Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)CC)C.CS(C)=O>>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: C1COCCN1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cn1
Temperature: 80 °C
Yield: 77.6 %

Procedure:
Into a 8-dram vial, 5-Bromo-2-nitro-pyridine (2.00 g, 9.85 mmol), Morpholine (1.12 g, 12.8 mmol), Triethylamine (1.37 mL, 9.85 mmol) and Dimethyl sulfoxide (10 mL, 100 mmol) were added. The reaction mixture was heated at 80° C. overnight. The reaction was cooled to RT and poured over ice. The solid was filtered and washed with water. The solid was washed with ethanol. The resulting solid was dried under vacuum to give 4-(6-Nitro-pyridin-3-yl)-morpholine as a white solid (1.60 g, 81%).
Reaction SMILES: [C:1]1([C@@:7]2([CH3:35])[C:11](=[O:12])[N:10]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([OH:16])=O)[C:9](=[O:21])[N:8]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=CC([C@@]2(C)C(=O)N([C@@H](CC(C)C)C(OC(C)(C)C)=O)C(=O)N2)=CC=1.C1(C2C=CC(CBr)=CC=2)C=CC=CC=1.C1([C@@]2(C)C(=O)N([C@@H](CC(C)C)C([O-])=O)C(=O)N2CC2C=CC=CC=2)C=CC=CC=1.[NH2:106][C@H:107]([C:116]1[CH:121]=[CH:120][C:119]2[O:122][CH2:123][O:124][C:118]=2[CH:117]=1)[CH2:108][C:109]([O:111]C(C)(C)C)=[O:110].FC(F)(F)C(O)=O>>[C:1]1([C@@:7]2([CH3:35])[C:11](=[O:12])[N:10]([C@@H:13]([CH2:17][CH:18]([CH3:19])[CH3:20])[C:14]([NH:106][C@H:107]([C:116]3[CH:121]=[CH:120][C:119]4[O:122][CH2:123][O:124][C:118]=4[CH:117]=3)[CH2:108][C:109]([OH:111])=[O:110])=[O:16])[C:9](=[O:21])[N:8]2[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:27][CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C[C@H](N)c1ccc2c(c1)OCO2
Reactant: CC(C)C[C@@H](C(=O)O)N1C(=O)N(Cc2ccc(-c3ccccc3)cc2)[C@@](C)(c2ccccc2)C1=O
Agent: BrCc1ccc(-c2ccccc2)cc1
Agent: CC(C)C[C@@H](C(=O)OC(C)(C)C)N1C(=O)N[C@@](C)(c2ccc(Br)cc2)C1=O
Agent: CC(C)C[C@@H](C(=O)[O-])N1C(=O)N(Cc2ccccc2)[C@@](C)(c2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)O)c1ccc2c(c1)OCO2)N1C(=O)N(Cc2ccc(-c3ccccc3)cc2)[C@@](C)(c2ccccc2)C1=O

Procedure:
(by reaction of (S)-2-((S)-4-phenyl-3-((4-biphenylyl)methyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetic acid (obtainable by reaction of 169.2 with 4-phenylbenzyl bromide analogously to the synthesis of 169.3 and subsequent reactions analogously to the preparation of 169.5) with tert-butyl (S)-3-amino-3-(3,4-methylenedioxyphenyl)propionate and subsequent cleavage of the tert-butyl ester with trifluoroacetic acid)
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[O:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([O-:29])=O)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>>[CH3:22][O:17][CH2:18][CH2:19][NH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:27](=[O:29])[C:26]3[CH:25]=[CH:24][C:23]([N:20]4[CH2:19][CH2:18][O:17][CH2:22][CH2:21]4)=[CH:31][CH:30]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccc(N2CCOCC2)cc1
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Product: COCCNc1ccc(C(=O)c2ccc(NC(=O)c3ccc(N4CCOCC4)cc3)cc2)cc1

Procedure:
Compound 493 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-morpholinobenzoate. [M+H]+ calcd for C27H29N3O4: 460.06; found: 460.12.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH2:4]C)([CH3:3])C.[CH3:16][C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1.ClCCl>N1C=CC=CC=1>[CH:1]([C:6]1[CH:7]=[CH:8][C:9]([S:12]([NH:22][C:20]2[N:19]([C:23]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:24]=3[CH:25]=[CH:26][CH:27]=[N:28]4)[N:18]=[C:17]([CH3:16])[CH:21]=2)(=[O:13])=[O:14])=[CH:10][CH:11]=1)([CH3:3])[CH3:4]
Reactant: Cc1cc(N)n(-c2cccc3ncccc23)n1
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(NS(=O)(=O)c2ccc(C(C)C)cc2)n(-c2cccc3ncccc23)n1
Temperature: 80 °C
Yield: 50 %

Procedure:
A mixture of 4-t-pentylbenzenesulfonyl chloride (0.028 g, 0.13 mmol) and 3-methyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (prepared from Example 4 step b, 0.023 g, 0.10 mmol) in pyridine (1.0 mL) was heated at 80° C. for 18 h with stirring. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.020 g, 0.05 mmol, 50%). 1H NMR (400 MHz, CDCl3) δ 9.02 (d, J=4.4 Hz, 1H), 8.43 (d, J=8.8 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.87-7.33 (m, 2H), 7.72-7.70 (m, 3H), 7.35 (s, 1H), 7.33 (s, 1H), 5.94 (s, 1H), 3.04-2.98 (m, 1H), 2.32 (s, 3H), 1.29 (s, 6H); MS: (ES) m/z calculated for C22H23N4O2S [M+H]+ 407.2. found 407.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([OH:16])=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]#[N:15])=[CH:6]1)[CH3:2].[Na].C(O)=O>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([C:14]#[N:15])[CH2:6]1)=[O:16])[CH3:2]
Reactant: CCOC(O)=C1C=C(C#N)c2ccccc21
Agent: [Pd]
Agent: [Na]
Solvent: O=CO
Solvent: CCO
Product: CCOC(=O)C1CC(C#N)c2ccccc21
Yield: 87 %

Procedure:
A solution of 3-(ethoxy-hydroxy-methylene)-3H-indene-1-carbonitrile, sodium salt, (1.00 g, 4.70 mmol) in ethanol (40 mL) in a pressure reactor was purged with nitrogen for 5 minutes and charged with 5% palladium on carbon (1.00 g, 0.230 mmol) and formic acid (0.180 mL, 4.70 mmol), pH=5 at reaction initiation. The pressure reactor was purged with nitrogen and evacuated three times, then purged with hydrogen and evacuated three times before charging the bomb with hydrogen at a pressure of 50 psi (3.4 atmospheres) and mechanically shaking. After 2 hours the reactor was evacuated and purged with nitrogen three times before filtering the reaction mixture through a nylon disk. Azeotropic removal of formic acid in vacuo with ethanol and concentrating in vacuo afforded 3-cyano-indan-1-carboxylic acid ethyl ester as a light yellow solid (880 mg, 87%). 1H NMR (400 MHz, CD3CN) δ 7.47–7.45 (m, 2H), 7.37–7.35 (m, 2H), 4.28 (t, 1H, J=8.0), 4.20 (m, 2H), 4.16 (t, 1H, J=3), 2.80 (m, 1H), 2.60 (m, 1H), 1.27 (t, 3H, J=7.2); 13C NMR (100 MHz, CD3CN) δ 172.3, 140.8, 138.5, 129.0, 128.7, 125.4, 124.7, 117.6, 61.3, 48.9, 33.4, 33.3, 13.8; 13C NMR (100 MHz, d4-MeOH) δ 172.6, 140.4, 138.1, 129.0, 128.8, 125.4, 124.7, 120.9, 61.4, 48.9, 33.2, 33.1, 13.4; IR (ATR, neat) 1732, 1478, 1457, 1370, 1324, 1263, 1208, 1180, 1035, 747.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:4]1[CH2:20][NH2:21].[C:22]([NH:32][CH2:33][C:34](O)=[O:35])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>>[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:4]1[CH2:20][NH:21][C:34](=[O:35])[CH2:33][NH:32][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: Cn1c(CN)c(-c2ccccc2Cl)c2cc(Cl)ccc21
Agent: Cl
Product: Cn1c(CNC(=O)CNC(=O)OCc2ccccc2)c(-c2ccccc2Cl)c2cc(Cl)ccc21

Procedure:
Using 1-methyl-2-aminomethyl-3-o-chlorophenyl-5-chloroindole hydrochloride and N-carbobenzoxy-glycine, the reaction is effected as in Example 12 (1), whereby 1-methyl-2-(N-carbobenzoxy-glycylaminomethyl)-3-o-chlorophenyl-5-chloroindole is obtained as crystals melting at 96° to 98° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]#[N:12])[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CC(C)=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]#[N:12])[C:5]([O:7][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:6]
Reactant: N#Cc1ccc(C(=O)O)cc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C(=O)OCc2ccccc2)cc1Br
Temperature: 25 °C
Yield: 45.3 %

Procedure:
To a solution of 3-bromo-4-cyanobenzoic acid (1.51 g, 6.69 mmol) in acetone (30 mL) was added cesium carbonate (4.4 g, 13.4 mmol) and benzyl bromide (790 uL, 6.69 mmol). The mixture was stirred at reflux for 15 hours at which point additional benzyl bromide was added (200 uL, 1.68 mmol). The mixture was stirred at reflux for a further 2 h and was then cooled to room temperature. Water and ethyl acetate were added and the layers were separated. The aqueous phase was then saturated with lithium chloride and extracted with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (4:1 hexanes:ethyl acetate) to provide phenylmethyl 3-bromo-4-cyanobenzoate (957 mg, 3.03 mmol, 45% yield) as a yellow orange oil that slowly solidified. 1H NMR (400 MHz, CDCl3): 8.35 (d, 1H), 8.09 (dd, 1H), 7.73 (d, 1H), 7.46-7.35 (m, 5H), 5.35 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[C:12]2B1OC(C)(C)C(C)(C)O1.Cl[C:38]1[CH:43]=[C:42]([O:44][CH3:45])[N:41]=[C:40]([NH:46][C@@H:47]2[CH2:52][CH2:51][CH2:50][N:49]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:48]2)[N:39]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:19])=[O:20])[CH:13]=[C:12]2[C:38]1[CH:43]=[C:42]([O:44][CH3:45])[N:41]=[C:40]([NH:46][C@@H:47]2[CH2:52][CH2:51][CH2:50][N:49]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:48]2)[N:39]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4c(F)cccc4F)ccc32)cc1
Reactant: COc1cc(Cl)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4c(F)cccc4F)cc23)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)n1
Temperature: 90 °C
Yield: 62 %

Procedure:
To a solution of 5-(2,6-difluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole (600 mg, 1.17 mmol), and (R)-tert-butyl 3-((4-chloro-6-methoxypyrimidin-2-yl)amino)piperidine-1-carboxylate (483 mg, 1.41 mmol) in DME (12 mL) and water (3 mL) was added Pd(PPh3)4 (270 mg, 0.234 mmol) and Na2CO3 (372 mg, 3.51 mmol) and argon gas was bubbled for 15 min. The above mixture was heated at 90° C. for 8 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 30% EtOAc in petroleum ether) to give (R)-tert-butyl 3-((4-(5-(2,6-difluorophenyl)-1-tosyl-1H-indol-3-yl)-6-methoxypyrimidin-2-yl)amino)piperidine-1-carboxylate (500 mg, 62.5%). MS (ESI, pos. ion) m/z: 690.2 (M+1); 1H-NMR (400 MHz CDCl3): δ ppm 8.16 (s, 1H), 8.09 (d, J=8 Hz, 1H), 7.84-7.90 (m, 3H), 7.26-7.46 (m, 6H), 7.02 (m, 2H), 6.41 (s, 1H), 5.07 (brs, 1H), 4.10-4.14 (m, 1H), 3.93 (s, 3H), 2.37 (s, 3H), 1.25-1.60 (m, 15H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=2[N+:10]([O-:12])=[O:11])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)cc(Cl)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Yield: 27.8 %

Procedure:
A solution of 1,3,5-trichloronitrobenzene (800 mg) and 1-t-butoxycarbonyl-piperazine (790 mg) in toluene (20 ml) was stirred at 80° C. under N2 for 15 hours. The reaction mixture was cooled to room temperature, partitioned between water and ethyl acetate, the organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was subjected to silica gel chromatography (cyclohexane:ethyl acetate 8:2) to afford 4-(3,5-dichloro-2-nitrophenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.37 g). 1H NMR (400 MHz, CDCl3) 1.5 (s, 9H), 2.9 (m, 4H), 3.5 (m, 4H), 7.0 (d, J=2 Hz, 1H), 7.16 (d, J=2 Hz, 1H); Retention Time HPLC 2.33 min; MS (ES+) 276/278 (M-BOC), 317/319 (M-isoprene).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CN[NH:21][S:22](Cl)(=[O:24])=[O:23].[CH3:26]N(C)C=O>>[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][S:22]([NH:21][CH3:26])(=[O:24])=[O:23])=[CH:14][CH:13]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: CNNS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: CNS(=O)(=O)Nc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
Sodium hydride (18 mg) was suspended in dimethylformamide, and to the suspension was added a solution of N-t-butyloxycarbonyl-p-aminobenzylamine (150 mg) and methylaminosulfamoylchloride (97 mg) in dimethylformamide while the temperature was controlled to 0° C., followed by stirring at room temperature for 3 hours. The reaction solution was evaporated under reduced pressure, and the residue was diluted with ethyl acetate (70 ml), washed with saturated aqueous sodium bicarbonate solution, water and saturated saline, and then evaporated under reduced pressrure. The obtained residue was purified by column-chromatography (hexane/ethyl acetate=5/1) to yield the compound 35-1a (170 mg, 79%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: ClC1C=C(CC2C=C3C(=C4C=CC=CC=24)N=CN([C@H]2CC[O:26][CH2:25][C@@H]2O)C3=O)C=CN=1.Cl[C:32]1[CH:37]=[C:36]([CH2:38][OH:39])[CH:35]=[CH:34][N:33]=1>>[CH3:25][O:26][C:32]1[CH:37]=[C:36]([CH2:38][OH:39])[CH:35]=[CH:34][N:33]=1
Reactant: OCc1ccnc(Cl)c1
Reactant: O=c1c2cc(Cc3ccnc(Cl)c3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Product: COc1cc(CO)ccn1

Procedure:
The title compound was prepared by the procedure described for the synthesis of 6-[(2-chloropyridin-4-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one in Example 15, substituting (2-methoxypyridin-4-yl)methanol for 2-chloropyridine-4-methanol. The resultant orange solid gave proton NMR spectra consistent with theory and a mass ion (ES+) of 418.1779 for [M+H]+ [Calc'd for C24H24N3O4, [M+H]+=418.1761]: 1H NMR (400 MHz, d6-DMSO) δ 9.01 (d, J=7.7 Hz, 1H), 8.71 (s, 1H), 8.11 (d, J=8.0 Hz, 1H), 8.05 (s, 1H), 7.81-7.74 (m, 2H), 7.56-7.54 (m, 1H), 5.32 (d, J=5.5 Hz, 1H), 4.64 (br s, 1H), 4.37 (s, 2H), 4.17 (br 5, 1H), 4.18-3.97 (m, 2H), 3.51-3.43 (m, 1H), 3.34 (s, 3H), 3.15 (t, J=10.3 Hz, 1H), 2.25 (br s, 1H), 1.91 (d, J=12.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][N:22]2[CH:26]=[C:25]([CH2:27][C:28]([O:30]CC)=[O:29])[C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:23]2)=[CH:17][CH:16]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][N:22]2[CH:26]=[C:25]([CH2:27][C:28]([OH:30])=[O:29])[C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:23]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccccc4)sc3C)nc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(Cn2cc(CC(=O)O)c(-c3ccccc3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
After a mixture of ethyl [1-[6-(5-methyl-2-phenyl-4-thiazolylmethoxy)-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetate (475 mg), 1N sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml), and ethanol (4 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (2 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain [1-[6-(5-methyl-2-phenyl-4-thiazolylmethoxy)-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetic acid (402 mg, yield: 89%). This was recrystallized from ethanol-hexane. Melting point: 140–141° C.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[C:9]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])=[N:10][O:11][C:12]=2[CH:13]([CH3:15])[CH3:14])=[CH:4][C:3]=1[CH3:26].C(=O)([O-])[O-].[Na+].[Na+].[C:33]([C:36]1[C:44]2[CH:43]=[C:42](B(O)O)[S:41][C:40]=2[CH:39]=[CH:38][CH:37]=1)([OH:35])=[O:34]>O1CCOCC1>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[C:9]1[C:8]([CH2:7][O:6][C:5]2[CH:24]=[CH:25][C:2]([C:42]3[S:41][C:40]4[CH:39]=[CH:38][CH:37]=[C:36]([C:33]([OH:35])=[O:34])[C:44]=4[CH:43]=3)=[C:3]([CH3:26])[CH:4]=2)=[C:12]([CH:13]([CH3:15])[CH3:14])[O:11][N:10]=1
Reactant: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)ccc1Br
Reactant: O=C(O)c1cccc2sc(B(O)O)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)ccc1-c1cc2c(C(=O)O)cccc2s1
Reaction time: 1 h
Yield: 27.2 %

Procedure:
To a 60° C. suspension of 4-(4-Bromo-3-methyl-phenoxymethyl)-3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazole (0.90 mmol; 410 mg) in a 2M solution of sodium carbonate (7.20 mmol; 3.6 mL) and 1.5 mL of deoxygenated dioxane under a nitrogen atmosphere is slowly added a solution of 4-carboxy-benzo[b]thiophen-2-boronic acid (1.08=mol; 240 mg) in 3.5 mL of deoxygenated dioxane over 1 h via an addition pump. The mixture is stirred for 1 h. The organic solvent is removed under reduced pressure and the residue is acidified with 1N HCl to pH 4. The resulting solution is extracted with dichloromethane. The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is chromatographed using a gradient from 100% dichloromethane to 100% ethyl acetate to obtain a solid which is washed with acetonitrile to yield the title compound (135 mg, 27%) as a white solid.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]1[S:20][CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li]CCCC.[CH3:42][Sn:43](Cl)([CH3:45])[CH3:44]>C1COCC1.C(OCC)(=O)C>[CH3:42][Sn:43]([CH3:45])([CH3:44])[C:17]1[S:16][C:15]([C:19]2[S:20][C:21]([Sn:43]([CH3:45])([CH3:44])[CH3:42])=[CH:22][C:23]=2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:18]=1
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCCCCCCCCCOc1ccsc1-c1sccc1OCCCCCCCCCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCOc1cc([Sn](C)(C)C)sc1-c1sc([Sn](C)(C)C)cc1OCCCCCCCCCCCC
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 81.5 %

Procedure:
A solution of 2.9 g (5.42 mmol) of 3,3′-didodecyloxy-2,2′-bithiophene (Org. Lett. 2008, 10, 5333) in 150 mL of THF was cooled to −78° C. The resulting suspension was treated dropwise with 5.2 mL (13.0 mmol) of n-BuLi (2.5 M in hexanes) and stirred for an additional 45 minutes. The dry ice bath was then removed and the mixture was stirred at ambient temperature for 1.25 hours. The suspension was cooled to −78° C. and treated with a solution of 3.02 g (15.2 mmol) of trimethyltin chloride in 15 mL of THF. The mixture was stirred for 90 minutes at ambient temperature. The mixture was diluted with 100 mL of ethyl acetate and washed successively with 50 mL of water and 50 mL of brine. The separated organic layer was dried over K2CO3, filtered, and concentrated in vacuo. The resulting solid was recrystallized from cold pentane to give 3.8 g (81% yield) of 5,5′-bis(trimethylstannyl)-3,3′-bis(dodecyloxy)2,2′-bithiophene as light tan needles. m.p. 66-67° C. 1H NMR (500 MHz) δ 6.88 (s, 2H), 4.11 (t, 4H, J=6.4 Hz), 1.84 (m, 4H), 1.55-1.30 (m, 36H), 0.88 (m, 6H), 0.36 (s, 18H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.C(OCC)C>CN(C)C=O.O>[Si:14]([O:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[CH:10]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: O=C(O)c1cc(O)cc(C(=O)O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1cc(C(=O)O)cc(C(=O)O)c1
Reaction time: 8 h
Yield: 68.2 %

Procedure:
5-Hydroxyisophthalic acid (9.11 g, 50.0 mmole) and t-butyldimethylsilyl chloride (25.2 g, 167 mmole) were dissolved in anhydrous N,N-dimethylformamide (55 ml). Upon adding imidazole (20.4 g, 300 mmole), the solution was stirred overnight before shaking with diethyl ether (200 ml) and water (600 ml). The organic layer was reduced in volume by evaporation to a clear oil, which was mixed with tetrahydrofuran (45 ml), water (30 ml), glacial acetic acid (30 ml) and acidified with 37% HCl solution. The reaction mixture was stirred for a couple of hours. Upon evaporating off THF, the solution was shaken with methylene chloride (200 ml) and water (200 ml). The organic was washed twice with water (200 ml each), and the insoluble product was collected by filtration. Additional product was collected by washing with water the solid residue from evaporating off the solvent. A total of 10.1 g (68%) of (a) was obtained with its structure validated by proton NMR spectroscopy.