Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1)([CH3:5])[CH3:4].[OH2:14].[O:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>C(OCC)C>[CH:3]([N:6]1[CH2:7][CH2:8][CH:9]([CH:12]=[CH:17][C:16]([O:15][CH2:19][CH3:18])=[O:14])[CH2:10][CH2:11]1)([CH3:4])[CH3:5]
Reactant: C1CCOC1
Reactant: CC(C)N1CCC(C=O)CC1
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C=CC1CCN(C(C)C)CC1
Reaction time: 0.33 h

Procedure:
Triethyl phosphonoacetate (7.96 g) is dissolved in tetrahydrofuran (50 ml) and thereto is added gradually 60% sodium hydride in oil (1.45 g) under ice-cooling. After stirring for 20 minutes under ice-cooling, to the mixture is added 1-isopropylpiperidine-4-carbaldehyde (5.03 g) obtained in Reference Example 134(2) in tetrahydrofuran (25 ml). The reaction solution is stirred for 3 hours, diluted with diethyl ether, thereto is added water and the mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1) to give ethyl 3-(1-isopropylpiperidin-4-yl)acrylate (6.87 g).
Reaction SMILES: C([Mg]Cl)(C)C.[CH3:6][C:7]1[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][C:8]=1[N:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@@H:24]([C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[C@@H:25]([CH3:32])[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:18]1=[O:43].Cl.[CH3:45][O:46][NH2:47]>O1CCCC1>[CH3:45][O:46][NH:47][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][C:7]([CH3:6])=[C:8]([N:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@@H:24]([C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=[CH:35][CH:34]=3)[C@@H:25]([CH3:32])[CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[C:18]2=[O:43])[CH:9]=1
Reactant: CON
Reactant: COC(=O)c1ccc(C)c(-n2ccnc(N[C@@H](c3cccc4ccccc34)[C@@H](C)CN3CCCC3)c2=O)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CONC(=O)c1ccc(C)c(-n2ccnc(N[C@@H](c3cccc4ccccc34)[C@@H](C)CN3CCCC3)c2=O)c1
Yield: 70.2 %

Procedure:
A solution of iso-propylmagnesium chloride (2M in diethyl ether, 1.2 mL) was added dropwise to a stirred mixture of 4-methyl-3-[3-[[(1R,2S)-2-methyl-1-(1-naphthalenyl)-3-(1-pyrrolidinyl)propyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzoic acid, methyl ester (Example 158b, 90 mg), O-methylhydroxylamine hydrochloride (65 mg) and tetrahydrofuran (2 mL) at room temperature. After 15 min the reaction was quenched with sat. aqueous NH4Cl and extracted into ethyl acetate. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound as a solid (65 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:15][CH2:16][NH:17][CH3:18])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>CC(C)=O>[CH2:25]([N:17]([CH3:18])[CH2:16][CH2:15][C:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]1)[CH:26]=[CH2:27]
Reactant: C=CCBr
Reactant: CNCCC1(c2cccc(OC)c2)C=CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN(C)CCC1(c2cccc(OC)c2)C=CCCC1

Procedure:
4.9 g of 1-(m-methoxyphenyl)-N-methyl-2-cyclohexene-1-ethylamine are dissolved in 50 ml of acetone. Thereupon, 3.5 g of potassium carbonate are added, 1.8 ml of allyl bromide are slowly added dropwise while stirring, and the mixture is stirred overnight. Subsequently, the precipitate is removed by filtration, and the filtrate is evaporated, and rac. N-allyl-1-(m-methoxyphenyl)-N-methyl-2-cyclohexene-1-ethylamine remains as the residue. The hydrochloride of this compound melts at 114°-116° C. (after recrystallization from ethyl acetate/diisopropyl ether).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:29]2[N:30]=[C:31]([O:39][C@@H:40]([C@H:42]3[CH2:46][NH:45][C:44](=[O:47])[CH2:43]3)[CH3:41])[C:32]3[N:33]([N:35]=[CH:36][C:37]=3[CH3:38])[CH:34]=2)[CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C>ClCCl>[C:1]([N:26]1[CH2:25][CH2:24][N:23]([C:22]2[CH:21]=[CH:20][C:19]([C:29]3[N:30]=[C:31]([O:39][C@@H:40]([C@H:42]4[CH2:46][NH:45][C:44](=[O:47])[CH2:43]4)[CH3:41])[C:32]4[N:33]([N:35]=[CH:36][C:37]=4[CH3:38])[CH:34]=3)=[CH:18][C:17]=2[O:16][CH3:15])[CH2:28][CH2:27]1)(=[O:3])[CH3:2]
Reactant: COc1cc(-c2cn3ncc(C)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1cc(-c2cn3ncc(C)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCN(C(C)=O)CC1
Reaction time: 1.5 h
Yield: 92 %

Procedure:
Acetic Anhydride (4 μl, 0.04 mmol) was added to a solution of (R)-4-((R)-1-(6-(3-methoxy-4-(piperazin-1-yl)phenyl)-3-methylpyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 2,2,2-trifluoroacetate 5.60 (18.1 mg, 0.03 mmol) and triethylamine (0.04 ml, 0.28 mmol) in dichloromethane (2 mL) at room temperature. After 90 min, reaction mixture was directly loaded onto silica gel and purified (0-8% methanol/dichloromethane) to yield (R)-4-((R)-1-((6-(4-(4-acetylpiperazin-1-yl)-3-methoxyphenyl)-3-methylpyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)pyrrolidin-2-one 5.61 (13.6 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[F:25])[CH:21]([CH3:26])[NH:20][CH2:19][CH2:18]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][C:24]([F:25])=[C:15]([F:14])[CH:16]=4)[CH:21]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2cc(F)c(F)cc21
Product: CC1c2cc(F)c(F)cc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-difluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][C:2]1[C:3](/[C:16](/[CH3:34])=[CH:17]/[C:18]2[N:19]=[C:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:21](S(=O)(=O)N(C)C)[CH:22]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.CI.[C:37]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[C:3](/[C:16](/[CH3:34])=[CH:17]/[C:18]2[N:19]=[C:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:21]([CH3:37])[CH:22]=2)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1nc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cn1S(=O)(=O)N(C)C
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)c1nc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cn1C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
Ethyl (E)-4-[2-(5,6,7,8 -tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]-1-N,N-dimethylsulfamoyl-2-imidazolecarboxylate (Compound 4, 70 mg, 0.18 mmol) was dissolved in acetone (10 mL) at room temperature and treated with methyl iodide (0.5 mL) and K2CO3 (350 mg). The suspension was stirred for 30 min, filtered through Celite and concentrated under reduced pressure. The residue was treated with water (5 mL) and the organic material was extracted with ethyl acetate, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexanes/ethyl acetate=5:1) to give the title compound as a light yellow solid (35 mg, 50%).
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:11][C:12]1ON=C(C=O)[CH:13]=1.O(C)[Na].[CH2:22]1[CH2:26]O[CH2:24][CH2:23]1>>[C:22]1([CH:26]=[CH:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:13]=[CH:12][CH:11]=[CH:24][CH:23]=1
Reactant: O=C(CO)c1ccccc1
Reactant: C1CCOC1
Reactant: Cc1cc(C=O)no1
Agent: CO[Na]
Product: O=C(C=Cc1ccccc1)c1ccccc1
Yield: 29 %

Procedure:
2.24 g (16.5 mmol) of 2-hydroxyacetophenone, 1.65 g of 5-methylisoxazole-3-carbaldehyde (14.9 mmol), and 10 ml of 25% NaOCH3 were reacted in 50 ml of dry THF to give 1.59 g (29%) of chalcone after purification. 1H NMR (300 MHz, CDCl3): δ 12.53 (s, 1H), 7.87 (d, d, J=0.6, 7.5 Hz, 1H), 7.80 (d, J=15.6 Hz, 1H), 7.69 (d, J=15.6 Hz, 1H), 7.56-7.51 (m, 1H), 7.05 (d, d, J=0.6, 8.4 Hz, 1H), 6.99-6.93 (m, 11H), 6.31 (d, J=0.3 Hz, 1H), 2.50 (s, 3H).
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36]1[C:37]([NH2:42])=[N:38][CH:39]=[CH:40][CH:41]=1.[NH4+].[Cl-]>C(Cl)Cl>[O:6]=[C:4]([NH:42][C:37]1[C:36]([NH:35][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)=[CH:41][CH:40]=[CH:39][N:38]=1)[C@@H:2]([NH:1][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:3]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ncccc1Nc1ccccn1
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ncccc1Nc1ccccn1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a −10° C. solution (NaCl-ice bath) of Boc-L-Ala-OH (1.214 g, 6.42 mmol) and N-methylmorpholine (0.741 mL, 6.74 mmol) in DCM (16.04 mL) was added isobutyl chloroformate (0.839 mL, 6.42 mmol). The resulting cloudy light yellow mixture was stirred at −10° C. After 15 min at −10° C., to the mixture was then added a solution of N3-(pyridin-2-yl)pyridine-2,3-diamine (0.5974 g, 3.21 mmol) in DCM (16 mL) at −10° C. with stirring. The resulting mixture was allowed to warm to rt with stirring. After 15.5 h at rt, to the mixture was added satd. NH4Cl (50 mL). The organic layer was separated. The aqueous mixture was extracted with DCM (50 mL×1). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min, then 50% isocratic of EtOAC in hexane for 14 min, then 50 to 100% gradient of EtOAc in hexane over 14 min, and then 100% isocratic of EtOAC for 30 min as eluent to give (S)-tert-butyl 1-oxo-1-(3-(pyridin-2-ylamino)pyridin-2-ylamino)propan-2-ylcarbamate as a light pink foamy solid: LC-MS (ESI) m/z 358.1 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:10]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:11]1[CH:16]=[C:15]([F:17])[C:14]([NH:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]3[N:25](S(C4C=CC(C)=CC=4)(=O)=O)[CH:26]=[C:27]([CH3:28])[C:20]=23)=[C:13]([F:39])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.C(OCC)(=O)C>C(O)C>[CH2:40]([N:10]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:11]1[CH:16]=[C:15]([F:17])[C:14]([NH:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]3[NH:25][CH:26]=[C:27]([CH3:28])[C:20]=23)=[C:13]([F:39])[CH:12]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(Nc4c(F)cc(N(Cc5ccccc5)Cc5ccccc5)cc4F)ccnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c[nH]c2nccc(Nc3c(F)cc(N(Cc4ccccc4)Cc4ccccc4)cc3F)c12
Reaction time: 8 h

Procedure:
5 ml of a 20% strength aqueous sodium hydroxide solution are added to a solution of 390 mg (0.66 mmol) of N4,N4-dibenzyl-2,6-difluoro-N1-{3-methyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}benzene-1,4-diamine in 15 ml of ethanol, and the mixture is stirred overnight. The reaction solution is then poured into a mixture of water and ethyl acetate and the aqueous phase is extracted two more times with ethyl acetate. Purification by preparative HPLC affords the target compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15]N(CC(NC3SC=CN=3)=O)[CH2:13][CH2:12]2)[C:5]([Br:26])=[CH:4][N:3]=1.BrC1C(Cl)=C([N+]([O-])=O)C(N)=NC=1.CCN(C(C)C)C(C)C.[O:48]([CH:55]1CCNCC1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(O)(C)C>[Br:26][C:5]1[C:6]([N:11]2[CH2:12][CH2:13][CH:55]([O:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:15][CH2:16]2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: c1ccc(OC2CCNCC2)cc1
Agent: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Nc1ncc(Br)c(N2CCC(Oc3ccccc3)CC2)c1[N+](=O)[O-]
Yield: 84 %

Procedure:
This was prepared using the same procedure as for 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide, but here using 5-bromo-4-chloro-3-nitropyridin-2-amine (162 mg, 0.64 mmol), DIPEA (3.5 eq, 2.24 mmol, 0.39 mL), isopropanol (3 mL) and 4-phenoxypiperidine (1.1 eq, 0.70 mmol, 125 mg). Concentration in vacuo to half volume after 18 h gave a bright yellow solid, which was filtered and washed with cold water (2×2 mL) to give the product (212 mg, 84%) as a yellow solid; δH (500 MHz, DMSO-d6) 1.74-1.81 (m, 2H, 2× piperidine CHAHB), 2.04-2.08 (m, br, 2H, 2× piperidine CHAHB), 2.98-3.03 (m, 2H, 2× piperidine NCHAHA), 3.24-3.27 (m, 2H, 2× piperidine NCHAHA), 4.63 (quintet, J=3.9 Hz, 1H, piperidine CH), 6.92 (t, J=7.4 Hz, 1H, phenyl H-6), 6.98 (s, br, 2H, NH2), 6.99 (d, J=7.8 Hz, 2H, phenyl H-2 & H-4), 7.28 (dd, J=8.6, 7.8 Hz, 2H, phenyl H-3 & H-5), 8.17 (s, 1H, pyridine H-6);
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]([OH:18])=O)[N:11]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1>C1COCC1>[CH3:19][N:20]1[CH2:21][CH2:22][CH:23]([N:26]2[CH2:31][CH2:30][N:29]([C:16](=[O:18])[CH2:15][N:12]3[CH:13]=[CH:14][C:10]([NH:9][C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:8])=[N:11]3)[CH2:28][CH2:27]2)[CH2:24][CH2:25]1
Reactant: O=C(O)Cn1ccc(NC(=O)c2ccc(Cl)s2)n1
Reactant: CN1CCC(N2CCNCC2)CC1
Solvent: C1CCOC1
Product: CN1CCC(N2CCN(C(=O)Cn3ccc(NC(=O)c4ccc(Cl)s4)n3)CC2)CC1

Procedure:
Using general method A, using THF instead of DMF as solvent, {3-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrazol-1-yl}-acetic acid (example 57.3) was reacted with 1-(N-methyl-4-piperidyl)-piperazine to give 5-chloro-thiophene-2-carboxylic acid (1-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazol-3-yl)-amide. Off-white solid. MS 451.3 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:8](O)([CH3:10])[CH3:9])[CH:7]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.FC1C=CC(O)=C(C(C2C=C(F)C=CC=2OC)(C)C)C=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:12][CH3:13])([CH3:10])[CH3:9])[CH:16]=1
Reactant: COc1ccc(F)cc1C(C)(C)O
Reactant: Oc1ccc(Cl)cc1
Agent: COc1ccc(F)cc1C(C)(C)c1cc(F)ccc1O
Product: COc1ccc(F)cc1C(C)(C)c1cc(Cl)ccc1O

Procedure:
2-(5-chloro-2-hydroxyphenyl)-2-(5-fluoro-2-methoxyphenyl)propane (m.p. 97° C.) was prepared from 2-(5-fluoro-2-methoxyphenyl)propan-2-ol and 4-chlorophenol following the method described in Example 3 for the preparation of 2-(5-fluoro-2-hydroxyphenyl)-2-(5-fluoro-2-methoxyphenyl)propane.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[NH2:8][OH:9].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[CH3:19]>CO>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([C:15](=[N:8][OH:9])[NH2:16])=[CH:13][C:12]=1[CH3:19]
Reactant: NO
Reactant: Cc1cc(C#N)ccc1Br
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: Cc1cc(C(N)=NO)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.8 %

Procedure:
Methanol (20 ml) at 5° C. was treated portionwise over 5 min. with stirring with potassium t-butoxide (1.68 g, 0.015 mole), then after a further 5 mins the solution was treated with hydroxylamine hydrochloride (1.11 g, 0.016 mole). The resulting mixture was allowed to warm to room temperature, stirred for 1 h, then treated with a solution of 4-bromo-3-methylbenzonitrile (2.0 g, 0.010 mole) in methanol (10 ml) and heated under reflux for 3 h. The mixture was allowed to cool, then filtered through kieselguhr and the filtrate concentrated in vacuo to afford the title compound as a white solid (2.56 g, 100%).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.Cl.[CH3:9][O:10][C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13]>>[CH3:9][O:10][C:11](=[O:15])[C@H:12]([CH3:14])[NH:13][C:5](=[O:7])[CH2:4][CH:1]1[CH2:2][CH2:3]1
Reactant: O=C(O)CC1CC1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Product: COC(=O)[C@H](C)NC(=O)CC1CC1

Procedure:
Following General Procedure D above, and using cyclopropylacetic acid (Aldrich) with L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared.
Reaction SMILES: ClC1C=C(CCNC(=O)C2C=CC(C(O)(C(F)(F)F)C(F)(F)F)=CC=2)C=CC=1Cl.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=1[C:40]([F:43])([F:42])[F:41])[C:34]([OH:36])=O.[F:44][C:45]([F:56])([F:55])[C:46]1[CH:47]=[C:48]([CH2:52][CH2:53][NH2:54])[CH:49]=[CH:50][CH:51]=1>>[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=1[C:40]([F:43])([F:42])[F:41])[C:34]([NH:54][CH2:53][CH2:52][C:48]1[CH:49]=[CH:50][CH:51]=[C:46]([C:45]([F:44])([F:55])[F:56])[CH:47]=1)=[O:36]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(Cl)c1
Reactant: NCCc1cccc(C(F)(F)F)c1
Agent: O=C(NCCc1ccc(Cl)c(Cl)c1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Product: O=C(NCCc1cccc(C(F)(F)F)c1)c1ccc(C(F)(F)F)c(Cl)c1
Yield: 82 %

Procedure:
The title compound was synthesized in analogy to N-[2-(3,4-dichloro-phenyl)-ethyl]-4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-benzamide (described in example S98) using 250 mg of 3-chloro-4-trifluoromethyl-benzoic acid (1.11 mmol) and 221 mg (1.17 mmol) of 2-(3-trifluoromethylphenyl)-ethylamine. The isolated residue was purified by flash column chromatography to give 360 mg of 3-chloro-4-trifluoromethyl-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide (82%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][C:27]=1[CH2:34]Br.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][C:27]=1[CH2:34][N:10]([CH2:9][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=1)[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21])(=[O:12])=[O:13]
Reactant: Cc1cnc(CNS(=O)(=O)c2ccccc2[N+](=O)[O-])c(C)c1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncc(C)cc1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
To a solution of N-(3,5-dimethyl-pyridin-2-ylmethyl)-2-nitro-benzenesulfonamide (0.60 g, 1.87 mmol) dissolved in CH3CN (10 mL) was added 2-bromomethyl-5-cyano-benzoic acid methyl ester (0.50 g, 1.96 mmol) and K2CO3 (0.72 g, 5.61 mmol). The mixture was stirred at 80° C. for 3 hours, then concentrated in vacuo and redissolved in CH2Cl2 (50 mL). Saturated aqueous NaHCO3 (50 mL) was added and the mixture was extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give a brown oil. Purification via column chromatography on silica gel (CH2Cl2:MeOH, 99:1, v/v) afforded 5-cyano-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(2-nitro-benzenesulfonyl)-amino]-methyl}-benzoic acid methyl ester as a yellow solid (0.90 g, 97%). 1H NMR (CDCl3) δ 2.15 (s, 3H), 2.22 (s, 3H), 3.88 (s, 2H), 5.15 (s, 2H), 7.05 (s, 1H), 7.61-7.72 (m, 5H), 7.83 (s, 1H), 7.95 (d, 1H, J=7.5 Hz), 8.06 (s, 1H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:11]=[C:10]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)[CH:9]=[CH:8][N:7]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl.O>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][C:10]3[CH:9]=[CH:8][N:7]=[C:6]([CH2:5][OH:4])[N:11]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: CC(=O)OCc1nccc(Oc2ccc3[nH]ccc3c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: OCc1nccc(Oc2ccc3[nH]ccc3c2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (4-(1H-indol-5-yloxy)pyrimidin-2-yl)methyl acetate (0.51 g, 1.8 mmol) in MeOH (18 mL) at 0° C. is added solid K2CO3 (0.6 g, 4.5 mmol). The reaction is stirred for 30 minutes at 0° C. and then warmed to room temperature and stirred for an additional 30 minutes. The reaction mixture is then diluted with DCM and water and the layers are separated. The aqueous layer is extracted 2 additional times with DCM. The organic layers are combined dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound. MS (ESI) m/z 242.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:12]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.Cl.CNC.C=O.[CH3:23]C(C)=O.C[C:28]([O:30]CC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:29]>>[O:16]=[C:13]([C:12]1[C:2]([CH3:1])=[CH:3][C:4]2[O:9][CH2:8][C:7](=[O:10])[NH:6][C:5]=2[CH:11]=1)[CH:14]([CH3:23])[CH2:15][C:28]([OH:30])=[O:29]
Reactant: CCC(=O)c1cc2c(cc1C)OCC(=O)N2
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: CC(C)=O
Agent: C=O
Agent: CNC
Agent: Cl
Product: Cc1cc2c(cc1C(=O)C(C)CC(=O)O)NC(=O)CO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
3,4-Dihydro-7-methyl-6-(1-oxopropyl)-3-oxo-1,4(2H)-benzoxazine (23.7 g) was added to a mixture of 13 g of dimethylamine hydrochloride and 15 ml of 37% aqueous formaldehyde solution in 68 ml of acetic anhdride. After heating on a steam bath for three hours, 50 ml of acetone was added and heating was continued for 15 minutes. The solvents were removed by evaporation at reduced pressure and the residue was dissolved in 1N HCl and washed with ethyl acetate. The aqueous layer was basified with sodium hydroxide and the resultant crystals were collected by filtration. This product was dissolved in 500 ml of acetone and 10 ml of iodomethane were added. After heating at reflux overnight, the solid which formed was collected by filtration and washed with acetone. The product was dissolved in 400 ml of 50% aqueous methanol and 18 g of potassium cyanide in 200 ml of water was added. After stirring overnight at room temperature, the solid was collected and washed with water. The damp filter cake was suspended in 500 ml of 6N HCl and heated at reflux for 1.5 hours. Upon cooling a white precipiate formed which was collected by filtration and washed with water to give 19.4 g (81% yield) of the title compound, mp 169.5°-172° C.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:3]=1[O:4]/[C:5](=[CH:11]\[C:12]([O:14]CC)=[O:13])/[C:6]([O:8]CC)=[O:7].[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:3]=1[O:4]/[C:5](=[CH:11]\[C:12]([OH:14])=[O:13])/[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)/C=C(\Oc1ccc(OC)cc1Br)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(O/C(=C\C(=O)O)C(=O)O)c(Br)c1
Yield: 88.5 %

Procedure:
Diethyl (2Z)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioate (29.9 g, 86.6 mmol) as prepared in Reference Example 2a was suspended in ethanol (55 ml) and a solution of sodium hydroxide (7.0 g, 0.175 mol) in water (55 ml) was added. The solution was refluxed for 1 h to give a clear orange solution. Most of the ethanol was removed in vacuo then 6 M HCl (50 ml) was added. The solid was filtered, washed with water and dried to give (2Z)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioic acid as a light orange solid (24.3 g, 88% yield).