Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:11])[C:5]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[C:16](Cl)(=O)C(Cl)=O.CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[C:7]([C:8]([O:10][CH3:16])=[O:9])=[C:6]([CH3:11])[C:5]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: Cc1c(OC(C)C)ccc(Br)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1c(Br)ccc(OC(C)C)c1C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 64.9 %

Procedure:
To a 0° C. solution of 6-bromo-2-methyl-3-(propan-2-yloxy)benzoic acid (Cpd OO, 1.30 g, 4.80 mmol) in DCM (5 mL) was added oxalyl chloride (810 mg, 6.19 mmol) followed by DMF (10 mL). The reaction mixture was stirred at 0° C. for 1.5 hours, then concentrated under vacuum. The residue was dissolved in MeOH (15 mL) and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under vacuum and the residue dissolved in EtOAc. The organic layer was washed with brine, dried with Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (0-50%, EtOAc/heptane) to give the title compound (Cpd PP, 894 mg, 65%) as an amber oil. 1H NMR (400 MHz, chloroform-d) δ 1.33 (d, J=6.11 Hz, 6H) 2.16 (s, 3H) 3.95 (s, 3H) 4.50 (dt, J=12.04, 6.08 Hz, 1H) 6.75 (d, J=8.80 Hz, 1H) 7.31 (d, J=8.80 Hz, 1H); MS 287 [M+H].
Reaction SMILES: [NH:1]1[C:5]2=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:14][C:15]1[CH:20]=[C:19]([C:21](=[O:27])[NH:22][CH2:23][CH2:24][O:25][CH3:26])[CH:18]=[C:17]([Cl:28])[C:16]=1[C:29](Cl)=[O:30]>>[C:11]([NH:10][C:6]1[N:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:29]([C:16]3[C:17]([Cl:28])=[CH:18][C:19]([C:21]([NH:22][CH2:23][CH2:24][O:25][CH3:26])=[O:27])=[CH:20][C:15]=3[Cl:14])=[O:30])=[CH:2][NH:1][C:5]=12)(=[O:13])[CH3:12]
Reactant: COCCNC(=O)c1cc(Cl)c(C(=O)Cl)c(Cl)c1
Reactant: CC(=O)Nc1nccc2cc[nH]c12
Product: COCCNC(=O)c1cc(Cl)c(C(=O)c2c[nH]c3c(NC(C)=O)nccc23)c(Cl)c1

Procedure:
4-{[7-(Acetylamino)-1H-pyrrolo[2,3-c]pyridin-3-yl]carbonyl}-3,5-dichloro-N-(2-methoxyethyl)benzamide was prepared analogously using N-(1H-pyrrolo[2,3-c]pyridin-7-yl) acetamide and 2,6-dichloro-4-(2-methoxyethylcarbamoyl)benzene carbonyl chloride (Compound No. 17).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([NH:15][C:16]([NH:18][C:19]3[CH:20]=[C:21]([CH2:25][C:26]([O:28]C)=[O:27])[CH:22]=[CH:23][CH:24]=3)=[O:17])[C:7]=2[CH:30]=1)#[N:2].O.[OH-].[Li+]>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([NH:15][C:16]([NH:18][C:19]3[CH:20]=[C:21]([CH2:25][C:26]([OH:28])=[O:27])[CH:22]=[CH:23][CH:24]=3)=[O:17])[C:7]=2[CH:30]=1)#[N:2]
Reactant: COC(=O)Cc1cccc(NC(=O)N[C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)Nc2cccc(CC(=O)O)c2)[C@@H]1O

Procedure:
A solution of (3S-trans)-3-[[[(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) amino]carbonyl]amino]-benzeneacetic acid, methyl ester (0.7 g, 1.7 mmol, title compound from Example 24) in methanol (15 ml) under argon was treated with lithium hydroxide hydrate (0.14 g, 3.4 mmol) and the reaction was stirred at room temperature for 16 hours. More lithium hydroxide (two equivalent) was added and the reaction mixture was stirred for 48 hours. It was concentrated in vacuo and the residue was diluted with water (50 ml) and extracted with ethyl acetate. Organic layer was discarded and aqueous layer was acidified to pH~1 with 10% hydrochloric acid and extracted with ethyl acetate (3×100 ml). It was washed with water (100 ml) and concentrated in vacuo. The residue was flash chromatographed on silica gel eluting with methylene chloride/methanol/acetic acid (1800:200:5) to give (3S-trans)-3-[[[(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)amino]carbonyl]amino]benzeneacetic acid as a colorless solid (0.5 g, 73.9%), m.p. 135-138° C. (with foaming): 1H NMR (DMSO-d6) δ 8.76 (s, 2 H), 7.62 (m, 2 H), 7.42 (m, 2 H), 7.25 (m, 2 H), 6.96 (d, J=8.3 Hz, 1 H), 6.90 (d, J=7.0 Hz, 1 H), 6.70 (d, J=8.2 Hz, 1 H), 4.77 (m, 2 H), 3.76 (m, 2 H), 1.51 (s, 3 H), 1.28 (s, 3 H); 13C NMR (CDCl3) 172.8, 156.3, 155.9, 140.3, 135.6, 132.7, 132.4, 128.6, 126.0, 122.4, 119.1, 118.8, 117.9, 116.2, 102.7, 80.3, 71.6, 49.4, 26.5, 18.9; IR (KBr) 1132.1, 1267.2, 1491.3, 1559.3, 1611.2, 1659.3, 1713.2, 2228.1, 2980.1, 3379.0 cm-1 ; [α]25D=-6.7° (c=0.683, DMF).
Reaction SMILES: [OH:1][Ge:2][OH:3].[CH:4]1[CH:5]=[CH:6][C:7]2[C:8](=[C:10]3[N:42]=[C:41]4[N:43]=[C:34]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=54)[N:33]=[C:31]4[NH:32][C:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=54)=[N:23][C:21]4=[N:22][C:14]([C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=54)=[N:13][C:12]=2[NH:11]3)[CH:9]=1.[C:44]1([CH:50]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][O:66][SiH2:67]O)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCOCC1>[C:48]1([CH:41]([C:40]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][O:66][SiH2:67][O:1][Ge:2][O:3][SiH2:67][O:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH:50]([C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:49]=1.[CH:5]1[CH:4]=[CH:9][C:8]2[C:7](=[C:12]3[N:13]=[C:14]4[N:22]=[C:21]([C:20]5[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=54)[N:23]=[C:24]4[NH:32][C:31]([C:30]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=54)=[N:33][C:34]4=[N:43][C:41]([C:40]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=54)=[N:42][C:10]=2[NH:11]3)[CH:6]=1
Reactant: O[SiH2]OCCCCCCCCCCCCCCCC(c1ccccc1)c1ccccc1
Reactant: O[Ge]O
Agent: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Solvent: C1COCCO1
Product: c1ccc(C(CCCCCCCCCCCCCCCO[SiH2]O[Ge]O[SiH2]OCCCCCCCCCCCCCCCC(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reaction time: 24 h

Procedure:
Variant b: 2 g (3.24 mmol) of dihydroxygermanium-phthalocyanine are boiled at reflux with 2 equivalents of diphenylhexadecyloxysilanol in 210 ml of dioxane for 39 hours. After 24 hours, 500 mg of dihydroxygermanium-phthalocyanine are added. The reaction mixture is allowed to cool and the residue is chromatographed on basic aluminium oxide (Alox B) using pure hexane and hexane/ethyl acetate (4:1) in succession as eluants. The product-containing fractions are combined and concentrated. The residue is recrystallised from pentane at -20° C., yielding blue crystals of bis(diphenylhexadecyloxy-siloxy)-germanium-phthalocyanine.
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:25]([F:26])=[CH:24][C:10]3[NH:11][C:12]([O:14][CH2:15][CH:16]4[CH2:18][CH:17]4[C:19]([O:21]CC)=[O:20])=[N:13][C:9]=3[C:8]=2[F:27])=[CH:3][CH:2]=1.O([Si](C)(C)C)[K]>C1COCC1.CCOC(C)=O>[C:1]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:25]([F:26])=[CH:24][C:10]3[NH:11][C:12]([O:14][CH2:15][CH:16]4[CH2:18][CH:17]4[C:19]([OH:21])=[O:20])=[N:13][C:9]=3[C:8]=2[F:27])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CC1COc1nc2c(F)c(-c3ccc(-c4ccccc4)cc3)c(F)cc2[nH]1
Agent: C[Si](C)(C)O[K]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)C1CC1COc1nc2c(F)c(-c3ccc(-c4ccccc4)cc3)c(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-({[5-(biphenyl-4-yl)-4,6-difluoro-1H-benzimidazol-2-yl]oxy}methyl)cyclopropanecarboxylate (0.046 g, 0.102 mmol) was dissolved in 1 mL of THF and treated with KOTMS (0.037 g, 0.288 mmol). The reaction mixture was stirred at ambient temperature overnight, and then diluted with EtOAc and washed with 2 N HCl. The acidic aqueous layer was separated and further extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound. LCMS: calculated for C24H18F2N2O3 420.41, observed m/e 420.9 (M+H)+ (Rt 2.21/4 min). 1H NMR (500 MHz, CD3OD): δ7.73-7.64 (m, 4H), 7.51 (d, 2H), 7.48-7.41 (m, 2H), 7.35 (m, 1H), 7.03 (d, 1H), 4.55 (dd, 1H), 4.29 (dd, 1H), 1.95 (m, 1H), 1.75 (m, 1H), 1.28 (m, 1H), 1.08 (m, 1H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.[O:11]1CCO[CH:12]1[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=1>>[CH:12]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=2)=[C:18]([O:23][CH3:24])[CH:17]=1)=[O:11]
Reactant: NC(=O)c1ccc(F)cn1
Reactant: COc1cc(C2OCCO2)ccc1O
Product: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)nc1
Yield: 16.2 %

Procedure:
Using a method similar to Example 388 Part D, using 5-fluoropyridine-2-carboxamide (Example 388 Part C) (0.400 g, 2.85 mmol) and 4-[1,3]dioxolan-2-yl-2-methoxyphenol (Example 386, Part C2) (0.560 g, 2.85 mmol) gives the title compound (0.126 g, 16%): MS ES+ 272.9 (M+H)+; HPLC [YMC-Pack Pro C-18 (150×4.6 min, S-5 microm). 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min. 5-95% over 19 min], tR=11.1 min. 97.2% purity.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[C:6]([C:10]1[CH:11]=[C:12]([OH:24])[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=2)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(OCC)C>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:24][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([C:20]([CH3:22])([CH3:21])[CH3:23])[CH:14]=2)[CH:19]=[C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(O)c2cc(C(C)(C)C)ccc2c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)c1cc(OP(=O)(Cl)Cl)c2cc(C(C)(C)C)ccc2c1
Reaction time: 0.5 h

Procedure:
Phosphorus oxychloride (0.145 mL, 1 equiv) and 3,7-di-tert-butylnaphthalen-1-ol (J. Org. Chem. 1995, 60, 2909-2911, 0.4 g, 1 equiv) were stirred in anhydrous diethyl ether (10 mL). Anhydrous triethylamine was added (0.217 mL, 1 equiv) at −78° C. and stirred for 30 min. The dichloridate is very unstable at room temperature. The progress of the reaction was monitored by 31P NMR. This crude mixture was considered to be a 100% conversion to dichloridate and was used directly.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[C:7]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[CH:6]=1)C.[OH-].[Na+].O.Cl>O1CCOCC1>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[CH2:16][CH2:15][O:14][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[O:11][CH2:12][CH3:13])[C:4]([OH:25])=[O:3]
Reactant: CCOC(=O)c1ccc(OCC)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
0.300 g (0.78 mmol) of 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-ethoxy-benzoic acid ethyl ester was dissolved in 10 ml of dioxan. 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 10 h. 5 ml water was added, followed by concentrated hydrochloric acid to give a pH of 1–2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, and then the product was filtered off and dried under reduced pressure.
Reaction SMILES: [N+:1]([C:4]1[C:13]([S:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[S:31])=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>>[N+:1]([C:4]1[C:13]([S:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:30]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[C:24]([C:32]([F:35])([F:33])[F:34])[CH:25]=3)=[S:31])=[CH:17][CH:16]=2)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2]
Reactant: Nc1ccc(Sc2ccc3ncccc3c2[N+](=O)[O-])cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: O=[N+]([O-])c1c(Sc2ccc(NC(=S)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccc2ncccc12

Procedure:
5-nitro-6-(4-aminophenylthio)quinoline 1.7 mmoles, 0.40 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate 1.7 mmoles, 0.47 g) were reacted according to procedure C to yield the title compound, 0.78 g, 86% product. Mass spec (FD) 534. Calculated for C23H14ClF3 N4O2S2 : C, 51.64; H, 2.64, N, 10.47 Found: C, 51.84; H, 2.73; N, 10.43.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:17][C@H:16]4[C@:18]5([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]5)[C@H:13]([CH2:14][CH2:15]4)[CH2:12][C:11]=3[CH:30]=2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB(C2C=CC3C[C@H]4[C@]5(CN(CC(F)(F)F)S(=O)(=O)N5)[C@H](CC4)CC=3C=2)O1.[C:64]([O:68][C:69]([N:71]1[CH2:76][CH:75]=[C:74](B2OC(C)(C)C(C)(C)O2)[CH2:73][CH2:72]1)=[O:70])([CH3:67])([CH3:66])[CH3:65]>CS(C)=O>[C:64]([O:68][C:69]([N:71]1[CH2:72][CH:73]=[C:74]([C:2]2[S:6][C:5]([C:7]3[CH:8]=[CH:9][C:10]4[CH2:17][C@H:16]5[C@:18]6([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]6)[C@H:13]([CH2:14][CH2:15]5)[CH2:12][C:11]=4[CH:30]=3)=[N:4][CH:3]=2)[CH2:75][CH2:76]1)=[O:70])([CH3:67])([CH3:65])[CH3:66]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=S1(=O)N[C@@]2(CN1CC(F)(F)F)[C@@H]1CC[C@H]2Cc2ccc(-c3ncc(Br)s3)cc2C1
Agent: CC1(C)OB(c2ccc3c(c2)C[C@H]2CC[C@@H](C3)[C@]23CN(CC(F)(F)F)S(=O)(=O)N3)OC1(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cnc(-c3ccc4c(c3)C[C@H]3CC[C@@H](C4)[C@]34CN(CC(F)(F)F)S(=O)(=O)N4)s2)CC1

Procedure:
Prepared using [6S,9R,11R]2′,3′,4′,5,5′,6,7,8,9,10-Decahydro-2-(5-bromothiazol-2-yl)-5′-(2,2,2-trifluoroethyl)-spiro[6,9-methanobenzocyclooctene-11,3′-[1,2,5]thiadiazole]1′,1′-dioxide (prepared using the homochiral boronate from Example 24 Step 1 by the method described for Example 36 Steps 1–2) and the boronate from Example 39 Step 2 using the method described for Example 36 Step 3. MS (ES+) 625 ([MH]+); [α]D=−11 (c=0.62, DMSO, 23° C.).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])[CH:3]=[N:2]1.Cl[CH2:18][C:19]1[C:20]([CH3:25])=[N:21][O:22][C:23]=1[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:25][C:20]1[C:19]([CH2:18][N:1]2[CH:5]=[C:4]([N:6]3[C:14](=[O:15])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7]3=[O:16])[CH:3]=[N:2]2)=[C:23]([CH3:24])[O:22][N:21]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cn[nH]c1
Reactant: Cc1noc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(C)c1Cn1cc(N2C(=O)c3ccccc3C2=O)cn1
Yield: 39.9 %

Procedure:
2-(1H-pyrazol-4-yl)isoindoline-1,3-dione (example 9-1a) (1.5 g, 7 mmol), 4-(chloromethyl)-3,5-dimethylisoxazole (1.5 g, 10 mmol), and cesium carbonate (3.3 g, 10 mmol) were stirred in DMF (20 mL) at 80° C. for 3 hours. The reaction was cooled, diluted with H2O (150 mL), and extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated on the rotovap. The solid product was triturated with ethyl acetate/hexanes (1/9) and re-crystallized from refluxing absolute ethanol (30 mL) to afford 2-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)isoindoline-1,3-dione (900 mg, 38%) as a bright, light yellow solid. 1H NMR (DMSO-d6, 400 MHz) 1.36 (d, 3H δ J2.16 (s, 3H), 2.41 (s, 3H)=7.2 Hz), 5.22 (s, 2H), 7.81 (s, 1H), 7.91-7.83 (m, 4H), 8.21 (s, 1H). MS M+H calculated 323.11. found 323.1. Melting point: 170-171° C. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.18 μM.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:46][NH2:47]>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]([CH3:23])[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:21])[N:16]=2)[CH2:11][C:12]([NH:47][OH:46])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)ON
Reactant: COC(=O)CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-(3-{[(2-methoxy-2-oxoethyl)(methyl)amino]carbonyl}-1,2,4-oxadiazol-5-yl)hexanoic acid (Preparation 39) (273 mg, 0.70 mmol) and N-methylmorpholine (85 μl, 0.77 mmol) in anhydrous dichloromethane (10 ml) was cooled to 0° C., treated with isobutyl chloroformate (100 μl, 0.77 mmol) and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. O-(Trimethylsilyl)hydroxylamine (250 μl, 2.10 mmol) was then added and the mixture stirred under a nitrogen atmosphere for 1 hour, being allowed to warm to room temperature over this time. The mixture was then quenched with methanol (10 ml) and stirred for 10 minutes. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The layers were separated and the organic layer was sequentially washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by HPLCa to afford the title compound as a colourless oil (187 mg).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.[CH2:7]=[C:8]1[O:12][C:10](=[O:11])[CH2:9]1>O1CCCC1>[OH:6][C@H:3]1[CH2:4][CH2:5][N:1]([C:10](=[O:11])[CH2:9][C:8](=[O:12])[CH3:7])[CH2:2]1
Reactant: O[C@H]1CCNC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N1CC[C@H](O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution of 21.8 g (0.25 mol) (S)-3-pyrrolidinol in 200 ml tetrahydrofuran was added dropwise to a solution of 20 g of diketene (0.24 mol) in 200 ml of tetrahydrofuran at −5 to 0° C. added. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 31.35 g (0.18 mol, 77% yield) of a colorless oil.
Reaction SMILES: [CH2:1]([C:4]1([CH2:17][C:18]([OH:20])=[O:19])[CH2:16][CH2:15][C:7]2([O:12][CH2:11][C:10]([CH3:14])([CH3:13])[CH2:9][O:8]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].CI.[C:23]([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:23][O:19][C:18](=[O:20])[CH2:17][C:4]1([CH2:1][CH:2]=[CH2:3])[CH2:16][CH2:15][C:7]2([O:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][O:12]2)[CH2:6][CH2:5]1
Reactant: O=C([O-])[O-]
Reactant: C=CCC1(CC(=O)O)CCC2(CC1)OCC(C)(C)CO2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCC1(CC(=O)OC)CCC2(CC1)OCC(C)(C)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (9-allyl-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetic acid (0.50 g), methyl iodide (0.12 mL), K2CO3 (0.37 g), and N,N-dimethylformamide (5 mL) is stirred at room temperature overnight. 10% aqueous K2CO3 solution is then added and the resulting mixture is extracted with ethyl acetate. The combined extract is washed with brine, dried (MgSO4), and concentrated to give the crude title compound that is used without further purification. Yield: 0.36 g (crude); LC (method 6): tR=1.65 min; Mass spectrum (ESI+): m/z=297 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[Cl:13].[H-].[Na+].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][N:12]3[C:5]4[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=4[C:3]([Cl:13])=[C:2]3[Cl:1])=[CH:25][CH:24]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: Cn1ncc2[nH]c(Cl)c(Cl)c2c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc2c(c(Cl)c(Cl)n2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.4 %

Procedure:
A solution of 2,3-dichloro-5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (404 mg) in DMF (70 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (10 ml) on an ice-water bath. After 3 hours of stirring at room temperature, a solution of 4-(4-chlorobenzoyl)benzyl bromide (681 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 18 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was then purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=2:1→1:1) to provide the title compound as white powder (351 mg, yield 39%). 1H-NMR (DMSO-d6) δ: 3.68(3H,s), 5.73(2H,s), 7.30(2H,d,J=8.6Hz), 7.61(2H,d,J=8.6Hz), 7.72(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 8.71(1H,s).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:19][CH2:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[C:15]([F:14])([F:24])[F:25])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(NCc3ccccc3C(F)(F)F)c2cn1
Temperature: 150 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (225 mg, 1.17 mmol) and 2-(trifluoromethyl)benzylamine (0.90 mL, 6.42 mmol) is stirred under N2 at 150° C. for 1 h. The resulting product is chromatographed on silica gel (5% EtOH/EtOAc) to give 7-amino-4-(2-trifluoromethylbenzyl) aminopyrido[4,3-d]pyrimidine (0.22 g, 59%) as a white solid. 1H NMR (DMSO) δ 9.16 (1H, s), 8.88 (1H, t, J=5.7 Hz), 8.23 (1H, s), 7.75 (1H, d, J=7.7 Hz), 7.62 (1H, t, J=7.5 Hz), 7.50 (1H, d, J=7.4 Hz), 7.47 (1H, t, J=7.6 Hz), 6.51 (2H, brs), 6.39 (1H, s), 4.92 (2H, d, J=5.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)cc1
Reactant: CCCCCI
Agent: [H-]
Agent: [Na+]
Product: CCCCCn1nc(-c2ccc(OC)cc2)c2cccc(C(F)(F)F)c21
Yield: 37.5 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-trifluoromethyl-1H-indazole (0.146 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 1-iodopentane (0.130 mL, 1.0 mmol) to give the title compound (0.068 g) as a white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:14]1([CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[OH:31])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C(Cl)Cl>[C:5]([C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([OH:31])=[C:21]([CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:30]=1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Oc1c(Cc2ccccc2)ccc2ccccc12
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(Cc2ccccc2)c(O)c2ccccc12
Reaction time: 3 h
Yield: 40 %

Procedure:
A mixture of aluminum chloride (1.25 g, 9.4 mmole) in methylene chloride (25 mL) was stirred at 0° and treated dropwise with benzoyl chloride (1.1 mL, 9.4 mmole) and stirred for 5 minutes. A solution of 2-(phenylmethyl)-1-naphthol (2.0 g, 8.5 mmole) in methylene chloride (6 mL) was added dropwise over 15 minutes, and stirring was continued at 0° for 3 hours. The mixture was poured into 1.0N hydrochloric acid, and the crude product was isolated by extraction with methylene chloride. Recrystallization from toluene provided the title compound (1.15 g, 40%) as pale yellow crystals, mp 152°-155°.