Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12]/[CH:13]=[C:14](/[CH2:16][CH2:17]/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20])\[CH3:15].C(N(CC)CC)C>C(Cl)Cl>[CH3:25][C:24]([CH3:26])=[CH:23][CH2:22][CH2:21]/[C:19](/[CH3:20])=[CH:18]/[CH2:17][CH2:16]/[C:14](/[CH3:15])=[CH:13]/[CH:12]=[O:11]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 102.1 %

Procedure:
To a stirred solution of 2.5 ml (28.7 mmol) of distilled oxalyl chloride in 50 ml of dry CH2Cl2 at -60° C. was added 4.2 ml (58.5 mmol) of DMSO in 10 ml of CH2Cl2 over 6 minutes between -60° C. and -55° C. with much gas evolution. After 7 minutes at -60° C., a solution of 5.0 g (22.50 mmol) of E,E-farnesol in 14 ml of CH2Cl2 was added over 15 minutes to give a thick white suspension. After 20 minutes at -65° C., 19 ml (136 mmol) of triethylamine was added over 7 minutes and 5 minutes later the cold bath was removed and the reaction was allowed to warm to room temperature over 50 minutes. The mixture was diluted with 400 ml of ether, washed with two 50 ml portions each of water and brine, dried over MgSO4, and evaporated. The residue was taken up in ether, filtered to remove some insoluble solid, and evaporated to provide 5.06 g (100%) of crude E,E-farnesal, contaminated with a trace of the 2Z-isomer.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:16][C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH2:9][C:8]=2[CH:17]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C1O[C:29]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)([CH2:30][CH2:31][CH2:32][Cl:33])[O:28]C1.Cl.[OH-].[Na+]>C(O)CCC.CO>[ClH:33].[F:40][C:37]1[CH:36]=[CH:35][C:34]([C:29]([CH2:30][CH2:31][CH2:32][N:13]2[CH2:12][CH2:11][C:10]3([CH2:9][C:8]4[CH:17]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=4[O:16]3)[CH2:15][CH2:14]2)=[O:28])=[CH:39][CH:38]=1
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Reactant: O=[N+]([O-])c1ccc2c(c1)CC1(CCNCC1)O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Solvent: CO
Product: O=C(CCCN1CCC2(CC1)Cc1cc([N+](=O)[O-])ccc1O2)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A stirred suspension of 5.2 g of 2,3-dihydro-5-nitrospiro[benzofuran-2,4'-piperidine] free base of C, 7.0 g of potassium carbonate, a few grains of potassium iodide and 6.2 g of γ-chloro-p-fluorobutyrophenone ethylene ketal in 200 ml of n-butyl alcohol is refluxed for 24 hours. Thereafter, the reaction mixture is permitted to cool to ambient temperature and then filtered. The filtrate is evaporated to dryness, leaving a brown oil. The oil is dissolved in 200 ml of methyl alcohol and 100 ml of 3N hydrochloric acid and this solution is stirred at ambient temperature for 18 hours and then basified with 6 N sodium hydroxide. The alkaline mixture is extracted with ethyl acetate and the ethyl acetate extracts are successively dried and evaporated to dryness, leaving an oil. The oil is chromatographed on a silica gel column eluting with chloroform which leads to a solid. The solid is dissolved in ether where it is converted to its hydrochloric acid salt, a white precipitate. The precipitate is recrystallized twice from ethyl alcohol to give the product 2,3-dihydro-1'-[3-(4-fluorobenzoyl)propyl]-5-nitrospiro[benzofuran-2,4'-piperidine]hydrochloride, mp 245°-247° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:23]1[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH:24]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.C(O)C.O>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:23]1[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH:24]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2ccccc2c1C1=CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc2ccccc2c(C2=CCC(C)(C)CC2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 35 °C
Reaction time: 48 h
Yield: 26 %

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(1-(4,4-dimethylcyclohex-1-enyl)-3-methylnaphthalen-2-yl)acetate (36 mg, 0.087 mmol) in tetrahydrofuran:ethanol:water (2:2:1, 5 mL) was added lithium hydroxide (21 mg, 0.88 mmol) and the reaction was heated to 35° C. overnight. The reaction was then heated to 45° C. for 2 hours, and subsequently 5 equivalents of lithium hydroxide was added, and the reaction stirred at room temperature over 2 days. The reaction was then heated to 50° C. overnight. The crude reaction was purified by reverse phase HPLC (Gemini, 20-100% ACN/H2O+0.1% TFA). Product was lyophilized to give a white powder (8.6 mg). 1H-NMR: 400 MHz, (CD3OD) δ: 7.82 (d, J=8.0 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.54 (s, 1H), 7.39 (m, 2H), 5.66 (m, 2H), 2.66 (m, 1H), 2.58 (s, 3H), 2.13 (m, 3H), 1.64 (m, 2H), 1.23 (s, 9H), 1.16 (s, 3H), 1.14 (s, 3H). LCMS-ESI− (m/z): [M−H]− calcd for C25H31O3: 379.24. found: 379.27.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[CH:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1.Cl>C(OCC)(=O)C.O1CCCC1.C1(C)C=CC=CC=1>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:19]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[OH:26])[CH:14]=1
Reactant: Brc1cccnc1
Reactant: O=Cc1cccnc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: OC(c1cccnc1)c1cccnc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
A 1.55 mol/L solution of n-butyllithium in hexane (2.24 mL, 3.48 mmol) was added to toluene (6 mL) and the mixture was cooled to −60° C. under a nitrogen atmosphere. To this, a toluene solution (2 mL) of 3-bromopyridine (500 mg, 3.16 mmol) was added dropwise and the mixture was stirred for 30 minutes. Tetrahydrofuran (2 mL) and nicotinaldehyde (0.358 mL, 3.79 mmol) were added to the reaction mixture and the mixture was stirred at a temperature of −60° C. to −15° C. for 30 minutes. After 4 mol/L hydrochloric acid (2.37 mL, 9.48 mmol) was added to the reaction mixture, extraction with ethyl acetate was performed, followed by washing with saturated sodium bicarbonate and brine, and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=12/1) to give dipyridin-3-ylmethanol (Compound EP) (235 mg, yield: 40%).
Reaction SMILES: C([O:4][P:5]([CH2:11][P:12]([O:18]C(C)C)(=[O:17])[O:13]C(C)C)(=[O:10])[O:6]C(C)C)(C)C.Br[C:23]1[C:24](Br)=[C:25]([CH3:30])[C:26]([CH3:29])=[CH:27][CH:28]=1>>[CH2:29]1[C:26]2[C:25](=[CH:24][CH:23]=[CH:28][CH:27]=2)[CH2:30][C:11]1([P:5]([OH:6])(=[O:10])[OH:4])[P:12]([OH:13])(=[O:17])[OH:18]
Reactant: Cc1ccc(Br)c(Br)c1C
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Product: O=P(O)(O)C1(P(=O)(O)O)Cc2ccccc2C1
Yield: 70 %

Procedure:
Using the procedure described in Example I, tetraisopropylmethanediphosphonate MDP was converted to the desired ester in 70% yield by reaction with dibromo-o-xylene at 80° C. for 3 h: mp 55°-57° C.; 1H NMR (CDCl3) 7.15 (s, 4H, aromatic), 5.00-4.55 (m, 4H, CH), 3.60 (t, 4H, J=17.6 Hz, CH2), 1.26 (t, 24H, J=6 Hz, CH3); 31P NMR (CDCl3) 24.7 ppm; Cl mass spectrum m/e 447 (MH+). Anal. calcd for C21H36O6P2 : C, 56.49; H, 8.13; P, 13.88. Found: C, 56.71; H, 8.24; P, 14.18.
Reaction SMILES: [CH2:1]([C@:4]1([CH2:37][CH2:38][OH:39])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][N:26]([CH3:33])[S:27]([CH:30]2[CH2:32][CH2:31]2)(=[O:29])=[O:28])[C:5]1=[O:36])[CH:2]=[CH2:3].N1C=CN=C1.[CH3:45][CH:46]([Si:48](Cl)([CH:52]([CH3:54])[CH3:53])[CH:49]([CH3:51])[CH3:50])[CH3:47]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([C@:4]1([CH2:37][CH2:38][O:39][Si:48]([CH:52]([CH3:54])[CH3:53])([CH:49]([CH3:51])[CH3:50])[CH:46]([CH3:47])[CH3:45])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][N:26]([CH3:33])[S:27]([CH:30]2[CH2:32][CH2:31]2)(=[O:28])=[O:29])[C:5]1=[O:36])[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(CCO)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C=CC[C@]1(CCO[Si](C(C)C)(C(C)C)C(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O
Temperature: 25 °C

Procedure:
To a solution of 2.52 g (4.25 mmol) N—((S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-hydroxyethyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide (Example 408, Step D), DMAP (0.026 g, 0.212 mmol), and imidazole (0.723 g, 10.61 mmol) in DCM (16.98 mL) at 0° C. was added slowly by syringe TIPS-Cl (1.17 mL, 5.52 mmol). The reaction was stirred at ambient temperature, with addition of reagents until reaction was judged complete by LCMS and TLC. The reaction mixture was quenched by addition of 6 mL of MeOH, then extracted with DCM (70 mls×2). The combined organics were washed with water (30 mL), satd. aq.NH4Cl solution (20 mL), dried over Na2SO4, filtered and the filtrate was concentrated. Purification by chromatography on silica gel (eluent: 0 to 40% EtOAc/DCM, gradient elution) provided the title compound as a clear, colorless oil. Mass Spectrum (ESI) m/z=749.4 (M+1).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH2:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][CH:42]([CH:45]=O)[CH2:41][CH2:40]2)=[C:35]([F:47])[C:34]=1[F:48])[CH3:31].O>C1COCC1>[CH2:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][CH:42]([CH:45]=[CH:2][O:3][CH3:4])[CH2:41][CH2:40]2)=[C:35]([F:47])[C:34]=1[F:48])[CH3:31]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1ccc(C2CCC(C=O)CC2)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(C2CCC(C=COC)CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
In a reactor under nitrogen atmosphere, 25 mL of THF was added to 7.7 g of methoxymethyltriphenylphosphonium chloride, and the mixture was cooled to −20° C., to which 2.5 g of t-BuOK was added, followed by stirring for 1 hour A solution containing 5.0 g of 4-(4-ethoxy-2,3-difluorophenyl)cyclohexane-carboaldehyde dissolved in 50 mL of THF was added dropwise thereto, followed by stirring for 1 hour. The temperature of the reaction mixture was increased to room temperature, and 100 mL of water was added to the reaction mixture, followed by extracting three times with 100 mL of toluene. The resulting organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was concentrated to about 100 mL under reduced pressure, and the concentrated solution was placed in 500 mL of toluene, followed by removing deposited solid matters. The solvent was distilled off from the resulting solution under reduced pressure, and the residue was purified by silica gel column chromatography to provide 4.9 g of 1-ethoxy-2,3-difluoro-4-[4-(2-methoxyvinyl)-cyclohexyl]benzene.
Reaction SMILES: NC1C2C=C(SC)C=C[C:4]=2[S:5]C=1C(OC)=O.C=O.Cl[C:20]1[C:28]2[C:27]([N:29]([CH3:31])[CH3:30])=[C:26]([C:32]([O:34][CH3:35])=[O:33])[S:25][C:24]=2[CH:23]=[CH:22][CH:21]=1>>[CH3:30][N:29]([CH3:31])[C:27]1[C:28]2[CH:20]=[C:21]([S:5][CH3:4])[CH:22]=[CH:23][C:24]=2[S:25][C:26]=1[C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)c1sc2ccc(SC)cc2c1N
Reactant: COC(=O)c1sc2cccc(Cl)c2c1N(C)C
Agent: C=O
Product: COC(=O)c1sc2ccc(SC)cc2c1N(C)C
Yield: 71 %

Procedure:
Prepared from methyl 3-amino-5-(methylthio)-benzo[b]thiophene-2-carboxylate by alkylation with formaldehyde as described in the preparation of methyl 4-chloro-3-(dimethylamino)benzo[b]thiophene-2-carboxylate. Yield 71% after recrystallization from ether-petroleum ether; mp=63°-66° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:12]2[C:11](=[O:13])[N:10]([CH3:14])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=2[N:6]=[CH:5]1.[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][CH:24]=2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[NH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([CH:20]2[CH2:21][CH2:22][N:17]([CH2:2][CH2:3][N:4]3[C:12]4[C:11](=[O:13])[N:10]([CH3:14])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=4[N:6]=[CH:5]3)[CH2:18][CH2:19]2)=[CH:24]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: Cn1c(=O)c2c(ncn2CCCl)n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Cn1c(=O)c2c(ncn2CCN2CCC(c3c[nH]c4ccccc34)CC2)n(C)c1=O
Yield: 50 %

Procedure:
A mixture of 5 parts of 7-(2-chloroethyl)-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione, 4 parts of 3-(4-piperidinyl)-1H-indole, 8 parts of sodium carbonate, 1 part of potassium iodide and 120 parts of 4-methyl-2-pentanone was stirred and refluxed overnight. The reaction mixture was cooled, water was added and the layers were separated. The organic phase was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone, yielding 4 parts (50%) of 7-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione; mp. 201.2° C. (compound 1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9](OS(C)(=O)=O)[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19]1)=[O:17])=[O:5])[CH3:2].[Cl:25][C:26]1[CH:31]=[C:30]([Br:32])[CH:29]=[CH:28][C:27]=1[SH:33]>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([S:33][C:27]2[CH:28]=[CH:29][C:30]([Br:32])=[CH:31][C:26]=2[Cl:25])[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:22][CH2:21][C:20]([F:23])([F:24])[CH2:19]1)=[O:17])=[O:5])[CH3:2]
Reactant: Sc1ccc(Br)cc1Cl
Reactant: CCOC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CCC(F)(F)C1
Product: CCOC(=O)[C@@H]1C[C@@H](Sc2ccc(Br)cc2Cl)C[C@H]1C(=O)N1CCC(F)(F)C1

Procedure:
The title compound was prepared in analogy to example 68/69 step 8 using (1R,2R,4R)-2-(3,3-Difluoro-pyrrolidine-1-carbonyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester (example 186 step 3) and 2-chloro-4-bromothiophenol. Light yellow oil (89%). MS (EI): 498.0 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:19]=[C:18](C(O)=O)[C:17]2[C:12](=[C:13]([CH3:23])[CH:14]=[CH:15][CH:16]=2)[N:11]=1)([OH:3])=[O:2].O.[OH-].[Na+]>N1C2C(=CC=CC=2)C=CC=1>[CH3:23][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[N:11]=[C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:1]([OH:3])=[O:2])[CH:19]=[CH:18]2
Reactant: Cc1cccc2c(C(=O)O)cc(-c3ccccc3C(=O)O)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: Cc1cccc2ccc(-c3ccccc3C(=O)O)nc12
Temperature: 170 °C
Yield: 58.4 %

Procedure:
In 5 ml of quinoline was dissolved 0.1 g of the 2-(2-carboxyphenyl)-8-methyl-4-quinolinecarboxylic acid obtained in Example 11 and the solution was heated at 170° C. for 1.5 hours. Then the reaction mixture was poured into water, made alkaline by adding sodium hydroxide and washed with toluene. The aqueous layer was neutralized with 3M hydrochloric acid until a precipitate was formed. After extracting with dichloromethane, 0.05 g of 2-(8-methylquinolin-2-yl)benzoic acid were obtained. NMR (270 MHz, CD3OD): δ 7.5-8.3 (m,9H); 2.63 (s,3H).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[S:10][C:9]2=[N:11][C:12]([C:14]([OH:16])=O)=[CH:13][N:8]2[CH:7]=1.[N-:17]=[N+:18]=[N-:19].[Na+]>O>[Br:5][C:6]1[S:10][C:9]2=[N:11][C:12]([C:14]([N:17]=[N+:18]=[N-:19])=[O:16])=[CH:13][N:8]2[CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Product: [N-]=[N+]=NC(=O)c1cn2cc(Br)sc2n1
Temperature: 85 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
Thionyl chloride (0.33 mol) was added to 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid (13.1 mmol). The reaction mixture was stirred at 85° C. during 3 hrs. The mixture was then concentrated under vacuum and the residue was taken in acetone (40 mL). The sodium azide (14.4 mmol) in water (5.2 mL) was added in one portion at 0° C. and the mixture was stirred at 0-10° C. for 45 min. Water was added, and the solid filtered off and washed with water and then with a mixture of water/acetone (50/50). The solid was dried in vacuo to give compound 9 as a beige solid in 80% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 8.27 (s, 1H), 8.49 (s, 1H); and MS (ESI, EI+) m/z=272.05-274.07 (MH+).
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36](=[CH:41][C:42]([O:44]C)=O)[C:37]([O:39][CH3:40])=[O:38])=[CH:31][CH:30]=1)([O-:28])=[O:27]>CCOCC.CO>[N+:26]([C:29]1[CH:30]=[C:31]2[C:32](=[CH:33][CH:34]=1)[NH:35][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:41][C:42]2=[O:44])([O-:28])=[O:27]
Reactant: COC(=O)C=C(Nc1ccc([N+](=O)[O-])cc1)C(=O)OC
Solvent: CCOCC
Solvent: CO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cc(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
To Dowtherm A (trademark, 30 ml) refluxed under heating was added dimethyl 2-[(4-nitrophenyl)amino]-2-butenedioate (6.32 g, 22.6 mmol) obtained in Example 131, Step 1 over 5 min by small portions. The mixture was refluxed under heating for 25 min and the reaction mixture was cooled to room temperature. The reaction mixture was diluted with ether and the resulting precipitate was filtrated. The obtained crude crystals were suspended in methanol and collected by filtration to give methyl 1,4-dihydro-6-nitro-4-oxo-2-quinolinecarboxylate (4.75 g, 85%, dark brown crystals).
Reaction SMILES: C(C1C=C([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=2)=[O:12])N(C2C=C(C=CC=2)C(OCC)=O)N=1)(C)(C)C.O=S(Cl)Cl>CCl>[C:14]1([NH:13][C:11](=[O:12])[NH2:10])[C:15]2[C:16](=[CH:19][CH:14]=[CH:15][CH:16]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Cl)cc2)c1
Agent: CCl
Solvent: O=S(Cl)Cl
Product: NC(=O)Nc1cccc2ccccc12
Yield: 451.1 %

Procedure:
A solution of Example C (1.66 g, 4.0 mmol) and SOCl2 (0.60 mL, 8.0 mmol) in CH3Cl (100 mL) was refluxed for 3 h and concentrated in vacuo to yield 1-{3-tert-butyl-1-[3-chloromethyl)phenyl]-1H-pyrazol-5-yl}-3-(naphthalen-1-yl)urea (1.68 g 97%) was obtained as white powder. 1H NMR (DMSO-d6): δ 9.26 (s, 1 H), 9.15 (s, 1 H), 8.42-7.41 (m, 11 H), 6.40 (s, 1 H), 4.85 (s, 2 H), 1.28 (s, 9 H). MS (ESI) m/z: 433 (M+H+).
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C=O)C.[C:10]([C:14]1[N:19]=[C:18](O)[CH:17]=[C:16]([C:21]([F:24])([F:23])[F:22])[N:15]=1)([CH3:13])([CH3:12])[CH3:11]>ClCCl>[C:10]([C:14]1[N:19]=[C:18]([Cl:3])[CH:17]=[C:16]([C:21]([F:24])([F:23])[F:22])[N:15]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1nc(O)cc(C(F)(F)F)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(Cl)cc(C(F)(F)F)n1
Yield: 96 %

Procedure:
Firstly 86.5 ml of thionyl chloride and then 8 ml of DMF were added dropwise to a solution of 60 g (0.27 mol) of 2-t-butyl-4-hydroxy-6-trifluoromethylpyrimidine in 800 ml of dichloromethane, and then the mixture was refluxed. The volatile constituents were removed under reduced pressure, the residue was taken up in 100 ml of dichloromethane, the pH was adjusted to 7 with saturated NaHCO3 solution and, after workup by extraction, 67 g (96%) of a clear oil were obtained.
Reaction SMILES: [CH2:1]([O:10][C:11]([C:13]1[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:17]([C:28]([OH:30])=[O:29])=[C:16]([CH3:31])[NH:15][C:14]=1[CH3:32])=[O:12])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:48]([S:50][CH2:51][CH2:52]O)[CH3:49]>CN(C)C1C=CN=CC=1.ClC(Cl)C>[N+:25]([C:21]1[CH:20]=[C:19]([CH:18]2[C:17]([C:28]([O:30][CH2:49][CH2:48][S:50][CH2:51][CH3:52])=[O:29])=[C:16]([CH3:31])[NH:15][C:14]([CH3:32])=[C:13]2[C:11]([O:10][CH2:1][CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:12])[CH:24]=[CH:23][CH:22]=1)([O-:27])=[O:26]
Reactant: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC=Cc2ccccc2)=C(C)N1
Reactant: CCSCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Product: CCSCCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC=Cc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Yield: 97.9 %

Procedure:
434 mg (1 mM) of 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid monocinnamyl ester, 226 mg (1.1 mM) of dicyclohexylcarbodiimide, 122 mg (1 mM) of 4-dimethylaminopyridine and 127 mg (1.2 mM) of 2-ethylthioethanol were dissolved in 10 ml of dichloroethane, and refluxed for 2 hours. After the reaction mixture was chilled, insoluble matters were filtered off. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 511 mg of cinnamyl 2-ethylthioethyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (yield 98%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][C:17]=1[C:27]([F:30])([F:29])[F:28]>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][C:17]=2[C:27]([F:28])([F:30])[F:29])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CN2CCN(C)CC2)c(C(F)(F)F)c1
Reaction time: 0.33 h

Procedure:
To a solution of N-methylpiperazine (5.8 g, 57.9 mmol, 1.0 eq.) in tetrahydrofuran (225 ml) containing anhydrous finely ground potassium carbonate (10.4 g, 75.2 mmol, 1.3 eq.) is added a solution of ethyl 4-bromomethyl-3-trifluoromethylbenzoate (18.0 g, 57.9 mmol, 1.0 eq.) in tetrahydrofuran with vigorous mechanical stirring within 20 min. Stirring is continued at room temperature for 20 h. The obtained suspension is filtered, and the filtrate is evaporated to give a brown oil. The crude product is purified by medium pressure chromatography (290 g silica gel, gradient: TBME to EtOH/TBME 1:4 within 30 min, then 25% NH3/EtOH/TBME 1:19:80 for 60 min). The fractions containing the title compound are pooled and evaporated to afford a yellow oil: HPLC: tR=4.75 min (purity: >99%, gradient A), ESI-MS: 331.4 [MH]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]([C:21]3[C:22]([O:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[N:23][CH:24]=[CH:25][CH:26]=3)=[O:20])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl.CO.ClCCl>C(O)(C)(C)C.O>[F:34][C:31]1[CH:32]=[CH:33][C:28]([O:27][C:22]2[C:21]([C:19]([NH:18][CH2:17][C:14]3[CH:15]=[CH:16][C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=4)=[CH:12][CH:13]=3)=[O:20])=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:29][CH:30]=1
Reactant: COC(=O)c1cccc(-c2ccc(CNC(=O)c3cccnc3Oc3ccc(F)cc3)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1cccc(-c2ccc(CNC(=O)c3cccnc3Oc3ccc(F)cc3)cc2)c1
Yield: 51.7 %

Procedure:
A mixture of 300 mg (0.66 mmol.) 4′-[[[2-[4-Fluorophenoxy]-pyridine-3-carbonyl]-amino]-methyl]-biphenyl-3-carboxylic acid methyl ester and 1.6 mL 1.0 N NaOH in 10 mL t-butanol and 3 mL water and refluxed for 4 hours. The mixture was poured into water, acidified to pH 1 with 2N HCl, then extracted with ethyl acetate. The ethyl acetate extracted were combined, washed successively with water, brine then dried (MgSO4) and concentrated to give an oil. Chromatography on Silica Gel eluting with methanol/dichloromethane (1:40) yielded a foam. Recrystallization from ethyl acetate/hexanes afforded 151 mg 4′-[[[2-[4-Fluorophenoxy]-pyridine-3-carbonyl]-amino]-methyl]-biphenyl-3-carboxylic acid as a solid, mp 184-6° C.