Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:10]([CH2:20][C@H:21]([NH:27][C:28](=[O:44])[CH2:29][C:30](=[O:43])[NH:31][C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([NH2:42])[CH:33]=1)[C@@H:22]([OH:26])[CH2:23][CH2:24][CH3:25])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[CH3:19])C1C=CC=CC=1.C=O.[C:48](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:19][C:13]1[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][CH2:20][C@H:21]([NH:27][C:28](=[O:44])[CH2:29][C:30]([NH:31][C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([NH:42][CH3:48])[CH:33]=1)=[O:43])[C@@H:22]([OH:26])[CH2:23][CH2:24][CH3:25]
Reactant: CCC[C@H](O)[C@H](CN(Cc1ccc(C)cc1C)C(=O)OCc1ccccc1)NC(=O)CC(=O)Nc1cc(N)cc(C(F)(F)F)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)NC(=O)CC(=O)Nc1cc(NC)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of {(2S,3S)-2-[2-(3-amino-5-trifluoromethyl-phenylcarbamoyl)-acetylamino]-3-hydroxyhexyl}-(2,4-dimethyl-benzyl)-carbamic acid benzyl ester (83 mg, 0.13 mmol, see procedure 12c) in 1,2-dichloroethane (2 mL) was charged with formaldehyde (0.008 mL of a 37% aq. solution, 0.10 mmol), stirred for 20 min at RT, and then charged with sodium triacetoxyborohydride (69 mg, 0.33 mmol). The reaction was stirred at RT for 40 min, quenched with water, and extracted with EtOAc (2×). The organic extracts were washed with water and brine, and then dried (Na2SO4), filtered, and concentrated in vacuo. The residue was dissolved in MeOH (2 mL). This solution was charged with 5% Pd/C, Degussa style (7 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. Purification of the residue by reverse-phase HPLC provided the title compound as a white powder after lyopholization. MS found: (M+H)+=509.3.
Reaction SMILES: [C:1]([OH:6])(=O)[C@H:2]([CH3:4])[OH:3].O.ON1C2C=CC=CC=2N=N1.Cl.CN(CCCN=C=NCC)C.C(N(CC)CC)C.[CH3:37][C@@H:38]1[NH:43][CH2:42][CH2:41][N:40]([C:44]2[N:45]([CH2:66][C:67]([F:70])([F:69])[F:68])[C:46]3[C:51]([N:52]=2)=[C:50]([N:53]2[CH2:58][CH2:57][O:56][CH2:55][CH2:54]2)[N:49]=[C:48]([C:59]2[CH:60]=[N:61][C:62]([NH2:65])=[N:63][CH:64]=2)[N:47]=3)[CH2:39]1>C(Cl)Cl.CO.CN(C)C=O.C(Cl)Cl>[NH2:65][C:62]1[N:63]=[CH:64][C:59]([C:48]2[N:47]=[C:46]3[C:51]([N:52]=[C:44]([N:40]4[CH2:41][CH2:42][N:43]([C:1](=[O:6])[C@@H:2]([OH:3])[CH3:4])[C@@H:38]([CH3:37])[CH2:39]4)[N:45]3[CH2:66][C:67]([F:69])([F:68])[F:70])=[C:50]([N:53]3[CH2:54][CH2:55][O:56][CH2:57][CH2:58]3)[N:49]=2)=[CH:60][N:61]=1
Reactant: C[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Reactant: C[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@H](O)C(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)C[C@@H]1C
Reaction time: 120 h
Yield: 47 %

Procedure:
L-Lactic acid (48.7 μl, 0.55 mmol), 1-hydroxybenzotriazole monohydrate (42.5 mg, 0.28 mmol), 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (106.3 mg, 0.55 mmol), and triethylamine (77.3 μl, 0.55 mmol) were added to a methylene chloride (3.0 ml)-N,N-dimethylformamide (3.0 ml) mixture solution of 5-{8-[(3S)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl}pyrimidin-2-amine (132.7 mg, 0.28 mmol) at room temperature. The resulting mixture was stirred for 5 days followed by the addition of L-lactic acid (48.7 μl, 0.55 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (106.3 mg, 0.55 mmol), and triethylamine (77.3 μl, 0.55 mmol). The resulting mixture was stirred for 1 day and the reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (72.4 mg, 47%) as a pale yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11](=O)[CH:12]=[CH:13][N:14]([CH3:16])C)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].N[C:19]1[C:23]([C:24]#[N:25])=C[NH:21][N:20]=1.C(N)(=O)C.C([BH3-])#N.[Na+]>C(O)(=O)C>[C:24]([C:23]1[CH:19]=[N:20][N:21]2[C:11]([C:7]3[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][CH:8]=3)=[CH:12][CH2:13][NH:14][C:16]=12)#[N:25]
Reactant: N#Cc1c[nH]nc1N
Reactant: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Agent: CC(N)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(C2=CCNc3c(C#N)cnn32)c1

Procedure:
A mixture of 7.0 g of 3'-actamido-3-(N,N-dimethylamino)acrylophenone and 3.3 g. of 3-amino-4-cyanopyrazole in 100 ml of acetic acid was heated at reflux for 8 hours. Crystals that formed on cooling were filtered and dried to give 7.4 g. of N-[3-(3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl)phenyl[acetamide, m.p. 254°-256° C. This was reacted with 14.8 g of sodium cyanoborohydride in 50 ml of acetic acid to give 3.0 g of N-[3-(3-cyano-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)phenyl]acetamide, m.p. 251°-254° C. This is reacted with chloroacetic anhydride and sodium carbonate in toluene as in Example 3 to give the title compound.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].C([N:13]1[CH2:27][CH2:26][C:25]2[C:16](=[N:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]=2[Cl:28])[CH2:15][CH2:14]1)C>C(Cl)Cl.CCOCC>[C:5]1([O:4][C:2]([N:13]2[CH2:27][CH2:26][C:25]3[C:16](=[N:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[C:24]=3[Cl:28])[CH2:15][CH2:14]2)=[O:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCN1CCc2nc3ccccc3c(Cl)c2CC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1CCc2nc3ccccc3c(Cl)c2CC1
Reaction time: 8 h

Procedure:
A solution of 1.2 gm (7.7 millimols) of phenyl chloroformate in 20 ml of methylene chloride was added dropwise to a mixture of 2 gm (7.7 millimols) of 3-ethyl-11-chloro-1,2,4,5-tetrahydro-3H-azepino[4,5-b]quinoline and 15 ml of methylene chloride at 5° C. After standing overnight, the resulting mixture was diluted with ether to double its volume and was then suction-filtered. The filter cake was recrystallized from acetone.
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])[C:3]=1[C:4]([OH:6])=O.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:4](=[O:6])[C:3]1[C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:8][N:9]=[CH:10][C:2]=1[F:1]
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1c(F)cncc1Nc1ccc(I)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccccc1NC(=O)c1c(F)cncc1Nc1ccc(I)cc1F
Yield: 55.6 %

Procedure:
100 mg of 3-fluoro-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (0.266 mmol, 1 eq.; Intermediate 1A) were suspended in 2 mL of DMF and then 28,754 mg 1,2-diaminobenzene (0.266 mmol, 1 eq.), 215,339 mg of HATU (0.566 mmol, 2.13 eq.) and 73,196 mg of N,N-Diisopropylethylamine (0.566 mmol, 2.13 eq.) were added and stirring was continued at 50° C. temperature for 18 h. The reaction mixture was partitioned between 20 ml of ethyl acetate and 20 ml of brine. The aqueouse layer was reextracted twice with 20 ml of ethyl acetate each. The combined organic layers were dried over a silicone filter and concentrated in vacuo. The residue was purified by flash chromatography to afford 69 mg of the target compound in 72% UV-purity. This material was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH2:11])=[CH:8][C:6]=2[N:7]=1.[C:18](Cl)(=[O:22])[CH:19]([CH3:21])[CH3:20]>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH:11][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine (35 mg) was reacted with 27 μL of isobutyryl chloride via General Procedure G to give N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)isobutyramide.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:15]=3[CH:16]=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:22][C:23]1[CH:27]=[CH:26][O:25][C:24]=1[C:28](O)=[O:29].CCN=C=NCCCN(C)C>ClCCCl.CN(C1C=CN=CC=1)C>[NH2:1][C:2]1[C:11]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][C:18]([NH:21][C:28]([C:24]4[O:25][CH:26]=[CH:27][C:23]=4[CH3:22])=[O:29])=[CH:17][C:15]=3[CH:16]=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: Cc1ccoc1C(=O)O
Reactant: COC(=O)c1cnc(N)c(-c2cc3cc(N)ccc3s2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: COC(=O)c1cnc(N)c(-c2cc3cc(NC(=O)c4occc4C)ccc3s2)c1
Reaction time: 2 h

Procedure:
To the mixture of methyl 6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate (120 mg, 0.4 mmol, 1 eq) and 3-methylfuranylcarboxylic acid (50.4 mg, 1 eq) in 1,2-dichloroethane (3 mL) at 60° C. was added catalytic amount of DMAP (10 mg, 0.2 eq) and EDCI (92.2 mg, 1.2 eq). The reaction was stirred at that temperature for 2 h and then partitioned between EtOAc and saturated aq NaHCO3. The organic layer was further washed with brine and then dried with anhydrous sodium sulfate. The organic layer was decanted, concentrated, and the solid residue which was treated with ethyl acetate with stirring at room temperature for an hour. Methyl 6-amino-5-{5-[(3-methyl-2-furoyl)amino]-1-benzothien-2-yl}nicotinate was obtained upon filtration as a white solid in amount of 128 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](=[O:23])[N:19]([CH3:24])[CH:18]=1)[CH2:5][NH:6]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:6][CH2:5][C:4]1[CH:14]=[CH:15][C:16]([C:17]2[CH:22]=[CH:21][C:20](=[O:23])[N:19]([CH3:24])[CH:18]=2)=[C:2]([F:1])[CH:3]=1
Reactant: Cn1cc(-c2ccc(CNC(=O)OC(C)(C)C)cc2F)ccc1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2ccc(CN)cc2F)ccc1=O

Procedure:
The crude tert-butyl 3-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)benzylcarbamate 21-6 (10 mg, obtained in Step 3) was stirred with trifluoroacetic acid (TFA, 0.3 mL) in dichloromethane (1 mL) overnight. Evaporation under reduced pressure (with the addition of some toluene to aid evaporation of the residual TFA) followed by lyophilization gave the crude 5-(4-(aminomethyl)-2-fluorophenyl)-1-methylpyridin-2(1H)-one 21-7.
Reaction SMILES: C[N:2]1[CH:6]=[C:5]([C:7](=[O:15])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10](Cl)[CH:9]=2)[C:4]([C:16]([O:18][CH3:19])=[O:17])=[CH:3]1.CN1C=CC(C([O-])=O)=C1>>[CH:8]1([C:7]([C:5]2[C:4]([C:16]([O:18][CH3:19])=[O:17])=[CH:3][NH:2][CH:6]=2)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: COC(=O)c1cn(C)cc1C(=O)c1cccc(Cl)c1
Agent: Cn1ccc(C(=O)[O-])c1
Product: COC(=O)c1c[nH]cc1C(=O)C1CCCCC1

Procedure:
Belgian Pat. No. 870,910 (published Mar. 29, 1979) generally discloses analogous compounds, specifically examplifying the preparation of methyl 1-methyl-4-(3-chlorobenzoyl)pyrrole-3-carboxylate by Friedel-Crafts acylation of 1-methylpyrrole-3-carboxylate.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:25]=3)[C:11]=2/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[O:6])[CH2:3][CH2:2]1>C(O)(=O)C.C(O)C.[C].[Pd]>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:29]=3)[C:11]=2[CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2/C=C/c2ccc(S(C)(=O)=O)cc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 64.9 %

Procedure:
To a solution of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-{(E)-2-[4-(methylsulfonyl)phenyl]vinyl}-1H-1,2,3-triazole-4-carboxamide (230 mg, 0.48 mmol) obtained in Example 401 in acetic acid (12 ml) and ethanol (4.0 ml) was added palladium-carbon (25 mg). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 5 days, and the insoluble material was filtered off. The solvent was evaporated, and the residue was purified by silica gel column (ethyl acetate/methanol=20/1 to 10/1). The resultant product was recrystallized from ethyl acetate/hexane to give the title compound as a colorless powder (150 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C:12]2[CH:19]=[CH:18][CH:17]=[C:14]([CH:15]=[O:16])[CH:13]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1
Yield: 91.7 %

Procedure:
4-Chloro-2-fluorobenzonitrile (1.00 g, 6.43 mmol), 3-hydroxybenzaldehyde (0.79 g, 6.43 mmol) and cesium carbonate (2.09 g, 6.43 mmol) were heated with stirring in dry DMF (5 ml) at 50° C. for 23 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water (3×), 10% aqueous sodium carbonate (2×), water, brine, and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(3-formyl-phenoxy)-benzonitrile (1.52 g, 91%) as a yellow oil which solidified.
Reaction SMILES: [C:1]1(=O)[O:5][CH2:4][CH2:3][O:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:13][CH:14]([S:17][C:18]1[CH:23]=[CH:22]C(O)=[CH:20][CH:19]=1)[CH2:15][CH3:16].O>CN(C=O)C>[CH3:13][CH:14]([S:17][C:18]1[CH:23]=[CH:22][C:1]([O:2][CH2:3][CH2:4][OH:5])=[CH:20][CH:19]=1)[CH2:15][CH3:16]
Reactant: O=C1OCCO1
Reactant: CCC(C)Sc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)Sc1ccc(OCCO)cc1

Procedure:
A mixture of ethylene carbonate (41.08 g, 460.0 mmol) and potassium carbonate (63.57 g, 460.0 mmol) in 100 ml of DMF is heated to 110° and 4-(1-methylpropylthio)phenol (40.19 g, 230.0 mmol) in 100 ml DMF is slowly added dropwise with stirring. The mixture is stirred at 100° for 8 hours. Water is added to the cooled reaction mixture and the aqueous phase is extracted with ether. The combined organic layers are washed with 5% NaOH, with water and with brine, dried and the solvent removed to give 2-[4-(1-methylpropylthio)phenoxy]ethanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH:5]([C:10]1[CH:11]=[C:12]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH:23]=[CH:24][CH:25]([CH3:27])[CH3:26])[CH2:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]>CO>[CH2:1]([O:3][C:4](=[O:38])[CH:5]([C:10]1[CH:11]=[C:12]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=2)[CH:13]=[C:14]([CH:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:20][CH2:21]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCN(CC=CC(C)C)CC2)c1
Solvent: CO
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCN(CCCC(C)C)CC2)c1
Reaction time: 4 h

Procedure:
A solution of a mixture of 4-methyl-2-{5-[1-(4-methyl-pent-2-enyl)-piperidin-4-yl]-4′-trifluoromethyl-biphenyl-3-yl}-pentanoic acid ethyl ester and methyl ester (69a) (25 mg, 0.05 mmol) in MeOH (2.0 mL) was flushed with N2. To this was added 10% Pd/C (5 mg). The suspension was hydrogenated at 20 psi for 4 h at room temperature. It was filtered through celite and the solid was washed with EtOAc. The filtrate was dried (MgSO4) and concentrated in vacuo to obtain 4-methyl-2-{5-[1-(4-methyl-pentyl)-piperidin-4-yl]-4′-trifluoromethyl-biphenyl-3-yl}-pentanoic acid ethyl ester and methyl ester. Calcd for C31H42F3NO2 (M+H) 518.67, Found 518.3 (methyl ester) and Calcd for C32H44F3NO2 (M+H) 532.69, Found 532.4 (ethyl ester).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][O:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.C(N(C(C)C)C(C)C)C>CCCCO>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][O:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CCCO4)c23)C1
Temperature: 160 °C
Reaction time: 16 h
Yield: 29 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-2-carboxamide (225 mg, 0.686 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (412 mg, 2.06 mmol), and N-ethyl-N-isopropylpropan-2-amine (239 μL, 1.37 mmol) in n-BuOH (5 mL) was purged under N2 and stirred at 160° C. in a sealed tube for 16 hours. The solvent was then removed in vacuo, and the residue obtained was purified by C-18 reverse phase column chromatography (Biotage Flash 25M+; C-18) on Biotage SP4 unit eluting with a gradient of 15-90% CH3CN/water (25 CV) to provide tert-butyl (3R)-1-(5-bromo-3-(tetrahydrofuran-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (101 mg, 0.199 mmol, 29.0% yield) as a solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)=[CH:9][C:8]=1[O:19][CH3:20])C.[NH3:22]>>[NH:18]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([NH2:22])=[O:3])=[C:8]([O:19][CH3:20])[CH:9]=1
Reactant: CCOC(=O)COc1ccc(Cc2ncc[nH]2)cc1OC
Reactant: N
Product: COc1cc(Cc2ncc[nH]2)ccc1OCC(N)=O

Procedure:
Treatment of 4-(1-imidazolylmethyl)-2-methoxyphenoxyacetic acid ethyl ester with ammonia as described in Example 8 gave 4-(1-imidazolylmethyl)-2-methoxyphenoxyacetamide, m.p. 124°-125° C. (from chloroform/petrol). Found: C, 59.39, H, 5.83, N, 16.07. C13H15N3O3 requires: C, 59.75, H, 5.78, N, 16.08%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][S:13][C:12]=2[C:22]([O:24][CH3:25])=[O:23])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:10])=O.[C:26]([O-:29])(=[O:28])[CH3:27].[Na+].C(OCC)C>C(OC(=O)C)(=O)C>[C:26]([O:29][CH2:10][S:8][C:7]1[CH:6]=[CH:5][C:4]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][S:13][C:12]=2[C:22]([O:24][CH3:25])=[O:23])=[CH:3][C:2]=1[F:1])(=[O:28])[CH3:27]
Reactant: COC(=O)c1scc(-c2ccccc2)c1-c1ccc(S(C)=O)c(F)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1scc(-c2ccccc2)c1-c1ccc(SCOC(C)=O)c(F)c1
Yield: 62.5 %

Procedure:
The methyl 3-[3-fluoro-4-(methylsulfinyl)phenyl]-4-phenyl-2-thiophenecarboxylate (4.13 g, 11.04 mmol) was dissolved in acetic anhydride (45.0 mL). Powdered sodium acetate (4.0 g, 48.7 mmol) was added and the solution was refluxed for 8 hours. The solution was poured into a 500 mL round bottom flask and solvent removed at reduced pressure. The residue was taken up in ethyl acetate (200 ml) and dichloromethane (20 mL). The solution was extracted with saturated sodium bicarbonate (3×100 mL) followed by saturated ammonium chloride (2×100 mL). The solvent was removed at reduce pressure and residue taken up in ether, dried over sodium sulfate and solvent removed at reduced pressure. Methyl 3-[4-[[(acetyloxy)methyl]thio]-3-fluorophenyl]-4-phenyl-2-thiophenecarboxylate (2.9 g, 6.90 mmol) was isolated by crystallization from diethyl ether and hexanes as white crystals. (62% yield). Mp 102.9-103.7° C. 1H NMR (CDCl3/300 MHz) 7.53 (s, 1H), 7.43 (t, 1H, J=7.8 Hz), 7.22-7.28 (m, 3H), 7.04-7.08 (m, 2H), 6.92-6.98 (m, 2H), 5.42 (s, 2H), 3.81 (s, 3H), 2.11 (s, 3H). ESHRMS m/z 434.0898 (calcd for M+NH4+, 434.0896)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][NH2:15])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[CH3:16][C:17]#N>CO.[Rh]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][NH:15][CH2:16][CH3:17])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CC#N
Reactant: CCOc1ccc(CCN)cc1OCC
Agent: [Rh]
Solvent: CO
Product: CCNCCc1ccc(OCC)c(OCC)c1
Reaction time: 72 h

Procedure:
To a solution of 0.43 g of 2-(3,4-diethoxy-phenyl)-ethylamine in 3 mL MeOH were added 270 mg of 5 wt % Rh/C and 0.22 mL of MeCN. The reaction mixture was stirred under a H2 atmosphere (balloon) for 3 days and then filtrated over a pad of celite and washed with 100 mL MeOH. Concentration in vacuo afforded 0.4 g of [2-(3,4-diethoxy-phenyl)-ethyl]-ethyl-amine as yellow oil.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].N1C=CC=CC=1.[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1)([O-:13])=[O:12]>O1CCCC1>[C:1]([O:4][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=1)(=[S:3])[CH3:2]
Reactant: CC(O)=S
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=S)OCc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Yield: 77.3 %

Procedure:
Thioacetic acid (20 cm3, 0.28 mol) and anhydrous pyridine (15.2 cm3, 0.188 mol) were added to a solution of 4-nitrobenzyl chloride (12.0 g, 70 mmol) in anhydrous tetrahydrofuran (200 cm3). The stirred reactants were heated at 50° C. for 24 h. The cooled products were filtered and the flltrate was evaporated under reduced pressure. The residue was dissolved in dichloromethane (300 cm3) and the resulting solution was washed with saturated aqueous sodium hydrogen carbonate (2×250 cm3), dried (MgSO4) and concentrated under reduced pressure. The residue was crystallized from ethyl acetate--petroleum ether (bp 60°-80° C.) to give 4-nitrobenzyl thioacetate 16a (11.43 g, 77%) as pale yellow needles, m.p. 55.5°-57.5° C.
Reaction SMILES: CON(C)[C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Mg]Cl>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:6]
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: Cl[Mg]c1ccccc1Cl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccccc1Cl

Procedure:
Prepared as described in Example 6 using (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (182 mg, 0.78 mmol) and (2-chlorophenyl)magnesium chloride (403 mg, 2.35 mmol). Yield 110 mg (50%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([Sn](CCCC)(CCCC)CCCC)=[CH:5][N:4]=[N:3]1.Br[C:21]1[CH:22]=[C:23]([C:27]([O:29][CH3:30])=[O:28])[S:24][C:25]=1[Cl:26].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:26][C:25]1[S:24][C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:22][C:21]=1[C:6]1[N:2]([CH3:1])[N:3]=[N:4][CH:5]=1
Reactant: COC(=O)c1cc(Br)c(Cl)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnnn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2cnnn2C)c(Cl)s1
Temperature: 110 °C
Yield: 31.7 %

Procedure:
A mixture of 1-methyl-5-(tributylstannanyl)-1H-1,2,3-triazole (2.0 g, 5.37 mmol), methyl 4-bromo-5-chloro-2-thiophenecarboxylate (1.25 g, 4.9 mmol), Pd(PPh3)2Cl2 (171 mg, 0.244 mmol), TRIETHYLAMINE (0.68 ml, 4.89 mmol) and toluene (3 ml) was heated at 110° C. for 4 hr under N2. The reaction mixture was purified via column chromatography (silica, 50%-70% EtOAc in hexane) to give the title compound as a white solid (400 mg, 32%): LCMS (ES) m/z 258.2 (M+H)+.