Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:12])[CH:2]([OH:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([C:15]1[CH:20]=[CH:19][C:18](S(O)(=O)=O)=[CH:17][CH:16]=1)[CH3:14].C(O[C:28]([O:35][CH2:36][CH3:37])([O:32]CC)OCC)C>C1(C)C=CC=CC=1>[CH2:3]([CH:2]1[CH2:1][O:12][C:28]2([O:32][CH2:37][CH:36]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:15][CH2:13][CH3:14])[O:35]2)[O:11]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC(O)CO
Reactant: CCc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(OCC)(OCC)OCC
Solvent: Cc1ccccc1
Product: CCCCCCCCC1COC2(OCC(CCCCCCCC)O2)O1
Temperature: 25 °C

Procedure:
In a 500 mL RB flask equipped with a reflux condenser, a stirrer and a Dean Stark trap were added 1,2-decanediol (38.48 g, 0.22 mol), and toluene (350 mL). After placing under nitrogen the resulting solution was heated to reflux for two h to remove water from the mixture. The solution was cooled to RT and 4-ethylbenzenesulfonic acid (0.35 g) and tetraethylorthocarbonate (21.3 g, 0.11 mol). The solution was heated to reflux and the azeotropic mixture collected. The reaction was refluxed until the temperature of the distillated reached 110° C. (boiling point of pure toluene). The collected azeotropic mixture was measured and weighed and then poured into brine, the organic phase was separate, which indicated ˜22 mL of ethanol was collected. The reaction was cooled to RT and triethylamine (2.5 mL) added. The toluene was removed at reduced pressure (rotovap) and the resulting liquid dried under vacuum. Vacuum distillation afforded the desired product as a water white clear liquid boiling at 195–197° C. at 240 Pa (25.44 g). 13C NMR indicated the product to be a mixture of isomers.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH:6]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)=[CH2:7].C(=O)=O>C(OCC)C>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[CH:6]([N+:8]1[CH:12]=[CH:11][NH:10][CH:9]=1)=[CH2:7]
Reactant: CS(=O)(=O)O
Reactant: C=Cn1ccnc1
Agent: O=C=O
Solvent: CCOCC
Product: C=C[n+]1cc[nH]c1
Product: CS(=O)(=O)[O-]
Yield: 95 %

Procedure:
First, 7 ml of methanesulfonic acid was added to 10 g of N-vinylimidazole, and the resultant mixture was stirred for 3 hours at a temperature kept at 0° C. and then added dropwise to diethyl ether cooled with dry ice. The resultant mixture was rapidly filtered by suction using a Nutsche aspirator provided with a glass filter to recover crystals on the glass filter. The crystals were dried to obtain 19.2 g of N-vinylimidazolium methanesulfonate. The yield was 95%, and the melting point was 5° C.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[CH:10]=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]([F:14])=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1.Br[CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH:32]=[O:33])[CH2:28][CH2:27]1.C(N(CC)CC)C>CN(C)C=O>[CH2:2]([N:3]1[C:9]2[C:8](=[CH:13][C:12]([F:14])=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([CH:32]=[O:33])[CH2:28][CH2:27]4)[CH2:17][CH2:16]3)[CH:10]=2)[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:1]
Reactant: O=CN1CCC(CBr)CC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC4CCN(C=O)CC4)CC3)cc21
Temperature: 100 °C
Yield: 75 %

Procedure:
A mixture of norfloxacin (0.96 g, 3 mmol), 4-bromomethyl-1-formylpiperidine (1.26 g, 6.1 mmol) and triethylamine (0.44 g, 0.6 mL, 4.3 mmol) in anhydrous dimethylformamide (15 mL) was heated at 100° C. for 2 hours. The solvent was removed under high vacuum and the residue was dissolved in methanol, filtered and precipitated by the addition of diethyl ether to give the product as a white solid (1.0 g, 75% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17]Cl)[N:9]=[CH:8][CH:7]=[C:6]2[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[O:28])=[CH:22][CH:21]=1)#[N:2].[CH3:38][NH:39][CH3:40]>CN(C)C=O.[Cl-].[Na+].O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:39]([CH3:40])[CH3:38])[N:9]=[CH:8][CH:7]=[C:6]2[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[O:28])=[CH:22][CH:21]=1)#[N:2]
Reactant: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCCCCCl)c(C#N)cc34)cc2)cc1
Reactant: CNC
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCCCCN(C)C)c(C#N)cc34)cc2)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
N-(4-(6-Cyano-7-(4-chlorobutoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea (120 mg) was dissolved in dimethylformamide (3 ml), and then a 50% dimethylamine solution (93 μl) was added and the mixture was heated and stirred at 70° C. for 5 hours. The reaction solution was poured into saturated brine and extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate and concentrated. The residue was passed through NH silica gel (Fuji Silysia Chemical) and eluted with a solvent (ethyl acetate), and then further eluted with another solvent (ethyl acetate:methanol=10:1) and concentrated. The obtained solid was passed through Merck Silica Gel using tetrahydrofuran, and after eluting the insoluble portion with tetrahydrofuran and ethyl acetate, it was further eluted with solvents (tetrahydrofuran:methanol:triethylamine=10:1:1, ethyl acetate:methanol:triethylamine=10:1:1) and concentrated to obtain 10 mg of the title compound as a solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[NH2:4].[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:15](Cl)=O.N>>[F:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:5]3[CH:10]=[CH:9][N:8]=[N:7][CH:6]=3)[N:4]=2)[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: NC(=NO)c1ccnnc1
Agent: N
Product: Fc1cc(F)cc(-c2nc(-c3ccnnc3)no2)c1

Procedure:
The titled compound was prepared according to the procedure of Method D using the product of Example 83D and 3,5-difluorobenzoyl chloride (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.40 (tt, J=8.9, 2.4 Hz, 1 H), 7.85-7.94 (m, 2 H), 8.39 (dd, J=5.4, 2.2 Hz, 1 H), 9.46 (dd, J=5.4, 1.4 Hz, 1 H), 9.87 (dd, J=2.2, 1.4 Hz, 1 H) ppm; MS (DCI/NH3) m/z=261 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[I-].[NH2:17][N+:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:11](=[O:15])[CH:12]([CH3:13])[CH3:14])=[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]3[N:17]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C#CC(=O)C(C)C)cc1
Reactant: N[n+]1ccccc1
Agent: [I-]
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(-c2nn3ccccc3c2C(=O)C(C)C)cc1
Yield: 44.4 %

Procedure:
Starting with 5.0 g (36.7 mmol) of 4-methoxyethynylbenzene, 3.85 ml of isobutyryl chloride, and 5.0 g ZnCl2, the corresponding 1-(4-methoxyphenyl)-4-methylpent-1-yn-3-one was prepared using the same procedure as in Example 5(a) to obtain 7.87 g of crude oil intermediate. Starting with 7.5 g (37 mmol) of 1-(4-methoxyphenyl)-4-methylpent-1-yn-3-one, 8.22 g (37 mmol) of 1-aminopyridinium iodide and 11.6 g DBU, 4.84 g (45%) of 1-(2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one was obtained as in Example 5(b). Compound 1021.
Reaction SMILES: [O:1]=[C:2]([N:19]1[C:27]2[C:22](=[C:23]([C:34]3[O:35][C:36](=[O:39])[NH:37][N:38]=3)[CH:24]=[C:25]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH:26]=2)[CH2:21][CH2:20]1)[C@@H:3]([NH:11]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[OH:46][C:40]([C:42]([F:45])([F:44])[F:43])=[O:41].[NH2:11][C@@H:3]([CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:2]([N:19]1[C:27]2[C:22](=[C:23]([C:34]3[O:35][C:36](=[O:39])[NH:37][N:38]=3)[CH:24]=[C:25]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH:26]=2)[CH2:21][CH2:20]1)=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCc2c(-c3n[nH]c(=O)o3)cc(-c3ccncc3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)C(=O)N1CCc2c(-c3n[nH]c(=O)o3)cc(-c3ccncc3)cc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
To a 100 ml flask containing (S)-tert-butyl 1-oxo-1-(4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-6-(pyridin-4-yl)indolin-1-yl)-3-phenylpropan-2-ylcarbamate was added 20 ml of DCM and 10 ml of TFA. The reaction was stirred at room temperature for 6 hours at which time the solvent was removed with a stream of nitrogen to give (S)-5-(1-(2-amino-3-phenylpropanoyl)-6-(pyridin-4-yl)indolin-4-yl)-1,3,4-oxadiazol-2(3H)-one TFA salt 57.1.C (97 mg, 100% yield), which was used in the next step with no further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[CH2:3][C:2]1=O.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:4]1[N:9]=[CH:8][CH:7]=[C:6]2[CH:3]=[CH:2][O:1][C:5]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1Cc2ncccc2O1
Product: Clc1nccc2ccoc12

Procedure:
Alternatively, furan-3-aldehyde is converted to furan-3-acrylic acid with acetic anhydride and potassium carbonate and the acid converted to the acid azide by first reacting the acid with ethoxycarbonyl chloride and triethylamine to form the acid chloride and then reacting the mixed anhydride with sodium azide in water. The furan-3-acrylic acid azide is then heated in diphenylmethane with tributylamine to a temperature of about 190° C. to about 210° C. to form the furopyridone represented by the formula ##STR11## The furopyridone is allowed to react with phosphorus oxychloride to form 7-chlorofuro[2,3-c]pyridine and the latter is reductively dechlorinated with zinc in acetic acid to provide furo[2,3-c]pyridine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(CO)cn4c3-c3ccccc3)cc2)CCC1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(C=O)cn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of {1-[4-(6-hydroxymethyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (200 mg) and triethylamine (0.125 mL) in DCM (1.9 mL) at 0° C. was treated with a solution of pyridine-sulfur trioxide complex (142 mg, 0.894 mmol) in DMSO (0.021 mL). The reaction mixture was warmed to rt and stirred for 2 hours. The mixture was partitioned between ethyl acetate and water and the organic phase washed with water, dried and concentrated in vacuo to give the crude title compound which was used in the next step without further purification.
Reaction SMILES: FC(F)([S:6]([O-:9])(=[O:8])=[O:7])C(F)F.[K+].FC(F)=C(F)F.S([O-])([O-])=[O:19].[K+].[K+].[S:24](=[O:27])([OH:26])[O-:25].FC(F)(S(O)(=O)=O)C(F)F>>[OH:7][S:6]([OH:9])(=[O:19])=[O:8].[O:25]=[S:24](=[O:27])=[O:26]
Reactant: O=S(=O)([O-])C(F)(F)C(F)F
Reactant: O=S([O-])O
Reactant: O=S([O-])[O-]
Agent: FC(F)=C(F)F
Agent: O=S(=O)(O)C(F)(F)C(F)F
Agent: [K+]
Product: O=S(=O)(O)O
Product: O=S(=O)=O

Procedure:
The Journal of Organic Chemistry, 2008, 73, 711-714 provides a process for the preparation of potassium 1,1,2,2-tetrafluoroethanesulfonate from tetrafluoroethylene in a buffered aqueous solution of potassium sulfite and bisulfite and then converted to 1,1,2,2-tetrafluoroethane sulfonic acid in 90% overall yield by distillation from oleum solution.
Reaction SMILES: Cl[C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=3[F:26])=[O:17])=[CH:11][CH:10]=2)[S:4][N:3]=1.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][NH2:36])[CH2:29][CH2:28]1.C([O-])([O-])=O.[Na+].[Na+].[Cl-].[Na+].O>CCOC(C)=O>[C:7]([C:6]1[C:2]([NH:36][CH2:35][CH2:34][CH2:33][N:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)=[N:3][S:4][C:5]=1[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=2[F:26])=[O:17])=[CH:11][CH:10]=1)#[N:8]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3snc(Cl)c3C#N)cc2)c1
Reactant: NCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3snc(NCCCN4CCOCC4)c3C#N)cc2)c1
Temperature: 70 °C
Yield: 16 %

Procedure:
A mixture of 1-[4-(3-chloro-4-cyanoisothiazol-5-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea (50 mg, 0.13 mmol) and 0.2 mL 3-morpholinopropylamine was heated at 70° C. for 18 hours. Then an aqueous Na2CO3/brine mixture and EtOAc workup was done, and the resulting material chromatographed eluting with CHCl3/MeOH. The resulting solid was then triturated with a 1:1/CHCl3/hexane mixture which gave the title compound as a pale yellow solid (10 mg, 16%).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[OH:18])[CH:13]=O.[NH2:19][C:20]1[CH:24]=[CH:23][NH:22][N:21]=1>>[Cl:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:2]3[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]=3[NH:19][C:20]3=[CH:24][CH:23]=[N:22][N:21]23)[CH:15]=[CH:16][C:17]=1[OH:18]
Reactant: O=C1CCCC(=O)C1
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: Nc1cc[nH]n1
Product: O=C1CCCC2=C1C(c1ccc(O)c(Cl)c1)n1nccc1N2

Procedure:
1,3-Cyclohexanedione, 3-chloro-4-hydroxybenzaldehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10][CH2:11][CH2:12][CH3:13])[N:7]=[C:6](Cl)[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C@@H:68]([NH2:72])([CH2:70][CH3:71])[CH3:69]>CCOCC.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10][CH2:11][CH2:12][CH3:13])[N:7]=[C:6]([NH:72][CH:68]([CH2:70][CH3:71])[CH3:69])[CH:5]=1
Reactant: CCCSc1cc(C(=O)OC)cc(Cl)n1
Reactant: CC[C@H](C)N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCSc1cc(C(=O)OC)cc(NC(C)CC)n1
Temperature: 90 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
Add 2-chloro-6-propylsulfanyl-isonicotinic acid methyl ester (1.35 g, 5.49 mmol) palladium acetate (0.123 g, 0.549 mmol, 0.1eq.), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.342 g, 0.549 mmol, 0.1 eq.), cesium carbonate (2.68 g, 8.24 mmol, 1.5 eq.) and toluene (20 mL) into a sealed vessel flushed with nitrogen. Slowly add (S)-sec-butylamine (0.824 mL, 8.24 mmol) and heat and stir the reaction mixture at 90° C. for 18 h. Cool the reaction mixture to room temperature, dilute with ether and filter through a filtering agent. Concentrate the filtrate and purify (silica gel chromatography, eluting with the 5:95 to 10:90 ethyl acetate:hexanes) to give the title compound (55%).
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[C:13]([C:14]([O:16]CC)=[O:15])[C:8]=2[C:7]([CH3:23])=[N:6]1)([CH3:4])[CH3:3].[OH-].[Na+]>CCO>[CH3:4][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:8]=2[C:7]([CH3:23])=[N:6]1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nc2c1c(C)nn2C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C(C)(C)C)c2nc(C(C)(C)C)cc(C(=O)O)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an EtOH solution (8 mL) of ethyl 1,6-bis(1,1-dimethylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (528 mg, 1.663 mmol) was added sodium hydroxide (2.77 mL, 8.32 mmol), and the mixture was stirred for at room temperature for 2 h. The volatiles were removed under reduced pressure and the aqueous phase was acidified using 1H HCl to ˜pH 3. The precipitate was filtered, washed with water, and dried under high vacuum to give the product as 445 mg (92%). LCMS E-S (M+H)=289.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.49 (s, 9 H), 1.76 (s, 9 H), 2.51 (s, 3 H), 7.51 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[C:9]([C:3]1[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(Br)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-Amino-5-bromo-phenyl)-phenyl-methanone and 103 mg of 4-Methoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 3.78 (s, 3H), 6.83 (d, 2H, J=9.2 Hz), 7.39 (b, 1H), 7.49 (d, 2H, J=6.4 Hz), 7.68 (m, 4H), 8.85 (d, 2H, J=6.0 Hz), 9.96 (b, 1H). MS: m/z 447.0 (M++1).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl.Cl[C:6]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[O:24])[CH:12]=2)[N:7]=1>CO>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:23]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[C:6]([O:2][CH3:1])[CH:15]=[C:14]3[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:24])=[CH:30][CH:29]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2nc(Cl)cc(-c3cccc(Cl)c3)c2c1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc2n1
Temperature: 80 °C
Yield: 62 %

Procedure:
NaOMe, 30% methanol (300 ml) was added to a mixture of intermediate (55) (0.127 mol) in methanol (285 ml) and the mixture was stirred at 80° C. for one night. The precipitate was filtered off, washed with ethanol and dried. The product (44.8 g, 87%) was taken up in DCM and the layers were separated. The organic layer was dried (MgSO4), filtered off and evaporated till dryness, yielding 32.3 g (62%) of (4-chlorophenyl)[4-(3-chlorophenyl)-2-methoxy-6-quinolinyl]-methanone (intermediate 56).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[CH:4]([C:10](Cl)=[O:11])[CH2:3]1.[NH2:14]C(C)(C)CO>C(Cl)Cl>[CH3:1][C:2]1([CH3:13])[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[CH:4]([C:10]([NH2:14])=[O:11])[CH2:3]1
Reactant: CC1CCCC(C)(C)CC1C(=O)Cl
Reactant: CC(C)(N)CO
Solvent: ClCCl
Product: CC1CCCC(C)(C)CC1C(N)=O

Procedure:
3,3,7-Trimethylcycloheptanecarbonyl chloride, prepared from the product of Part A by the method of Example 26 Part B, (0.5 g. 0.0025 mole) in 10 ml methylene dichloride was added to a stirred solution of 2-amino-2,2-dimethylethanol (0.5 g) in 50 ml methylene dichloride. After 3 hours the solution was washed with 2N HC1, then with NaHCO3 solution and then dried (MgSO4). Removal of the solvent left an oil which was distilled to yield N-1', 1'-dimethyl-2'-hydroxyethyl)-3,3,7-trimethylcycloheptanecarboxamide, bp. 135°/0.015 mm.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:19][C:20]([C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])=[CH:21][N:22]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:28]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:28][C:21]1[N:22]=[C:18]([CH:7]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[NH:19][C:20]=1[C:23]([CH:25]1[CH2:27][CH2:26]1)=[O:24]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2ncc(C(=O)C3CC3)[nH]2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2nc(Br)c(C(=O)C3CC3)[nH]2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
To a solution (5 mL) of (2-{2-cyclopentyl-1-[4-(methylsulfonyl)phenyl]ethyl}-1H-imidazol-5-yl)(cyclopropyl)methanone (0.038 g) in N,N-dimethylformamide was added N-bromosuccinimide (0.024 g) and the mixture was stirred at 50° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-50:50, volume ratio) and recrystallized from diisopropyl ether-hexane to give the title compound (0.026 g, yield 56%) as colorless crystals. melting point 160-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([OH:14])=O)=[C:5]2[OH:15].CN(C)C=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([NH:39][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([Cl:33])=[CH:35][CH:36]=1)=[O:14])=[C:5]2[OH:15]
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1cnc2ccc(Cl)cc2c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(Cl)cc2c1O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a mixture of 0.365 g of 6-chloro-4-hydroxy-3-quinolinecarboxylic acid (J. Amer. Chem. Soc., 68, 1264 (1946)) and 5 mL of dimethylformamide is added 0.29 g of carbonyldiimidazole. The mixture is stirred 18 h at 60° C. and then it is cooled to 25° C. To the resulting solution is added 0.22 mL of 4-chlorobenzylamine. After stirring for 18 hours the mixture is diluted with 10 mL of distilled water. After 30 minutes the precipitate is collected by filtration and it is washed with two successive mL portions of water. It is then washed with 5 mL of diethyl ether. It is dried for 48 h at 85° C. and 20 torr. This procedure yields the title compound as 251 mg of an off-white solid.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[N:16]=[C:7]2[CH:8]=[C:9]([C:12]([O:14]C)=[O:13])[CH:10]=[CH:11][N:6]2[N:5]=1>CO>[Br:3][C:4]1[N:16]=[C:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=[CH:11][N:6]2[N:5]=1
Reactant: COC(=O)c1ccn2nc(Br)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccn2nc(Br)nc2c1
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
A 1 N sodium hydroxide aqueous solution (150 ml) was added to a methanol (150 ml) suspension of the methyl 2-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (10 g) obtained in (Example 3.15) <Step 2>, and the obtained mixture was then stirred for 30 minutes. Thereafter, about half of the solvent was distilled away under reduced pressure, and the residue was then adjusted to pH 4 by addition of 3 N hydrochloric acid (50 ml). The precipitated solid was collected by filtration, and was then successively washed with water (50 ml) and methyl tert-butyl ether (20 ml). The obtained solid was subjected to azeotropy with toluene to obtain the title compound (9.0 g) in the form of a white solid.