Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([OH:36])[C:33]3[C:28](=[CH:29][C:30]([CH3:37])=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:45]([O:52][C:53](=[O:56])[CH2:54]Br)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][CH2:54][C:53]([O:52][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:56])[C:33]3[C:28](=[CH:29][C:30]([CH3:37])=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)c3ccc(C)cc3n2)CC1
Reaction time: 16 h

Procedure:
To a solution of 26.4 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester (prepared analogously as in example 1) in 150 ml of DMF, 18 g of cesium carbonate and 12.7 g of Bromo-acetic acid benzyl ester was added and stirred for 16 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate (3×300 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 23.6 g.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Cl:18][S:19](O)(=[O:21])=[O:20].C(=O)(O)[O-].[Na+]>>[N:7]1([C:4]2[CH:5]=[CH:6][C:1]([C:12]3[CH:13]=[CH:14][C:15]([S:19]([Cl:18])(=[O:21])=[O:20])=[CH:16][CH:17]=3)=[CH:2][CH:3]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: c1ccc(-c2ccc(N3CCCC3)cc2)cc1
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=S(=O)(Cl)c1ccc(-c2ccc(N3CCCC3)cc2)cc1
Temperature: 60 °C

Procedure:
6 g (0.023 mol) of the product from stage 1 was introduced into 11 ml of chlorosulfonic acid in portions with cooling and under protecting gas and the mixture was heated at 60° C. for 3.5 h. The solution was added to ice, the suspension was brought to pH 8 by addition of solid sodium bicarbonate, and the precipitated product was filtered off with suction and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N+:5]([O-])=[C:4]([O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[C:3]=1[CH3:21].P(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[C:3]=1[CH3:21]
Reactant: CCc1cc(Cl)c(C)c(Oc2c(C)cc(C)cc2C)[n+]1[O-]
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: CCc1cc(Cl)c(C)c(Oc2c(C)cc(C)cc2C)n1
Temperature: 25 °C

Procedure:
To a solution of 4-Chloro-6-ethyl-3-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine 1-oxide in methylene chloride was added PCl3 and the resulting mixture was heated at reflux for 20 min, cooled to rt. The mixture was concentrated to dryness. The residue was worked-up using standard procedure to give the title compound. After silica gel purification, the titel compound was prepared as a white solid, mp. 42-44° C. Anal. For C17H20ClNO calc. C, 70.46; H, 6.96; N, 4.83; found, C, 70.35; H, 7.13; N, 4.58.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:35]S(C)(=O)=O)=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[O:22])=[CH:14][CH:13]=3)[C:6]=2[CH:34]=1.[C:40](Cl)(=[O:42])[CH3:41].O>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:35][C:40](=[O:42])[CH3:41])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:25])=[O:26])=[O:22])=[CH:14][CH:13]=3)[C:6]=2[CH:34]=1
Reactant: CCc1nc2cc(NS(C)(=O)=O)c(Cl)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCc1nc2cc(NC(C)=O)c(Cl)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
To a solution of 6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ylamine (step 6 of Example 110, 100 mg, 0.3 mmol) in pyridine (7 mL) was added dropwise acetyl chloride (0.03 mL, 0.33 mmol) under nitrogen atmosphere at 0° C., and the reaction mixture was stirred at room temperature for 1.5 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with 2N aqueous NaOH (30 mL), brine (30 mL), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:3) to afford 110 mg (98%) of the title compound as white solids: 1H-NMR (CDCl3) δ 8.66 (1H, s), 7.56 (1H, br.s), 7.45 (2H, d, J=8.2 Hz), 7.29 (2H, d, J=8.2 Hz), 7.12 (1H, s), 3.82 (2H, t, J=7.1 Hz), 3.19 (2H, t, J=7.1 Hz), 2.77 (2H, q, J=7.6 Hz), 2.26 (3H, s), 1.34 (3H, t, J=7.6 Hz).
Reaction SMILES: [OH:1][CH:2]([CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6]2)=[CH:31][CH:30]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCCCCCCCCCCCCCCCOCC(O)CN1CCNCC1
Product: CCCCCCCCCCCCCCCCOCC(O)CN1CCN(Cc2ccc(Cl)cc2)CC1

Procedure:
Following the procedure of Example 5, 1-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine was reacted with 4-chlorobenzylchloride to form 1-(4-chlorobenzyl)-4-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine, mp 237°-239° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16](C(F)(F)F)=[CH:15][CH:14]=3)[C:8]2=[O:23])[S:4][C:3]=1[C:24](O)=[O:25].C(N1CCN(C2SC(C(O)=O)=C(C)C=2)C1=O)C1C=CC=CC=1.[NH2:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1>>[CH2:12]([N:9]1[CH2:10][CH2:11][N:7]([C:5]2[S:4][C:3]([C:24]([NH:49][CH2:50][C:51]3[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=3)=[O:25])=[C:2]([CH3:1])[CH:6]=2)[C:8]1=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1cc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 46 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-benzyl-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 46% yield: mp 130-131° C.; 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.51 (s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.38-7.22 (m, 6H), 6.18 (t, J=5.6 Hz, 1H), 6.07 (s, 1H), 4.58 (d, J=5.6 Hz, 2H), 4.44 (s, 2H), 3.81-3.74 (m, 2H), 3.47-3.40 (m, 2H), 2.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.5, 155.9, 149.2, 148.8, 142.6, 141.8, 135.9, 135.5, 128.8, 128.2, 127.9, 123.6, 118.9, 112.3, 48.1, 42.7, 41.5, 41.2, 16.1; MS (ES+) m/z 407.3 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[C:8](=[O:11])[C:7]1[C:12]([OH:20])=[C:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=[CH:15][C:6]=1[O:5]2.[OH-].[K+]>CO.C(OCC)(=O)C.[Ni]>[OH:16][C:14]1[C:13]([CH2:17][CH2:18][CH3:19])=[C:12]([OH:20])[C:7]2[C:8](=[O:11])[N:9]3[CH:10]=[CH:2][CH:3]=[C:4]3[O:5][C:6]=2[CH:15]=1
Reactant: CCCc1c(O)cc2oc3cc(Cl)cn3c(=O)c2c1O
Agent: [Ni]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1c(O)cc2oc3cccn3c(=O)c2c1O
Yield: 36.4 %

Procedure:
A solution of 60 mg (0.18 mmol) of 2-chloro-6,8-dihydroxy-7-propyl-9H-pyrrolo [2,1-b][1,3]benzoxazin-9-one in 4 mL of methanol was subjected to hydrogenation with 0.1 g Ra-Ni, 0.4 mL of 0.5N KOH in methanol, and H2 at 20 psi. The mixture was diluted with ethyl acetate and extracted with 1N HCl. The organic layer was dried (Na2SO4), concentrated, and the residue purified by preparative TLC (Silica Gel: CH2C2) to give 17 mg of the title compound: mp 170-171° C.
Reaction SMILES: [CH:1]1([C:4]2[C:9]3[C:10]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[N:11][O:12][C:8]=3[C:7]([OH:18])=[C:6]([C:19](OCC)=[O:20])[N:5]=2)[CH2:3][CH2:2]1.[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+]>C(=O)(O)[O-].[Na+]>[CH:1]1([C:4]2[C:9]3[C:10]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[N:11][O:12][C:8]=3[C:7]([OH:18])=[C:6]([C:19]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:20])[N:5]=2)[CH2:3][CH2:2]1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C2CC2)c2c(-c3cccs3)noc2c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(C2CC2)c2c(-c3cccs3)noc2c1O
Temperature: 25 °C
Yield: 70.5 %

Procedure:
Ethyl 4-cyclopropyl-7-hydroxy-3-(thiophen-2-yl)isoxazolo[4,5-c]pyridine-6-carboxylate (47 mg, 0.142 mmol) and glycine (428 mg, 5.70 mmol) were added to sodium methoxide solution (8.5 mL, 4.27 mmol, 0.5 M in MeOH) and the mixture was refluxed for 48 h. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was redissolved in 10 mL of water and acidified to pH 3 by addition of concentrated hydrochloric acid. The resulting precipitate was isolated by filtration to give 51 mg of crude solid. The solid was dissolved in saturated sodium bicarbonate (20 mL), and washed with EtOAc. The aqueous layer was acidified to pH 3 with 4M HCl and extracted with EtOAc. The combined organic layer was dried over MgSO4 and concentrated to give 36 mg of the title compound. MS: (−) m/z 358.30 (M−1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([NH:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.[Li+].[OH-]>C1COCC1.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([NH:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(NS(=O)(=O)c2cccc3cccnc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(NS(=O)(=O)c2cccc3cccnc23)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of sulfonamide VII (34 gm, 95.5 mmol) in THF and water (1:1), LiOH (20 gm, 47.66 mmol) was added and the resulting mixture was allowed to stir at 80° C. overnight. After completion of reaction, the crude mixture was washed with EtOAc. The aqueous layer was acidified with citric acid and filtered. Thus obtained solid was washed with Et2O and azeotroped by toluene, under reduced pressure to afford acid VIII (30 gm, 95.8% yield) which was taken forward for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[Cl:16])=[CH:4][CH:3]=1.[C:18]1([OH:24])C=CC=C[CH:19]=1.ClC1C=CC(Cl)=CC=1C(Cl)=O.C(Cl)(=O)C>>[C:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[Cl:16])=[CH:6][CH:7]=1)(=[O:24])[CH3:19]
Reactant: O=C(c1ccc(O)cc1)c1cc(Cl)ccc1Cl
Reactant: Oc1ccccc1
Agent: O=C(Cl)c1cc(Cl)ccc1Cl
Solvent: CC(=O)Cl
Product: CC(=O)Oc1ccc(C(=O)c2cc(Cl)ccc2Cl)cc1

Procedure:
4'-Acetoxy-2,5-dichlorobenzophenone is prepared by treating 4'-Hydroxy-2,5-dichlorobenzophenone, which is prepared by the Friedel-Crafts acylation of phenol with 2,5-dichlorobenzoyl-chloride, with acetyl chloride.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][S:11]([CH2:14][CH2:15][NH:16][C:17]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:18])(=[O:13])=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[N:25]([CH2:28][CH2:29][CH3:30])=[C:26]=[O:27]>ClCCl.CN(C1C=CN=CC=1)C>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([C:26]([NH:25][CH2:28][CH2:29][CH3:30])=[O:27])[S:11]([CH2:14][CH2:15][NH:16][C:17]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:18])(=[O:12])=[O:13])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1
Reactant: CCCN=C=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCNC(=O)N(C1CCN(C(C)C)CC1)S(=O)(=O)CCNC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 200 mg (0.50 mmol) 5-chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide in 3 ml dichloromethane were added 0.1 ml (2 equiv.) 1-isocyanato-propane and 6 mg DMAP. The reaction mixture was stirred overnight at room temperature. The next day further 0.1 ml (2 equiv.) 1-isocyanato-propane and 6 mg DMAP were added. After stirring for 48 h at room temperature, the reaction mixture was washed with 3 ml water and concentrated under reduced pressure. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid {2-[(1-isopropyl-piperidin-4-yl)-propylaminocarbonyl-sulfamoyl]-ethyl}-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)=[CH:6][N:5]=[CH:4][C:3]=1[CH2:20][NH:21][C:22]([C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:23].[H-].[Na+].[CH3:33]I>>[CH3:33][N:21]([CH2:20][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)[C:2]=1[CH3:1])[C:22]([C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:23]
Reactant: CI
Reactant: Cc1c(CNC(=O)c2ncccc2Cl)cncc1-c1ccc2c(c1)CCC(=O)N2C
Agent: [H-]
Agent: [Na+]
Product: Cc1c(CN(C)C(=O)c2ncccc2Cl)cncc1-c1ccc2c(c1)CCC(=O)N2C

Procedure:
In analogy to the procedure described for the preparation of example 195, 3-chloro-pyridine-2-carboxylic acid [4-methyl-5-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-ylmethyl]-amide (example 224) has been reacted with sodium hydride and methyl iodide to give the title compound as light brown amorphous solid. MS: 435.5 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)=[N:4][CH:3]=1.C1C(=O)N([Br:24])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:24][CH2:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)=[N:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(-c2cccc(C(F)(F)F)c2)o1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: FC(F)(F)c1cccc(-c2ncc(CBr)o2)c1
Yield: 56.4 %

Procedure:
To a solution of 5-methyl-2-[3-(trifluoromethyl)phenyl]-1,3-oxazole (Example 370B) (1.0 g, 4.4 mmol) was added NBS (0.784 g, 4.4 mmol) and benzoyl peroxide (0.100 g, 0.41 mmol). The mixture was refluxed for 1 h and the solids were filtered. The filtrate was concentrated and purified by radial chromatography (0-20% EtOAc-hexanes gradient) to afford the title compound (0.760 g, 56% yield): MS (ES) m/z 306 (M+1) and 308 (M+1, isotope).
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[N:18]1([C:1]([N:3]2[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]3[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]2=3)=[CH2:2])[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: c1c[nH]cn1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: C=C(n1ccnc1)n1c2c(c3cc(C)ccc31)CN(C)CC2
Temperature: 25 °C
Yield: 23.1 %

Procedure:
A mixture of 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (300 mg, 1.33 mmol), 1H-imidazole (182 mg, 2.66 mmol), TBAF.3H2O (1.2 g, 3.80 mmol) and dichloro bis(triphenylphosphine) palladium (II) (47 mg, 0.06 mmol) was heated at 85° C. for 30 min. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100-200 mesh) eluting with 4% MeOH-DCM to yield 90 mg of 5-(1-imidazol-1-yl-vinyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. The free base was converted into the di-HCl salt by treatment with ethanolic HCl. 1H NMR (CD3OD, D1-HCl salt) δ (ppm): 9.21 (s, 1H), 7.78 (d, 2H), 7.38 (s, 1H), 7.1 (d, 1H), 6.92 (d, 1H), 6.21 (d, 1H), 5.75 (d, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 3.83 (m, 1H), 3.6 (m, 1H), 3.18 (m, 5H), 2.4 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[C:23](Cl)(=[O:26])[CH:24]=[CH2:25].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([NH:2][CH2:1][C:23](=[O:26])[CH:24]=[CH2:25])=[CH:8][CH:7]=1
Reactant: CNc1ccc(CC(=O)OC)cc1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)CNc1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl (4-methylaminophenyl)acetate (4.00 g, 22.3 mmol) and N,N-diisopropylethylamine (7.78 mL, 44.6 mmol) in DCM (20.0 mL) at 0° C. was slowly added 2-propenoyl chloride (2.18 mL, 26.8 mmol). The reaction mixture was stirred at room temperature for 2 h and then saturated aqueous sodium bicarbonate (20.0 mL) was added. This mixture was extracted with DCM (10 mL) and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used in the next reaction without further purification.
Reaction SMILES: [CH:1]1([C:4]#[CH:5])[CH2:3][CH2:2]1.[Li]CCCC.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1.C1COCC1>[Si:11]([C:5]#[C:4][CH:1]1[CH2:3][CH2:2]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CC1CC1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)C#CC1CC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 42 %

Procedure:
To a stirred, cooled (0° C.) solution of 188 mL (658 mmol) of a 3.5 M solution of cyclopropylacetylene in toluene was added 200 mL of THF. The solution was re-cooled to 0° C. and treated with 264 mL (660 mmol) of a 2.5 M solution of n-BuLi in hexanes over 15 min. The solution was stirred an additional 40 min. at 0° C. and treated with 100 g(663 mmol) of t-butyldimethylsilyl chloride in 60 mL of THF over 10 min. After stirring 90 min. at 0° C. the reaction was quenched with saturated aq. NH4Cl and poured into 500 mL of water. The mixture was extracted with 500 mL of ether, and the organic extract was washed three times with water and once with brine. Concentration under reduced pressure followed by distillation afforded 49 g(42%) of 1-(t-butyldimethylsilyl)-2-cyclopropylacetylene as a colorless oil (b.p. 39-42° C. at 0.5 torr). 1H NMR(CDCl3, 300 MHz) δ1.17-1.24(m, 1H); 0.95(s, 9H); 0.61-0.75(m, 4H); 0.00(s, 6H).
Reaction SMILES: [CH2:1]([N:3]1[C:14](=[O:15])[CH2:13][CH2:12][C@H:4]1[C:5]([O:7]C(C)(C)C)=[O:6])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:3]1[C:14](=[O:15])[CH2:13][CH2:12][C@H:4]1[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCN1C(=O)CC[C@H]1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1,1-Dimethylethyl 1-ethyl-5-oxo-prolinate (0.965 g) was dissolved in dichloromethane (˜5 ml) and treated with trifluoroacetic acid (1 ml). The mixture was stirred at room temperature for 1.5 hrs and then evaporated. The resulting material was mostly starting material so a further amount of trifluoroacetic acid (1 ml) and dichloromethane (˜5 ml) was added and the mixture stirred at room temperature for 36 hrs. The mixture was evaporated and then toluene was added to the residue and this was in turn also evaporated. After repeating this process once more, crude 1-ethyl-5-oxo-proline was obtained as a dark yellow oil which was used without additional purification.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][C@@H:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:7]1)=O)C.[OH-].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>CCOCC.C(O)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[F:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][C@@H:9]2[CH2:10][CH2:11][NH:6][CH2:7][C@H:8]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)N1CC[C@@H](Oc2ccc(F)cc2)[C@H](c2ccccc2)C1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: Fc1ccc(O[C@@H]2CCNC[C@H]2c2ccccc2)cc1

Procedure:
A mixture of 3.44 g of trans-1-ethoxycarbonyl-4-(4-fluorophenoxy)-3-phenylpiperidine of Example 47, 50 ml of absolute ethanol and 26 ml of 20% aqueous NaOH solution is refluxed 18 hours under a nitrogen atmosphere. The ethanol is removed in vacuo, and the aqueous residue is partitioned between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate, and the combined organic extracts are washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated in vacuo to an oil which quickly crystallizes to a solid. The solid is triturated with hexane and filtered to afford a solid, m.p. 99°-101° C. This material is dissolved in 100 ml of ether and treated dropwise with a solution of 1.05 g of fumaric acid in a mixture of 60 ml of ether and 15 ml of absolute ethanol. The resultant solid is filtered, washed with ether and dried to afford a salt of trans-4-(4-fluorophenoxy)-3-phenylpiperidine fumarate, m.p. s 142.5°, 143° C. dec.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](I)[C:7]([CH:11]([CH3:13])[CH3:12])=[CH:6][C:5]=1[NH2:14].[CH3:16][N:17]1[C:21]([Sn](CCCC)(CCCC)CCCC)=[CH:20][CH:19]=[N:18]1.O1CCOCC1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:21]2[N:17]([CH3:16])[N:18]=[CH:19][CH:20]=2)[C:7]([CH:11]([CH3:13])[CH3:12])=[CH:6][C:5]=1[NH2:14]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Reactant: COC(=O)c1cc(I)c(C(C)C)cc1N
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(C(C)C)cc1N
Temperature: 100 °C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
2-Amino-5-iodo-4-isopropyl-benzoic acid methyl ester (300 mg, 0.94 mmol) and 1-methyl-5-tributylstannanyl-1H-pyrazole (523 mg, 1.5 equiv) were weighed in air and added in a flame-dried flask. [Bistriphenylphosphine]dichloropalladium (67.3 mg, 0.1 equiv) was added and the flask was closed by a septum. Dioxane (1 mL) was added and the mixture was stirred for 18 h (TLC control) at 100° C. The mixture was dissolved with EtOAc, filtered and evaporated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc/hexanes (4:6)) to yield 2-amino-4-isopropyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (169 mg, 66%) as a yellow solid. (ESI-MS: m/z 274 [M+H]+, rt 5.20 min).