28]3)[C:24](=[O:30])[CH2:23][CH2:22]2)[CH:36]=[CH:35][CH:34]=1
Reactant: O=C1CCC(c2cccc(F)c2)(c2cccc(F)c2)C2CNCC12
Reactant: COc1ccccc1CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2cccc(F)c2)(c2cccc(F)c2)C2CN(C(=O)Cc3ccccc3)CC12
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
A solution of (2-methoxyphenyl)acetic acid (0.46 g) in dry dichloromethane (15 cc) is cooled to 0° C., then treated with N,N'-carbonyldiimidazole (0.45 g) and stirred for 1 hour at 0° C. A solution of 7,7-bis(3-fluorophenyl)perhydro-4-isoindolone hydrochloride (1 g) and triethylamine (0.76 cc) in dichloromethane (20 cc) is added dropwise. The reaction mixture is stirred for 3 hours at 25° C. and then washed with water (2×50 cc) and with saturated sodium chloride solution (50 cc). The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.063 mm, diameter 2.2 cm, height 23 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (70:30 by volume) and collecting 15-cc fractions. Fractions 4 to 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa), and the product obtained is recrystallized in acetonitrile. The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-Bis(3-fluorophenyl)-2-(phenylacetyl)perhydro-4-isoindolone (0.76 g) is obtained. M.p. 194° C.
Reaction SMILES: CCCCCC.[Na].[C:8]([CH2:10][C:11]1[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][CH:16]=1)#[N:9].[CH3:19][OH:20]>>[CH3:19][O:20][C:8]1[CH:10]=[C:11]2[C:12](=[C:17]([NH2:18])[N:9]=1)[N:13]=[CH:14][CH:15]=[CH:16]2
Reactant: N#CCc1cccnc1C#N
Reactant: CO
Agent: [Na]
Solvent: CCCCCC
Product: COc1cc2cccnc2c(N)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
To an oven-dried 250 mL flask under a nitrogen atmosphere was added anhydrous MeOH (200 mL). Na metal (1.07 g, 44 mmol) was weighed to a small beaker containing hexane and then transferred to the reaction vessel. After dissolution of the sodium, 3-cyanomethyl-pyridine-2-carbonitrile (5.3 g, 37 mmol) dissolved in anhydrous MeOH (10 mL) was added to the reaction. The resulting solution was heated at 80° C. for 3 hours, then stirred at room temperature overnight. The reaction mixture was concentrated to remove MeOH and extracted into CH2Cl2 (2×200 mL). The organic phases were combined, dried over Na2SO4, filtered, concentrated and unsuccessfully chromatographed (2% MeOH/CH2Cl2). The mixed fractions were combined and recrystalized from EtOAc/hexane affording 1.16 g (18%) of the title compound as a yellow solid. The mother liquor was rechromatographed (50% EtOAc/hexanes) to afford an additional 560 mg (9%) of product: mp decomposes above 110° C.; MS(+)APCI m/z 176 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9](=[O:12])[C:8]2[CH2:7][O:6][C:5]([C:17]([O:19][CH3:20])=[O:18])([C:13]([O:15][CH3:16])=[O:14])[CH2:4][C:3]1=2.C(O[CH:25]=[CH:26][CH:27]=[CH2:28])(=O)C>C1(C)C=CC=CC=1>[CH3:20][O:19][C:17]([C:5]1([C:13]([O:15][CH3:16])=[O:14])[O:6][CH2:7][C:8]2[C:9](=[O:12])[C:10]3[C:11]([C:2](=[O:1])[C:3]=2[CH2:4]1)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:18]
Reactant: C=CC=COC(C)=O
Reactant: COC(=O)C1(C(=O)OC)CC2=C(CO1)C(=O)C=CC2=O
Solvent: Cc1ccccc1
Product: COC(=O)C1(C(=O)OC)CC2=C(CO1)C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5,8-dioxo-3,3 bis (methoxycarbonyl)-5,8-dihydroisochroman (50 mg; 0.17 mmol) in toluene (4 ml) at room temperature was added 1-acetoxy-1,3 butadiene (113 μl; 1 mmol). The resulting mixture was stirred at room temperature for 24 hours. Air was then bubbled through for 30 minutes and the mixture was concentrated to a volume of ~1 ml and applied to silica gel column. Elution with 30% ethyl acetate in hexane afforded pure title compound (20 mg; 34%) as a yellow solid; m.p.: 210°-222° C. (dec):
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.[CH3:9][O:10][C:11](=[O:23])[CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2.BrCCBr>C1COCC1>[N:19]1[C:20]2[C:15](=[CH:14][C:13]([C:12]3([C:11]([O:10][CH3:9])=[O:23])[CH2:3][CH2:2]3)=[CH:22][CH:21]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)Cc1ccc2ncccc2c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COC(=O)C1(c2ccc3ncccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.1 %

Procedure:
LDA (1.8 M solution in toluene, 14.8 mL, 26.6 mmol) was added dropwise to a solution of quinolin-6-yl-acetic acid methyl ester (2.14 g, 10.64 mmol) in dry THF (40 mL) under nitrogen at −78° C. After 30 min, 1,2-dibromoethane (2.40 g, 12.76 mmol) was added dropwise over 3 min. The resulting mixture was stirred for 1 h at rt, then quenched with saturated aqueous NH4Cl, extracted with DCM, washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with EtOAc/hexane gradient to afford the title compound as a yellow solid (463 mg, 20%). 1H-NMR (400 MHz, CDCl3) δ ppm 8.91 (dd, 1H), 8.12 (d, 1H), 8.07 (d, 1H), 7.77-7.74 (m, 2H), 7.40 (dd, 1H), 3.65 (s, 3H), 1.73-1.71 (m, 2H), 1.33-1.30 (m, 2H). LCMS (method A): [MH]+=228, tR=4.37 min.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:11][C:12]1[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:19]=[CH:18][C:13]=1[O:14][CH2:15][CH2:16][NH2:17].C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[CH3:11][C:12]1[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:19]=[CH:18][C:13]=1[O:14][CH2:15][CH2:16][NH:17][C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2sccc12
Reactant: CCCCCc1ccc(OCCN)c(C)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCc1ccc(OCCNc2ncnc3sccc23)c(C)c1
Yield: 76 %

Procedure:
3.4 g (0.02 mole) of 4-chlorothieno[2,3-d]pyrimidine, 4.4 g (0.02 mole) of 2-(2-methyl-4-pentylphenoxy)ethylamine and 2 g (0.02 mole) of triethylamine were dissolved in 50 ml of toluene, and the solution was heated under reflux for 4 hours. At the end of this time, water was added to the reaction mixture, and the mixture was then extracted with toluene. The extract was dried over anhydrous sodium sulphate, and the solvent was distilled off, after which the residue was recrystallised from a mixture of toluene and hexane, to give 5.4 g (yield 76%) of the title compound in the form of colourless crystals melting at 93°-95° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13]O)=[C:11]([CH3:15])[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][N:20]3[C:16](=[O:26])[C:17]4[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:19]3=[O:21])=[C:11]([CH3:15])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1onc(-c2ccc(F)cc2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(F)cc2)c1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of [3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (5.0 g, 24 mmol) in THF (290 mL) was added phthalimide (4.7 g, 32 mmol) and triphenylphosphine (8.4 g, 32 mmol) at ambient temperature under an argon atmosphere. Then a solution of diethyl azodicarboxylate (40% in toluene, 12.5 mL, 32 mmol) was added and the reaction mixture was stirred for 1 h at room temperature. Concentration and repeated trituration and then purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (6.0 g, 74%) as a white solid. MS: m/e=337.1 [M+H]+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.Br[CH2:23][CH:24]=[CH2:25]>C1COCC1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH2:25][CH:24]=[CH2:23])[C:19]([OH:21])=[O:20])=[CH:16][CH:17]=1
Reactant: C=CCBr
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(C(=O)O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 43.2 %

Procedure:
Step AA (1): NaHMDS (1.0 M in THF, 46.7 mL, 46.7 mmol) was added to a stirred solution of 2-(4-fluorophenyl)acetic acid (3.6 g, 23.4 mmol) in THF (50 mL) at 0° C. The resulting mixture was stirred for 20 min at 0° C. and neat 3-bromoprop-1-ene (2.02 mL, 23.4 mmol) was added. The mixture was allowed to warm to rt. After 16 hr, the reaction was quenched with water (3 mL). The crude mixture was concentrated in vacuo. Aqueous NaOH (1 M, 150 mL) was added to the residue and the resulting mixture was extracted with Et2O (2×100 mL). The basic layer was acidified with aqueous HCl (1 M, 200 mL) and the resulting solution was extracted with Et2O (2×100 mL). The combined organic layers from the acidic extraction were washed with mixture of brine/1N HCl/sodium sulfite, dried (MgSO4), filtered, and concentrated in vacuo. The residue was dissolved in toluene (˜50 mL) and left to sit at rt for 3 days. A white solid was collected by vacuum filtration. The solid was dried under high vacuum to afford 2-(4-fluorophenyl)pent-4-enoic acid (2.03 g, 10.1 mmol, 43% yield) as an off-white crystalline solid. 1H NMR (500 MHz, chloroform-d) δ ppm 7.28-7.34 (m, 2 H) 6.99-7.07 (m, 2 H) 5.71 (dddd, J=17.09, 10.22, 6.87, 6.71 Hz, 1 H) 5.08 (dd, J=17.09, 1.53 Hz, 1 H) 5.01-5.05 (m, 1 H) 3.65 (t, J=7.63 Hz, 1 H) 2.75-2.87 (m, 1 H) 2.52 (dt, J=14.27, 7.06 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[N:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][OH:14])[CH:8]=2)[N:3]=1.[F:15][C:16]([F:22])([F:21])[CH2:17][N:18]=[C:19]=[S:20]>C(#N)C>[F:15][C:16]([F:22])([F:21])[CH2:17][NH:18][C:19](=[S:20])[NH:1][C:2]1[CH:6]=[N:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][OH:14])[CH:8]=2)[N:3]=1
Reactant: Nc1cnn(-c2cccc(CO)c2)n1
Reactant: FC(F)(F)CN=C=S
Solvent: CC#N
Product: OCc1cccc(-n2ncc(NC(=S)NCC(F)(F)F)n2)c1
Reaction time: 8 h

Procedure:
A mixture of this sample of unpurified 4-amino-2-(3-hydroxymethylphenyl)-1,2,3-triazole, 2,2,2-trifluoroethylisothiocyanate (0.202 g.) and acetonitrile (5 ml.) was kept at room temperature overnight. The mixture was evaporated to leave a residue of unpurified 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-(3-hydroxymethylphenyl)-1,2,3-triazole which was used without further purification.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:15]([C:16]#[N:17])=[C:14]([CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[NH:13][C:12]4=[N:24][NH:25][CH:26]=[C:11]34)=[CH:8][CH:7]=[CH:6][C:5]=12.C=O.[C:29]([BH3-])#N.[Na+].C(O)(=O)C>CO>[N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:15]([C:16]#[N:17])=[C:14]([CH:18]4[CH2:19][CH2:20][N:21]([CH3:29])[CH2:22][CH2:23]4)[NH:13][C:12]4=[N:24][NH:25][CH:26]=[C:11]34)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: N#CC1=C(C2CCNCC2)Nc2n[nH]cc2C1c1cccc2nonc12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCC(C2=C(C#N)C(c3cccc4nonc34)c3c[nH]nc3N2)CC1
Reaction time: 8 h
Yield: 43.9 %

Procedure:
To a solution of 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine (0.7 g) in MeOH (200 mL) was added 37% formaldehyde (0.18 g), sodium cyanoborohydride (0.19 g) and acetic acid (0.36 g) at room temperature and the mixture was stirred overnight. After alkalification with sodium bicarbonate, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was washed with acetonitrile, and the precipitated crystals were collected by filtration to give the title compound (0.32 g) as yellow crystals.