Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:9](I)=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([Cl:18])[CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.CN([CH:28]=[O:29])C>C1COCC1>[CH2:1]([C:8]1[C:9]([CH:28]=[O:29])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([Cl:18])[CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc2cc(Cc3ccccc3)c(I)nc2c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=Cc1nc2cc(Cl)ccc2cc1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 110.5 %

Procedure:
To a solution of 3-benzyl-7-chloro-2 iodo-quinoline (1.5 g, 3.95 mmol) in 15 mL of anhydrous THF at −78° C., was added isopropylmagnesium chloride (5.93 ml, 11.85 mmol). After stirring at −78° C. for 30 minutes, DMF (1.53 ml, 19.8 mmol) was added. The reaction mixture was allowed to slowly warm to ambient temperature over two hours. It was then quenched with saturated NH4Cl and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over MgSO4, and the solvent was removed in vacuo yielding 1.23 g of 3-benzyl-7-chloroquinoline-2-carbaldehyde 24 as brown oil.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[C:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[C:19]([C:23](Cl)=[O:24])[CH:18]=1>ClCCl>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:16][C:23](=[O:24])[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH3:26])[CH:18]=1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Solvent: ClCCl
Product: Cc1cccc(C(=O)Nc2ccc3oc4c(c3c2)CCCCCC4)c1
Yield: 81.4 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.15 g, 0.70 mmol), m-toluoyl chloride (0.096 mL, 0.73 mmol), and poly(vinylpyridine) (0.5 g) in dichloromethane (17 mL) provided N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)-3-methylbenzamide (0.19 g). MS (ESI) m/z 334 ([M+H]+).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)[CH2:3][OH:4].[C:15]1([CH:21]2[CH2:23][CH:22]2[C:24](O)=[O:25])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[OH:4][CH2:3][CH:2]([NH:1][C:24]([CH:22]1[CH2:23][CH:21]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:25])[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1
Reactant: N[C@@H](CO)c1ccc2ccccc2c1
Reactant: O=C(O)C1CC1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC(CO)c1ccc2ccccc2c1)C1CC1c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.5 %

Procedure:
A mixture of (R)-2-amino-2-naphthalen-2-yl-ethanol (0.2 mmol), 2-phenyl-cyclopropanecarboxylic acid (0.2 mmol), EDAC.HCl (0.4 mmol), DMAP (0.2 mmol), and triethylamine (0.6 mmol) in dichloromethane (2 mL) was stirred at room temperature for 12 h. The reaction mixture was purified by flash chromatography eluting with 50% hexanes in ethyl acetate to give the desired product (52 mg) as a solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH:9]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.O>[Cl:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH2:9][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(O)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(CN2CCCC2)c(Cl)c1
Yield: 56.1 %

Procedure:
Pyrrolidine (22.0 mL, 0.255 mol) was added to a suspension of intermediate 14, 2-chloro-4-hydroxybenzaldehyde (30.8 g, 0.196 mol) in dichloromethane (620 mL). The reaction mixture was cooled with an ice bath. Sodium triacetoxyborohydride (65.8 g, 0.295 mol) was added in portions under stirring. The reaction mixture was stirred for 12 h at room temperature. Water (600 mL) and dichloromethane (600 mL) were added. The reaction mixture was acidified with concentrated HCl to pH˜2. The organic layer was separated. The aqueous one was subjected to extraction with EtOAc (2×500 mL), and the extracts were discarded. The aqueous fraction was alkalized with a saturated solution of potassium carbonate to pH 9-10. The product was extracted with CHCl3 (3×500 mL). The organic layer was dried with anhydrous Na2SO4 (50 g). The solvent was evaporated in vacuo. The obtained oil was refluxed in Et2O (400 mL) for 1 h. Then hexane (200 mL) was added, and the mixture was cooled. The formed residue was separated by filtration and dried. 1H NMR spectrum showed the presence of acetic acid (2.3% w/w). The residue was dissolved in a mixture of Et2O (100 mL) and CH2Cl2 (100 mL), and a solution of NaOH (0.4 g) in water (4 mL) was added. The product was extracted form the organic layer. The extract was dried with anhydrous Na2SO4 (50 g), evaporated, and coevaporated with dioxane. The title compound (23.5 g, 0.11 mol, 56%) was obtained as a pale-yellow powder. LC/MS data: 212.0 and 214.0 (M+H)+ (calculated for C22H14ClNO 211.7). 1H NMR data (DMSO-d6): 9.73 (br.s., 1H, OH); 7.24 (d, 1H, J=8.3 Hz, Ar—H); 6.78 (d, 1H, J=2.4 Hz, Ar—H); 6.70 (d.d., 1H, J1=8.3 Hz, J2=2.4 Hz, Ar—H); 3.54 (s, 2H, CH2Ar); 2.40-2.47 (m, 4H); 1.63-1.70 (m, 4H).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Cl[CH2:12][CH2:13][C:14]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([OH:19])[CH2:15][C:16]([CH3:18])=[CH2:17].[Br:26][C:27]1[CH:32]=[CH:31][C:30]([C@@H:33]([N:35]=[C:36]=[O:37])[CH3:34])=[C:29]([CH3:38])[CH:28]=1.C(O)(=O)C>O1CCCC1.O>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([C@@H:33]([N:35]2[CH2:12][CH2:13][C@:14]([CH2:15][C:16]([CH3:18])=[CH2:17])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:19][C:36]2=[O:37])[CH3:34])=[C:29]([CH3:38])[CH:28]=1
Reactant: C=C(C)CC(O)(CCCl)c1ccccc1
Reactant: Cc1cc(Br)ccc1[C@H](C)N=C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: C=C(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2C)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium hexamethyldisilazide (1 mol/L in tetrahydrofuran, 18.7 mL) was added dropwise (at such a rate that the solution temperature maintains below 25° C.) to a solution of 1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol (3.82 g) and (S)-4-bromo-1-(1-isocyanato-ethyl)-2-methyl-benzene (4.49 g) in tetrahydrofuran (140 mL) chilled in an ice bath. The solution was stirred in the cooling bath for 30 min and at room temperature for another 60 min. Then acetic acid (1.9 mL) in water (40 mL) was slowly added to the reaction mixture. The resulting mixture was concentrated under reduced pressure and the residue was taken up in tert-butyl methyl ether. The resulting solution was washed with water, dried (MgSO4), and concentrated. The residue was submitted to chromatography on silica gel (cyclohexane/ethyl acetate 90:10→40:60) to afford the title compound as a colorless solid. Besides the title compound a diastereomer thereof, 3-[(S)-1-(4-bromo-2-methyl-phenyl)-ethyl]-6-(S)-(2-methyl-allyl)-6-phenyl-[1,3]oxazinan-2-one, was isolated as an oil {1.55 g, Mass spectrum (ESI+): m/z=428/430 (Br) [M+H]+}. Yield: 1.34 g (18% of theory); Mass spectrum (ESI+): m/z=428/430 (Br) [M+H]+; 1H NMR (400 MHz, DMSO-d6) 1.40 (d, J=6.8 Hz, 3H), 1.53 (s, 3H), 1.71 (s, 3H), 1.81-190 (m, 1H), 1.98-2.08 (m, 1H), 2.43-ca. 2.51 (m, 3H), 2.86-2.94 (m, 1H), 4.58 (hardly resolved m, 1H), 4.77 (hardly resolved m, 1H), 5.30 (q, J=6.8 Hz, 1H), 7.15-7.19 (m, 2H), 7.24-7.35 (m, 6H). The assignment of the stereogenic centers of the title compound is based on the comparison of the 1H NMR data with the data of the known analog 3-[(S)-1-(4-bromo-phenyl)-ethyl]-(R)-6-(2-methyl-allyl)-6-phenyl-[1,3]oxazinan-2-one.
Reaction SMILES: C1(C)C=CC(C([C:9]2[N:13]([CH3:14])[C:12](CC#N)=[CH:11][CH:10]=2)=O)=CC=1.[OH-:19].[Na+].Cl.[CH2:22]([OH:24])[CH3:23]>>[CH3:14][N:13]1[CH:9]=[CH:10][CH:11]=[C:12]1[CH2:23][C:22]([OH:19])=[O:24]
Reactant: Cc1ccc(C(=O)c2ccc(CC#N)n2C)cc1
Reactant: [OH-]
Reactant: CCO
Agent: Cl
Agent: [Na+]
Product: Cn1cccc1CC(=O)O

Procedure:
A solution of 3.67 g. (0.015 mole) of 5-(ρ-toluoyl)-1-methyl-pyrrole-2-acetonitrile, 24 ml. of 1N sodium hydroxide, and 50 ml. of 95% ethanol is stirred and refluxed for twenty-four hours. The resulting solution is poured into ice acidified with dilute hydrochloric acid. A white solid precipitates which is extracted into ether. The ether phase is washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is evaporated and a white solid, 5-ρ-toluoyl)-1-methylpyrrole-2-acetic acid, is obtained which is recrystallized twice from isopropanol, M.P., 155°-157° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[S:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:21]Br.O>ClCCl.[Fe]>[Br:21][C:16]1[C:17]([CH3:19])=[CH:18][C:13]2[S:12][CH2:11][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[C:14]=2[C:15]=1[CH3:20]
Reactant: Cc1cc(C)c2c(c1)SCC2c1ccc(C(C)C)cc1
Reactant: BrBr
Agent: [Fe]
Solvent: O
Solvent: ClCCl
Product: Cc1cc2c(c(C)c1Br)C(c1ccc(C(C)C)cc1)CS2
Reaction time: 1 h
Yield: 80 %

Procedure:
To a mixture of 3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothiophene synthesized in Reference Example 212 (4.45 g, 15.8 mmol) and iron powder (59 mg, 1.05 mmol) in dichloromethane (20 mL) was added bromine (0.81 mL, 15.8 mmol) at 0° C., and the mixture was stirred at the same temperature for 1 hour. Water was poured into the reaction mixture, which was extracted with ethyl acetate. The extract was washed with a saturated sodium hydrogen carbonate solution and water, was dried over magnesium sulfate, was filtered and then was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10) to obtain 4.6 g (yield 80%) of the title compound. Melting point: 98-100° C. (hexane-ethyl acetate).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]2[C@H:7]([O:15][C@@H:16]3[O:21][C@H:20]([CH2:22][OH:23])[C@@H:19]([OH:24])[C@H:18]([OH:25])[C@H:17]3[OH:26])[O:8][CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C@H:5]2[CH2:4][C@@H:3]1[OH:27].[C:28](Cl)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>N1C=CC=CC=1>[CH3:1][C@@H:2]1[C@H:6]2[C@H:7]([O:15][C@@H:16]3[O:21][C@H:20]([CH2:22][O:23][C:28]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C@@H:19]([OH:24])[C@H:18]([OH:25])[C@H:17]3[OH:26])[O:8][CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C@H:5]2[CH2:4][C@@H:3]1[OH:27]
Reactant: COC(=O)C1=CO[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H]2[C@@H](C)[C@@H](O)C[C@H]12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)C1=CO[C@@H](O[C@@H]2O[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H](O)[C@H](O)[C@H]2O)[C@@H]2[C@@H](C)[C@@H](O)C[C@H]12
Temperature: 45 °C
Reaction time: 36 h
Yield: 65 %

Procedure:
The loganin was dissolved in pyridine and trityl chloride was added in 1.5 equivalents and stirred at 45° C. for 36 hrs to give the compound 6′-O-trityl loganin (2) in 65% yield.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[C:7](Cl)(=[O:10])[CH:8]=[CH2:9]>>[C:7]([N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6])(=[O:10])[CH:8]=[CH2:9]
Reactant: O=C1CCCN1
Reactant: C=CC(=O)Cl
Product: C=CC(=O)N1CCCC1=O

Procedure:
2-pyrrolidone and acryloyl chloride were used to synthesize the title compound with the similar synthesis method to described in Example 1.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([OH:13])=[C:7]([O:14][CH3:15])[C:6]=1[CH3:16])(=[O:3])[CH3:2].Br[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]2[C:26]([CH2:34][CH3:35])=[N:27][O:28][C:29]=2[C:30]=1[CH2:31][CH2:32][CH3:33]>>[C:1]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]3[C:26]([CH2:34][CH3:35])=[N:27][O:28][C:29]=3[C:30]=2[CH2:31][CH2:32][CH3:33])=[C:7]([O:14][CH3:15])[C:6]=1[CH3:16])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCBr)ccc2c(CC)noc12
Reactant: COc1cc(OC(C)=O)c(C)c(OC)c1O
Product: CCCc1c(OCCCOc2c(OC)cc(OC(C)=O)c(C)c2OC)ccc2c(CC)noc12
Yield: 39.1 %

Procedure:
The procedure from Example 76 Step C was followed using methyl-3,5-dimethoxy-4-hydroxyphenyl acetate (108 mg) and 3-bromo-1-(3-(Ethyl)-7-(propyl)-6-benz-[4,5]-isoxazoloxy)propane (156 mg) to afford a colorless oil (88 mg). NMR (CDCl3); δ 7.41 (d,2H), 6.99 (d,2H), 6.45 (s,2H), 3.76 (s,6H), 3.71 (s,3H), 3.55 (s,3H), 1.43 (t,3H), 0.92 (t,3H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]#[CH:10])=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[C:4]([NH2:17])[N:3]=1.[CH:18]([NH:20][NH2:21])=O.CN(C)C=O>O>[C:11]1([C:6]2[N:5]=[C:4]([NH2:17])[N:3]3[CH:18]=[N:20][N:21]=[C:2]3[C:7]=2[CH2:8][C:9]#[CH:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#CCc1c(Cl)nc(N)nc1-c1ccccc1
Reactant: NNC=O
Solvent: CN(C)C=O
Solvent: O
Product: C#CCc1c(-c2ccccc2)nc(N)n2cnnc12

Procedure:
1.7 Parts of 4-chloro-6-phenyl-5-(2-propynyl)pyrimidin-2-amine and 0.84 part of formylhydrazine are added to 20 parts by volume dimethylformamide containing 2.0 parts of molecular sieve 3A and refluxed under nitrogen for two hours. The solution is allowed to cool and is poured into cold water. The crystalline product is filtered out, washed with water and dried. The product is chromatographed to give 7-phenyl-8-(2-propynyl)-1,2,4-triazolo[4,3-c]pyrimidin-5-amine having the formula: ##STR6##
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][CH2:5][C:6](=[CH:8][CH2:9][C:10](=[O:19])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:7]=1.N1C=CC=CC=1.[CH3:26][N:27]=[C:28]=[O:29]>O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:10]([CH2:9][CH:8]=[C:6]2[CH2:5][S:4][C:3]([NH:2][C:28]([NH:27][CH3:26])=[O:29])=[N:7]2)=[O:19])=[CH:13][CH:14]=1
Reactant: NC1=NC(=CCC(=O)Nc2ccc(Cl)cc2)CS1
Reactant: CN=C=O
Agent: Br
Solvent: O
Solvent: c1ccncc1
Product: CNC(=O)NC1=NC(=CCC(=O)Nc2ccc(Cl)cc2)CS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
A reaction flask was charged with 3.9 g (0.011 mole) of 2-amino-4-(4-chlorophenylcarbamoylethylidene) thiazole hydrobromide (M.P. 112°-16°; prepared from 4-bromo-4'-chloro-2-methylacetoacetanilide and thiourea in ethanol), 30 ml of pyridine and 1.1 g (0.018 mole) of methyl isocyanate. The solution was allowed to stir overnight at ambient temperature. On the following morning, the pyridine solution was poured into water. The water was decanted from the residual oil. With stirring, the addition of fresh water caused the residue to solidify. The solid was dissolved in hot ethanol. The crystalline material in the cooled mixture was collected on a vacuum filter. There was obtained 1.4 g (38%) of white solid, M.P. 203°-205°. N.M.R. (dimethyl-d6 sulfoxide, CDCl3) ∂1.3-1.6 (CH3, doublet), 2.5-2.8 (NCH3, doublet), 3.5-3.8 (CH), 6.5 (hetero-aromatic), 7.1-7.7 (aromatic), 9.9 and 10.4 [NHC(O)NH].
Reaction SMILES: [NH:1]1[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].C(N(CC)CC)C.O.[CH3:28][C:29]([O:32][C:33](ON=C(C1C=CC=CC=1)C#N)=[O:34])([CH3:31])[CH3:30]>CC(C)=O>[N:1]1([C:33]([O:32][C:29]([CH3:31])([CH3:30])[CH3:28])=[O:34])[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: O=C(O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 9 h
Yield: 144.5 %

Procedure:
To a solution of L-Pro-L-Phe (1.0 g, 3.8 mmol) and triethylamine (0,794 ml, 5.7 mmol) in 1:1 water:acetone (38 ml) was added Boc-ON (1.13 g, 4.6 mmol), and the reaction mixture stirred at room temperature for 9 hours. Acetone was removed by evaporation under reduced pressure and the resulting aqueous solution diluted with a solution of saturated sodium bicarbonate and then washed with ether. The remaining aqueous phase was acidified to pH 2.0 and extensively extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated to yield 1.99 g of N-Boc-L-Pro-L-Phe as a white glassy solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([C:8]1[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=1)=[O:7]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([C:8]1[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)=[O:7]
Reactant: COC(=O)Cc1ccc(C(=O)c2ccc(OC)c(OC)c2)n1C
Solvent: CC(=O)O
Product: COc1ccc(C(=O)c2ccc(CC(=O)O)n2C)cc1OC

Procedure:
The transformation of the acetic acid ester of part (A) to its acetic acid is performed according to example 11 part B to yield 5-(3',4'-dimethoxybenzoyl)-1-methylpyrrole-2-acetic acid
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([CH3:17])=[CH:15][CH3:16])[C:8]=1[NH2:9].C(N(CC)CC)C>C(Cl)Cl>[CH3:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([CH3:17])=[CH:15][CH3:16])[C:8]=1[NH:9][C:3](=[O:4])[CH2:2][Cl:1]
Reactant: CC=C(C)c1cccc(C)c1N
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC=C(C)c1cccc(C)c1NC(=O)CCl
Reaction time: 8 h
Yield: 102.2 %

Procedure:
0.007 mole of chloroacetyl chloride was added dropwise to a mixture of 0.007 moles of 2-methyl-6-(1-methylprop-1-enyl)-aniline and 0.008 moles (1.15 ml) of triethylamine in methylene chloride at about but below 20° C. The mixture was then refluxed and then allowed to stand overnight at room temperature. The mixture was then again refluxed and allowed to stand for two days (over the weekend) at room temperature. Thin layer chromatographic (plate) analysis showed the presence of a small amount of starting material. An additional 0.55 ml of triethylamine and 0.3 ml of chloroacetyl chloride was added and the mixture again refluxed and allowed to stand overnight at room temperature. The mixture was then washed with aqueous sodium bicarbonate, dried and evaporated affording 1.7 g of the title compound as a slightly crystallized oil (m.p. 71°-74° C.).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].[C:13]([O-:16])(=[O:15])[CH3:14].[Na+]>C(O)(=O)C>[C:13]([O:16][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4])(=[O:15])[CH3:14]
Reactant: O=C(CCl)c1ccc(F)cc1F
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCC(=O)c1ccc(F)cc1F
Yield: 75.9 %

Procedure:
A solution of 2-chloro-2',4'-difluoroacetophenone (19.0 g) and anhydrous sodium acetate (16.4 g) in acetic acid (50 ml) was heated under reflux for 4 hours and then evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with sodium bicarbonate solution and dried (Na2SO4). Evaporation of the solvent gave an oil which was triturated with hexane. The resulting solid was filtered off, washed with hexane and dried to give the title compound, (16.2 g), m.p. 54°-56°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11](O)[C:12]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[C:17]4[C:13]=3[CH:14]=[CH:15][N:16]4C(OC(C)(C)C)=O)=[N:8][C:7]=2[CH:32]=1)#[N:2].C[O:34][C:35]([O:39][Si](C)(C)C)=[C:36]([CH3:38])[CH3:37].C([O-])(O)=O.[Na+]>C(Cl)Cl.O.Cl[Ti](Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([C:12]3[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH3:23])=[C:17]4[C:13]=3[CH:14]=[CH:15][NH:16]4)[C:36]([CH3:38])([CH3:37])[C:35]([OH:39])=[O:34])=[N:8][C:7]=2[CH:32]=1)#[N:2]
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)c1nc2cc(C#N)ccc2o1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cc(C)c2[nH]ccc2c1C(c1nc2cc(C#N)ccc2o1)C(C)(C)C(=O)O
Reaction time: 0.25 h

Procedure:
A solution of (±)-tert-butyl 4-((5-cyanobenzo[d]oxazol-2-yl)(hydroxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 125-A) (133 mg, 0.31 mmol) in DCM (10 mL) was treated with TiCl4 (1M in DCM, 1 mL, 1 mmol) at 0° C. The reaction mixture was stirred for 15 min, followed by the addition of ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (0.36 g, 2 mmol). The mixture was allowed to reach room temperature over 1 h. The reaction mixture was then poured into aqueous NaHCO3. The organic layer was extracted with ethyl acetate (2×50 mL), and the combined organic layers were dried over Na2SO4, filtered and concentrated to provide a residue. The resulting residue was suspended in water (5 mL) and was treated wtih Dowex ion exchange resin (200% w/w) (washed with water twice). The reaction was stirred at 120° C. overnight in a sealed tube. Reaction was cooled, filtered and directly subjected to purification by FCC1-5% (MeOH:DCM) to obtain the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.05 (br. s., 1H) 7.46-7.61 (m, 1H) 7.23 (t, J=2.78 Hz, 1H) 7.10 (d, J=8.34 Hz, 2H) 6.69 (s, 1H) 6.31-6.51 (m, 1H) 4.19 (s, 1H) 3.72 (s, 3H) 2.45 (s, 3H) 1.60 (s, 3H) 0.93 (s, 3H). HMRS calcd. for C23H21N3O4 (M+H)+ 404.1602. found 404.1595.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:14]([NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:26]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[O:7])(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH2:19]([O:18][C:16]([NH:15][CH:14]1[CH2:13][CH:12]=[CH:11][CH2:10][N:9]([S:26]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)(=[O:27])=[O:28])[CH:8]1[C:6]([OH:7])=[O:5])=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)OCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N2CC=CCC(NC(=O)OCc3ccccc3)C2C(=O)O)cc1

Procedure:
3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (28 mg, 0.054 mmol) is dissolved in 4 ml Dichloro-methane/Trifluoroacetic Acid; 3:1 and stirred for 5h at room temperature. The solvent/reagent are evaporated and the remaining oil is co-evaporated from Toluene twice. Flash-chromatography, Hexane/Ethylacetate; 1:1 afforded the desired product: Cal. 460.51, found (M)+460.9.
Reaction SMILES: Br[CH2:2][Br:3].[C:4](=[O:7])([O-])[O-:5].[Cs+].[Cs+].CN(C=O)C.Br[C:16]1[CH:17]=[C:18](O)[C:19](O)=[N:20]C=1>O>[Br:3][C:2]1[N:20]=[C:19]2[O:5][CH2:4][O:7][C:18]2=[CH:17][CH:16]=1
Reactant: BrCBr
Reactant: Oc1cc(Br)cnc1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2c(n1)OCO2
Reaction time: 8 h
Yield: 13.1 %

Procedure:
Dibromomethane (91 mg) and cesium carbonate (380 mg) were added to a tube containing a DMF (4 ml) solution containing 5-bromopyridin-2,3-diol (100 mg) and the tube was sealed, followed by stirring at 100° C.-110° C. for 8 hours. The reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=50:1 to 4:1), and a brown solid of 5-bromo-[1,3]dioxolo[4,5-b]pyridine (13.8 mg) was thus obtained.