Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[C:19]1([C:25]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:33]3[CH:29]([CH2:30][NH:31][CH2:32]3)[C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])([OH:34])[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[C:43]1([C:25]2([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:33]3[CH:29]([CH2:30][N:31]([C:15](=[O:16])[CH2:14][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:32]3)[C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])([OH:34])[CH2:27][CH2:26]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1ccccc1C1(O)CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1C1(O)CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3)CC21
Reaction time: 24 h

Procedure:
0.35 cm3 of triethylamine and then 0.33 cm2 of phenylacetyl chloride are added to a suspension of 1.1 g of (3aRS,4RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride in 25 cm3 of dry dichloromethane at room temperature. The reaction mixture is stirred at this temperature for 24 hours, diluted with 200 cm3 of dichloromethane, washed with 100 cm3 of a saturated solution of sodium bicarbonate, with 100 cm3 of water (twice) and then with an aqueous saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 22 cm) by eluting under a nitrogen pressure of 50 kPa with a mixture of cyclohexane and ethyl acetate (55/45 by volume) and collecting fractions of 20 cm3. Fractions 11 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is crystallized from 70 cm3 of acetonitrile and the crystals are filtered off and dried. 0.5 g of (3aRS,4RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-(phenylacetyl)perhydroisoindol-4-ol is obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.Cl.[CH3:18][S:19]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]N)=[CH:24][CH:23]=1)(=[O:21])=[O:20].C(N(C(C)C)CC)(C)C.P(=O)(O)(O)O>O1CCCC1.CO>[Cl:1][C:2]1[N:11]=[C:10]([CH2:26][C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:29][CH:28]=2)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Agent: Cl
Agent: O=P(O)(O)O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2nc(Cl)nc(Cc3ccc(S(C)(=O)=O)cc3)c2cc1OC
Temperature: 25 °C

Procedure:
A mixture of commercially available 2,4-dichloro-6,7-dimethoxyquinazoline (200 mg, 0.772 mmol, 1 eq), 4-methylsulfonylbenzylamine hydrochloride (180 mg, 0.810 mmol, 1.05 eq) and diisopropylethylamine (0.40 mL, 2.32 mmol, 3 eq) in tetrahydrofuran (7.7 mL) was heated at reflux for 15.25 h. The reaction mixture was then cooled to rt and concentrated in vacuo. The resultant solid was slurried in methanol (10 mL) collected by filtration, washed with methanol and dried to provide 282 mg (89%) of A1.1 as an off-white solid. LC/MS: 408 [M+H]+; HPLC: 98% at 3.19 min (Phenomenex 5 μm C18 column 4.6×50 mm, 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 254 nm); 1H NMR (400 MHz, DMSO-d6): δ 8.98 (m, 1 H), 7.91 (d, J=8.3 Hz, 2 H), 7.69 (s, 1 H), 7.62 (d, J=8.3 Hz, 2 H), 7.11 (s, 1 H), 4.84 (apparent d, J=5.7 Hz, 2 H), 3.90 (s, 3 H), 3.89 (s, 3 H), 3.19 (s, 3 H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][N:12]([C:14]1[CH:19]=[C:18]([CH2:20][OH:21])[CH:17]=[C:16]([Cl:22])[CH:15]=1)[CH3:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:13][N:12]([C:14]1[CH:19]=[C:18]([CH:20]=[O:21])[CH:17]=[C:16]([Cl:22])[CH:15]=1)[CH3:11]
Reactant: CN(C)c1cc(Cl)cc(CO)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1cc(Cl)cc(C=O)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 92.6 %

Procedure:
To a solution of DMSO (7.58 g, 97.0 mmol) in CH2Cl2 (100 μL) at −78° C. was added oxalyl chloride (6.16 g, 48.5 mmol) over the course of 10 min. After an additional 15 min at −78° C., a solution of 3-chloro-5-N,N-dimethylaminobenzyl alcohol (8.18 g, 44.1 mmol; see step (i) above) in CH2Cl2 (100 mL) was added over the course of 15 min. The resulting solution was stirred at −78° C. for 1 h prior to the addition of DIPEA (28.5 g, 220.5 mmol). The solution was warmed to 25° C. and stirred for 18 h, before being concentrated in vacuo to give the crude product. Flash chromatography on silica gel, eluting with Hex:EtOAc (5:1), gave 7.50 g (93%) of the sub-title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.CC#N>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[CH:12][N:11]([CH:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:21])[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: BrCCc1ccccc1
Reactant: Cc1nnc2ccc3[nH]ccc3n12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1nnc2ccc3c(ccn3C(C)c3ccccc3)n12
Temperature: 45 °C

Procedure:
To a mixture of 1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (10 mg, 0.058 mmol, isolated from Example 2, Step 5 during a preparation wherein the methylation of Step 2 of that Example was incomplete) and K2CO3 (0.024 g, 0.17 mmol) in DMF (0.22 mL) was added 1-(bromoethyl)benzene (12 μL, 0.087 mmol, Acros). The mixture was heated to 45° C. for 3 hours. The mixture was diluted with MeCN and filtered, then the product was isolated by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (3.3 mg, 20%).
Reaction SMILES: C[N:2]([CH3:13])[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH3:11].[OH:14][CH:15]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21]C#N)[CH2:16]1>>[OH:14][CH:15]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:13]2[NH:2][C:3](=[O:12])[C:4]3[C:5]([CH:11]=2)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=3)[CH2:16]1
Reactant: N#CCCN1CCC(O)C1
Reactant: Cc1cccc(C(=O)N(C)C)c1C
Product: Cc1cccc2c(=O)[nH]c(CCN3CCC(O)C3)cc12
Yield: 5.4 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-dimethyl-2,3-dimethylbenzamide (4.10 g) and 3-(3-hydroxypyrrolidin-1-yl)propionitrile (1.5 g), 3-[2-(3-hydroxypyrrolidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (157.5 mg) was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CC1C=CC(S([O-])(=O)=O)=CC=1.[O:85]1[CH2:89][CH2:88][C@@H:87]([NH3+:90])[CH2:86]1>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:90][C@@H:87]4[CH2:88][CH2:89][O:85][CH2:86]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: [NH3+][C@@H]1CCOC1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)N[C@@H]1CCOC1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 μL, 0.14 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added (R)-tetrahydrofuran-3-aminium 4-methylbenzenesulfonate (24 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of (R)-tetrahydrofuran-3-aminium 4-methylbenzenesulfonate were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (15-40_90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N—((R)-tetrahydrofuran-3-yl)acetamide. (41 mg, 0.085 mmol, 61%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C@:11]1([CH3:29])[CH2:16][S:15](=[O:18])(=[O:17])[C:14]([CH3:20])([CH3:19])[C:13]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:12]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:40](Br)[CH:41]=[CH2:42]>C1COCC1>[CH2:42]([C@H:16]1[S:15](=[O:18])(=[O:17])[C:14]([CH3:20])([CH3:19])[C:13]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:12][C@@:11]1([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1])[CH3:29])[CH:41]=[CH2:40].[CH2:42]([C@@H:16]1[S:15](=[O:18])(=[O:17])[C:14]([CH3:20])([CH3:19])[C:13]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:12][C@@:11]1([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1])[CH3:29])[CH:41]=[CH2:40]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc([N+](=O)[O-])ccc2F)CS(=O)(=O)C1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC[C@@H]1[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C(NC(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Product: C=CC[C@H]1[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C(NC(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
To a solution of (R)-tert-butyl (5-(2-fluoro-5-nitrophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (600 mg, 1.397 mmol) in THF (14 ml) was added potassium bis(trimethylsilyl)amide, (1M in THF) (8.38 ml, 8.38 mmol) dropwise at −78° C. and the mixture was stirred for 30 min at −78° C. Neat allyl bromide (0.363 ml, 4.19 mmol) was then added dropwise and the mixture was stirred for 30 min. The reaction mixture was quenched with sat. aq. NH4Cl solution at −78° C., then allowed to reach RT and extracted with ethyl acetate. The organic extracts were washed with brine and concentrated. The residue was separated by silica gel chromatography on a 40 g RediSep Gold column using 10-60% EtOAc/heptane solvent gradient to afford less polar trans-isomer tert-butyl ((5R,6R)-6-allyl-5-(2-fluoro-5-nitrophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (170 mg, 0.362 mmol, 25.9% yield), and more polar cis-isomer tert-butyl ((5R,6S)-6-allyl-5-(2-fluoro-5-nitrophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (263 mg, 0.560 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].Cl[C:13](OC1C=CC([N+]([O-])=O)=CC=1)=[O:14].C(N(C(C)C)CC)(C)C.[Cl:34][C:35]1[CH:44]=[C:43]2[C:38]([C:39]([N:45]3[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]3)=[CH:40][CH:41]=[N:42]2)=[CH:37][CH:36]=1>>[Cl:34][C:35]1[CH:44]=[C:43]2[C:38]([C:39]([N:45]3[CH2:50][CH2:49][N:48]([C:13]([NH:6][C:5]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=4)=[O:14])[CH2:47][CH2:46]3)=[CH:40][CH:41]=[N:42]2)=[CH:37][CH:36]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: COc1ccc(N)cc1OC
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)cc1OC

Procedure:
As described for example 78, 3,4-dimethoxyaniline, p-nitrophenyl chloroformate, diisopropylethyl amine, and 7-chloro-4-piperazinylquinoline are reacted to afford the product. LC-MS: 427 (M++1). 1H NMR (CDCl3) δ 8.80 (d, 1H), 8.05 (s, 1H), 7.95 (d, 1H), 7.50 (d, 1H), 7.20 (s, 1H), 6.85 (d, 1H), 6.80 (d, 1H), 6.75 (m, 1H), 6.40 (s, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 380 (m, 4H), 3.25 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=O)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:3]=1.C(Cl)(=O)C(Cl)=O.C1COCC1.C[N:41](C=O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:41])=[O:21])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:3]=1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Reaction time: 18 h
Yield: 55.7 %

Procedure:
To a stirred suspension of 4-[4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (0.5 g, 1.24 mmol) in THF/DMF (9.0 mL; 8:1) was added oxalyl chloride (0.33 mL, 3.7 mmol) and the mixture stirred for 18 hours. The solvent was concentrated and the residue co-evaporated with toluene. To the residue was added a solution of ammonia in dioxane (0.5 M, 20 mL) and the mixture stirred for 18 hours. The reaction mixture was diluted with 10% MeOH in DCM (50 mL) and absorbed onto silica. The crude product was chromatographed by flash column chromatography (3% MeOH in DCM) to give the product as pale yellow solid (0.278 g, 55.7%).
Reaction SMILES: [C:1]1([CH2:7][C:8](=[N:10][OH:11])[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][CH:13]([CH3:17])[C:14](Cl)=O.C(N(CC)CC)C>CC(C)=O>[CH2:7]([C:8]1[N:9]=[C:14]([CH:13]([Cl:12])[CH3:17])[O:11][N:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(Cc1ccccc1)=NO
Reactant: CC(Cl)C(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(Cl)c1nc(Cc2ccccc2)no1
Temperature: 0 °C
Yield: 95.2 %

Procedure:
First, 15.0 grams (0.1 mole) of phenyl acetamide oxime was combined with 100 milliliters of dry acetone in a 250 milliliter flask fitted with a thermometer and dropping funnel. The solution was stirred and cooled to 0° C. Next, 12.7 grams (0.1 mole) of 2-chloro propionyl chloride and 10.1 grams (0.1 mole) of triethyl amine was added. During the additions, the temperature was maintained at 0 to 5° C. After the additions were complete, the reaction mass was stirred at room temperature for 30 minutes and then was filtered free of salt. The filtrate was evaporated in vacuo at 50° and the residue was taken up in 300 milliliters of toluene. The toluene solution was charged to a 500 milliliter flask fitted with a Dean Stark water trap, 0.1 gram of toluene sulfonic acid was added, and the solution was heated under reflux until water ceased to be evolved. The toluene solution was then treated with activated carbon, filtered and evaporated in vacuo at 50° C. to yield 21.2 grams (95% of theory) of 3-benzyl-5-(1-chloroethyl)1,2,4-oxadiazole. nD30 1.5040.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][CH3:8])[C:3]([NH:5][NH2:6])=O.CO[C:12]1[CH2:17][CH:16]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:19]=2)[CH2:15][CH2:14][N:13]=1.C(=O)(O)[O-].[Na+]>CO>[CH3:1][C:2]([C:3]1[N:13]2[CH2:12][CH2:17][CH:16]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:19]=3)[CH2:15][C:14]2=[N:6][N:5]=1)([CH3:9])[CH2:7][CH3:8]
Reactant: COC1=NCCC(c2nc(-c3ccccc3)no2)C1
Reactant: CCC(C)(C)C(=O)NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCC(C)(C)c1nnc2n1CCC(c1nc(-c3ccccc3)no1)C2
Yield: 59.3 %

Procedure:
Reflux 2,2-dimethyl-butyric acid hydrazide (0.053 g, 0.48 mmol) and 5-(2-methoxy-3,4,5,6-tetrahydropyridin-4-yl)-3-phenyl-1,2,4-oxadiazole (0.1 g, 0.39 mmol) in methanol (1.55 mL) overnight. Remove the methanol under reduced pressure and replace with acetic acid (2 mL). Reflux the reaction for 3 hours and pour over aqueous saturated sodium bicarbonate. Extract with dichloromethane and dry the organics over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography eluting with 5-15% ethyl acetate in dichloromethane. Recrystallize from ethyl acetate and hexane to afford the title compound as a crystalline solid (0.078 g). Mass spectrum (m/z): 338 (M+1).
Reaction SMILES: [OH:1][CH:2]([C:7]([O:20][CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28](S(C)(=O)=O)[N:27]=1.O>CN(C)C=O.C(O)(=O)C>[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28]([O:1][CH:2]([C:7]([O:20][CH3:21])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([O:5][CH3:6])=[O:4])[N:27]=1
Reactant: COC(=O)C(O)C(OC)(c1ccccc1)c1ccccc1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(OC)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
2.86 g (10 mmol) of methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate were dissolved in 40 ml of dimethylformamide, and 0.3 g (12 mmol) of sodium hydride was added. The mixture was stirred for 1 h and then 2.2 g (10 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine were added. After stirring at room temperature for 24 h, cautious hydrolysis was carried out with 10 ml of water, the pH was adjusted to 5 with acetic acid, and the solvent was removed by distillation under high vacuum. The residue was taken up in 100 ml of ethyl acetate, washed with water and dried over magnesium sulfate, and the solvent was distilled out. The residue was mixed with 10 ml of ether, and the resulting precipitate was filtered off with suction. After drying, 3.48 g (82%) of a white powder remained. Melting point 81° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21](C(O)=O)=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:31]([CH2:34]C)CC.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:43])C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:25]([F:28])([F:27])[F:26])=[C:21]3[NH:31][C:34]2=[O:43])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1c(C(F)(F)F)ccnc1Nc1ccc(OCc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=c1[nH]c2c(C(F)(F)F)ccnc2n1-c1ccc(OCc2ccccc2)cc1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To a solution of 2-{[4-(benzyloxy)phenyl]amino}-4-(trifluoromethyl)pyridine-3-carboxylic acid (221 mg) and Et3N (0.238 mL) in toluene (15 mL) was added diphenylphosphoryl azide (0.245 mL) at room temperature. The mixture was stirred at 110° C. for 4 h. After cooling, the solvent was evaporated, and the precipitate was collected by filtration to give the title compound (197 mg).
Reaction SMILES: [C:1]1([C:7]2[C:11]([O:12][CH2:13][CH2:14][CH3:15])=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:9]([CH3:22])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:23]([O:28]C)([O:26][CH3:27])(=[O:25])=[O:24]>C1(C)C=CC=CC=1>[CH3:27][O:26][S:23]([O-:28])(=[O:25])=[O:24].[CH3:22][N+:9]1[N:8]([CH3:27])[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([O:12][CH2:13][CH2:14][CH3:15])[C:10]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCOc1c(-c2ccccc2)nn(C)c1-c1ccccc1
Reactant: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: CCCOc1c(-c2ccccc2)n(C)[n+](C)c1-c1ccccc1
Product: COS(=O)(=O)[O-]
Reaction time: 8 h
Yield: 96 %

Procedure:
3,5-Diphenyl-1-methyl-4-n-propoxypyrazole (2.77 g, 0.0095 mole) in molecular sieve dried toluene (80 ml) is heated to 50°C and dimethyl sulfate (2.5 g, 0.02 mole) is added. The mixture is stirred and heated under reflux for 6 hours, cooled and set aside overnight. The reaction mixture is then extracted with water, the water layer evaporated to dryness under vacuum to afford the title compound as a hygroscopic solid in 96% yield.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([B:8]([OH:10])[OH:9])=[CH:5][CH:4]=1)=O.[CH3:11][NH:12][CH3:13]>COCCOC.C1COCC1>[CH3:11][N:12]([CH2:1][C:3]1[O:7][C:6]([B:8]([OH:10])[OH:9])=[CH:5][CH:4]=1)[CH3:13]
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: CNC
Solvent: COCCOC
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(B(O)O)o1
Reaction time: 0.08 h

Procedure:
To a solution of (5-formyl-2-furyl)boronic acid (50 mg, 0.36 mmol) in DME (1.0 mL) was added a 2.0M solution of dimethylamine in THF (0.53 mL, 1.0 mmol). The reaction mixture stirred for 5 minutes before resin bound MP-BH(OAc)3 (2.2 mmol/g, 0.33 g, 0.714 mmol) was added. The reaction mixture was stirred at room temperature for five hours and an additional 1 equivalent of dimethylamine in THF was added and stirring continued overnight. The reaction mixture was filtered through a plug of glass wool and the resin was washed with DME. The THF/DME filtrate solution containing the desired compound was used immediately in subsequent reactions.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[C:5](=[CH:10][C:11]([CH2:16]Br)=[C:12]([CH2:14]Br)[CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[OH:19][C:20]1[CH:21]=[C:22]([C:29]#[N:30])[C:23](=[CH:26][C:27]=1[OH:28])[C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:4]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]2[CH2:16][O:19][C:20]3[CH:21]=[C:22]([C:29]#[N:30])[C:23]([C:24]#[N:25])=[CH:26][C:27]=3[O:28][CH2:14][C:12]=2[CH:13]=1)=[O:18]
Reactant: N#Cc1cc(O)c(O)cc1C#N
Reactant: COC(=O)c1cc(CBr)c(CBr)cc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2c(cc1C(=O)OC)COc1cc(C#N)c(C#N)cc1OC2
Temperature: 25 °C

Procedure:
A slurry of 4,5-bis-bromomethyl-phthalic acid dimethyl ester (1.57 g, 4.12 mmol), 4,5-dihydroxy-phthalonitrile (660 mg, 4.12 mmol) and potassium carbonate (1.1 g, 8.24 mmol) in DMF (20 mL) was heated to 60° C. for 1 h under an atmosphere of argon. The resulting slurry was cooled to room temperature and diluted with water. A white precipitate was collected via filtration and re-crystallized from EtOAc to yield 2,3-dicyano-6,11-dihydro-5,12-dioxa-dibenzo[a,e]cyclooctene-8,9-dicarboxylic acid dimethyl ester as a white solid. C20H14N2O6; MS (ESI) m/z 378.9 (MH)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24](O)[CH2:25][OH:26]>C1(C)C=CC=CC=1>[N+:10]([C:7]1[CH:6]=[CH:5][C:4]([C:2]2([CH3:1])[O:26][CH2:25][CH2:24][O:3]2)=[CH:9][CH:8]=1)([O-:12])=[O:11]
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(c2ccc([N+](=O)[O-])cc2)OCCO1
Temperature: 25 °C

Procedure:
A mixture of 4-nitroacetophenone (1.65 g, 10.0 mmol), p-toluenesulfonic acid (172 mg, 1.00 mmol) and ethylene glycol (1.7 mL, 30 mmol) in dry toluene (20 mL) was heated at reflux with a Dean-Stark apparatus under nitrogen for 24 h. The mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was taken up in ether (20 mL) and the solution was washed with saturated sodium bicarbonate solution (2×10 mL) and brine (1×10 mL), then dried (Na2SO4) and concentrated under reduced pressure. Recrystallisation from ether and hexanes afforded 2-(4-nitrophenyl)-2-methyl-1,3-dioxolane (25) as a pale yellow crystals (1.52 g, 73%; yield based from the first crop of crystals). 1H nmr (300 MHz, CDCl3) 1.66 (s, 3H, CH3), 3.71-3.83 (m, 2H, OCH2), 4.02-4.13 (m, 2H, OCH2), 7.63-7.73 (d, J=8.8 Hz, 2H, 2×ArH), 8.16-8.26 (d, J=8.8 Hz, 2H, 2×ArH).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[CH:6]=[CH:7][C:8](O)=[O:9])([O-])=O>C(O)C.[Pd]>[NH:1]1[C:4]2[C:5](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:7][C:8]1=[O:9]
Reactant: O=C(O)C=Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: O=C1CCc2ccccc2N1

Procedure:
A solution of 25 g of o-nitrocinnamic acid in 250 ml of ethanol was shaken with 2.5 g of 10% palladium on carbon under hydrogen at a pressure of 3 atmospheres. When the theoretical amount of hydrogen had been absorbed the catalyst was filtered off, washed with hot ethanol and the filtrate evaporated under reduced pressure to give 3,4-dihydrocarbostyril, m.p. 168°-169° C.