Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:20][C:21]([NH:23][C@H:24]([C:28]([OH:30])=O)[CH:25]([CH3:27])[CH3:26])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:46][CH2:47][CH2:48][S:49]([OH:52])(=[O:51])=[O:50]>>[C:1]([O:18][CH:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:20][C:21]([NH:23][C@H:24]([C:28]([NH:46][CH2:47][CH2:48][S:49]([OH:52])(=[O:51])=[O:50])=[O:30])[CH:25]([CH3:26])[CH3:27])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NCCS(=O)(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)O)C(C)C
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)NCCS(=O)(=O)O)C(C)C
Yield: 26.8 %

Procedure:
Starting from N-(3-hexadecanoyloxyoctadecanoyl)-L-valine (1.28 g) and taurine (1 g), N-[N-(3-hexadecanoyloxyoctadecanoyl)-L-valyl]taurine (400 mg) was obtained as powder according to a similar manner to that of Example 32.
Reaction SMILES: O[Li].O.[CH:4]([C:6]1[C:11]2[CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[O:14][C:10]=2[CH:9]=[CH:8][C:7]=1[OH:20])=[O:5]>O.C1COCC1>[CH:4]([C:6]1[C:11]2[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[O:14][C:10]=2[CH:9]=[CH:8][C:7]=1[OH:20])=[O:5]
Reactant: CCOC(=O)c1cc2c(C=O)c(O)ccc2o1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1c(O)ccc2oc(C(=O)O)cc12
Temperature: 50 °C
Yield: 99.4 %

Procedure:
The solution of LiOH—H2O (1.26 g, 60 mmol) in H2O (15 mL) was added dropwise to the solution of ethyl 4-formyl-5-hydroxybenzofuran-2-carboxylate (4.6 g, 20 mmol) in THF (40 mL). The reaction mixture was heated to 50° C. for 2 h. After cooled to RT, the reaction mixture was concentrated, then acidified with 3 M HCl to pH=2. The formed precipitate was filtered and washed with water, dried to give 4-formyl-5-hydroxybenzofuran-2-carboxylic acid (4.1 g. 87.8% yield). 1HNMR (DMSO, 400 MHz): δ 10.91 (s, 1H, OH), 10.47 (s, 1H, CHO); 7.92 (d, 1H, J=0.8 Hz, ArH), 70.87 (dd, 1H, J=9.2 Hz, 0.8 Hz, ArH), 7.13 (d, 1H, J=9.2 Hz, ArH); MS [ESI, MH+]: 207.1.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]([NH:9][CH:10]=[C:11]2[C:16](=[O:17])OC(C)(C)OC2=O)=[CH:7][C:6]=1[O:23][CH3:24])(=[O:3])[CH3:2].CCOCC>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[C:1]([O:4][C:5]1[CH:22]=[C:21]2[C:8](=[CH:7][C:6]=1[O:23][CH3:24])[NH:9][CH:10]=[CH:11][C:16]2=[O:17])(=[O:3])[CH3:2]
Reactant: COc1cc(NC=C2C(=O)OC(C)(C)OC2=O)ccc1OC(C)=O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cc2[nH]ccc(=O)c2cc1OC(C)=O
Temperature: 195 °C

Procedure:
A suspension of 5-((4-acetoxy-3-methoxyanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (11.5 g) in DOWTHERM A, (trade mark of Fluka Chemie AG), (125 ml) was heated at 195° C. for 30 minutes. After cooling, ether was added (100 ml) and the precipitate was collected by filtration. The solid was washed with ether and dried under vacuum to give 6-acetoxy-7-methoxy-1,4-dihydroquinolin-4-one which was used without further purification for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([OH:7])=O.[NH2:20][CH2:21][CH2:22][CH2:23][OH:24]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])=[O:7]
Reactant: NCCCO
Reactant: O=C(O)c1cc(Br)ncc1Nc1ccc(I)cc1F
Product: O=C(NCCCO)c1cc(Br)ncc1Nc1ccc(I)cc1F

Procedure:
2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-N-(3-hydroxy-propyl)-isonicotinamide was synthesized according to General method 3, starting with 145 mg (0.33 mmol) of 2-bromo-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid and 62 mg (0.82 mmol) of 3-Amino-propan-1-ol. LC/MS: [9.15 min, 494, 496]
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=4)=[CH:10]3)[C:6]=2[CH:22]=1.[CH:23]([N:26]1[CH2:31][CH2:30][CH:29]([SH:32])[CH2:28][CH2:27]1)([CH3:25])[CH3:24].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:23]([N:26]1[CH2:31][CH2:30][CH:29]([S:32][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[C:7](=[N:8][C:9]([C:15]5[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=5)=[CH:10]4)[C:6]=3[CH:22]=2)[CH2:28][CH2:27]1)([CH3:25])[CH3:24]
Reactant: CC(C)N1CCC(S)CC1
Reactant: Cc1cccnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1cccnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)C)CC3)ccc1OCC2
Temperature: 120 °C
Yield: 53.7 %

Procedure:
A mixture of 9-bromo-2-(3-methylpyridin-2-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (107 mg, 0.30 mmol), 1-isopropylpiperidine-4-thiol (72 mg, 0.45 mmol), Pd2(dba)3 (14 mg, 0.015 mmol, 5 mol %), XantPhos (17 mg, 0.030 mmol, 10 mol %) and DIPEA (210 μl, 1.20 mmol) in dioxane (4 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. The reaction mixture was diluted with DCM (75 mL) and purified by column chromatography (Si-PCC, gradient 0-10% 2M NH3/MeOH in DCM followed by C18, gradient 5-45% MeOH in 0.5% TFA/H2O). The product containing fractions were combined and concentrated in vacuo and the resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The basic fractions were concentrated under reduced pressure affording 9-(1-Isopropylpiperidin-4-ylsulfanyl)-2-(3-methylpyridin-2-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene as a colorless gum (70 mg, 54%). LCMS: RT1.83 min [M+H]+ 435.1
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10](=O)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:10]1[N:9]=[N:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][C:11]=1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]nc(-c2ccccc2)nc1Cc1ccccc1
Solvent: O
Product: Clc1nnc(-c2ccccc2)nc1Cc1ccccc1

Procedure:
Heat a solution of 15 mmol (4 g) of 3-phenyl-5-benzyl-1,2,4-triazin-6-one obtained in Step C of Example 28 in 30 ml of phosphorus oxychloride to a temperature of 80° C. After cooling, pour into iced water, render alkaline and extract with ethyl acetate. Dry the organic phase, filter, evaporate to dryness and purify by chromatography on silica (eluant ethyl acetate/hexane: 27/75)
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9](C(=O)C)[CH2:10][CH2:11][N:12]=2)=[C:6](Cl)[N:5]([NH2:17])[CH:4]([CH3:18])[N:3]=1.[Na].[CH2:20]([OH:22])[CH3:21]>>[Cl:1][C:2]1[C:7]([C:8]2[NH:9][CH2:10][CH2:11][N:12]=2)=[C:6]([O:22][CH2:20][CH3:21])[N:5]([NH2:17])[CH:4]([CH3:18])[N:3]=1
Reactant: CCO
Reactant: CC(=O)N1CCN=C1C1=C(Cl)N(N)C(C)N=C1Cl
Agent: [Na]
Product: CCOC1=C(C2=NCCN2)C(Cl)=NC(C)N1N

Procedure:
3.0 g 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine are introduced at room temperature into a solution of 0.5 g sodium in 10 ml ethanol. Subsequently, the solution is heated for 30 minutes to 75° C., filtered, the filtrate is concentrated, the residue is placed in ice water, and the crystals are vacuum dried. After recrystallization from nitromethane, 1.2 g (45%) of 4-chloro-6-ethoxy-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine, melting point 221° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:26]([NH:25][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:27])=[CH:7][CH:6]=3)=[C:9]([CH3:18])[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1sc2ncnc(N)c2c1-c1ccc(N)cc1
Solvent: ClCCl
Product: Cc1sc2ncnc(N)c2c1-c1ccc(NC(=O)Nc2ccccc2)cc1
Reaction time: 8 h
Yield: 91.4 %

Procedure:
A 0° C. solution of Example 1E (80 mg, 0.3 mmol) in dichloromethane (4 mL) was treated with phenyl isocyanate (0.037 mL, 0.34 mmol), stirred overnight, and filtered. The filter cake was dried to provide 0.103 g (87%) of the desired product. MS (CI) m/e 376 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.89 (s, 1H); 8.75 (s, 1H); 8.26 (s, 1H); 7.63 (d, J=8.7 Hz, 2H); 7.47 (d, J=8.7 Hz, 2H); 7.33-7.26 (m, 4H); 6.99 (t, J=7.5 Hz, 1H); 2.30 (s, 3H); Anal. Calcd. for C20H17N5OS.0.1CH2Cl2: C, 62.88; H, 4.52; N, 18.24. Found: C, 62.85; H, 4.64; N, 18.15.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:13]=[N:12][C:11]([Cl:14])=[C:10]2[NH:15][CH:16]=[C:17]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:9]=12.Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CN(C=O)C>[Br:7][C:8]1[CH:13]=[N:12][C:11]([Cl:14])=[C:10]2[N:15]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:16]=[C:17]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:9]=12
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)Cc1c[nH]c2c(Cl)ncc(Br)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(CC(=O)OC(C)(C)C)c2c(Cl)ncc(Br)c12
Reaction time: 0.5 h

Procedure:
Cesium carbonate (185 mg, 0.568 mmol) was added to a solution of methyl (4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridin-3-yl)acetate from Step C (115 mg, 0.379 mmol) and tert-butyl bromoacetate (0.0810 mL, 0.417 mmol) in DMF (2 mL). After 30 min, the mixture was partitioned between H2O (5 mL) and EtOAc (10 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=419 (M+1).
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[CH:10]=[N:9]1)(OC(C)(C)C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:28]([C:32]1[CH:37]=[CH:36][C:35]([C:38]2[O:39][C:40](=[O:47])[C:41]3[S:46][CH:45]=[CH:44][C:42]=3[N:43]=2)=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:28]([C:32]1[CH:37]=[CH:36][C:35]([C:38]([NH:43][C:42]2[CH:44]=[CH:45][S:46][C:41]=2[C:40]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[N:9][NH:8]3)=[CH:12][CH:13]=2)=[O:47])=[O:39])=[CH:34][CH:33]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1ccc(-c2nc3ccsc3c(=O)o2)cc1
Reactant: CC(C)(C)OC(=O)n1ncc2ccc(N)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccsc2C(=O)Nc2ccc3cn[nH]c3c2)cc1
Reaction time: 0.25 h
Yield: 18.9 %

Procedure:
To a stirring solution of 1-Boc-6-aminoindazole (100 mg, 0.43 mmol) in tetrahydrofuran (2 mL) at 0 ° C. was added a solution of potassium bis(trimethylsilyl)amide (180 mg, 0.90 mmol) in tetrahydrofuran (2 mL). After 15 min, this solution was transferred via syringe to a stirring solution of 2-(4-t-butylphenyl)-4-oxo-4H-thieno[3,2-d][1,3]oxazine (122 mg, 0.43 mmol) in tetrahydrofuran (2 mL). After 45 min, saturated ammonium chloride was added, the mixture was diluted with ethyl acetate, and the phases were separated. The aqueous phase was extracted 3 times with ethyl acetate. The combined ethyl acetate extracts were then washed once with brine, dried over magnesium sulfate, filtered, and the solvent removed in vacuo. The crude product was purified by column chromatography over silica gel using an eluent of 40% ethyl acetate in hexane and 50% ethyl acetate in hexane to afford the product (34 mg, 15%).
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([C:13]([OH:15])=O)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][NH2:31])=[C:25]([CH3:32])[N:24]=1)([CH3:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][NH:31][C:13]([C:11]2[O:12][C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][N:10]=2)=[O:15])=[C:25]([CH3:32])[N:24]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(O)c1ncc(Cc2ccccc2)o1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1ncc(Cc2ccccc2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-Benzyl-oxazole-2-carboxylic acid (0.86 g, 2.8 mmol), (5-Aminomethyl-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (0.70 g, 2.8 mmol), HATU (1.4 g, 3.6 mmol) and DIPEA (2.0 mL, 11.7 mmol) in 10 mL DMF was stirred at room temperature for 16 h. The mixture was evaporated and the residue was partitioned between ethyl acetate and 1 N aq. HCl. The organic layer was dried over MgSO4 and evaporated in vacuo. The crude product was purified by preparative HPLC (Waters Sunfire Prep C18 PBD 5 um, 30×100 mm, 5 to 100% ACN and 0.1% TFA, flow 40 ml/min). LCMS (method A) RtA=1.719 min; [M+H]+=437.0
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[K+]>C(O)C>[OH:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)CC(O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC(O)c1ccccc1

Procedure:
Ethyl 3-hydroxy-3-phenylpropanoate (19 g, 0.1 mole) was refluxed in a solution of KOH (10 g, 0.2 mole) in ethanol for two hours. The solvent was removed in vacuo and the residue was dissolved in H2O. The H2O solution was extracted with ethyl ether, then acidified with 37% hydrochloric acid. The oily product was extracted out with chloroform and the chloroform was removed in vacuo to yield 10 g (62.5%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:24])[N:7]=1)=[O:5])[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH2:32][CH3:33])[CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH2:32][CH3:33])[CH:30]=3)[C:14]=2[CH3:24])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCCn1cc(Br)cn1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)n1
Product: CCCn1cc(-n2c(C)c(Sc3cccc(C(=O)OCC)n3)c3ccc(Cl)c(F)c32)cn1

Procedure:
Prepared according to the procedure described in Example 9, Step 4, using the following starting materials: 6-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-pyridine-2-carboxylic acid ethyl ester and 4-bromo-1-propyl-1H-pyrazole.
Reaction SMILES: C(C(CCCC=C)(C(O)=O)C(O)=O)CCC=C.C(OCC)(=O)CC(OCC)=O.[H-].[Na+].BrCCCCC=C.[CH2:38]([C:44]([CH2:51][CH2:52][CH2:53][CH2:54][CH:55]=[CH2:56])(C(O)=O)[C:45]([OH:47])=[O:46])[CH2:39][CH2:40][CH2:41][CH:42]=[CH2:43]>C1COCC1>[CH2:51]([CH:44]([CH2:38][CH2:39][CH2:40][CH2:41][CH:42]=[CH2:43])[C:45]([OH:47])=[O:46])[CH2:52][CH2:53][CH2:54][CH:55]=[CH2:56]
Reactant: C=CCCCCC(CCCCC=C)(C(=O)O)C(=O)O
Agent: C=CCCCC(CCCC=C)(C(=O)O)C(=O)O
Agent: C=CCCCCBr
Agent: [H-]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: C1CCOC1
Product: C=CCCCCC(CCCCC=C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
Using a procedure identical to that described in Example 58 for the synthesis of di(4-pentenyl)malonic acid, diethyl malonate (25 g, 156 mmol) was dissolved in 150 mL dry THF in a 3 necked round bottom flask, and was reacted with NaH (18.74 g of 60% dispersion in mineral oil, 469 mmol, 3.0 eq.) and 6-bromo-1-hexene (63.6 g, 390 mmol, 2.5 eq.) and saponified/neutralized. The resultant yellow-brown oil, 2,2-di-(5-hexenyl)malonic acid, was placed in an oversized round-bottomed flask equipped with a reflux condenser, and heated with vigorous magnetic stirring to 200–210° C. using an oil bath. Gas evolution was observed upon reflux. After a 1 hour period, decarboxylation (evidenced by vigorous frothing) was complete. The mixture was cooled to room temperature and fractionally distilled at 115–118° C./0.1 torr, then further purified by flash chromatography using 15% ethyl acetate:hexanes as mobile phase to give 2-(5-hexenyl)-7-octenoic acid (9.5 g, 13.6%). 1H NMR (CDCl3): δ 11.2–12.2 (br, 1H), 5.6–6.0 (m, 2H), 4.8–5.0 (m, 4H), 2.2–2.4 (m, H), 1.9–2.1 (m, 4H), 1.8–1.9 (m, 2H), 1.2–1.8 (m, 10H) ppm.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[N:16]1([C:21]2[CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=[CH:23][N:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:25]2[CH:24]=[CH:23][N:22]=[C:21]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[CH:26]=2)[C:11]=1[CH3:12]
Reactant: CC1(C)OB(c2ccnc(N3CCCC3)c2)OC1(C)C
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccnc(N3CCCC3)c2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.5 g, 2.0 mmol), 2-(pyrrolidin-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.608 g, 2.22 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.0 mmol) in toluene (4.0 mL) at 100° C. for 18 h to give 4-chloro-5,7-difluoro-3-methyl-2-(2-(pyrrolidin-1-yl)pyridin-4-yl)quinoline as a yellow solid. Mass Spectrum (ESI) m/e=360.0 (M+1).
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][NH:12][S:13]([C:16]3[CH:36]=[CH:35][C:19]4[O:20]C(C5C=CC=CC=5)(C5C=CC=CC=5)[O:22][C:18]=4[CH:17]=3)(=[O:15])=[O:14])[N:10]=[C:6]2[N:5]=[C:4]([CH3:37])[CH:3]=1.CC(O[CH2:42][C:43]1[CH2:52][S:51][C@@H:46]2[C@H:47]([NH2:50])[C:48](=[O:49])[N:45]2[C:44]=1[C:53]([OH:55])=[O:54])=O.B(F)(F)F>C(#N)C>[NH2:50][C@@H:47]1[C:48](=[O:49])[N:45]2[C@@H:46]1[S:51][CH2:52][C:43]([CH2:42][S:1][C:2]1[N:7]3[N:8]=[C:9]([CH2:11][NH:12][S:13]([C:16]4[CH:36]=[CH:35][C:19]([OH:20])=[C:18]([OH:22])[CH:17]=4)(=[O:14])=[O:15])[N:10]=[C:6]3[N:5]=[C:4]([CH3:37])[CH:3]=1)=[C:44]2[C:53]([OH:55])=[O:54]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1cc(S)n2nc(CNS(=O)(=O)c3ccc4c(c3)OC(c3ccccc3)(c3ccccc3)O4)nc2n1
Agent: FB(F)F
Solvent: CC#N
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)n2nc(CNS(=O)(=O)c3ccc(O)c(O)c3)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
N-[[7-Mercapto-5-methyl-s-triazolo[1,5-a]pyrimidin-2-yl]methyl]-2,2-diphenyl-1,3-benzodioxol-5-sulphonamide (0.27 g) and 0.14 g of 7-aminocephalosporanic acid are stirred at room temperature for 4 hours with 3.0 ml of a 20% solution of boron trifluoride in acetonitrile. After the addition of 5 ml of ice-water the reaction mixture is partitioned between water and ethyl acetate. The pH value is adjusted to 7.0 with 3N aqueous sodium hydroxide solution. The phases are separated. The aqueous phase is adjusted to pH 2.0 with concentrated aqueous hydrochloric acid. The precipitate formed is filtered off. The still moist precipitate is dissolved in trifluoroacetic acid and stirred at room temperature for 2 hours. The trifluoroacetic acid is evaporated in a water-jet vacuum and the residue is treated with ethyl acetate. The precipitate is filtered off and dried under a high vacuum. There is obtained 0.2 g of (6R,7R)-7-amino-3-[[[2-[(3,4-dihydroxybenzenesulphonamido)methyl]-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a pale beige powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([CH3:16])[N:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:8][C:9]1[N:10]=[C:11]([CH3:16])[N:12]=[C:13]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1
Reactant: Nc1ccccc1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1nc(Cl)cc(Nc2ccccc2)n1

Procedure:
To a solution of Aniline (205 mg, 2.2 mmol) and 4,6-dichloro-2-methylpyrimidine (2.7 mmol) in 5 mL of Ethanol, is added 500 mg of Potassium carbonate. The reaction mixture is stirred at room temperature until formation of the desired compound. Solvent is removed under reduced pressure. The residue can be purified by silica gel flash chromatography.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:9][C:8]([CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[CH:7][CH:6]=1)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>C(O)C>[C:15]1(=[O:16])[N:11]([CH2:10][C:8]2[S:9][C:5]([C:3]3[N:22]=[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]4[CH:2]=3)=[CH:6][CH:7]=2)[C:12](=[O:21])[C:13]2=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]12
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1ccc(CN2C(=O)c3ccccc3C2=O)s1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(-c2cn3ccccc3n2)s1
Yield: 48.1 %

Procedure:
5-Bromoacetyl-2-(phthalimidomethyl)thiophene (0.80 g) and 2-aminopyridine (0.23 g) were dissolved in anhydrous ethanol (50 ml) and heated under reflux for 6 hours. The resulting crystals were collected by filtration and purified by a silica gel column chromatography (chloroform:methanol=100:1) to give 0.38 g of the title compound.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[CH:4]=[C:5]([O:10][C:11]2[C:16]([F:17])=[C:15]([CH2:18]Br)[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:6]=[C:7]([Cl:9])[CH:8]=1>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]([O:10][C:11]2[C:16]([F:17])=[C:15]([CH2:18][NH2:1])[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: Fc1c(CBr)ccc(Cl)c1Oc1cc(Cl)cc(Br)c1
Reactant: N
Solvent: ClCCl
Product: NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a flask containing ammonia (7.0 M solution in methanol) (132 ml, 927 mmol) was added a solution of 2-[(3-bromo-5-chlorophenyl)oxy]-4-(bromomethyl)-1-chloro-3-fluorobenzene (4.97 g, 11.59 mmol) in DCM (15 ml) dropwise and the mixture was stirred overnight at room temperature. The solvent was removed and the crude material was purified via silica gel chromatography to give ({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (3.70 g, 10.14 mmol, 87% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.34-7.85 (m, 3H), 7.06 (s, 1H), 6.99 (t, 1H), 3.72 (s, 2H), 1.85 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:19][C:14]4[CH:15]=[N:16][N:17]=[CH:18][C:13]=4[CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)#[N:21].C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[O:11]=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:26]3[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=3)[C:20]#[N:21])[CH:10]=2)[CH2:6][C:7]21[CH2:19][C:14]1[CH:15]=[N:16][N:17]=[CH:18][C:13]=1[CH2:12]2
Reactant: O=C1c2cc(Br)ccc2CC12Cc1cnncc1C2
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(Cc4cnncc4C2)C3)c1
Temperature: 110 °C
Reaction time: 0.03 h
Yield: 60.2 %

Procedure:
A 10 mL microwave tube was charged with 6′-bromo-5,7-dihydrospiro[cyclopenta[d]pyridazine-6,2′-inden]-1′(3′H)-one (0.0600 g, 0.19 mmol), 3-cyanophenylboronic acid (0.1221 g, 0.83 mmol), Cs2CO3 (0.2822 g, 0.87 mmol), 1,4-dioxane (4 mL), water (1 mL), and PdCl2(PPh3)2 (0.0360 g, 0.05 mmol). The tube was heated in a CEM microwave reactor at 110° C. for 30 min. The reaction mixture was diluted with CH2Cl2 and dried over Na2SO4. After the solvent was evaporated under reduced pressure, the residue was purified by reversed-phase HPLC (SunFire™ Prep C18 OBD™ μm 19×50 mm column, 10%→90% MeOH/H2O, 0.1% CF3COOH over 8 min and then 90% MeOH/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford 0.0386 g (60%) of 3-(1′-oxo-1′,3′,5,7-tetrahydrospiro[cyclopenta[d]pyridazine-6,2′-inden]-6′-yl)benzonitrile. LC-MS tR=1.43 min in 3 min chromatography, m/z 338 (MH+).