Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH:3]1([C:6]2[O:10][N:9]=[C:8]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[C:7]=2[CH2:19][O:20][CH:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[CH:40]=[CH:39][C:31]4[C:32]([C:35]([O:37]C)=[O:36])=[N:33][S:34][C:30]=4[CH:29]=3)[CH2:23][CH2:22]2)[CH2:5][CH2:4]1>C(O)C.O1CCCC1>[CH:3]1([C:6]2[O:10][N:9]=[C:8]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[C:7]=2[CH2:19][O:20][CH:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[CH:40]=[CH:39][C:31]4[C:32]([C:35]([OH:37])=[O:36])=[N:33][S:34][C:30]=4[CH:29]=3)[CH2:23][CH2:22]2)[CH2:5][CH2:4]1
Reactant: COC(=O)c1nsc2cc(N3CCCC(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1nsc2cc(N3CCCC(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)ccc12
Temperature: 60 °C
Reaction time: 24 h
Yield: 51.7 %

Procedure:
Potassium hydroxide (0.118 g, 2.10 mmol) is added to a solution of methyl 6-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)azepan-1-yl)benzo[d]isothiazole-3-carboxylate (0.30 g, 0.52 mmol) in ethanol (2 ml) and tetrahydrofuran (6 mL). The mixture is stirred at 60° C. for 24 h and concentrated in vacuo. The residue is dissolved in water (8 ml), acidified to pH˜5 with 1 N HCl and extracted with dichloromethane (2×10 ml). The organic extracts are dried over sodium sulfate and the solvent is evaporated in vacuo to give 0.15 g (51.0%) of the title compound as an off white solid. ES/MS m/z 558.06 (M+1).
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:30])[C@H:15]([CH3:29])[C@@H:16]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[CH:23]=1)[O:17][Si:18]([CH3:21])([CH3:20])[CH3:19])C1C=CC=CC=1.[Li+].[BH4-].[NH4+].[Cl-].CC(OC)(C)C>C1COCC1>[Br:28][C:24]1[CH:23]=[C:22]([C@@H:16]([O:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[C@@H:15]([CH3:29])[CH2:14][OH:30])[CH:27]=[CH:26][CH:25]=1
Reactant: C[C@@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O[Si](C)(C)C)c1cccc(Br)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: C[C@@H](CO)[C@H](O[Si](C)(C)C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-4-benzyl-3-((2R,3S)-3-(3-bromophenyl)-2-methyl-3-(trimethylsilyloxy)propanoyl)oxazolidin-2-one in anhydrous THF is added a solution of LiBH4 in THF under argon. The reaction mixture is stirred for 18 h at room temperature and a saturated aqueous solution of NH4Cl is slowly added followed by MTBE. The mixture is stirred for 15 mins, layers are separated, organic layer is washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography (5 to 40% EtOAc/hexane gradient) to give (2S,3S)-3-(3-bromophenyl)-2-methyl-3-(trimethylsilyloxy)propan-1-ol.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][N:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:38])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:39].C(OCC)(=O)C>>[ClH:39].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][N:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:38])[CH2:22][CH2:21]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3cnccc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=c1ccc2cnccc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 0.15 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxo-1,6-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 10 mL of a 4 mol/L hydrogen chloride/ethyl acetate solution was added, and the mixture was stirred at room temperature for 2 hours 30 minutes. Thereto was further added 5 mL of a 4 mol/L hydrogen chloride/ethyl acetate solution, the mixture was reacted at room temperature for 20 hours, and the solvent was distilled off under reduced pressure. The mixture was dissolved in 8 mL of 6 mol/L hydrochloric acid, and then the solvent was distilled off under reduced pressure. Ethanol was added to the resultant residue, and the solvent was distilled off under reduced pressure, and ethyl acetate was then added to the resultant residue, and the solid was filtered off to obtain 0.13 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-1,6-naphthyridin-2(1H)-one hydrochloride as a light yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:36]([F:39])([F:38])[F:37])[N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][C@H:16]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:17][C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=3[F:26])[CH2:10][C:9]=12)=[O:4].[OH-].[Na+].Cl>CO>[C:31]([O:30][C:28]([NH:27][C@H:16]([CH2:17][C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])[CH2:15][C:14]([N:11]1[CH2:12][CH2:13][N:8]2[C:7]([C:36]([F:38])([F:39])[F:37])=[N:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]2[CH2:10]1)=[O:35])=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Yield: 98.6 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester 1n (2.0 g, 3.5 mmol) was dissolved in 50 mL of methanol under stirring, and 4 N sodium hydroxide solution (30 mL) was added to the solution. The reaction mixture was reacted at room temperature for an hour until thin lay chromatography showed the starting material disappeared, and was adjusted to pH 3 with a 2 N hydrochloric acid solution. The reaction mixture was extracted with ethyl acetate (50 mL×4), and the combined organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (R)-7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (1.9 g) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:15]([O-])=O)[CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][F:13])[C:8](=[O:14])[CH2:7]2.[Cl-].[NH4+]>C(O)C.O.ClCCl.[Fe]>[NH2:15][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([F:1])[CH:3]=1)[N:9]([CH2:11][CH2:12][F:13])[C:8](=[O:14])[CH2:7]2
Reactant: O=C1Cc2cc([N+](=O)[O-])cc(F)c2N1CCF
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: Nc1cc(F)c2c(c1)CC(=O)N2CCF
Temperature: 25 °C

Procedure:
Iron powder (0.416 g, 7.43 mmol) is added in small portions to 7-fluoro-1-(2-fluoro-ethyl)-5-nitro-1,3-dihydro-indol-2-one (Step 3, 0.45 g, 1.86 mmol) and ammonium chloride (0.987 g, 18.6 mmol) in ethanol (40 ml) and water (20 ml) at 90° C. The reaction mixture is stirred vigorously and heated for 30 min, cooled to room temperature, and diluted with dichloromethane (100 ml). The mixture is filtered through celite, the organic layer separated and washed with water and brine, dried over sodium sulfate and evaporated to give the title compound as a dark brown solid. HPLC r.t. 2.34 min; MS for C10H10F2N2O m/z 213.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[O:5][C:6]1[C:7]([CH2:13][NH:14][C:15](=O)[CH2:16][C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:19][N:18]=2)=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[O:5][C:6]1[C:7]2[N:8]([C:15]([CH2:16][C:17]3[C:25]4[C:20](=[N:21][CH:22]=[CH:23][CH:24]=4)[NH:19][N:18]=3)=[N:14][CH:13]=2)[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccnc(CNC(=O)Cc2n[nH]c3ncccc23)c1Oc1cc(Cl)cc(Br)c1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccn2c(Cc3n[nH]c4ncccc34)ncc2c1Oc1cc(Cl)cc(Br)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N-{[3-(3-bromo-5-chlorophenoxy)-4-methylpyridin-2-yl]methyl}-2-(1H-pyrazolo[3,4-b]pyridin-3-yl)acetamide (77 mg, 0.158 mmol) in toluene (2 mL) was added phosphorus oxychloride (120 μL, 0.79 mmol). The resulting mixture was then heated at 100° C. for 1 hour, after which the solvent was removed in vacuo and the residue was stirred with CH2Cl2 (50 mL) and saturated aqueous Na2CO3 (30 mL) for 30 minutes. The layers were partitioned and the organic extract was dried over MgSO4, filtered and the solvent removed in vacuo. This residue was purified using RediSep column (12 g) eluting with a gradient of 0-10% MeOH/CH2Cl2. The pure fractions were combined and the solvent removed in vacuo to give the title compound. LRMS (M+1)=469.7.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH2:11][CH2:10]3)=[CH:3][CH:2]=1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[C:16]1([NH:22][C:23]([N:12]2[C:13]3[C:9](=[CH:8][C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[CH:15][CH:14]=3)[CH2:10][CH2:11]2)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1cc(-c2ccc3c(c2)CCN3)ccn1
Reactant: O=C=Nc1ccccc1
Solvent: CC#N
Product: O=C(Nc1ccccc1)N1CCc2cc(-c3ccncc3)ccc21
Temperature: 80 °C
Reaction time: 6 h
Yield: 46.7 %

Procedure:
To a solution of 5-(4-pyridinyl)indoline (80 mg) in acetonitrile (10 mL) was added phenyl isocyanate (53 mg) and the mixture was stirred at 80° C. for 6 hours. The mixture was evaporated to dryness and the residue was purified by column chromatography on silica gel eluting with ethyl acetate/methanol (10:1) to give N-phenyl-5-(4-pyridinyl)-1-indolinecarboxamide (60 mg) as a light-brown powder.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([NH2:9])=[O:8])=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>>[Br:1][C:2]1[O:6][C:5]([C:7]2[O:8][CH:14]=[C:12]([CH2:11][Cl:10])[N:9]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Br)o1
Reactant: O=C(CCl)CCl
Product: ClCc1coc(-c2ccc(Br)o2)n1
Yield: 23 %

Procedure:
In substantially the same manner as in Reference Example 47, 5-bromo-2-furancarboxamide was allowed to react with 1,3-dichloroacetone to give 2-(5-bromo-2-furyl)-4-chloromethyloxazole. The yield was 23%. Recrystallization from diethyl ether-hexane gave colorless needles, mp 90-92° C.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18]([OH:20])=O)=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:20])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 91.8 %

Procedure:
In the same manner as in Example 278 and using 2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoic acid (250 mg, 0.71 mmol), aniline (184 mg, 2.0 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (380 mg, 1.0 mmol), N,N-diisopropylethylamine (270 mg, 2.0 mmol) and N,N-dimethylformamide (7 mL) as starting materials, the title compound (280 mg, 93%) was obtained as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][C:8]1([C:33]([O:35]C(C)(C)C)=[O:34])[O:12][N:11]=[C:10]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([O:20][C:21](=[O:32])[C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH2:31])=[NH:30])=[CH:24][CH:23]=3)[CH:14]=2)[CH2:9]1)(C)(C)C.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[NH:28]([C:25]1[CH:24]=[CH:23][C:22]([C:21]([O:20][C:15]2[CH:14]=[C:13]([C:10]3[CH2:9][C:8]([CH2:7][C:6]([OH:40])=[O:5])([C:33]([OH:35])=[O:34])[O:12][N:11]=3)[CH:18]=[C:17]([CH3:19])[CH:16]=2)=[O:32])=[CH:27][CH:26]=1)[C:29]([NH2:31])=[NH:30]
Reactant: Cc1cc(OC(=O)c2ccc(NC(=N)N)cc2)cc(C2=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C2)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OC(=O)c2ccc(NC(=N)N)cc2)cc(C2=NOC(CC(=O)O)(C(=O)O)C2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 5-(2-tert-butoxy-2-oxoethyl)-3-(3-((4-carbamimidamidobenzoyl)oxy)-5-methylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (407 mg) and TFA (4 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and then, the residue was washed with diethyl ether to obtain the title compound (289 mg).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=3)=[CH:34][C:33]2=[O:47])=[CH:28][C:27]=1[NH:48][CH3:49].C(N(CC)C(C)C)(C)C.[CH3:59][CH:60]1[CH2:62][CH:61]1[C:63](O)=O>CN(C=O)C>[Cl:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][O:38][C:35]2[CH:36]=[CH:37][N:32]([C:29]3[CH:30]=[CH:31][C:26]4[N:25]=[C:63]([CH:61]5[CH2:62][CH:60]5[CH3:59])[N:48]([CH3:49])[C:27]=4[CH:28]=3)[C:33](=[O:47])[CH:34]=2)=[CH:45][CH:44]=1
Reactant: CNc1cc(-n2ccc(OCc3ccc(Cl)cc3)cc2=O)ccc1N
Reactant: CC1CC1C(=O)O
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: CC1CC1c1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of HATU (101 mg), 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (90 mg), N,N-diisopropylethylamine (0.130 ml), 2-methylcyclopropanecarboxylic acid (0.049 ml) and DMF (2 ml) was stirred at room temperature for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in AcOH (2.00 ml), and the mixture was stirred at 90° C. for 2 h. After evaporation, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH to give the title compound (3 mg) as a diastereomeric mixture. The filtrate was concentrated in vacuo and the precipitate was recrystallized from THF to give the title compound (17 mg) as a diastereomeric mixture.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].I[C:27]1[CH:28]=[C:29]([C:34]([F:37])([F:36])[F:35])[C:30]([NH2:33])=[N:31][CH:32]=1>>[F:37][C:34]([F:35])([F:36])[C:29]1[C:30]([NH2:33])=[N:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=1
Reactant: Nc1ncc(I)cc1C(F)(F)F
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Nc1ncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1C(F)(F)F

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 g, 1.0 mmol) and 5-iodo-3-trifluoromethyl-pyridin-2-ylamine (example B.48) (288 mg, 1.0 mmol) according to general procedure II. Obtained as an off-white solid (370 mg, 72%). MS (ISP) 516.2 [(M+H)+]; mp 230° C.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([CH:19]2[NH:23][CH:22]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:21]3([C:36]4[C:31](=[CH:32][C:33]([Cl:37])=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:38])[CH:20]2[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:40]=2[F:46])=[O:18])=[CH:12][CH:11]=1)=[O:9])(C)(C)C.Cl>O1CCCC1>[OH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([CH:19]2[NH:23][CH:22]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:21]3([C:36]4[C:31](=[CH:32][C:33]([Cl:37])=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:38])[CH:20]2[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:40]=2[F:46])=[O:18])=[CH:12][CH:11]=1)=[O:9]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(=O)CO[Si](C)(C)C(C)(C)C)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(=O)CO)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid {4-[2-(tert-butyl-dimethyl-silanyloxy)-acetyl]-phenyl}-amide (0.1 g, 0.14 mmol) in tetrahydrofuran (5 mL) was added aqueous HCl solution (1N, 5 mL, 5 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and aqueous saturated NaHCO3 solution. The organic layer was separated, washed with water, brine, dried over Na2SO4, then concentrated. The residue was purified by chromatography (silica gel, 5-80% of EtOAc in hexanes) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [4-(2-hydroxy-acetyl)-phenyl]-amide as a yellow solid (Yield, 35 mg, 42%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:11])[CH2:6]2.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16]([Mg]Br)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1>CCOCC>[F:12][C:13]([F:26])([F:27])[C:14]1[CH:15]=[C:16]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[C:5]([CH3:11])[CH2:6]3)[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=1
Reactant: FC(F)(F)c1cc([Mg]Br)cc(C(F)(F)F)c1
Reactant: CC1=Cc2c(Br)cccc2C1
Solvent: CCOCC
Product: CC1=Cc2c(cccc2-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1

Procedure:
4-Bromo-2-methylindene (10.7 g, 51 mmol) and NiCl2(Ph3)2 (1.8 g, 2.8 mmol) were dissolved in 150 mL of Et2O. 3,5-bis(trifluoromethyl)phenylmagnesium bromide (51 mmol) as a Et2O solution was added under vigorous stirring and the reaction stirred overnight at room temperature. After overnight stirring, the reaction was slowly quenched with H2O to neutralize unreacted Grignard. The solution was subsequently treated with 100 mL of 10% HCl(aq), and neutralized with saturated sodium bicarbonate aqueous solution. The organic layer was dried with magnesium sulfate and the solvent was removed by rotary evaporation. The remaining residue was loaded onto a silica gel column and eluted with hexane. Yield was 2.2 g (13%).
Reaction SMILES: ClC(N(C)C)=C(C)C.[CH3:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1.[NH2:20][C:21]1[N:25](C(OC(C)(C)C)=O)[N:24]=[C:23]([CH2:33][CH2:34][C:35]2[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[CH:36]=2)[CH:22]=1.N1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:42][O:41][C:39]1[CH:40]=[C:35]([CH2:34][CH2:33][C:23]2[CH:22]=[C:21]([NH:20][C:15](=[O:17])[C:14]3[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:19][CH:18]=3)[NH:25][N:24]=2)[CH:36]=[C:37]([O:43][CH3:44])[CH:38]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc(CCc3cc(OC)cc(OC)c3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52 %

Procedure:
1-Chloro-N,N,2-trimethylprop-1-en-1-amine (89 μl, 0.63 mmol, 1.05 eq) was added dropwise to 4-methoxybenzoic acid (97 mg, 0.63 mmol, 1 eq) in DCM (1.5 ml) at ambient temperature. After stirring at ambient temperature for 1.5 h, a solution of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate (199 mg, 0.57 mmol, 0.9 eq) and pyridine (142 μL, 1.74 mmol, 2.75 eq) in DCM (2 ml) was added to the reaction mixture and stirring was continued at ambient temperature for a further 3 h. A solution of TFA (386 μL, 5.2 mmol, 8.25 eq) in DCM (3.5 ml) was then added and stirring was continued at ambient temperature for 18 h. The reaction mixture was concentrated and the crude product was purified by reverse-phase prep. HPLC (basic) using a 33-53% gradient of acetonitrile in water containing 1% ammonium hydroxide solution. The clean fractions were taken and evaporated to afford the title compound as a colourless foamy solid (113 mg, 52% yield).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)=[O:5].[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>N1C=CC=CC=1>[C:18]([O:1][C:2]1[CH:16]=[C:15]([O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:12][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:10][CH:11]=1)=[O:5])(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)c2ccc(OC(=O)C(C)(C)C)cc2OC(=O)C(C)(C)C)cc1
Reaction time: 2 h

Procedure:
A solution of 2.3 g (0.01 mole) of 2,4,4'trihydroxybenzophenone was warmed to 50° C. with 3.65 g (0.035 mole) of pivaloyl chloride in 75 mls of dry pyridine. After 2 hrs. at 5° C., the solvent was evaporated under N2 stream and H2O added to the residue. The oily material was extracted with CH2Cl2 and washed with dilute K2CO3. The organic layer was dried over MgSO4. The glass which was recovered after solvent removal was crystallized from ethanol; 4.20 g (86%) yield; M.P.~94°-96° C.
Reaction SMILES: CS([C:5]([CH2:12][C:13](=[O:15])[O-:14])([CH2:7][N+:8]([CH3:11])([CH3:10])[CH3:9])[OH:6])(=O)=O.[N-:16]=[N+:17]=[N-:18]>>[N:16]([C:5]([CH2:12][C:13](=[O:15])[O-:14])([CH2:7][N+:8]([CH3:11])([CH3:10])[CH3:9])[OH:6])=[N+:17]=[N-:18]
Reactant: C[N+](C)(C)CC(O)(CC(=O)[O-])S(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Product: C[N+](C)(C)CC(O)(CC(=O)[O-])N=[N+]=[N-]

Procedure:
A process for producing aminocarnitine is described, wherein methanesulfonylcarnitine is converted to a lactone which is reacted with an azide to give azidocarnitine. The catalytic hydrogenation of azidocarnitine gives aminocarnitine.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24](=[O:43])[NH:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:42])NOC3C=CC([N+]([O-])=O)=CC=3)[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:44]([NH2:53])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24](=[O:43])[NH:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:42])[NH:53][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NOc1ccc([N+](=O)[O-])cc1)OCCCNC(=O)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Reactant: CCCCCCCCCN
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCCNC(=O)OCCCNC(=O)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A solution of the carbonate (2.0 g, 3.4 mmol) produced in Example 17 in 20 mL of anhydrous dimethylformamide was added dropwise under nitrogen to a solution of nonylamine (760 μl, 4.1 mmol) and triethylamine (2.4 mL, 17 mmol) in 20 mL of anhydrous dimethylformamide at ice bath temperature. After the addition the solution was stirred at ice bath temperature for 2 hrs and at room temperature overnight. The reaction was diluted with ethyl acetate, extracted five times with water, one time with 1N HCl, five times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 1.94 g of an off-white solid. Recrystallization from diisopropyl ether gave 1.55 g (77%) of the title compound as a white crystalline solid, mp 89-91° C.