Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[S:17][CH:18]=[C:19](C)[C:20]=2[Br:21])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:24]1SC(C)=CC=1.C([N-]C(C)C)(C)C.[Li+].C(OC(N1CCC(C(=O)N(OC)C)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[S:17][C:18]([CH3:24])=[CH:19][C:20]=2[Br:21])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1csc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1Br
Reactant: Cc1ccc(Br)s1
Agent: CC(C)[N-]C(C)C
Agent: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Product: Cc1cc(Br)c(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)s1

Procedure:
Prepared essentially as in 29a except that 2-bromo-5-methyl thiophene is used as the starting material. In addition, 1.20 equivalents of lithium diisopropylamide and 1.24 equivalents of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester are used for the reaction. Accordingly, stirring time of the reaction mixture may vary. Purification of the residue via flash column chromatography uses a gradient with a mixture of ethyl acetate:n-heptane (1:9) to ethyl acetate:n-heptane (2:8) to yield a yellow oil. LC/MS (ESI), m/e 332 (M−56) and 388 (MH+), retention time 2.15 minutes. Condition II.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[OH:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]2[CH:23]=[N:24][N:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=23)[N:17]=1.F[P-](F)(F)(F)(F)F.[N:40]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[N:41]1.N12CCCN=C1CCCCC2>CN(C=O)C>[C:31]([C:28]1[CH:29]=[CH:30][N:25]2[N:24]=[CH:23][C:22]([C:18]3[N:17]=[C:16]([NH:1][C@@H:2]4[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]4)[CH:21]=[CH:20][N:19]=3)=[C:26]2[CH:27]=1)#[N:32].[N:40]1([O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]3[CH:23]=[N:24][N:25]4[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][C:26]=34)[N:17]=2)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[N:41]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: N#Cc1ccn2ncc(-c3nccc(O)n3)c2c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccnc(-c3cnn4ccc(C#N)cc34)n2)C1
Product: N#Cc1ccn2ncc(-c3nccc(On4nnc5ccccc54)n3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
Tert-butyl (3R)-3-aminopiperidine-1-carboxylate (1.49 g, 7.46 mmol) was added to a stirred solution of 3-(4-hydroxypyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile (Preparation 3b, 0.70 g, 2.98 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1.71 g, 3.88 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.67 mL g, 4.48 mmol) in N,N′-dimethylformamide (15 mL) and the resulting mixture was stirred at room temperature for 16 hours. Then the solvent was removed under reduced pressure and the residue was taken up in a mixture of dichloromethane and 4% aqueous sodium hydrogencarbonate solution. The organic layer was separated, dried (MgSO4) and evaporated in vacuo. The crude product was purified by flash chromatography (99:1 dichloromethane/methanol) to give a residue that was repurified by reverse phase chromatography (C-18 silica from Waters, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give the title compound (0.83 g, 66%) and 3-(4-(1H-benzo[d][1,2,3]triazol-1-yloxy) pyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile (0.10 g) as the main reaction byproduct.
Reaction SMILES: C([O:3][C:4]1[C:5](=O)[CH:6]([C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH:9]=1)C.O.[NH2:19][NH2:20]>C(O)C>[O:3]=[C:4]1[C:5]2[NH:20][N:19]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]=2[CH2:7][CH2:8][CH2:9]1
Reactant: CCOC(=O)C(=O)C1CCC=C(OCC)C1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1n[nH]c2c1CCCC2=O
Yield: 70 %

Procedure:
1 g (4.2 mmol) of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate were dissolved in 10 mL of ethanol, 0.21 mL of hydrazine hydrate were added and the solution stirred at reflux for a day. The solvent was then evaporated and the residue redissolved with dichloromethane. The organic layer was washed with water, dried over Na2SO4 and concentrated. The crude was triturated with diethyl ether and filtered to give (70% yield) the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:16])COC)=[CH:8][CH:7]=2)[CH2:3]1.[OH2:17].[OH-].[Li+].Cl>O.CO.C1COCC1>[OH:1][CH:2]1[CH2:3][N:4]([C:6]2[CH:7]=[CH:8][C:9]([C:12]([OH:16])=[O:17])=[CH:10][CH:11]=2)[CH2:5]1
Reactant: COCC(=O)c1ccc(N2CC(O)C2)cc1
Reactant: O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(N2CC(O)C2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A mixture of 1-[4-(3-hydroxyazetidin-1-yl)phenyl]-2-methoxyethanone (1.33 g, 6.00 mmol) and lithium hydroxide monohydrate (504 mg, 12.0 mmol) in water (4 mL), methanol (3 mL) and THF (6 mL) was stirred at 40° C. overnight. The mixture was neutralized with 3 N HCl aqueous solution (˜4 mL) to pH about 7, extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product (1.10 g, 94.9%) which was directly used in the next step without further purification. LCMS cacld. for C10H12NO3 (M+1)+: m/z=194.1. Found: 194.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][OH:18])[CH2:13][CH2:12]2)=[N:6][CH:7]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].N1C(C)=CC=CC=1C.O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][C:5]([NH:8][CH2:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][O:18][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:13][CH2:12]2)=[N:4][CH:3]=1
Reactant: OC[C@H]1CC[C@H](CCNc2ncc(Br)cn2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)OC[C@H]1CC[C@H](CCNc2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 481 mg (1.53 mmol) of trans-{4-[2-(5-Bromo-pyrimidin-2-ylamino)-ethyl]-cyclohexyl}-methanol in 14 ml CH2Cl2 was treated at 0 C with 0.13 ml (1.68 mmol) methanesulfonylchloride and 0.27 ml (2.30 mmol) 2,6-lutidine. The reaction was stirred for 20 h at room temperature, water (2 ml) was added and stirred for 5 min. After extraction with aqueous saturated NaHCO3/Et2O(3×), the organic phase was washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 970 mg of crude trans-Methanesulfonic acid 4-[2-(5-bromo-pyrimidin-2-ylamino)-ethyl]-cyclohexylmethyl ester, MS: 392 (MH+, 1Br).
Reaction SMILES: [CH2:1]1[O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20]>CO>[CH2:19]([NH:20][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][CH2:1][CH:2]([OH:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC1CO1
Reactant: NCCCCCCN
Solvent: CO
Product: CCCCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCCCC
Reaction time: 8 h

Procedure:
A solution of 1-undecene oxide (88.8 g.), hexamethylenediamine (1,6-hexanediamine, 30.3 g.) and methanol (400 ml.) was allowed to stand at 0° C. overnight, then at room temperature over the weekend. The solid was collected and recrystallized from ethanol, affording N,N'-(1,6-hexylene)-bis[2-hydroxyundecylamine] (I: R = CH3 (CH2)8, R' = H, X = (CH2)6 ; Z = H)(m.p. 122.6°-129.0° C.).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.Cl[S:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)(=[O:19])=[O:18].O>C1COCC1>[N:10]1([S:17]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.4 %

Procedure:
To a solution of diisopropylethylamine (1.76 g, 13.6 mmol, 2.37 ml) and morpholine (1.98 g, 22.7 mmol, 1.98 ml) in THF (40 ml) was added, dropwise over 0.5 h, a solution of 4-(chlorosulfonyl)benzoic acid (2.50 g, 11.3 mmol) in THF (17 ml). After stirring at room temperature for 18 h the reaction was poured into H2O (150 ml) and washed with EtOAc. The aqueous layer was acidified (pH 1) with concentrated HCl, and the precipitate collected, washed with cold H2O, and dried under vacuum over P2Os to give 2.68 g (87%) of 4-(4-morpholinylsulfonyl)-benzoic acid as an off-white solid.
Reaction SMILES: [C:1]1([C@H:11]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]3[CH:43]=[CH:42][C:23]([C:24]([C@:26]([C@H:30]([C@@H:32]([C@@H:34]([C:36]([O:38]CC=C)=[O:37])[OH:35])[OH:33])[OH:31])([OH:29])[CH:27]=[O:28])=[O:25])=[CH:22][CH:21]=3)[CH2:15]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1CCCC1>O1CCCC1>[C:1]1([C@H:11]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]3[CH:43]=[CH:42][C:23]([C:24]([C@:26]([C@H:30]([C@@H:32]([C@@H:34]([C:36]([OH:38])=[O:37])[OH:35])[OH:33])[OH:31])([OH:29])[CH:27]=[O:28])=[O:25])=[CH:22][CH:21]=3)[CH2:15]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C=CCOC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@](O)(C=O)C(=O)c1ccc(N2CCC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: C[C@@H](N[C@H]1CCCN(c2ccc(C(=O)[C@](O)(C=O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O)cc2)C1)c1cccc2ccccc12
Yield: 38.4 %

Procedure:
In 6 ml of tetrahydrofuran was dissolved 615 mg of allyl 2-[4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethyl]aminopiperidin-1-yl]-benzoyl]-D-glucuronate, and the mixture was stirred under ice-cooling and in nitrogen atmosphere. To the mixture were added 91 μl of pyrrolidine, and then, 123 mg of tetrakistriphenylphosphine palladium, and the resulting mixture was stirred for 30 minutes. The residue obtained by concentration under reduced pressure was purified by LC-MS. Ether was added to the obtained solid, the solid was pulverized, collected by filtration, and dried to obtain 220 mg of 2-[4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethyl]aminopiperidin-1-yl]-benzoyl]-D-glucuronic acid (Example 12.030 in the following Table X). (HPLC purity: 67.7%)
Reaction SMILES: N(C(OC)=O)=NC(OC)=O.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]([O:25][CH:26]([CH3:28])[CH3:27])([CH2:22][CH2:23][CH3:24])[CH2:20]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:48]1[CH:52]=[N:51][CH:50]=[N:49]1>O1CCCC1>[N:48]1([CH2:20][C:19]([O:25][CH:26]([CH3:28])[CH3:27])([C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[Cl:11])[CH2:22][CH2:23][CH3:24])[CH:52]=[N:51][CH:50]=[N:49]1
Reactant: c1nc[nH]n1
Reactant: CCCC(CO)(OC(C)C)c1ccc(Cl)cc1Cl
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(Cn1cncn1)(OC(C)C)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.5 g (30 mmoles) of dimethyl azodicarboxylate is added dropwise, at room temperature, to a solution of 5.8 g (20 mmoles) of 2-(2,4-dichlorophenyl)-2-isopropoxypentan-1-ol, 7.9 g (30 mmoles) of triphenylphosphine and 1.66 g (24 mmoles) of 1,2,4-triazole in 100 ml of absolute tetrahydrofuran, and the reaction mixture is then stirred for 3 hours at room temperature and then for a further 16 hours at 50° C. and is evaporated; the residue is digested with 100 ml of diethyl ether, the insoluble residue is filtered off, and the ether phase is concentrated again and purified by column chromatography (silica gel; 1:1 ethyl acetate/petroleum ether). This gives a colourless oil having physical data which agree entirely with those in Example 3b).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:21](=[O:23])[CH3:22])[CH:8]=[C:9]([O:11][CH2:12][CH2:13][O:14]C2CCCCO2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br-:24].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CC(=O)OCC>CO.C1COCC1>[Br:24][CH2:22][C:21]([C:7]1[CH:8]=[C:9]([O:11][CH2:12][CH2:13][OH:14])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)=[O:23]
Reactant: CC(=O)c1cc(OCCOC2CCCCO2)cc(C(C)(C)C)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(OCCO)cc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.7 %

Procedure:
1-{3-tert-Butyl-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}ethanone (O2.061; 3.9 g) was dissolved in methanol/THF (60 ml/60 ml) and admixed while stirring with phenyltrimethylammonium tribromide (5.03 g). After stirring at RT for 3 h, the reaction mixture was added to 20% citric acid and stirred for 1 h. After adding EA, the EA phase was removed, dried and concentrated. The residue was purified using silica gel (80 g cartridge, n-heptane/EA gradient of 0-50% within 60 min). 2.56 g of the title compound were obtained.
Reaction SMILES: O=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[C:11]([O:17][CH3:18])[CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[CH:5]=CC.C(OCC)(=[O:22])C.CCCCCC>ClCCl.CO>[O:22]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[C:11]([O:17][CH3:18])[CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19]
Reactant: CCOC(C)=O
Reactant: CC=CCC1Cc2cccc(OC)c2C1=O
Agent: O=[O+][O-]
Solvent: CO
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1cccc2c1C(=O)C(CC=O)C2
Reaction time: 0.75 h
Yield: 71 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted while stirring for 45 minutes through a solution, cooled to -70°, of 9.9 g of (RS)-2-(2-buten-1-yl)-7-methoxy-1-indanone in 200 ml of anhydrous dichloromethane and 100 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 5 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 200 ml of dichloromethane and, after the addition of 20 ml of water and 20 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 100 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 100 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 150 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate, concentrated in a vacuum and the crude product obtained was cystallized from ethyl acetate/hexane. 6.6 g (71%) of (RS)-2-(2-oxoethyl)-7-methoxy-1-indanone were obtained as a white solid with m.p. 102°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([N:9]([CH:22]([CH3:24])[CH3:23])[S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])(=[O:12])=[O:11])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[S:33][C:34]2[CH2:61][CH2:60][CH2:59][CH2:58][C:35]=2[C:36]=1[C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][C:48]2[CH:57]=[CH:56][C:51]([C:52]([O:54][CH3:55])=[O:53])=[CH:50][CH:49]=2)=[CH:42][CH:41]=1)=[O:38]>CN(C=O)C.C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([N:9]([CH:22]([CH3:23])[CH3:24])[S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:31][C:32]2[S:33][C:34]3[CH2:61][CH2:60][CH2:59][CH2:58][C:35]=3[C:36]=2[C:37]([NH:39][C:40]2[CH:41]=[CH:42][C:43]([CH2:46][CH2:47][C:48]3[CH:49]=[CH:50][C:51]([C:52]([O:54][CH3:55])=[O:53])=[CH:56][CH:57]=3)=[CH:44][CH:45]=2)=[O:38])=[O:17])(=[O:12])=[O:11])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(N)sc4c3CCCC4)cc2)cc1
Reactant: CCOC(=O)C1(N(C(C)C)S(=O)(=O)c2cccc(C(=O)O)c2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1(N(C(C)C)S(=O)(=O)c2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCc5ccc(C(=O)OC)cc5)cc3)CCCC4)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
A mixture of 307 mg of 3-{[1-(ethoxycarbonyl)cyclopropyl](isopropyl)sulfamoyl}benzoic acid, 0.10 mL of oxalyl chloride, 2.5 mL of dichloromethane, and one drop of DMF was stirred at room temperature for 2 hours, and then the reaction mixture was concentrated under reduced pressure. A mixture of the obtained crude product and 2.5 mL of dichloromethane was added to a mixture of 0.050 mL of pyridine, 250 mg of methyl 4-[2-(4-{[(2-amino-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, and 2.5 mL of methylene chloride, followed by stirring at room temperature overnight. The reaction mixture was purified by silica gel column chromatography (hexane-chloroform) to obtain 279 mg of methyl 4-(2-{4-[({2-[(3-{[1-(ethoxycarbonyl)cyclopropyl](isopropyl)sulfamoyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate as a yellow foamed solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:25])[NH:11][N:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1F.[F:26][C:27]1[CH:28]=[C:29](Br)[CH:30]=[CH:31][C:32]=1[F:33].N>>[F:26][C:27]1[CH:28]=[C:29]([N:11]2[C:10](=[O:25])[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[CH:13]=[N:12]2)[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(F)c(F)c2)cc1
Reactant: Fc1ccc(Br)cc1F
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2-c2cccc(F)c2)cc1

Procedure:
The title compound was prepared as described in Example 62, starting with 4-(3,4-difluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 3,4-difluorobromobenzene in place of 1-bromo-4-fluorobenzene (yield: 185 mg, 46.5%). mp 182-185° C. 1H NMR (300 MHz, DMSO-d6) δ 3.23 (s, 3H), 6.98 (d, J=9 Hz, 1H), 7.18 (m, 2H), 7.32 (m, 1H), 7.52 (d, J=9 Hz, 2H), 7.6 (m, 2H), 7.85 (m, 1H), 7.9 (d, J=9 Hz, 2H), 8.3 (s, 1H). MS (DCI/NH3) m/z 457 (M+H)+, 474 (M+NH4)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccc(O)cc1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCc1ccc(OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Allylphenol, (6.14 g, 0.046 moles), 4-methoxybenzyl chloride, (6.3 ml, 0.046 moles), potassium carbonate (8.3 g, 0.06 moles) and a catalytic amount of potassium iodide were mixed together in about 200 ml acetone, and heated to reflux, with stirring. The reaction was allowed to proceed overnight, then cooled to room temperature and diluted with about 100 ml water. The product was extracted into ethyl acetate (3 times, 300 ml each time), and then dried over magnesium sulfate/potassium carbonate, filtered and concentrated in vacuo to yield the title compound as a light yellow solid, m.p. 59°-61° C.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[C:19](=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[CH3:19][O:10][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:7]=1[CH3:6]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1C

Procedure:
300 μl of concentrated sulfuric acid is added to a suspension of 2 g of 2-methyl-5-nitrobenzoic acid in 7 ml of methanol. It is refluxed for 6 hours. Then, the reaction mixture is diluted with ethyl acetate and poured into saturated sodium bicarbonate solution. The phases are separated, and the aqueous phase is extracted with ethyl acetate. The combined organic phases are then washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. The crude product that is obtained is incorporated without purification into the next step.
Reaction SMILES: O[C:2]1([C:10]2[CH:11]=[CH:12][C:13]([Br:16])=[N:14][CH:15]=2)[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.S(=O)(=O)(O)O>>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([C:2]23[CH2:3][N:4]([CH2:5][CH2:6]2)[CH2:9][CH:8]=[CH:7]3)=[CH:15][N:14]=1
Reactant: OC1(c2ccc(Br)nc2)CN2CCC1CC2
Agent: O=S(=O)(O)O
Product: Brc1ccc(C23C=CCN(CC2)C3)cn1
Temperature: 190 °C

Procedure:
9.4 g (0.033 mol) of 3-hydroxy-3-(2-bromopyridin-5-yl)-l-azabicyclo[2.2.2]octane and 35 ml of concentrated sulphuric acid are introduced into a 100 ml three-necked flask and the mixture is heated at 190° C. for 1 h 45.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].[CH2:11]([C:15]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=2)=[C:18]([CH2:38][OH:39])[N:17]([CH:40](C)[CH3:41])[N:16]=1)[CH2:12][CH2:13][CH3:14].CC(=CC)C>O.C1COCC1.C(O)(C)(C)C>[CH2:11]([C:15]1[C:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[CH:25][CH:26]=2)=[C:18]([C:38]([OH:39])=[O:6])[N:17]([CH2:40][CH3:41])[N:16]=1)[CH2:12][CH2:13][CH3:14]
Reactant: O=P([O-])(O)O
Reactant: CCCCc1nn(C(C)C)c(CO)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: CCCCc1nn(CC)c(C(=O)O)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 0.33 h
Yield: 98.5 %

Procedure:
A solution of sodium chlorite (80%;0.44 g) and sodium dihydrogen phosphate (0.44 g) in water (5 ml) was added to a mixture of the product of Example 27 (203 mg), 2-methyl-2-butene (2M,0.62 ml) and t-butanol (4 ml) in THF (10 ml) at room temperature. The mixture was stirred vigorously for 20 mins. The mixture was partitioned between ethyl acetate (3×15 ml) and water (15 ml). The combined organic extracts were dried. The solvent was evaporated to give a colourless foam (0.2 g) which was purified by column chromatography on silica gel eluting with System G (50:50:1) to give the title compound as a colourless solid (60 mg).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:10])=[CH:8][CH:9]=1)[CH3:3].C(OC([NH:19][C@H:20]([C:25](O)=O)[C@@H:21]([CH3:24])[O:22][CH3:23])=O)(C)(C)C>>[CH3:23][O:22][C@H:21]([CH3:24])[C@@H:20]([C:25]1[NH:10][C:7]2[CH:8]=[CH:9][C:4]([CH:2]([CH3:1])[CH3:3])=[CH:5][C:6]=2[N:11]=1)[NH2:19]
Reactant: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)c1ccc(N)c(N)c1
Product: CO[C@H](C)[C@H](N)c1nc2cc(C(C)C)ccc2[nH]1

Procedure:
The title compound was prepared according to Method 4 using 4-(1-methylethyl)-1,2-benzenediamine and N-(tert-butoxycarbonyl)-O-methyl-L-threonine (Preparation 51). The residue was purified by elution through an SCX cartridge.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.Cl[CH2:18][C:19]1(OC)[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH2:20]1.[OH:35][CH2:36]C1C=CC(O)=CC=1.BrCC1C=CC(OC)=CC=1.ClCC1(C(F)(F)F)C=CC(OCC2C=CC=CC=2)=CC1>>[CH3:36][O:35][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][O:25][C:22]2[CH:21]=[CH:20][C:19]([CH2:18][S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)=[CH:24][CH:23]=2)=[CH:32][CH:31]=1
Reactant: COC1(CCl)C=CC(OCc2ccccc2)=CC1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Reactant: OCc1ccc(O)cc1
Agent: COc1ccc(CBr)cc1
Agent: FC(F)(F)C1(CCl)C=CC(OCc2ccccc2)=CC1
Product: COc1ccc(COc2ccc(CSc3ccc(OCC(=O)O)c4c3CCC4)cc2)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 12C and 4-chloromethyl-(4-methoxy-benzyloxy-benzene) prepared from 4-hydroxymethyl-phenol and 1-bromomethyl-4-methoxy-benzene in the manner analagous to Examples 14A and 14B. MS m/z 465 (M+1).