Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[S:3]1[C:7]2[CH2:8][CH2:9][CH:10]([C:12]([O:14]CC)=[O:13])[CH2:11][C:6]=2[N:5]=[CH:4]1>CO>[S:3]1[C:7]2[CH2:8][CH2:9][CH:10]([C:12]([OH:14])=[O:13])[CH2:11][C:6]=2[N:5]=[CH:4]1
Reactant: CCOC(=O)C1CCc2scnc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCc2scnc2C1
Reaction time: 6 h

Procedure:
6 ml of 2N NaOH are added to a solution of 0.42 g of ethyl 4,5,6,7-tetrahydrobenzothiazole-5-carboxylate [952203-30-8] and 24 ml of MeOH at room temperature. After 6 hours, the reaction mixture is evaporated. The residue is acidified with 4N HCl, diluted with water and extracted with ethyl acetate (2×)—the combined organic phases are dried with sodium sulphate and evaporated. The crude title compound is obtained from the residue.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].CC[O-].[Na+].Br[CH:21]([CH2:27][CH2:28][CH2:29][CH3:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CCO>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][CH:21]([CH2:27][CH2:28][CH2:29][CH3:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: CCCCC(Br)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCC(Oc1ccc(C(C)(C)C)cc1C(C)(C)C)C(=O)OCC
Temperature: 140 °C
Yield: 98 %

Procedure:
206 g (1 mol) of 2,4-di-tert-butylphenol were melted and heated to 140° C. under nitrogen. 234 g (1.03 mol) of a 30% strength NaOEt solution in EtOH and 245 g (1.1 mol) of ethyl 2-bromocaproate were metered in simultaneously in the course of 1 hour. During the addition, EtOH was distilled off. After the addition, the reaction was ended. The mixture was cooled to 90° C. and 250 ml of water were added. After separation of the phases and washing with 200 ml of water, 347 g of a viscous yellow oil of the following composition (0.3% of ethyl bromocaproate, 0.5% of residual phenol and 98% of ethyl 2-(2,4-di-tert-butylphenoxy)caproate, remained. This corresponds to a yield of 98% of theory, based on the phenol employed.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[N+:19]([C:22]1[N:23]=[C:24]2[N:29]([CH:30]=1)[CH2:28][CH2:27][C@H:26]([CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]3[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]3)=[CH:35][CH:34]=1)[O:25]2)([O-:21])=[O:20].[F:46][C:47]([F:65])([F:64])[O:48][C:49]1[CH:63]=[CH:62][C:52]([CH2:53][O:54][C:55]2[CH:60]=[CH:59][C:58]([NH2:61])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>C(Cl)Cl.ClCCCl>[N+:19]([C:22]1[N:23]=[C:24]2[N:29]([CH:30]=1)[CH2:28][CH2:27][C@H:26]([CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]3[CH2:44][CH2:43][CH:42]([NH:61][C:58]4[CH:57]=[CH:56][C:55]([O:54][CH2:53][C:52]5[CH:62]=[CH:63][C:49]([O:48][C:47]([F:46])([F:64])[F:65])=[CH:50][CH:51]=5)=[CH:60][CH:59]=4)[CH2:41][CH2:40]3)=[CH:35][CH:34]=1)[O:25]2)([O-:21])=[O:20]
Reactant: Nc1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Reactant: O=C1CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCC(Nc4ccc(OCc5ccc(OC(F)(F)F)cc5)cc4)CC3)cc1)CC2
Temperature: 25 °C
Reaction time: 120 h
Yield: 67 %

Procedure:
Sodium triacetoxyborohydride (0.32 g) and acetic acid (1 ml) were added to a 1,2-dichloroethane solution (8 ml) of 1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-one (0.40 g) and 4-(4-trifluoromethoxybenzyloxy)phenylamine (0.33 g), and the mixture was stirred at room temperature for 5 days. The reaction mixture was diluted with methylene chloride. The result was washed with a potassium carbonate aqueous solution and water in this order, and then dried over magnesium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=1:0→methylene chloride:methanol=9:1) to afford the title compound as a yellow powder (0.46 g).
Reaction SMILES: C[O:2][C:3]1[N:4]=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([CH2:13][C:14]([OH:16])=[O:15])[CH:7]=2.Br>>[OH:2][C:3]1[N:4]=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([CH2:13][C:14]([OH:16])=[O:15])[CH:7]=2
Reactant: COc1cc2ccc(CC(=O)O)cc2cn1
Agent: Br
Product: O=C(O)Cc1ccc2cc(O)ncc2c1

Procedure:
Refluxing 1 part of 3-methoxy-2-azanaphthalene-7-acetic acid in 25 parts by volume of 16% hydrobromic acid followed by extraction with methylene chloride and isolation provides 3-hydroxy-2-azanaphthalene-7-acetic acid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:16]CC(C1C=CC(N2CCCCC2)=CC=1)=O>>[Br:16][CH2:14][C:13]([C:10]1[CH:9]=[CH:8][C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:12][CH:11]=1)=[O:15]
Reactant: O=C(CBr)c1ccc(N2CCCCC2)cc1
Reactant: CC(=O)c1ccc(N2CCOCC2)cc1
Product: O=C(CBr)c1ccc(N2CCOCC2)cc1

Procedure:
This compound was prepared from 1-[4-(4-morpholinyl)phenyl]ethanone (Aldrich) by procedures analogous to those used to prepare 2-bromo-1-[4-(1-piperidinyl)phenyl]ethanone (Example 7).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:14])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:3][CH2:4][OH:5].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[S:21]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:14])[CH2:10][CH:11]([CH3:13])[CH3:12])([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=CCCC(C)CCO)CC(C)C
Solvent: c1ccncc1
Product: CC(=CCCC(C)CCOS(=O)(=O)c1ccc(C)cc1)CC(C)C
Temperature: 0 °C

Procedure:
79.5 g. of 3,7,9-trimethyl-6-decen-1-ol and 75 ml. of pyridine are treated portionwise with 76 g. of toluene-4-sulphonic acid chloride while cooling with ice and stirring. The thus-obtained thick, cream-colored mass is then stirred for a further 5 hours at 0°-5° C. For the working-up, the mixture is poured on to 420 ml. of ice-water and 140 ml. of concentrated aqueous hydrochloric acid and extracted twice with 300 ml. of ether each time. The extracts are washed twice with water, then with semisaturated aqueous sodium chloride solution and finally with saturated sodium chloride solution dried over sodium sulphate/potassium carbonate and evaporated. There is obtained 1-tosyloxy-3,7,9-trimethyl-6-decene.
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4N(CCC#N)C(=O)COC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:39][C:40]1([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[C:51]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)=[CH:52][C:53]4[N:58]([CH3:59])[C:57](=[O:60])[CH:56]([CH2:61][O:62][CH3:63])[O:55][C:54]=4[N:64]=3)=[CH:46][CH:45]=2)[CH2:43][CH2:42][CH2:41]1)(C)(C)C>>[NH2:39][C:40]1([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[C:51]([C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)=[CH:52][C:53]4[N:58]([CH3:59])[C:57](=[O:60])[CH:56]([CH2:61][O:62][CH3:63])[O:55][C:54]=4[N:64]=3)=[CH:46][CH:45]=2)[CH2:41][CH2:42][CH2:43]1
Reactant: COCC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N(C)C1=O
Agent: N#CCCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Product: COCC1Oc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc2N(C)C1=O
Yield: 98.8 %

Procedure:
Following the procedure for 3-(6-(4-(1-aminocyclobutyl)phenyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)propanenitrile, tert-butyl(1-(4-(3-(methoxymethyl)-1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (35 mg, 0.066 mmol) was reacted to afford the title compound (28 mg). 1H NMR (500 MHz, CH3OD) 7.49 (s, 1H), 7.42 (d, 2H), 7.38 (d,2H), 7.31 (m, 3H), 7.25 (m, 2H), 5.19 (t, 1H), 4.02 (dd, 1H), 3.92 (dd, 1H), 3.44 (s, 3H), 2.74-2.79 (m, 2H), 2.56-2.60 (m, 2H), 2.21-2.26 (m, 1H), 1.94-1.99 (m, 1H). LCMS (Method D): RT=0.79 min, M+H+=430.2.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:24]=[CH:23][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)=[N:12][S:13](=[O:15])(=[O:14])[C:9]=2[CH:8]=1.[NH:25]1[CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:24]=[CH:23][C:10]3[C:11]([C:16]4[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=4)=[N:12][S:13](=[O:14])(=[O:15])[C:9]=3[CH:8]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: O=S1(=O)N=C(c2ccc(Br)cc2)c2ccc(OCCCCBr)cc21
Reactant: C1CNC1
Product: O=S1(=O)N=C(c2ccc(Br)cc2)c2ccc(OCCCCN3CCC3)cc21

Procedure:
According to the method in example 9, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole 1,1-dioxide and azetidine were converted to yield 6-(4-Azetidin-1-yl-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole 1,1-dioxide as yellow solid, MS: 449 (MH+, 1Br).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].[CH2:15]([O:17][C:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29](O)=[O:30])[CH:27]=2)[CH:22]=[CH:21]1)=[O:19])[CH3:16].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(O)(C(F)(F)F)=O>CN(C=O)C.CO.O>[CH:8]1([NH:7][C:5]([C:4]2[CH:11]=[CH:12][C:13]([CH3:14])=[C:2]([NH:1][C:29]([C:26]3[CH:27]=[C:28]4[C:23]([CH:22]=[CH:21][N:20]4[C:18]([O:17][CH2:15][CH3:16])=[O:19])=[CH:24][CH:25]=3)=[O:30])[CH:3]=2)=[O:6])[CH2:9][CH2:10]1
Reactant: CCOC(=O)n1ccc2ccc(C(=O)O)cc21
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCOC(=O)n1ccc2ccc(C(=O)Nc3cc(C(=O)NC4CC4)ccc3C)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-amino-N-cyclopropyl-4-methylbenzamide (0.025 g, 0.11 mmol) in anhydrous DMF (0.5 mL), are sequentially added 1-(ethoxycarbonyl)-1H-indole-6-carboxylic acid (0.026 g, 0.11 mmol, prepared according to a similar procedure outlined for step A, Example 128 in WO 2002/014308) triethylamine (61 μL, 0.44 mmol) and BOP (0.098 g, 0.22 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h, diluted with MeOH (0.5 mL) and subjected to reverse phase preparative HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA). The desired fractions were collected, and concentrated using speedVac® Plus (SC250DDA) to yield the title compound (Example 218, 0.010 g). HPLC Ret. time (YMC S5 Combiscreen ODS; 4.6×50 mm (4 min. gradient); Solvent A=10% MeOH, 90% H2O, 0.2% H3PO4; solvent B=90% MeOH, 10% H2O, 0.2% H3PO4): 3.18 min. LCMS [M+H]+ 406.3.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[H-].[Na+].[F:11][C:12]([F:22])([F:21])[C:13]([F:20])([F:19])[C:14](OCC)=[O:15].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[F:19][C:13]([F:20])([C:12]([F:22])([F:21])[F:11])[C:14](=[O:15])[CH2:2][C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)=[O:3]
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Reactant: CC(=O)c1cccs1
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(CC(=O)C(F)(F)C(F)(F)F)c1cccs1
Reaction time: 0.25 h

Procedure:
2-Acetylthiophene (4.3 ml) was dissolved in dry toluene (40 ml). Sodium hydride (60%, 3.2 g) was added slowly and the mixture was stirred for 15 minutes. Ethyl pentafluoropropionate (13.44 g) was added and the stirring was continued overnight. Sulfuric acid (10%, 50 ml) was added and the phases were separated. The organic phase was washed with water (50 ml) and it was evaporated to dryness. The residue was distilled (b.p. 92–94° C./0.15 mbar) to give the product (9.0 g). 1H NMR (CDCl3): 6.50 (s, 1 H); 7.21 (dd, 1 H, J=3.9 & 4.9); 7.77 (dd, 1 H, J=1.1 & 4.9 Hz); 7.85 (dd, 1 H, J=1.1 & 3.9 Hz). IR (film): 1592 (C═O); 1202 (C—F).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]([O:17][CH2:18][CH3:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[C:13]([F:16])([F:15])[F:14].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[O:26][C:27]=1[CH3:28].FC1C=CC=CC=1C=O.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([O:17][CH2:18][CH3:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[F:35])[O:26][C:27]=2[CH3:28])=[CH:8][C:7]=1[C:13]([F:16])([F:14])[F:15]
Reactant: CCO[C@@H](Cc1ccc(O)cc1C(F)(F)F)C(=O)OC
Reactant: Cc1oc(-c2ccccc2F)nc1CCl
Agent: O=C([O-])[O-]
Agent: O=Cc1ccccc1F
Agent: [Cs+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3F)oc2C)cc1C(F)(F)F)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-2-ethoxy-3-(4-hydroxy-2-trifluoromethyl-phenyl)-propionic acid methyl ester (example 21 f]) was reacted with with 4-chloromethyl-2-(2-fluoro-phenyl)-5-methyl-oxazole (prepared from 2-fluoro-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 5 a] and 2 b]) in the presence of cesium carbonate and potassium iodide to yield (S)-2-ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-trifluoromethyl-phenyl}-propionic acid methyl ester as colorless solid.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24]>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:19][C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25][CH3:26])=[O:24])=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: COC(=O)c1cccc(N)c1
Agent: [Na+]
Product: COC(=O)c1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1
Yield: 43 %

Procedure:
The product is prepared according to the procedure described in Example 19, using 653 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 and 567 mg of methyl 3-aminobenzoate in place of the 3-(tert-butyl)aniline. 400 mg of methyl 3-({[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}amino)benzoate are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=2[S:6][C:7]=1[C:8](O)=[O:9].S(Cl)([Cl:17])=O>CN(C)C=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]2[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=2[S:6][C:7]=1[C:8]([Cl:17])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C(=O)O)sc2ccccc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(=O)Cl)sc2ccccc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
An ice-cooled suspension of 3-methoxybenzo[b]thiophene-2-carboxylic acid (0.62 g, 0.003 m) and dried methylene chloride (25 ml) was treated under nitrogen with thionyl chloride (2.0 ml) and dimethylformamide (1 drop). After stirring overnight two times at ambient temperatures, the volatiles were removed in vacuo, and the solid residue washed twice by addition and removal in vacuo of small portions of benzene. The resultant off-white solid was used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12]O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:38]I>C1(C)C=CC=CC=1>[I:38][CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(CCCCO)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CCCCI)cc1
Temperature: 65 °C

Procedure:
To a stirred solution of 4-(4-methoxyphenyl)butan-1-ol (9.37 g, 52 mmol, Aldrich) in dry toluene (185 mL) under an argon atmosphere was added triphenylphosphine (17.8 g, 67.6 mmol) and imidazole (10.6 g, 156 mmol). After ten minutes I2 (17.1 g, 67.6 mmol) was added. The reaction was then heated at 65 ° C. for 30 minutes. Upon cooling to room temperature the reaction was concentrated to 1/4 volume. The remaining solution was diluted with Et2O and washed with H2O and brine and dried (MgSO4). The solvent was removed and the resulting residue was dissolved in CH2Cl2 and applied to a flash chromatography column (silica). Elution with 2% EtOAc in hexane provided a colorless oil: 1H NMR (250 MHz, CDCl3) δ7.08 (d, J=8.7 Hz, 2H, phenyl), 6.82 (d, J=8.7 Hz, 2H, phenyl), 3.78 (s, 3H, OMe), 3.17 (t, J=7.4 Hz, 2H, I-CH2), 2.54 (t, J=7.2 Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 160 (m, 2H, CH2).
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[Na].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[N:9]=1>C1COCC1.CCOC(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[N:9]=1
Reactant: Brc1cccc(Br)n1
Reactant: OC1CCC1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1cccc(OC2CCC2)n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To cyclobutanol (1 mL), was added sodium (36 mg, 1.56 mmol). When the sodium was consumed, the mixture was diluted with 1 mL THF and 2,6-dibromopyridine (250 mg, 1.06 mmol). The mixture was stirred at 90° C. for 3 h, then was diluted with EtOAc. The organic phase was washed with water (2×) and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash chromatography (0 to 10% EtOAc/hexanes gradient) to afford 106 mg of 158.1 as a colorless oil. LCMS (2 min gradient) RT=1.87 min, 228.17 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH2:11].CO[C:15]([CH3:17])=[CH2:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][CH:15]([CH3:17])[CH3:16]
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: C=C(C)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)ccc1NC(C)C
Temperature: 25 °C
Reaction time: 84 h
Yield: 79.7 %

Procedure:
To a solution of 500 mg of 2-amino-5-chlorobenzoic acid methyl ester (2.69 mmol) were added slowly 380 μl of 2-methoxypropene (4.04 mmol), 154 μl of acetic acid (2.69 mmol) and 951 mg of sodium triacetoxyborohydride (4.04 mmol). The reaction mixture was stirred at RT for 3.5 d, then 1N NaOH solution was added and the mixture was extracted with DCM. The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The remaining residue was purified by column chromatography (silica gel; heptane 100% to heptane/EtOAc 9:1) to give 488 mg (80%) of a yellow liquid. MS (ISP) 228.1 (M+H)+.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[OH:11].I[C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:23])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1>[Cu].O>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[O:11][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:23])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1
Reactant: CC(C(=O)O)c1ccc(I)cc1
Reactant: Oc1ccc(F)cc1F
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)c1ccc(Oc2ccc(F)cc2F)cc1
Reaction time: 2 h

Procedure:
Potassium hydroxide (3.4 g.) was fused at 180°C. with water (1 ml.), and 2,4-difluorophenol (5.2 g.) added. 2-(4-Iodophenyl)propionic acid (5.5 g.) and copper bronze (0.2 g.) were then added to the melt, and the resulting mixture was stirred at 160°-170°C. for 2 hours. The cooled solid was extracted with methylene chloride containing a little dilute hydrochloric acid, filtered, and the solution extracted with dilute potassium carbonate solution. The aqueous extract was washed with ether and acidified with dilute hydrochloric acid; the resulting oil was isolated in ether and evaporated to dryness. The resulting solid was purified by preparative layer chromatography using 5% acetic acid/petroleum ether b.p. 62°-68°C. and eluting with ethyl acetate; recrystallization from petroleum ether b.p. 80°-100°C. gave 2-[4-(2,4-difluorophenoxy)phenyl] propionic acid, m.p. 105°-106°C.
Reaction SMILES: [CH3:1][C:2]([N+:15]([O-:17])=[O:16])([CH3:14])[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:7]2=[N:6][CH:5]=1.Cl[CH2:19][C:20]([NH2:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[CH3:14][C:2]([N+:15]([O-:17])=[O:16])([CH3:1])[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][C:11]([O:13][CH2:19][C:20]([NH2:22])=[O:21])=[CH:12][C:7]2=[N:6][CH:5]=1
Reactant: CC(C)(Cc1cnc2cc(O)ccn12)[N+](=O)[O-]
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(Cc1cnc2cc(OCC(N)=O)ccn12)[N+](=O)[O-]
Yield: 34.3 %

Procedure:
3-(2-Methyl-2-nitropropyl)imidazo[1,2-a]pyridin-7-ol (1.5 g, 6.38 mmol), chloroacetamide (1.19 g, 12.73 mmol), potassium carbonate (6.4 mmol) and a small amount of potassium iodide in 2-butanone (30 ml) is heated at reflux overnight. The solids are removed by filtration and the filtrate is concentrated under reduced pressure. The residue is chromatographed on silica gel with dichloromethane/methanol 3:1 to 1:1 to give 640 mg of 2-[3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridin-7-yloxy]-acetamide (34%).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O.[OH-].[Li+]>O1CCCC1.O>[C:16]([O:15][C:13]([NH:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][C:3]([OH:20])=[O:2])=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)Cc1ccccc1CNC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccccc1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 5a in tetrahydrofuran (0.3 M) at room temperature was added a solution of lithium hydroxide monohydrate (1.2 M) in H2O (0.4 M). The reaction was stirred at room temperature overnight. The tetrahydrofuran was removed under reduced pressure. The remaining aqueous phase was acidified with concentrated hydrochloric acid. The precipitated product was filtered off and dried to afford a white solid. (98%) 1H NMR (400 MHz, DMSO-d6) δ 12.34 (br s, 1H), 7.29 (m, 1H), 7.19 (m, 4H), 4.12 (m, 2H), 3.65 (s, 2H), 1.38 (s, 9H).
Reaction SMILES: [CH:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][CH3:29])=[O:27])=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)=[CH:2][CH2:3][CH3:4].[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].N1C=CN=C1>CN(C=O)C>[CH:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][CH3:29])=[O:27])=[CH:16][CH:15]=2)[C:7]([CH2:11][O:12][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[C:8]([Cl:10])[N:9]=1)=[CH:2][CH2:3][CH3:4]
Reactant: CCC=Cc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCC=Cc1nc(Cl)c(CO[Si](C)(C)C(C)(C)C)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 83.8 %

Procedure:
2-(But-1-en-1-yl)-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloro-5-(hydroxymethyl)imidazole (1.4 g), t-butyldimethylsilyl chloride (0.55 g), and imidazole (0.5 g) were mixed and stirred in DMF (5 mL) for 18 hours at room temperature. Dilution with ethyl acetate and washing the organic phase with water followed by drying (MgSO4), evaporation of the solvent in vacuo, and flash chromatography in 3:1 hexane/ethyl acetate yielded 1.5 g of a clear oil. NMR (200 MHz, CDCl3) δ 7.83 (d, 1H); 7.52 (t, 1H); 7.40 (t, 1H); 7.33-7.24 (m, 3H); 7.08 (d, 2H); 6.83 (d of t, 1H); 6.13 (d, 1H); 5.30 (s, 2H); 4.57 (s, 2H); 3.64 (s, 3H); 2.21 (quint., 2H); 1.04 (t, 3H); 0.86 (s, 9H); 0.05 (s, 6H).