Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]1([C:12]2[S:13][CH:14]=[C:15]([C:17](OCC)=[O:18])[N:16]=2)[CH:11]=[CH:10][CH:9]=[N:8]1.[OH-].[Na+].O>C1COCC1>[N:7]1([C:12]2[S:13][CH:14]=[C:15]([CH2:17][OH:18])[N:16]=2)[CH:11]=[CH:10][CH:9]=[N:8]1
Reactant: CCOC(=O)c1csc(-n2cccn2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1csc(-n2cccn2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
LiAlH4 (247 mg; 6.49 mmol) was added in 20 mg portions over 30 minutes to a solution of ethyl 2-pyrazol-1-ylthiazole-4-carboxylate (1.45 g; 6.49 mmol) in anhydrous THF (20 ml) cooled to 0° C. and under nitrogen. After 30 minutes, 10% NaOH (about 5 ml) and water (about 5 ml) were added to the reaction mixture. The mixture was stirred for 30-45 minutes, filtered through Celite and evaporated, and the residue was taken up in saline solution and ethyl acetate. Drying and evaporation under vacuum gave (2-pyrazol-1 -ylthiazole-4-yl)methanol (1.13 g; 96% yield).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N+:6]([C:9]1[CH:33]=[CH:32][C:12]([CH2:13][O:14][C:15]([CH2:17][O:18][N:19]=[C:20]([C:24]2[N:25]=[C:26]([NH:29][CH:30]=[O:31])[S:27][CH:28]=2)[C:21]([OH:23])=O)=[O:16])=[CH:11][CH:10]=1)([O-:8])=[O:7].[NH2:34][CH:35]1[C:47](=[O:48])[N:37]2[C:38]([C:44]([OH:46])=[O:45])=[C:39]([CH:42]=[CH2:43])[CH2:40][S:41][C@H:36]12.C[Si](CC(N)=O)(C)C>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][O:14][C:15]([CH2:17][O:18][N:19]=[C:20]([C:24]2[N:25]=[C:26]([NH:29][CH:30]=[O:31])[S:27][CH:28]=2)[C:21]([NH:34][CH:35]2[C:47](=[O:48])[N:37]3[C:38]([C:44]([OH:46])=[O:45])=[C:39]([CH:42]=[CH2:43])[CH2:40][S:41][C@H:36]23)=[O:23])=[O:16])=[CH:32][CH:33]=1)([O-:8])=[O:7]
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=CNc1nc(C(=NOCC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)O)cs1
Agent: C[Si](C)(C)CC(N)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OCc3ccc([N+](=O)[O-])cc3)c3csc(NC=O)n3)[C@H]2SC1
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
Vilsmeir reagent was prepared from N,N-dimethylformamide (1.67 ml) and phosphorus oxychloride (1.98 ml) in dry tetrahydrofuran (50.4 ml) in a conventional manner. 2-(p-Nitrobenzyloxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (7.35 g) was added to the stirred suspension of Vilsmeir reagent under ice-cooling, followed by stirring for 30 minutes at the same temperature. To a solution of 7-amino-3-vinyl-3-cephem-4-carboxylic acid (3.4 g) and trimethylsilylacetamide (11.8 g) in ethyl acetate (35 ml) was added the activated acid solution obtained above at -20° C., and the reaction mixture was stirred at -20° C. to -10° C. for an hour. After water and ethyl acetate were added to the resultant solution, the separated organic layer was washed with water and then dried. A conventional work-up of the solution gave 7-[2-(p-nitrobenzyloxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (6.8 g) as yellowish powder.
Reaction SMILES: C[O:2][C:3]1[C:13]2[C:14]3[C:6]([CH2:7][CH:8]([N:15]4[CH2:20][CH2:19][CH:18]([N:21]5[C:25]6[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=6[N:23]([CH2:30][C:31]([NH:33][CH3:34])=[O:32])[C:22]5=[O:35])[CH2:17][CH2:16]4)[C:9]=3[CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CC(C)=O>[OH:2][C:3]1[C:13]2[C:14]3[C:6]([CH2:7][CH:8]([N:15]4[CH2:16][CH2:17][CH:18]([N:21]5[C:25]6[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=6[N:23]([CH2:30][C:31]([NH:33][CH3:34])=[O:32])[C:22]5=[O:35])[CH2:19][CH2:20]4)[C:9]=3[CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1
Reactant: CNC(=O)Cn1c(=O)n(C2CCN(C3Cc4ccc(OC)c5cccc3c45)CC2)c2ccccc21
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CNC(=O)Cn1c(=O)n(C2CCN(C3Cc4ccc(O)c5cccc3c45)CC2)c2ccccc21
Temperature: -50 °C

Procedure:
2-{3-[1-(5-Methoxyacenaphthen-1-yl)piperidin-4-yl]-2,3-dihydro-2-oxo-benzimidazol-1-yl}-N-methylacetamide (780 mg) was dissolved in dichloromethane (50 ml), a solution (8.0 ml) of boron tribromide (1.0 mol) in dichloromethane was added dropwise under a nitrogen stream while cooling to −50° C., and the mixture was gradually warmed over 1 hr. After completion of the reaction, the reaction mixture was poured into an aqueous potassium carbonate solution by small portions, during which unnecessary substances were dissolved in acetone), the mixture was extracted with chloroform, and the extract was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by NH-coating silica gel column chromatography to give a crude product of the title compound.
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)=[CH:6][N:7](C)C)C.[NH:16]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1)N.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)C>[CH3:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([N:16]2[C:4](=[O:15])[C:5]([N:10]3[CH:14]=[CH:13][N:12]=[N:11]3)=[CH:6][NH:7]2)[CH:23]=1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Reactant: Cc1ccnc(NN)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: Cc1ccnc(-n2[nH]cc(-n3ccnn3)c2=O)c1

Procedure:
250 mg (1.19 mmol) of the compound from Example 3A, 122 mg (0.99 mmol) of the compound from Example 1A and 23 mg (99 μmol) camphor-10-sulfonic acid are dissolved in 5 ml anhydrous ethanol and the mixture is heated under reflux overnight. Thereafter, the reaction mixture is allowed to cool and is pre-purified by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) and subsequent flash chromatography over silica gel (mobile phase: methylene chloride/methanol gradient). Renewed purification by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) finally gives 21 mg (9% of th.) of the title compound.
Reaction SMILES: N.CC(C)(C)CC[NH2:6].[O:9]=[C:10]1[C:18]2([C:22]3=[CH:23][C:24]4[O:28][CH2:27][O:26][C:25]=4[CH:29]=[C:21]3[O:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]1[CH2:30][C:31]1[O:35][C:34]([C:36]([F:39])([F:38])[F:37])=[C:33]([C:40](O)=[O:41])[CH:32]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC(O)=O>CO>[O:9]=[C:10]1[C:18]2([C:22]3=[CH:23][C:24]4[O:28][CH2:27][O:26][C:25]=4[CH:29]=[C:21]3[O:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]1[CH2:30][C:31]1[O:35][C:34]([C:36]([F:38])([F:39])[F:37])=[C:33]([C:40]([NH2:6])=[O:41])[CH:32]=1
Reactant: CC(C)(C)CCN
Reactant: O=C(O)c1cc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)oc1C(F)(F)F
Agent: N
Agent: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Solvent: CO
Product: NC(=O)c1cc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)oc1C(F)(F)F

Procedure:
Following the procedure as described in EXAMPLE 12.49 and making non-critical variations using 7 N ammonia solution in methanol to replace 3,3-dimethylbutylamine, and 5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxylic acid to replace (2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetic acid, 5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxamide was obtained (86%) as a colorless solid: mp 172-174° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.32-7.27 (m, 1H), 7.20-7.17 (m, 1H), 7.11-7.06 (m, 1H), 6.97-6.94 (m, 1H), 6.70 (s, 1H), 6.49 (s, 1H), 6.09-6.02 (m, 3H), 5.83 (ABq, 2H), 5.85-5.84 (m, 2H), 5.03-4.85 (m, 3H), 4.67-4.64 (m, 1H); MS (ES+) m/z 473.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([N:6]([CH2:8][CH2:9][NH:10]C(=O)OC(C)(C)C)[CH3:7])=[O:5].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:10][CH2:9][CH2:8][N:6]([CH3:7])[C:4](=[O:5])[C:3]1[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=1[OH:1]
Reactant: CN(CCNC(=O)OC(C)(C)C)C(=O)c1ccccc1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCN)C(=O)c1ccccc1O
Temperature: 0 °C
Reaction time: 16 h
Yield: 378.6 %

Procedure:
To a solution of tert-butyl 2-(2-hydroxy-N-methylbenzamido)ethylcarbamate (0.2 g, 0.68 mmol) in CH2Cl2 (5 mL) at 0° C. was added trifluoroacetic acid (1.8 mL, 23.4 mmol). The mixture was stirred (0° C., 16 h), concentrated under reduced pressure and neutralized with saturated NH3 in CH3OH. The mixture was concentrated under reduced pressure to afford N-(2-aminoethyl)-2-hydroxy-N-methylbenzamide as a colorless oil (0.5 g). This compound was used in the next step without further purification. Mass calculated for C10H14N2O2=194.23; found: [M+H]+=195.1.
Reaction SMILES: [CH3:1][CH:2]([C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C@@H:24]([O:38]COC)[CH2:25][C@@H:26]2[O:34]COC)=[CH:21][CH:20]=3)[CH2:17][CH2:16]1)[CH2:3]OS(C1C=CC(C)=CC=1)(=O)=O.[Li].C([Cu]CCC(C)C)CC(C)C.[CH2:54]([Li])[CH2:55][CH:56]([CH3:58])[CH3:57].[Cl-].[NH4+]>C(OCC)C>[CH3:57][CH:56]([CH2:55][CH2:54][CH2:3][C@H:2]([C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C@@H:24]([OH:38])[CH2:25][C@@H:26]2[OH:34])=[CH:21][CH:20]=3)[CH2:17][CH2:16]1)[CH3:1])[CH3:58]
Reactant: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)COS(=O)(=O)c5ccc(C)cc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OCOC)C1
Reactant: [Li]CCC(C)C
Agent: CC(C)CC[Cu]CCC(C)C
Agent: [Cl-]
Agent: [Li]
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A solution of 78 mg of 20-methyl-1α,3β-bis(methoxymethoxy)-21-p-toluenesulfonyloxypregna-5,7-diene in 2 ml of diethyl ether was added dropwise, at -50° C. to -60° C., to a diethyl ether solution of diisoamylcopper lithium prepared from 100 mg of cuprous iodide and 0.9 ml of a 1.1N diethyl ether solution of isoamyllithium in 2 ml of diethyl ether. After stirring at -30° C. for 1 hour, the reaction mixture was poured into a cold aqueous solution of ammonium chloride, followed by extraction with diethyl ether. The extract was washed with 10% aqueous ammonia, water and an aqueous solution of sodium chloride, dried over sodium sulfate and concentrated. The residue was dissolved in 1 ml of methanol, 1 ml of 1N hydrochloric acid was added, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was diluted with water and extracted with methylene chloride. The extract was washed with an aqueous solution of sodium hydrogen carbonate and an aqueous solution of sodium chloride, dried over sodium sulfate and concentrated. The residue was washed with cold ethyl acetate to give 37 mg of cholesta-5,7-diene-1α,3β-diol, whose 1H NMR spectrum was identical with that obtained in Reference Example 8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:26][O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14]([NH:32][C:31]3[CH:33]=[CH:34][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: COc1ccc(N)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc(OC)cc3)nc21

Procedure:
A solution of 0.100 g (0.25 mmol) of 6-(2,6-dichlorophenyl)-8-ethyl-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 68 and 0.061 g (0.50 mmol) of 4-methoxyaniline in 0.5 mL of dimethylformamide was heated at reflux for 10 minutes. Three drops of water were added. Crystals separated on inducement. An additional 3 drops of water were added to precipitate additional tacky solid. After decantation, the solid was triturated with 0.5 mL of ethyl acetate and 0.5 mL of petroleum ether. The solids were filtered and washed with 50% ethyl acetate/petroleum ether and dried; wt 0.080 g. Purification was effected by filtering an ethyl acetate solution through a layer of silica gel. Concentration of the filtrate to 1 mL volume yielded pure crystalline product; wt 0.033 g; mp 213°-215° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.F[C:21]1[C:26](C(F)(F)F)=[CH:25][CH:24]=[CH:23][C:22]=1[C:31]([C:33]1C=CC=[CH:35][CH:34]=1)=[O:32]>>[CH3:35][C:34]1[C:33]([C:31]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:21]=2)=[O:32])=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]2[C:2](=[C:7]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=2)[N:1]=1
Reactant: Nc1c(C(=O)c2ccccc2)cccc1C(F)(F)F
Reactant: O=C(c1ccccc1)c1cccc(C(F)(F)F)c1F
Product: Cc1nc2c(C(F)(F)F)cccc2c(-c2ccccc2)c1C(=O)c1ccccc1

Procedure:
[2-amino-3-(trifluoromethyl)phenyl](phenyl)methanone: The title compound was prepared from (2-Fluoro-3-trifluoromethyl-phenyl)-phenyl-methanone following the procedure of Example 457, Step 3: MS (ESI) m/z 266; HRMS: calcd for C14H10F3NO+H+, 266.07872; found (ESI, [M+H]+), 266.0771
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:13]=3[NH2:14])=[CH:10][N:9]([CH3:23])[C:8]=12.[CH:24]1([CH:29]=O)[CH2:28][CH2:27][CH2:26][CH2:25]1>ClC(Cl)C.C(O)(=O)C>[CH:24]1([CH2:29][NH:14][C:13]2[CH:15]=[CH:16][C:17]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:18][C:12]=2[C:11]2[C:7]3[C:8](=[C:3]([O:2][CH3:1])[N:4]=[CH:5][CH:6]=3)[N:9]([CH3:23])[CH:10]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3N)cn(C)c12
Reactant: O=CC1CCCC1
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3NCC3CCCC3)cn(C)c12
Yield: 30.6 %

Procedure:
The product from Example 44A (55 mg, 0.166 mmol) and cyclopentanecarbaldehyde (58.64 mg, 0.597 mmol) in dichloroethane/acetic acid (1:1, 1 mL) was heated in a sealed tube at 60° C. for 24 hours, cooled, and concentrated. Purification by reverse phase HPLC (C18, CH3CN/water (0.1% TFA), 10-100%) afforded the title compound (0.021 g, 31%).
Reaction SMILES: C([O-])=O.[NH4+].[C:5]1([CH2:11][CH2:12][NH:13][C:14](=[O:35])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([NH:22][C:23](=[O:34])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=3)[CH:16]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=1>[Pd].CO>[CH:5]1([CH2:11][CH2:12][NH:13][C:14](=[O:35])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([NH:22][C:23](=[O:34])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=3)[CH:16]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COc1ccc(C(=O)Nc2cc(C(=O)NCCC3=CCCCC3)ccc2C)cc1OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1ccc(C(=O)Nc2cc(C(=O)NCCC3CCCCC3)ccc2C)cc1OC
Yield: 90.2 %

Procedure:
Ammonium formate (0.224 g) was added to a stirred mixture of 10% palladium-on-carbon (0.015 g), N-(2-cyclohexen-1-ylethyl)-3-(3,4-dimethoxybenzamido)-4-methylbenzamide (0.15 g) and methanol (15 ml) and the reaction mixture was heated to reflux for 1.25 hours. The reaction mixture was allowed to cool and was filtered through diatomaceous earth. The filtrate was evaporated and the residue was triturated under water. The solid so obtained was dried under vacuum at 55° C. to give the title compound as a powder (0.136 g); NMR Spectrum: (CDCl3) 0.8-2.3 (m, 13H), 2.37 (s, 3H), 3.45 (m, 2H), 3.96 (m, 6H), 6.12 (m, 1H), 6.93 (d, 1H), 7.26 (m, 1H), 7.46 (d, 1H), 7.56 (m, 2H), 7.92 (s, 1H), 8.16 (s, 1H); Mass Spectrum: M+H+ 425.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][CH:28]([C:30]4[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][C:31]=4[Cl:38])[CH3:29])[CH:20]=3)[C:12]=2[CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:38][C:31]1[CH:32]=[C:33]([C:36]#[N:37])[CH:34]=[CH:35][C:30]=1[CH:28]([O:27][C:21]1[CH:20]=[C:19]([N:18]2[C:12]3[CH:11]=[C:10]([CH2:9][OH:8])[N:15]=[CH:14][C:13]=3[N:16]=[CH:17]2)[S:23][C:22]=1[C:24]([NH2:26])=[O:25])[CH3:29]
Reactant: CC(Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccc(C#N)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccc(C#N)cc1Cl
Temperature: 0 °C

Procedure:
A mixture of 350 mg of 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[1-(2-chloro-4-cyanophenyl)ethoxy]thiophene-2-carboxamide in 20 ml THF is cooled to 0° C. At 0° C. 0.23 ml tetra-n-butylammonium fluoride (˜75% in H20) is added. The reaction mixture is allowed to warm to room temperature and stirred over night.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][C:4](=O)[C:5]([OH:7])=[O:6].[NH2:10][C@H:11]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14])[CH3:12].C([BH3-])#N.[Na+]>>[C:5]([CH:4]([NH:10][C@H:11]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14])[CH3:12])[CH2:3][CH:2]([CH3:9])[CH3:1])([OH:7])=[O:6]
Reactant: CC(C)CC(=O)C(=O)O
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)CC(N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O)C(=O)O

Procedure:
4-Methyl-2-oxopentanoic acid (1.29 g) and L-alanyl-L-proline (0.32 g) were treated with sodium cyanoborohydride (0.32 g) as described above. A fluffy white solid, N-(1-carboxy-3-methylbutyl)-L-alanyl-L-proline, was obtained (0.40 g). A portion was purified by chromatography. The mass spectrum showed a peak at 429 (molecular ion of disilyl derivative minus methyl, 444-15). The nmr spectrum showed resonances centered at 4.4, 3.6, 2.1, 1.6, and 0.95 ppm.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:18][N:19]([CH2:32][CH3:33])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[CH2:32]([NH:19][CH2:18][C@@H:17]([NH:16][C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1)[C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH3:33]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CCN(C[C@@H](N)c1cc(F)c(F)cc1F)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CCNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1cc(F)c(F)cc1F

Procedure:
Compound 58 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-N-ethyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [391 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.13 (s, 1H), 9.02 (d, 1H), 8.57 (s, 1H), 8.38 (t, 1H), 8.18 (s, 1H), 7.66 (dd, 1H), 7.53 (td, 1H), 5.71 (s, 1H), 3.15 (dd, 1H), 2.95 (dd, 1H), 2.67-2.55 (q, 2H), 0.98 (t, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:29]=1[CH:30]=O.[OH-].[Na+]>CO>[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:29]=1[CH:30]=[CH:2][C:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: CC(=O)c1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(=O)C=Cc2c(Cl)cccc2Cl)cc1
Reaction time: 72 h
Yield: 85 %

Procedure:
To a stirred solution at room temperature of III (150 mg, 0.42 mmol), 2,6-dichlorobenzaldehyde (148 mg, 0.85 mmol) or aldehyde (1.5–2.0 equiv.) in MeOH (10 ml) was added a solution of NaOH (1.7 ml, 1N in H2O). A pale yellow precipitate appeared. After 3 days, the reaction mixture was filtered off, rinsed with H2O. The solid residue was then dissolved in AcOEt, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was finally purified by flash chromatography on silica gel (AcOEt/hexane:20/80→40/60) to afford the title compound IVc (185 mg, 0.36 mmol, 85% yield) as a pale yellow foam. 1H NMR (300 MHz, CDCl3) δ(ppm): 9.48 (bs, 1H), 8.11 (s, 4H), 7.96 (d, J=17.1 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.68 (d, J=16.3 Hz, 1H), 7.42 (d, J=7.9 Hz, 2H), 7.35–7.15 (m, 4H), 6.68 (s, 1H), 1.54 (s, 9H).
Reaction SMILES: [N:1]1[N:5]2[C:6](=O)[CH:7]=[CH:8][NH:9][C:4]2=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:13])=O.C(N(C(C)C)CC)(C)C>>[Cl:13][C:6]1[N:5]2[N:1]=[CH:2][CH:3]=[C:4]2[N:9]=[CH:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc[nH]c2ccnn12
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccnc2ccnn12
Temperature: 90 °C
Reaction time: 8 h
Yield: 14.6 %

Procedure:
Pyrazolo[1,5-a]pyrimidin-7(4H)-one (0.50 g, 3.70 mmols), phosphorus oxychloride (0.88 ml, 9.62 mmols) and diisopropylethylamine (DIEA, 0.13 ml, 0.74 mmols) were mixed and stirred at 90° C. overnight. It was poured onto water/ice, extracted with dichloromethane and washed with brine. It was dried, filtered and concentrated in vacuum. It was purified by chromatography (Silica gel, Hexane/Ethyl acetate 9:1) to afford the expected compound (83 mg, 71%).
Reaction SMILES: C(OC([N:8]1[CH:13]([CH3:14])[CH2:12][N:11]([C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[N:24][C:25]([NH2:29])=[C:26]([OH:28])[CH:27]=3)=[CH:18][CH:17]=2)[CH2:10][CH:9]1[CH3:31])=O)(C)(C)C.Br[CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([F:44])([F:43])[F:42])[CH3:34].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[NH2:29][C:25]1[N:24]=[CH:23][C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:15]([N:11]3[CH2:10][CH:9]([CH3:31])[NH:8][CH:13]([CH3:14])[CH2:12]3)=[O:30])=[CH:21][CH:20]=2)=[CH:27][C:26]=1[O:28][CH:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([F:42])([F:43])[F:44])[CH3:34]
Reactant: CC1CN(C(=O)c2ccc(-c3cnc(N)c(O)c3)cc2)CC(C)N1C(=O)OC(C)(C)C
Reactant: CC(Br)c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CN(C(=O)c2ccc(-c3cnc(N)c(OC(C)c4ccccc4C(F)(F)F)c3)cc2)CC(C)N1
Temperature: 70 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
To a mixture of 4-[4-(6-Amino-5-hydroxy-pyridin-3-yl)-benzoyl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (50 mg, 0.12 mmol) and 1-(1-bromo-ethyl)-2-trifluoromethyl-benzene (32 mg, 0.12 mmol) in DMF (2 ml) was added 2 M Cs2CO3 (0.18 mL, 0.35 mmol), followed by water (0.5 mL), the mixture was stirred overnight then heated at 70° C. for 8 hr, LCMS showed that the reaction was completed. The DMF and water were removed. TFA (2 mL was added to the residue and stirred at room temperature for 3 hr. The TFA was removed, followed by addition of methanol. The residue was purified by prep-HPLC to afford (4-{6-amino-5-[1-(2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-(3,5-dimethyl-piperazin-1-yl)-methanone (20 mg, yield 34.2%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:33])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[CH:27]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[Br:32][C:28]1[CH:27]=[C:26]([C:24]2[CH2:23][C:22](=[O:33])[NH:21][C:9]3[CH:10]=[C:11]([C:17]([F:20])([F:19])[F:18])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=3[N:7]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(Br)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(Br)c1)=N2

Procedure:
) The title compound was prepared from the above described {2-[3-(3-bromo-phenyl)-3-oxo-propionylamino]-5-ethoxy-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (1.459 g, 2.675 mmol) and TFA (10 mL) according to general procedure I step 2. Obtained as a light yellow solid (0.940 g, 82%). MS (ISP) 427.1 [(M+H)+] and 429.1 [(M+2+H)+].