Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Br[C@H:4]1[C@H:9](O)[C:8]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:7]=2[O:6][CH2:5]1.[O:17]1CCCC1>>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:7]2[O:6][CH2:5][C:4](=[O:17])[CH2:9][C:8]=2[CH:11]=1
Reactant: COc1ccc2c(c1)[C@@H](O)[C@H](Br)CO2
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(c1)CC(=O)CO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2.0 g sodium hydride in 100 ml of dry tetrahydrofuran is added with stirring a solution of 20 g of trans-3-bromo-4-hydroxy-6-methoxy-3,4-dihydro-2H-[1]-benzopyran in 200 ml of dry tetrahydrofuran in a dropwise fashion. After 30 minutes stirring at room temperature, the reaction mixture is filtered through filter-cel and the solvent is removed in vacuo. The residue is dissolved in 100 ml of toluene, 1.0 g of anhydrous zinc iodide is added and the mixture is heated at 80° for 1 hour. The reaction mixture is filtered through 120 g of silica gel with methylene chloride as the eluent to afford a product which is recrystallized from ether to give 6-methoxy-2H-[1]-benzopyran-3-one, m.p. 67°-72°.
Reaction SMILES: [CH3:1][C:2]([C:4]#[CH:5])=[CH2:3].[Li]CCCC.[CH:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:3][C:2](=[CH2:1])[C:4]#[C:5][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:18]
Reactant: C#CC(=C)C
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Product: C=C(C)C#CC(O)c1ccccc1
Yield: 93.9 %

Procedure:
2-Methylbut-1-en-3-yne (3.45 g, 52.19 mmol), nBuLi (36.0 mL, 57.6 mmol) and benzaldehyde (6.642 g, 62.63 mmol) were used according to the general method mentioned above. Purification of the resulting clear yellow-brown crude product yielded the pure product as a clear yellow-brown oil (8.442 g, 49.02 mmol, 93.9%): Rf 0.72 (hexanes/Et2O, 4:1); 1H NMR (300 MHz, CDCl3) δ 7.49-7.69 (m, 2H, H-8), 7.30-7.49 (m, 3H, H-9, 10), 5.58 (d, J=6.2 Hz, 1H, H-1), 5.37 (bs, 1H, H-5), 5.28 (p, J=1.5 Hz, 1H, H-5), 2.43 (d; J=6.2 Hz, 1H, —OH), 1.93 (bs, 3H, H-10); 13C NMR (300 MHz, CDCl3) δ 140.6 (C-7), 128.6 (C-9), 128.3 (C-10), 126.6 (C-8), 126.1 (C-4), 126.6 (C-5), 87.8 (C-2/3), 87.7 (C-2/3), 64.9 (C-1), 23.3 (C-6); HRMS calcd for C12H12O (M+) 172.0888. found 172.0885.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:10][NH2:11])=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH:12](O)=O>>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]2[N:4]([CH:12]=[N:11][N:10]=2)[N:3]=1
Reactant: O=CO
Reactant: Cc1c(Cl)nnc(NN)c1C
Product: Cc1c(Cl)nn2cnnc2c1C

Procedure:
In a procedure similar to those of the preceding examples, 40 grams of 3-chloro-4,5-dimethyl-6-hydrazinopyridazine and 200 milliliters of aqueous 80 percent formic acid were heated at reflux for 90 minutes to obtain 6-chloro-7,8-dimethyl-s-triazolo[4,3-b]pyridazine. This triazolopyridazine (9.18 grams, 0.05 mole) was mixed with 12.25 grams N-methylpiperazine in 80 milliliters of ethanol, and the mixture was heated at reflux for 3 hours. The product was recovered by evaporation, partitioning the oily residue between methylene chloride and water and evaporation of the organic layer. The resulting 6-(N-methylpiperazino)-7,8-dimethyl-s-triazolo[4,3-b]pyridazine was obtained as colorless crystals. Thin layer chromatography on silica gel developed with 90 percent chloroform: 10 percent methanol indicated the presence of triazolopyridazine intermediate in the product. The product was taken up in excess N-methylpiperazine and heated at reflux for 12 hours, followed by 2 hours of reflux in 20 milliliters of N-methylpiperazine. The resulting 6-(N-methylpiperazino)-7,8-dimethyl-s-triazolo[4,3-b]pyridazine was obtained as colorless crystals. Thin layer chromatography on silica gel developed with 90 percent chloroform: 10 percent methanol indicated the presence of triazolopyridazine intermediate in the product. The product was taken up in excess N-methylpiperazine and heated at reflux for 12 hours, followed by 2 hours of reflux in 20 milliliters of N-methylpiperazine. The resulting 6-(N-methylpiperazino)-7,8-dimethyl-s-triazolo[4,3-b]pyridazine was separated as before, crystallized from benzene-hexane and found to melt at 170°-172° C. (Calculated: C, 58.51; H, 7.37; N, 34.12. Found: C, 58.70; H, 7.27; N, 34.18.)
Reaction SMILES: [F:1][C@H:2]1[C@@H:6]([O:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[C:15]([C:18]2[N:22]4[CH:23]=[CH:24][C:25]([C:27]5[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=5)=[CH:26][C:21]4=[N:20][CH:19]=2)[CH:14]=[CH:13]3)[CH2:5][N:4](C(OCC2C=CC3C(=CC=CC=3)C=2)=O)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C@H:2]1[CH2:3][NH:4][CH2:5][C@H:6]1[O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([C:18]1[N:22]3[CH:23]=[CH:24][C:25]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:26][C:21]3=[N:20][CH:19]=1)[CH:14]=[CH:13]2
Reactant: O=C(OCc1ccc2ccccc2c1)N1C[C@@H](F)[C@@H](Oc2cccc3ccc(-c4cnc5cc(-c6cccnc6)ccn45)nc23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: F[C@H]1CNC[C@H]1Oc1cccc2ccc(-c3cnc4cc(-c5cccnc5)ccn34)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
A solution of cis-naphthalen-2-ylmethyl 3-fluoro-4-(2-(7-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)quinolin-8-yloxy)pyrrolidine-1-carboxylate (2.0 mg, 0.003 mmol) in 1 ml DCM was cooled to 0° C. and 1 ml TFA was added. The mixture was stirred for 16 hours at ambient temperature and then concentrated. The residue was purified by preparative TLC, eluting with 15% MeOH/0.5% NE4OH in chloroform to give the title compound as a film (1.1 mg, 78% yield). MS APCI (+) m/z 426.2 (M+1) detected.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([CH2:16][C:17]#[N:18])=[CH:5][CH:4]=1.[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21]>C(#N)C.C(OCC)(=O)C>[CH3:24][O:23][C:19](=[O:22])[CH2:20][CH2:21][C:16]([C:17]#[N:18])([C:6]1[C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:21][CH2:20][C:19]([O:23][CH3:24])=[O:22]
Reactant: COc1ccc(CC#N)c2c1oc1ccccc12
Reactant: C=CC(=O)OC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC)c2oc3ccccc3c12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of (4-methoxy-dibenzofuran-1-yl)-acetonitrile (7 g, 0.029 mol) in acetonitrile (200 ml), Triton B (2.7 ml, 0.0147 mol) was added under N2 at RT. The reaction mass was heated to reflux and at reflux temperature methyl acrylate (28.25 ml, 0.295 mol) was added drop wise. The reaction mass was stirred for 4 hrs at 90° C. Once the product is formed, the reaction mass was diluted with ethyl acetate and concentrated under vacuum. 4-cyano-4-(4-methoxy-dibenzofuran-1-yl)-heptane dioic acid dimethyl ester was isolated by column chromatography. Yield 8 g (65%)
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:9][CH2:8][CH:7](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:6]1)[CH2:2][CH2:3][CH3:4].[C-:21]#[N:22].[Na+].CS(C)=O>O>[CH2:1]([C@H:5]1[CH2:9][CH2:8][CH:7]([C:21]#[N:22])[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1CCC(OS(=O)(=O)c2ccc(C)cc2)C1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCC[C@H]1CCC(C#N)C1
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
A mixture of 190 mg of (1S,3RS)-1-butyl-3-(p-toluene-sulphonyloxy)cyclopentane (prepared in Reference Example 12), 150 mg of sodium cyanide and 1.5 ml of anhydrous dimethyl sulphoxide was stirred for 30 mins. at 50° C. After diluting with 3 ml of water, the mixture was extracted with 10 ml of a mixture of pentane and diethyl ether (1:1). The extract was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulphate, and concentrated under ambient pressure at 50° C. The residue was purified by column chromatography on silica gel using a mixture of hexane and ethyl acetate (1:3) as eluent to give 73 mg of the title compound having the following physical characteristics.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:6]([CH:9]=1)[CH2:7][NH2:8].[O:30]=[C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33](=[O:40])[N:32]1[CH2:41][CH2:42][S:43](Cl)(=[O:45])=[O:44].C(N(CC)CC)C>C(Cl)Cl.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:6]([CH:9]=1)[CH2:7][NH:8][S:43]([CH2:42][CH2:41][N:32]1[C:31](=[O:30])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]1=[O:40])(=[O:44])=[O:45]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CN
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CNS(=O)(=O)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
To a solution of (2R,5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzyl amine (0.060 g, 0.143 mmol) in methylene chloride (3 mL) was added 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (0.043 g, 0.150 mmol) and triethylamine (0.060 mL, 0.43 mmol) and the solution was stirred 1 hr at ambient temperature. The reaction was diluted with saturated aqueous sodium hydrogen carbonate and extracted with methylene chloride. The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.073 g, 77%).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[CH3:8])([O-:11])=[O:10]
Reactant: Oc1ccccc1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.2 %

Procedure:
A mixture of 5-fluoro-2-nitrotoluene (9.8 g), phenol (11.89 g), potassium carbonate (12.22 g) and copper bronze (1.0 g) was boiled for 16 hours. After cooling to room temperature the mixture was extracted with boiling diethyl ether (2×500 ml) and the combined organic phases washed with aqueous 1N sodium hydroxide (6×100 ml) and water (3×100 ml). After drying (MgSO4), solvent was removed at reduced pressure and the residue column chromatographed (silica gel, hexane→5% diethyl ether/hexane eluant) to give 2-nitro-5-phenoxytoluene (2.06 g) as an oil.
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[C:9]([NH:10][C:11]([CH:13]2[CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:7]=[C:6]([F:16])[C:5]=1[CH2:17]Br.CCN(CC)CC.[CH2:27]([O:29][C:30]1[CH:31]=[C:32]([C@H:38]([NH2:44])[CH2:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH3:28]>CN(C=O)C>[CH2:27]([O:29][C:30]1[CH:31]=[C:32]([C@H:38]([N:44]2[C:3](=[O:19])[C:4]3[C:5](=[C:6]([F:16])[CH:7]=[CH:8][C:9]=3[NH:10][C:11]([CH:13]3[CH2:14][CH2:15]3)=[O:12])[CH2:17]2)[CH2:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH3:28]
Reactant: COC(=O)c1c(NC(=O)C2CC2)ccc(F)c1CBr
Reactant: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3c(F)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 90 °C
Yield: 54.4 %

Procedure:
To a solution of 2-bromomethyl-6-(cyclopropanecarbonyl-amino)-3-fluoro-benzoic acid methyl ester (1 g, 3 mmol) and Et3N (1.25 ml, 9 mmol) in DMF (10 ml) was added (1S)-1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (870 mg, 3.2 mmol). The mixture was heated at 90° C. for 20 hrs. The reaction mixture was cooled to room temperature and extracted with water (50 ml) and EtOAc (50 ml). The organic layer was washed with water (50 ml), brine (25 ml), dried over Na2SO4 and concentrated. The resulted oil was purified by chromatography to give (1S)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-7-fluoro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (800 mg, 55% yield): mp, 176–178° C.; 1H NMR (CDCl3) δ 0.88–0.92 (m, 2H, c-propylCH2), 1.09–1.12 (m, 2H, c-propylCH2), 1.47 (t, J=7.0 Hz, 3H, OCH2CH3), 1.64–1.68 (m, 1H, c-propylCH), 2.98 (s, 3H, CH3), 3.63–3.73 (m, 1H, CHHSO2), 3.87 (s, 3H, CH3), 4.05–4.28 (m, 4H, CHHSO2+CNHH+OCH2CH3), 4.49 (d, J=18 Hz, 1H, CHHN), 6.85–6.92 (m, 1H, NCH), 6.86–6.93 (m, 3H, Ar), 7.04 (t, J=8 Hz, 1H, Ar), 8.45–8.55 (m, 1H, Ar), 10.32 (s, 1H, NHCO); 13C NMR (CDCl3) δ 8.26, 8.27, 14.67, 16.04, 41.50, 44.67, 51.30, 55.39, 55.96, 64.65, 111.63, 112.21, 118.95, 119.26, 119.68, 119.92, 126.43, 126.74, 128.99, 134.48, 134.53, 148.98, 149.88, 150.31, 154.22, 168.89, 172.39. Anal Calcd for C24H27FN2O6S: C, 58.76; H, 5.55; N, 5.71. Found: C, 58.60; H, 5.33; N, 5.65.
Reaction SMILES: [OH:1][NH:2]/[C:3](=[N:14]\[H])/[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.[O:16]=[C:17]1[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][N:18]1[CH2:29][C:30](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[C:23]1([CH:22]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:29][C:30]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=4)[N:14]=3)[C:17]2=[O:16])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Reactant: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C1C(c2ccccc2)CCCN1Cc1nc(-c2ccc(C(F)(F)F)cc2)no1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A solution of (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide (0.142 g, 0.698 mmol), 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (0.148 g, 0.634 mmol; Example 91D) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.158 g, 0.825 mmol) were stirred together in dichloroethane (0.5 mL) at room temperature for 2 hours. The reaction was then heated to 85° C. and stirred overnight. The reaction was cooled, loaded onto a SF15-12 column (Analogix®) and the product eluted using a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate over 25 minutes (Flow=30 mL/minute). The residue was dissolved in ethyl acetate and concentrated to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J=8.2, 2H), 7.77 (d, J=8.3, 2H), 7.42-7.15 (m, 5H), 5.19 (d, J=16.7, 1H), 4.73 (d, J=16.7, 1H), 3.84-3.76 (m, 1H), 3.70 (ddd, J=5.3, 7.6, 12.7, 1H), 3.59 (dt, J=5.5, 11.2, 1H), 2.43-2.18 (m, 1H), 2.18-1.82 (m, 3H); MS (ESI+) m/z 402.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([O:20]CC)=[O:19])=[C:5]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:29]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30]>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:36]3[CH:37]=[CH:38][C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:34][CH:35]=3)=[CH:10][CH:9]=2)[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]1[C:18]([OH:20])=[O:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1Cc1ccccc1
Product: CC(C)(C)c1ccc(Nc2ccc3c(c2)c(-c2ccccc2)c(C(=O)O)n3Cc2ccccc2)cc1

Procedure:
The title compound was prepared from ethyl 5-amino-1-benzyl-3-phenyl-1H-indole-2-carboxylate and 4-tert-butylbenzeneboronic acid according to the procedure of Example 1 Step 3 as a pale green solid: 1H NMR (DMSO-d6) δ 1.22 (s, 9 H), 5.81 (s, 2 H), 6.87 (d, J=6.7 Hz, 2 H), 7.10-7.50 (m, 15 H), 12.85 (br s, 1 H); MS (ESI) m/z 475 (MH+); MS (ESI) m/z 473 ([M-H]−); Anal. calcd. for C32H30N2O2.0.5H2O: C, 79.78; H, 6.46; N, 6.02. Found: C, 79.42; H, 6.28; N, 6.01.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[C:21]([S:23][CH3:24])[N:20]=[C:19]([C:25](O)=[O:26])[CH:18]=3)[CH2:13][CH2:12]2)=[O:9])[NH:5][C:6]=1[CH3:7].[NH3:28]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[C:21]([S:23][CH3:24])[N:20]=[C:19]([C:25]([NH2:28])=[O:26])[CH:18]=3)[CH2:13][CH2:12]2)=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: N
Reactant: CSc1nc(C(=O)O)cc(N2CCC(NC(=O)c3cc(Br)c(C)[nH]3)CC2)n1
Solvent: CO
Product: CSc1nc(C(N)=O)cc(N2CCC(NC(=O)c3cc(Br)c(C)[nH]3)CC2)n1

Procedure:
Title compound was synthesized by an analogous method to Example 8 by coupling 6-(4-{[(4-bromo-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-(methylthio) pyrimidine-4-carboxylic acid (Example 35) with 2 M ammonia in MeOH (commercially available).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14]CC)=[O:13])[CH:10]=2)[NH:5][CH:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][S:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:3]1.O.[OH-].[Li+].[OH-].[Na+]>C(O)C.O>[CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[NH:5][CH:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][S:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:3]1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1ccccc1NS(=O)(=O)c1cccnc1)N2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2cccnc2)Nc2ccc(C(=O)O)cc21
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 4,4-dimethyl-2-(2-(pyridine-3-sulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (crude 0.62 mmol) in ethanol was added a solution of lithium hydroxide monohydrate (129 mg, 3.08 mmol) and sodium hydroxide (50 mg, 1.23 mmol) in water (1.5 mL) at room temperature. The reaction mixture was stirred at 85° C. overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water, adjusted pH=3˜4 by 1M aqueous hydrochloric acid, extracted with ethyl acetate. The combined organic layer was washed by brine, dried over anhydrous Sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give 4,4-dimethyl-2-[2-(pyridine-3-sulfonylamino)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid. LC/MS m/e obsd. (ESI+) [(M+H)+] 438.20.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][NH2:8])[C:4]([OH:6])=[O:5].[C:9]1([C:15]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>CO>[C:9]1([C:15]2[N:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[N:2][C:17]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCC(N)C(=O)O
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 25 °C

Procedure:
The monohydrochloride of 2,3-diaminopropionic acid (500 mg, 3.56 mmol) and benzil (890 mg, 4.23 mmol) were added to a solution of sodium hydroxide (677 mg, 16.93 mmol) in methanol (10 ml). An extra portion of methanol was added (5 ml) and the reaction mixture was refluxed for 20 minutes. The mixture was cooled to 25° C. and air was bubbled through for 30 minutes. Hydrochloric acid (aq, 2 M) was added until the reaction mixture reached pH 2. The solution was extracted with diethyl ether. The combined diethyl ether phases were dried (MgSO4), filtrated and evaporated under reduced pressure to give the crude product. MS m/z 277 (M+H)+. The crude product was used in steps described below without further purification.
Reaction SMILES: [CH2:1](/[C:3](=[CH:9]/O)/[C:4](OCC)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[C:17](=[NH:40])([O:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=2)=[CH:24][CH:23]=1)[NH2:18]>CN1C(=O)CCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][C:25]2[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][O:19][C:17]3[NH:18][CH:9]=[C:3]([CH2:1][CH3:2])[C:4](=[O:5])[N:40]=3)=[CH:27][CH:26]=2)=[CH:30][C:31]=1[C:36]([F:39])([F:38])[F:37]
Reactant: CCOC(=O)/C(=C\O)CC
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCc1c[nH]c(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Temperature: 160 °C
Yield: 38.5 %

Procedure:
To the suspension of ethyl (2Z)-2-ethyl-3-hydroxy-2-propenoate (281 mg, 1.951 mmol) and K2CO3 (270 mg, 1.951 mmol) in NMP (10 mL) was added 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl imidocarbamate (350 mg, 0.976 mmol). The reaction mixture was heated with a microwave reactor at 160° C. for 1.5 h. Purification via MDAP then afforded the title compound (165 mg, 38.5% yield). LCMS: rt=3.89 min, [M+H+]=439
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[N:3]=[CH:2]1.[CH3:10][N:11]=[C:12]=[S:13]>C(O)C>[CH3:10][NH:11][C:12]([N:6]1[CH2:7][CH2:8][C:9]2[NH:1][CH:2]=[N:3][C:4]=2[CH2:5]1)=[S:13]
Reactant: c1nc2c([nH]1)CCNC2
Reactant: CN=C=S
Solvent: CCO
Product: CNC(=S)N1CCc2[nH]cnc2C1

Procedure:
A solution of 1 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (Farmaco, Ed. Sci., 1967, 22, 821) and 0.65 g of methyl isothiocyanate in 20 ml of ethanol are refluxed for 8 h. The solution is cooled and filtered: 1.15 g of 5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine, m.p. 228°, are collected.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[O:8]C)(=[O:3])[CH3:2].[C:13](Cl)(=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:10]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:7]([OH:8])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1cccc(NC(C)=O)c1
Reactant: CCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC(=O)c1ccc(NC(C)=O)cc1O
Temperature: 0 °C

Procedure:
The mixture consisting of 49.5 g of N-acetyl-m-anisidine, 72.3 cc of valeric acid chloride and 200 cc of methylene chloride is cooled to 0° C. 120 g of aluminum chloride are added little by little. The reaction mixture is refluxed for 2 hours with stirring, cooled, then poured in ice water. The resulting oily product is extracted with chloroform. The chloroform phase in turn is extracted with 2N sodium hydroxide solution which is then acidified. Thus, 24 g of 5-acetamido-2-valeryl phenol (MP 113° C.) are obtained.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10](=[O:21])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1)(=O)[CH3:2].FC(F)(F)C(O)=O>C(Cl)(Cl)(Cl)Cl>[CH3:20][O:19][C:13]1[CH:14]=[C:15]([O:17][CH3:18])[C:16]2[C:1]([CH3:2])=[C:4]3[N:5]([C:10](=[O:21])[C:11]=2[CH:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9]3
Reactant: COc1cc(OC)cc(C(=O)N2CCCCC2C(C)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(OC)c2c(C)c3n(c(=O)c2c1)CCCC3
Temperature: 25 °C

Procedure:
Reflux a solution of 2-acetyl-1-[3,5-bis(methoxy)benzoyl]piperidine (4.62 g), trifluoroacetic acid (3 ml), and carbon tetrachloride (97 ml) for 20 hours under nitrogen. Cool the solution to 25° C., and sequentially wash it with water, 1M sodium bicarbonate solution, and with water. Concentrate the dried, filtered organic solution, and cool it to induce crystallization. Recrystallize the resulting solid to obtain 8,10-bis(methoxy)-1,2,3,4-tetrahydro-11-methyl-6H-benzo[b]quinolizin-6-one, m.p. 165°-168° C. (from EtOAc).