Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1.CCCCC.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([N:11]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]=2[C:4]2[C:12]1=[CH:13][CH:14]=[C:2]([Cl:1])[CH:3]=2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCc2[nH]c3ccc(Cl)cc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: O=C1CCCc2c1c1cc(Cl)ccc1n2Cc1ccccc1
Reaction time: 0.45 h
Yield: 92.5 %

Procedure:
6-Chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.4010 g, 0.0018 mol) is added to a slurry of pentane-washed NaH (0.0902 g, 0.0023 mol) in DMF (2 mL) and after stirring for 27 min, benzyl bromide (0.26 mL, 0.0022 mol) is added. After stirring for 2.5 h at room temperature, the mixture is partitioned between aq. sodium bicarbonate and ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated to dryness. The resulting solids are chromatographed on silica gel (200 mL) using dichloromethane/heptane (60/40 and 100/0) to give 0.5158 g (91%) of the title compound. An aliquot (0.0625 g) is recrystallized from ethyl acetate/heptane to give 0.0415 g of product; mp 196.5-197° C.; MS (ESI+) for C19H16ClNO m/z 310.1 (M+H)+; 1H NMR (CDCl3) δ2.24, 2.58, 2.87, 5.31, 6.99, 7.16, 7.29, 8.28. Anal. Calcd for C19H16ClNO: C, 73.66; H, 5.20; N, 4.52. Found: C, 73.18; H, 5.19; N, 4.58.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][CH:9]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:24]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:10][CH:9]=1)[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ccccc2O)cc1
Reactant: CCCCCBr
Product: CCCCCOc1ccccc1-c1ccc(CNC(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 20 using tert-butyl N-(2′-hydroxybiphenyl-4-ylmethyl)carbamate instead of tert-butyl N-(3′-hydroxybiphenyl-4-ylmethyl)carbamate and 1-bromopentane instead of 1-bromopropane.
Reaction SMILES: [CH:1]1([N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7](I)=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)C4)=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[N:23]4)=[CH:28][CH:27]=3)=[CH:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ncnc2c1c(I)cn2C1CCC1
Reactant: CC1(C)CB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2C1CCC1

Procedure:
Following the general procedure for the Suzuki coupling, 7-cyclobutyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (142.5 mg, 0.4536 mmol) was reacted with 2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline (150.2 mg, 0.4533 mmol), Na2CO3 (120 mg, 1.13 mmol) and Pd(PPh3)4 (32 mg, 0.028 mmol) in DMF (10 mL)/water (2 mL). The crude material was purified by column chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with CH2Cl2 (1-12)→1% MeOH in CH2Cl2 (13-37)→2% MeOH in CH2Cl2 (38-61)], yielding the title compound as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ=1.88-2.00 (m, 2H), 2.44-2.56 (m, 2H), 2.56-2.65 (m, 2H), 5.27 (brs, 2H), 5.35 (quint, J=8.6 Hz, 1H), 7.35 (s, 1H), 7.46-7.51 (m, 11H), 7.52-7.58 (m, 2H), 7.70 (dd, J=1.8, 8.2 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 8.17-8.22 (m, 2H), 8.26 (d, J=8.4 Hz, 1H), 8.28-8.31 (m, 1H), 8.36 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=15.03 (−), 31.11 (2C, +), 48.26 (+), 101.15 (Cquart), 115.99 (Cquart), 118.99 (+), 120.86 (+), 125.97 (Cquart), 127.42 (+), 127.55 (2C, +), 128.26 (+), 128.48 (+), 128.87 (2C, +), 129.52 (+), 136.49 (Cquart), 136.55 (+), 139.43 (Cquart), 148.52 (Cquart), 150.79 (Cquart), 151.97 (+), 156.97 (Cquart), 158.12 (Cquart). MS (ES+): m/z 392.1 (17) [MH+], 338.2 (22) [MH+-cyclobutene]. HPLC: tR=3.0 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1.O>[CH3:20][S:21]([O:13][CH2:12][CH:10]1[CH2:11][N:8]([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)OCC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.2 %

Procedure:
To a solution of [1-(diphenylmethyl)azetidin-3-yl]methanol (30.0 g, 118.4 mmol) in pyridine (200 mL) was slowly added methanesulfonyl chloride (17.0 g, 148.4 mmol), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with water, and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 1N sodium hydroxide, and the ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained solid was washed with hexane to give the title compound (30.3 g, yield 77%) as a pale yellow solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH2:13]([N:15](CC)CC)C.CS(Cl)(=O)=O>ClCCl>[C:13]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)#[N:15]
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
In dichloromethane (20 ml), methyl 4-hydroxymethylbenzoate (1.00 g) was dissolved, followed by the addition of triethylamine (0.9 ml). Under ice cooling, a solution of methanesulfonyl chloride (0.70 g) in dichloromethane (dichloromethane: 5 ml) was added to the resulting solution. The resulting mixture was stirred at room temperature for 15 hours. After dilution with dichloromethane, the reaction mixture was washed with water and was then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in acetonitrile (12 ml). To the resulting solution, potassium cyanide (0.80 g) and 18-Crown-6 (0.16 g) were added, followed by stirring at room temperature for 40 hours. After concentration under reduced pressure, the concentrate was diluted with dichloromethane, washed with water and then, dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane), whereby colorless crystals (0.91 g, 86%) was obtained. A portion of the resulting crystals was recrystallized from a mixed solvent of hexane and ethyl acetate, whereby colorless crystals were obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][S:7](=[O:15])(=[O:14])[NH:8][C:9](=[O:13])[CH2:10][CH2:11]Cl)=[O:5].C(N(CC)CC)C>CC(C)=O>[C:9]([NH:8][S:7](=[O:14])(=[O:15])[NH:6][C:4](=[O:5])[CH:3]=[CH2:2])(=[O:13])[CH:10]=[CH2:11]
Reactant: O=C(CCCl)NS(=O)(=O)NC(=O)CCCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C=CC(=O)NS(=O)(=O)NC(=O)C=C
Temperature: 25 °C

Procedure:
60 g (0.208 mol) of N,N'-bis-(3-chloropropionyl)-sulphuric acid diamide are dissolved in 1 l of absolute acetone. 100 g (0.99 mol) of absolutle triethylamine are added over the course of 15 minutes from a dropping funnel. The mixture is stirred at room temperature until no further precipitate forms and is filtered. The filtrate is concentrated until crystallisation commences. It is then allowed to complete crystallisation at 10°C and after filtration, washing with absolute ether and drying N,N'-bis-acryloyl-(sulphuric acid diamide) mono-triethylamminium salt of melting pont 104°C is obtained. This can be purified further by recrystallisation or can be obtained as free N,N'-bis-acryloyl-sulphuric acid diamide by dissolving in water and acidifying with hydrochloric acid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:30])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=1)[C:10]([CH3:32])([CH3:31])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:31][C:10]1([CH3:32])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:30])[NH:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)Nc3ccccc3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(C(=O)Nc2ccccc2)c1
Temperature: 45 °C
Reaction time: 48 h
Yield: 46.7 %

Procedure:
A mixture of 3,3-dimethyl-2-(3-phenylcarbamoyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.8 g, 1.87 mmol) in methanol (15 mL) and tetrahydrofuran (20 mL), 30% sodium hydroxide in water (10 mL) was stirred at 45° C. for 48 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-(3-phenylcarbamoyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (350 mg, 46%) as a white solid: LC/MS m/e calcd for C25H24N2O3 (M+H)+: 401.48, observed: 401.1.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[N:17][C:18]=3[NH:28][NH2:29])[N:13]=2)=[CH:8][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:40][N:41]1[CH:45]=[C:44]([C:46](O)=O)[N:43]=[CH:42]1.C(Cl)CCl>CN(C=O)C.O.C(O)(=O)C>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:18]4=[N:28][N:29]=[C:46]([C:44]5[N:43]=[CH:42][N:41]([CH3:40])[CH:45]=5)[N:17]4[CH:16]=[CH:15][C:14]=3[N:13]=2)=[CH:8][CH:7]=1
Reactant: Cn1cnc(C(=O)O)c1
Reactant: NNc1nccc2nc(-c3ccc(C4OCCO4)cc3)c(-c3ccccc3)cc12
Agent: On1nnc2ccccc21
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cnc(-c2nnc3c4cc(-c5ccccc5)c(-c5ccc(C6OCCO6)cc5)nc4ccn23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-4 (5 g, 13 mMol), HOBT (1.9 g, 14.3 mMol), and 1-methyl-1H-imidazole-4-carboxylic acid (2 g, 15.6 mMol) in anhydrous DMF (100 mL) was added EDC (2.7 g, 14.3 mMol). The solution was stirred overnight at ambient temperature. The solution was then treated with 24 mL of acetic acid and was heated to 80° C. in an oil bath for 5 hours. Upon cooling to room temperature, an equal volume of water was added and the resulting suspension was filtered and washed with copious amounts of water. The collected solid was dried azeotropically with toluene three times to yield 13-1 as a tan solid. Mass (M+1) calculated: 475.1877 observed: 475.1871
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][N:16]([CH3:34])[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][N:25]=3)=[C:19]([CH3:33])[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:43][C:44]([F:55])([F:54])[C:45]1[CH:53]=[CH:52][C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Pt].[C]>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][N:16]([CH3:34])[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[N:25]=[CH:26][C:27]([NH:30][C:49](=[O:50])[C:48]4[CH:52]=[CH:53][C:45]([C:44]([F:43])([F:54])[F:55])=[CH:46][CH:47]=4)=[CH:28][CH:29]=3)=[C:19]([CH3:33])[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(N(C)CC(=O)N2CCN(Cc3ccccc3)CC2)ccc1Oc1ccc([N+](=O)[O-])cn1
Agent: [Pt]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(N(C)CC(=O)N2CCN(Cc3ccccc3)CC2)ccc1Oc1ccc(NC(=O)c2ccc(C(F)(F)F)cc2)cn1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a suspension of 1-(4-benzylpiperazin-1-yl)-2-{methyl[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]amino}ethanone (2.85 g, 6.0 mmol) in ethyl acetate (30 mL) was added 5% platinum-carbon (0.30 g) under a nitrogen atmosphere, and the resulting solution was stirred for 3 hours at 40° C. under a hydrogen atmosphere. The platinum-carbon was separated off with Celite, and the filtrate was concentrated. The residue was dissolved in THF (30 mL), and to this solution was added triethylamine (1.26 mL, 9.1 mmol) under ice cooling. To the resulting solution was then added dropwise 4-(trifluoromethyl)benzoyl chloride (1.16 mL, 7.8 mmol). This reaction solution was stirred overnight, then a saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1). The resulting product was then recrystallized from a mixed solvent consisting of diisopropyl ether-acetone, to thereby yield 1.37 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:5]=1[O:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:5]=1[O:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCOc1cc(CO)ccc1C(=O)OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOc1cc(C=O)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a 0° C. solution of 2-butoxy-4-hydroxymethyl-benzoic acid methyl ester (0.270 g, 1.13 mmol) in methylene chloride (10 mL) are added sodium bicarbonate (0.14 g, 1.7 mmol) and Dess-Martin periodinane (0.58 g, 1.4 mmol) sequentially. The reaction mixture is stirred at room temperature for 1.0 h and quenched with water (10 mL). The reaction mixture is partitioned between CH2Cl2 (30 mL) and water (20 mL). The organic phase is washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography to give the title compound as a syrup (240 mg, 90%). LC-ES/MS: 237.3 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[NH2:10].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=1)[C:17](O)=[O:18]>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=1)[C:17]([NH:10][C:2]1[S:1][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=1)=[O:18]
Reactant: Nc1nc2c(s1)CCCC2
Reactant: COc1ccc(Cl)cc1C(=O)O
Product: COc1ccc(Cl)cc1C(=O)Nc1nc2c(s1)CCCC2

Procedure:
Commercially available 4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (Aldrich) and 5-chloro-2-methoxybenzoic acid (Aldrich) were processed using the method described in Example 58 to afford the title compound. MS (ESI+) m/z 323 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([I:10])[CH:9]=1)[CH:5]=O.[F:12][C:13]([F:22])([F:21])/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([I:10])[CH:7]=[C:4]2[C:3]=1[O:11][CH:14]([C:13]([F:12])([F:22])[F:21])[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2
Reactant: O=Cc1cc(I)cc(Cl)c1O
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(I)cc(Cl)c2OC1C(F)(F)F
Temperature: 100 °C
Yield: 37.7 %

Procedure:
To 18 g (63.7 mmole) of 3-chloro-2-hydroxy-5-iodobenzaldehyde in 16 mL of DMF was added 14.3 mL (16.1 g, 95.6 mmole) of ethyl trifluorocrotonate and 9.69 g (70 mmole) of K2CO3. The mixture was heated to 100° C. for 2 h. The mixture was allowed to cool, treated with 300 mLs of H2O and extracted three times with Et2O. The combined extracts were washed with water and filtered through a silica plug (4.5×6 cm). The silica was washed with methylene chloride and combined filtrates concd to give 10.39 g of a yellow solid. Recystalization in hexanes gave 6.64 g (24.1%) of a crystalline, yellow solid: 1H NMR (CDCl3/400 MHz) 1.35 (t, 3H, J=7.1 Hz), 4.33 (m, 2H), 5.81 (q, 1H, J=6.6 Hz), 7.44 (d, 1H, J=2.0 Hz), 7.62 (s, 1H), 7.66 (d, 1H, J=2.0 Hz); 19F NMR (CDCl3/400 MHz) −79.0 (d, 3F, J=6.8 Hz); 13C NMR (CDCl3/100 MHz) 13.1, 60.8, 70.4 (q, J=33.7 Hz), 82.6 (C-I), 117.7, 121.2, 121.8, 121.9 (q, J=287.2 Hz), 133.6, 134.9, 139.9, 147.9, 162.0; MS (ESI+) 433 (M+1, 100); HRMS (EI) m/z calcd for (C13H9O3IClF3) 431.9237, found 431.9221.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([CH2:7][CH:8]([OH:13])[C:9]([O:11]C)=[O:10])[CH2:4][CH2:3]1>O>[O:1]=[C:2]1[NH:6][CH:5]([CH2:7][CH:8]([OH:13])[C:9]([OH:11])=[O:10])[CH2:4][CH2:3]1
Reactant: COC(=O)C(O)CC1CCC(=O)N1
Solvent: O
Product: O=C1CCC(CC(O)C(=O)O)N1

Procedure:
5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid, methyl ester (1.87 g), and Amberlite (IR-120H+) (1.9 g) in 20 ml of water is warned at 60° C. for 36 hours, filtered, and the solvent removed under reduced pressure. The resulting solid is washed with ethyl acetate and filtered to yield 5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid. NMR (DMSOD6) and 7.89 (d, J=11 Hz, 1HO, 5.35 (bs, 1H), 3.99 (m, 1HO, 3.44 (m, 1/2H), 3.30 (m, 1/2H), 2.48-1.21 (m, 6H). IR (cm-1) 3370, 3280, 2940, 1694, 1355, 1213, 1120.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Cl>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([S:15][CH2:20][C:19]4[CH:22]=[CH:23][CH:24]=[C:17]([Cl:16])[CH:18]=4)=[N:12][N:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: ClCc1cccc(Cl)c1
Reactant: Sc1nnc(-c2ccc3occc3c2)o1
Product: Clc1cccc(CSc2nnc(-c3ccc4occc4c3)o2)c1
Yield: 89 %

Procedure:
In the same manner as in Example 1 and using 5-(1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-chlorobenzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 89%) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34](O)=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)[CH:10]=[CH:11][CH:12]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C[O:66][C:67](=[O:86])[C@@H:68]([NH2:85])[CH2:69][C:70]1[CH:75]=[CH:74][C:73]([O:76][C:77]2[CH:82]=[CH:81][N:80]=[C:79]([CH3:83])[C:78]=2[CH3:84])=[CH:72][CH:71]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34]([NH:85][C@@H:68]([CH2:69][C:70]5[CH:75]=[CH:74][C:73]([O:76][C:77]6[CH:82]=[CH:81][N:80]=[C:79]([CH3:83])[C:78]=6[CH3:84])=[CH:72][CH:71]=5)[C:67]([OH:66])=[O:86])=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(Oc2ccnc(C)c2C)cc1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)O3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)C(=O)O)OC[C@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)O3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 49.9 %

Procedure:
(3S,8S)-3-[3-(3,4-Dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (25 mg), EDCl (10 mg), HOBT (8 mg) and (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester (16 mg) were taken up in 1 mL of anhydrous DCM and stirred for 5 minutes. The reaction mixture was cooled to 0° C. and DIEA (21 mg) was added and reaction was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was loaded on a silica gel column (1:3 EtOAc:hexanes to 4% MeOH in 1:1 EtOAc:hexanes) to get purified (S)-2-{[(3S,8S)-3-[3-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester (22 mg). This was hydrolyzed according to General Procedure B to give the title compound (18 mg). LCMS (m/z): 873.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])([CH3:3])[CH3:2].S(Cl)([Cl:16])=O>>[CH:1]([C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:5]=1[C:6]([Cl:16])=[O:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(F)ccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: CC(C)c1cc(F)ccc1C(=O)Cl

Procedure:
Reaction of 2-isopropyl-4-fluorobenzoic acid with thionyl chloride affords 2-isopropyl-4-fluorobenzoyl-chloride, which, on reaction with diethylamine, affords 2-isopropyl-4-fluoro-N,N-diethylbenzamide. Reaction of the latter with s-butyl lithium and reaction of the resulting lithium salt with sulfur dioxide followed by sodium hydroxylamine-O-sulfonate affords 2-isopropyl-4-fluoro-6-aminosulfonyl-N,N-diethylbenzamide, which, on heating in glacial acetic acid, affords 4-isopropyl-6-fluorosaccharin.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]([CH2:26][CH3:27])([CH2:24][CH3:25])[C:20]([NH:22][CH3:23])=[O:21]>>[CH2:24]([C:19]([NH:18][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:20](=[O:21])[NH:22][CH3:23])[CH2:26][CH3:27])[CH3:25]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: CCC(N)(CC)C(=O)NC
Product: CCC(CC)(NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 15, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g; 100 mg, 0.42 mmol) and 2-amino-2-ethyl-N-methyl-butyramide (78.2 mg, 0.64 mmol) as starting materials, and isolated (12 mg, 9.44%) as colorless sticky solid, LC-MS (UV peak area, ESI) 97.47%, 361.4 (M+H).
Reaction SMILES: Cl[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)[C:3]([CH3:6])([CH3:5])[CH3:4].[C:18](=[O:20])=[O:19]>>[C:3]([CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)[C:18]([OH:20])=[O:19])([CH3:6])([CH3:5])[CH3:4]
Reactant: O=C=O
Reactant: CC(C)(C)C(Cl)c1ccc(OC(F)(F)F)cc1
Product: CC(C)(C)C(C(=O)O)c1ccc(OC(F)(F)F)cc1

Procedure:
The neopentyl chloride prepared in Example 37 is converted to the Grignard reagent and subsequent carbonation with carbon dioxide according to the procedure of Weinstein and Morse [Journal of the American Chemical Society 74, 1133 (1952)] gives the desired acid as a white solid.