Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][C:6](=[C:8]([NH:14][CH:15]=[O:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][C@@H:4]([CH3:17])[O:3]1>CO.[B-](F)(F)(F)F.C[C@H]1CC[C@H](C)P1CCP1[C@@H](C)CC[C@@H]1C.C1CC=CCCC=C1.[Rh]>[CH3:17][C@@H:4]1[CH2:5][CH:6]([C@H:8]([NH:14][CH:15]=[O:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][C@@H:2]([CH3:1])[O:3]1
Reactant: CCOC(=O)C(NC=O)=C1C[C@@H](C)O[C@H](C)C1
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: C[C@H]1CC[C@H](C)P1CCP1[C@@H](C)CC[C@@H]1C
Solvent: CO
Solvent: C1=CCCC=CCC1
Product: CCOC(=O)[C@@H](NC=O)C1C[C@@H](C)O[C@H](C)C1
Reaction time: 72 h
Yield: 101.4 %

Procedure:
Nitrogen was bubbled through a solution of ethyl 2-((2R,6R)-2,6-dimethyl-2H-pyran-4(3H,5H,6H)-ylidene)-2-formamidoacetate (17.0 g, 70.5 mmol) in MeOH (480 mL) for 10 min in a 2.5 L Parr hydrogenation vessel. Then (−)-1,2-bis((2S,5S)-2,5-dimethylphospholano)ethane(cyclooctadiene)-rhodium (I) tetrafluoroborate (0.706 g, 1.27 mmol) was added and the reaction vessel was sealed, vacuum flushed with nitrogen (4×) and then vacuum flushed with hydrogen (4×). The reaction solution was shaken under 60 psi of hydrogen for 3 d, removed from the shaker and concentrated to a dark red oil. The crude oil was purified with a Biotage® Horizon chromatography (300 g SiO2, 50-75% EtOAc/hexanes) to yield (S)-ethyl 2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-formamidoacetate (17.4 g, contains 5.9% w/w solvents (EtOAc and DCM) by 1H-NMR) as a light yellow viscous oil. The 1H-NMR data indicates a 10:1 mixture of two amide rotamers. 1H-NMR (400 MHz, CDCl3) δ 8.26 (s, 0.9H), 8.01 (d, J=11.8 Hz, 0.1H), 6.15 (d, J=8.5 Hz, 0.9H), 5.96-5.84 (m, 0.1H), 4.68 (dd, J=9.0, 5.0 Hz, 0.9H), 4.33-4.17 (m, 3H), 3.87 (dd, J=10.2, 6.4 Hz, 0.1H), 3.75 (dqd, J=11.5, 6.0, 2.0 Hz, 1H), 2.41-2.29 (m, 0.9H), 2.29-2.19 (m, 0.1H), 1.72-1.28 (m, 3H), 1.28-1.23 (m, 6H), 1.17-1.10 (m, 3H), 1.09-0.96 (m, 1H). 13C-NMR (101 MHz, CDCl3) δ 170.6, 160.3, 68.1, 64.0, 61.4, 54.2, 36.0, 33.1, 30.6, 21.9, 16.7, 13.9. LC-MS retention time 1.64 min; m/z 244.25 (M+H)+. LC data were recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3μ C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min. Solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid, and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data were determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.O>[O:21]([CH2:20][CH2:19][O:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCCOc1ccccc1
Reactant: Oc1cc2ccccc2cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cc2ccccc2cc1OCCOc1ccccc1
Temperature: 135 °C
Yield: 40 %

Procedure:
A mixture of 2,3-dihydroxynaphthalene (5.6 g) and sodium bicarbonate powder (2.9 g) in dimethylformamide (50 mL) was stirred and heated at 135° C. for 1 hour. When the gas evolution ceased, the mixture was cooled to about 60° C. and beta-bromophenetole (7 g) was added. The mixture was stirred at 60° C. overnight, cooled, diluted with water and filtered. The solids were crystallized from dichloromethane-diethyl ether to give 3.9 g of 3-(2-phenoxyethoxy)-2-naphthol as a colorless solid, mp 141°-142° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([O:23][CH3:22])[CH:29]=4)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)ccc2o1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccc3oc(-c4cc([N+](=O)[O-])ccc4OC)nc3c2)c1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-6-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.14 mmol) and 3-methoxyphenylboronic acid (261 mg, 1.71 mmol) the subtitle compound was obtained (280 mg, 51%). The product was used directly in the next step without purification.
Reaction SMILES: [H-].[Na+].[Br-].[OH:4][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6].[Cl:30][C:31]1[CH:44]=[CH:43][C:34]([CH2:35][C:36]2[S:40][C:39]([CH:41]=O)=[CH:38][CH:37]=2)=[CH:33][CH:32]=1>CS(C)=O>[Cl:30][C:31]1[CH:44]=[CH:43][C:34]([CH2:35][C:36]2[S:40][C:39]([CH:41]=[CH:10][CH2:9][CH2:8][CH2:7][C:5]([OH:6])=[O:4])=[CH:38][CH:37]=2)=[CH:33][CH:32]=1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Cc2ccc(Cl)cc2)s1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)CCCC=Cc1ccc(Cc2ccc(Cl)cc2)s1

Procedure:
This compound is prepared analogously to Example 7b from: 6.3 g of sodium hydride (=7.8 g of 80% strength mineral oil suspension) in 180 ml of dimethylsulphoxide, 57.9 g of 4-hydroxycarbonylbutyl-triphenylphosphonium bromide in 180 ml of dimethylsulphoxide and 25.0 g of 5-(4-chlorobenzyl)-thiophene-2-aldehyde in 20 ml of dimethylsulphoxide.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(C(C)C)CC)(C)C.[CH:32]1([C:35]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[O:36])[CH2:34][CH2:33]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(#N)C>[CH:32]1([C:35]([N:37]2[CH2:42][CH2:41][N:40]([C:4]([C:3]3[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=3[F:1])[CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[NH:14][N:13]=3)=[O:6])[CH2:39][CH2:38]2)=[O:36])[CH2:33][CH2:34]1
Reactant: O=C(C1CC1)N1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCN(C(=O)C2CC2)CC1
Temperature: 18 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (D)(15.23 g, 51.07 mmol) was suspended with stirring under nitrogen in acetonitrile (96 ml). Diisopropylethylamine (19.6 ml, 112.3 mmol) was added followed by 1-cyclopropylcarbonylpiperazine (1)(9.45 g, 61.28 mmol) and acetonitrile (1 ml). The reaction mixture was cooled to 18° C. O-Benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (25.18 g, 66.39 mmol) was added over 30 minutes and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was cooled to 3° C. and maintained at this temperature for 1 hour, before being filtered. The filter cake was washed with cold (3° C.) acetonitrile (20 ml) before being dried in vacuo at up to 40° C. to give the title compound as a pale yellow solid (20.21 g).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9]/[C:8](=[CH:11]/[C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=O)/[CH:7]=[C:6]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[CH3:3].C1CCC(N=C=NC2CCCCC2)CC1.O[CH:45]1[CH2:50][C:49](=O)[NH:48][C:46]1=O.C(NCC)C.[Cl-].[Na+]>CN(C)C=O>[CH3:3][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9]/[C:8](=[CH:11]/[C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([N:48]([CH2:49][CH3:50])[CH2:46][CH3:45])=[O:17])/[CH:7]=[C:6]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[CH3:1]
Reactant: O=C1CC(O)C(=O)N1
Reactant: COc1cccc(C2=C/C(=C\c3cccc(C(=O)O)c3)CCC2CN(C)C)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1cccc(/C=C2\C=C(c3cccc(OC)c3)C(CN(C)C)CC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
1.8 g of the Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid base prepared according to example 4 were dissolved in 50 ml analytical grade dimethylformamide, and 2 g DCC and 1.1 g hydroxysuccinimide were added at 0° C. to 15° C. The mixture was stirred at 0° C. for one hour and 2 ml diethylamine were then added dropwise at this temperature. The mixture was stirred at 0° C. for an additional hour and then at room temperature for four days. The reaction mixture was poured on to 300 ml saturated sodium chloride solution and the mixture was then extracted 3 times with 250 ml ethyl acetate each time. The organic phases were washed with 50 ml saturated sodium chloride solution and then dried over magnesium sulfate. The solvent was removed in vacuo. The residue was chromatographed on silica gel with ethyl acetate/methanol=6/5. 0.87 g Z-3-[4-dimethylaminomethyl-3-(3-methoxy-phenyl)-cyclohex-2-enylidenemethyl]-N,N-diethyl-benzamide base was obtained in this way in the form of an orange-yellow oil. To liberate the hydrochloride, the oil was dissolved in 5 ml acetone, and an equimolar amount of trimethylchlorosilane and water was added. 0.52 g (22.1% of theory) of the title compound 34 was obtained in this way in the form of white crystals.
Reaction SMILES: BrC1C=CC(C)=CC=1C(O)=O.[Br:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[C:18](C3C=CC=CC=3C(F)(F)F)[NH:19][C:20]2=[O:23])=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[C:21]([CH:22]=1)[C:20]([NH:19][CH3:18])=[O:23]
Reactant: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(Br)cc12
Agent: Cc1ccc(Br)c(C(=O)O)c1
Product: CNC(=O)c1cc(Br)ccc1C

Procedure:
5-Bromo-2,N-dimethylbenzamide was prepared by a method similar to that in Step A of Example 1 from 2-bromo-5-methylbenzoic acid that can be prepared by the method disclosed in WO2002/083066 or U.S. Pat. No. 4,282,365. Using this compound as a starting material, 7-bromo-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one was synthesized by a method similar to that in Step B of Example 1.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:36])[C:5]2[CH:11]=[C:10]([CH2:12][NH:13][C:14]3[CH:35]=[CH:34][C:17]([C:18]([NH:20][C@H:21]([C:29]([O:31]CC)=[O:30])[CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[O:19])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1.[OH-].[Na+]>CS(C)=O>[NH2:1][C:2]1[N:3]=[C:4]([NH2:36])[C:5]2[CH:11]=[C:10]([CH2:12][NH:13][C:14]3[CH:35]=[CH:34][C:17]([C:18]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:19])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(NCc2cnc3nc(N)nc(N)c3c2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1nc(N)c2cc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2n1
Reaction time: 6 h

Procedure:
A solution of the product obtained in Example 2, VII (R1 =C2H5) (359 mg, 0.724 mmol) in dimethyl sulfoxide (10 ml) under N2 was treated with 1 N NaOH (1.81 ml, 1.81 mmol), stirred in a stoppered flask under N2 for 6 hours, and evaporated to dryness in vacuo at <30° C. A solution of the residue in water (18 ml) was filtered and acidified to pH 3.6 with 1 N HCl. The precipitate was collected by filtration, washed with water at pH 3.6 and dried in vacuo (P2O5); yield 297 mg (87%), mp indefinite (softens above 200° C.); mass spectrum, m/e 440 (M+1)+ ; λmax nm (ε×10-3): 0.1 N HCl --218 (40.5), 280 sh (16.9), 300 (18.8); pH 7--218 (38.5), 2.45 (19.2), 280 (23.9), 296 sh (22.7); 0.1 N NaOH --248 (22.0), 280 (24.4), 296 sh (22.7), 345 (7.75); 1H-NMR (DMSO-d6, 6% w/v), δ2.00 m (CH2CH2CO), 2.29 t (CH2CO), 4.36 m (CHN, CH2N), 6.66 d, 7.68 d (C6H4), 7.41 (NH2), 8.04 m (NH2, NH, CO2H), 8.52 d, 8.70 d (5 --CH, 7 --CH).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.BrBr.[CH2:14]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+]>CO.O1CCOCC1>[CH3:10][CH:9]([N:24]1[CH2:25][CH2:26][CH:21]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:22][CH2:23]1)[CH:8]([OH:11])[C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: CCC(=O)c1ccc(O)cc1
Reactant: c1ccc(Cc2ccncc2)cc1
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C(O)c1ccc(O)cc1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
To 4 ml of dioxane were added 6.0 g of 4'-hydroxypropiophenone. 6.8 Grams of bromine were added dropwise to the mixture with stirring at room temperature, and the reaction liquid was stirred for an additional 5 minutes. To the reaction liquid were then added 8.1 g of 4-benzylpyridine, 100 ml of methanol and 3.3 g of anhydrous sodium acetate, and the mixture was refluxed under heating for 5 hours. After refluxing the mixture, the reaction mixture was worked up in the same manner as described in Example 46, whereby 12.3 g (79.9%) of ifenprodil were obtained as white crystals.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([CH:6](O)[C:7](O)=[O:8])=[CH:4][CH:3]=1.COC(=O)CC1C=CC=CC=1.O.[NH2:25][NH2:26]>C(O)C>[C:5]1([CH2:6][C:7]([NH:25][NH2:26])=[O:8])[CH:11]=[CH:12][CH:2]=[CH:3][CH:4]=1
Reactant: O=C(O)C(O)c1ccc(F)cc1
Reactant: NN
Agent: COC(=O)Cc1ccccc1
Solvent: CCO
Solvent: O
Product: NNC(=O)Cc1ccccc1

Procedure:
The following representative compounds in Table 1 were synthesized according to (i) the foregoing procedures by selecting appropriate starting materials (for example, 4-fluoro mandelic acid derivatives (e.g., examples 12-1 and 12-3) were synthesized using commercially available 4-fluoromandelic acid) and (ii) known organic synthesis techniques (for example, treatment of commercially available α-phenylacetic acid methyl ester with hydrazine hydrate in ethanol under with heating provides phenyl-acetic acid hydrazide (see, e.g., Pandeye, S, N.; Manjula, H.; Stables, J. P.; Pharmazie; 2001, 56, 121-124) and treatment of phenyl acetic acid hydrazide with a substituted benzaldehyde in ethanol with heating and in the presence of catalytic acetic acid provides the corresponding substituted phenyl-acetic acid benzylidenehydrazide (see, e.g., Stephanidou-Stephanatou, J.; Lefkopoulou, S; Journal of Heterocyclic Chemistry; 1982; 19; 705-711.0)).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[N:4]([CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[N:3]=1.[Cl-].[NH4+]>C(O)C.[Fe]>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[N:4]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc2c(Br)nn(CCN3CCCC3)c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccc2c(Br)nn(CCN3CCCC3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
A mixture of 3-bromo-6-nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole (0.90 g, 2.7 mmol), iron powder (1.5 g, 26 mmol), and ammonium chloride (73 mg, 1.3 mmol) in 80% ethanol was heated to reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was taken up and stirred in triethylamine/ethyl acetate (1/4, 20 mL) for about 15 minutes, filtered through a plug of silica gel, which was rinsed with triethylamine/ethyl acetate (1/4), and the filtrate concentrated under reduce pressure to provide the title compound (0.78 g, 95%). 1H NMR (300 MHz, DMSO-d6) ppm 1.64 (m, 4H), 2.46 (m, 4H), 2.79 (t, 2H, J=6.44), 4.23 (t, J=6.44, 2H), 5.56 (s, 2H), 6.49 (m, 1H), 6.58 (m, 1H), 7.16 (m, 1H); MS (DCI/NH3) m/z 309 [M+H]+.
Reaction SMILES: S(O[C:6]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:7]=1[CH:8]([CH3:12])[C:9]([OH:11])=[O:10])(C)(=O)=O.CO.[H][H]>[Pd].C(N(CC)CC)C>[CH3:17][C:14]1[CH:13]=[C:7]([CH:6]=[CH:16][CH:15]=1)[CH:8]([CH3:12])[C:9]([OH:11])=[O:10]
Reactant: [H][H]
Reactant: Cc1ccc(OS(C)(=O)=O)c(C(C)C(=O)O)c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cccc(C(C)C(=O)O)c1

Procedure:
To a solution of 1.29 g. of 2-mesyloxy-5-methyl-hydratropic acid in 25 ml. of methanol 1.4 ml. of triethylamine and 0.2 g. of a 5% palladium-on-charcoal catalyst are added. The mixture is hydrogenated at 25° C., under atmospheric pressure until the calculated amount of hydrogen is used up. The catalyst is filtered off and the solution is evaporated. The evaporation residue is taken up in water, acidified with a 20% aqueous hydrochloric acid solution and shaken with ether. Ether is distilled off to give 3-methyl-hydratropic acid as an oily residue. The corresponding cyclohexylamine salt melts at 168° C. to 169° C.
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[CH2:17][C@H:16]([NH:18][C:19](=[O:34])[C:20]([OH:33])([CH3:32])[C:21]([NH:23][CH2:24][C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])=[O:22])[C:15](=[O:35])[N:14]([CH2:36][C:37]([F:40])([F:39])[F:38])[C:13]2[CH:41]=[CH:42][CH:43]=[CH:44][C:12]1=2)C1C=CC=CC=1>CO.[Pd]>[OH:33][C:20]([CH3:32])([C:21]([NH:23][CH2:24][C:25]([F:31])([F:30])[C:26]([F:27])([F:28])[F:29])=[O:22])[C:19]([NH:18][C@@H:16]1[C:15](=[O:35])[N:14]([CH2:36][C:37]([F:39])([F:40])[F:38])[C:13]2[CH:41]=[CH:42][CH:43]=[CH:44][C:12]=2[N:11]([CH2:10][CH2:9][OH:8])[CH2:17]1)=[O:34]
Reactant: CC(O)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@H]1CN(CCOCc2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Agent: [Pd]
Solvent: CO
Product: CC(O)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@H]1CN(CCO)c2ccccc2N(CC(F)(F)F)C1=O
Reaction time: 24 h

Procedure:
A solution of 72 mg of the first eluting epimer (R or S)-N-[(S)-5-(2-benzyloxy-ethyl)-2-oxo-1-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-2-hydroxy-2-methyl-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide in 3.0 ml of methanol was treated with 24 mg of palladium on carbon (10%) and stirred for 24 hours under an atmosphere of hydrogen. For the working-up, the reaction mixture was filtrated over Dicalit and the solvent evaporated under reduced pressure. The crude material was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100/0 to 30/60 as the eluent, and 46 mg (79% of theory) of the title compound were obtained as a white foam; MS (m/e): 551 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15]>ClCl>[CH3:16][C:13]([NH:12][C:4](=[O:5])[C:3]1[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=1[F:11])([CH3:17])[CH2:14][OH:15]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CC(C)(N)CO
Agent: ClCl
Product: CC(C)(CO)NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A solution of 2,6-difluorobenzoyl chloride (50 g, 283 mmol) in CH2 Cl2 (200 mL) was added rapidly dropwise to an ice water-cooled solution of 2-amino-2-methyl-1-propanol (63.1 g, 708 mmol) in CH2 Cl2 (400 mL). The resulting mixture was stirred at RT and monitored to completion by GLC, then was extracted twice with 10% HCl and once with sat aq NaHCO3. The organic phase was dried (MgSO4), and concentrated to afford 61.9 g N-(1,1-dimethyl-2-hydroxyethyl)-2,6-difluorobenzamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:44][O:45][C:46](=[O:53])[CH2:47][CH2:48][NH:49][CH:50]([CH3:52])[CH3:51]>CN(C=O)C>[CH3:44][O:45][C:46](=[O:53])[CH2:47][CH2:48][N:49]([C:5](=[O:7])[C:4]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]([Cl:1])[CH:3]=1)[CH:50]([CH3:52])[CH3:51]
Reactant: COC(=O)CCNC(C)C
Reactant: COc1cc(Cl)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCN(C(=O)c1cc(Cl)cc(OC)c1)C(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.1 %

Procedure:
To a stirred solution of 3-chloro-5-methoxy-benzoic acid (0.932 g), TBTU (3.21 g) and in DMF (10 ml) was added DIPEA (1.73 ml) followed by 3-isopropylamino propionic acid methyl ester (0.871 g) after 10 min. The reaction mixture was stirred at room temperature for 48 h and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was washed with further water and 2M aqueous sodium hydroxide, water and dried with brine and over sodium sulphate and concentrated under reduced pressure to give the title compound as a brown oil (1.6 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:15]([O:22][C:23]([NH:25][CH:26]([CH:34]1[O:36][CH2:35]1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCOC(C)=O>CN(C=O)C>[CH2:15]([O:22][C:23]([NH:25][CH:26]([CH:34]([OH:36])[CH2:35][N:12]1[CH2:11][CH2:10][CH:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:14][CH2:13]1)[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: O=C(NC(Cc1ccccc1)C1CO1)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NC(Cc1ccccc1)C(O)CN1CCC(Cc2ccc(F)cc2)CC1)OCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 4-(4-fluorophenyl)methyl-piperidine (0.515 g, 2.314 mmoles) and 2-benzyloxycarbonylamino-1-phenyl-3,4-epoxy-butane (0.688 g, 2.314 mmoles) in 5 mL of DMF was stirred for 4 hours at 100° C. and cooled to room temperature. After addition of EtOAc (30 mL), the mixture was washed with water (2×) and brine. The oranic solution was dried over Na2SO4, and evaporated to give an oily residue. It was then purified by passing through a plug of silica gel with elution by EtOAc to give pure product.
Reaction SMILES: C(OC)#N.N1C2C(=CC=CC=2)CC1.C([N:17]1[C:25]2[C:20](=[C:21]([CH3:39])[C:22]([CH2:34][O:35]C(=O)C)=[C:23]([CH3:33])[C:24]=2[NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:19][CH2:18]1)(=O)C.[OH-].[Na+]>CCO.O>[OH:35][CH2:34][C:22]1[C:21]([CH3:39])=[C:20]2[C:25](=[C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:29])([CH3:30])[CH3:31])[C:23]=1[CH3:33])[NH:17][CH2:18][CH2:19]2
Reactant: CC(=O)OCc1c(C)c2c(c(NC(=O)C(C)(C)C)c1C)N(C(C)=O)CC2
Agent: COC#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(CO)c(C)c(NC(=O)C(C)(C)C)c2c1CCN2
Yield: 52.2 %

Procedure:
1.27 (9H, s, —C(CH3)3), 2.04 (3H, s, OCOCH3), 2.23, 2.26, 2.30 (9H, s×3, —CH3×2, >NCOCH3), 3.00 (2H, br, Indoline C3-H), 4.05 (2H, br, Indoline C2—H), 5.20 (2H, s, —CH2O—), 9.10 (1H, br, >NH). (2) N-(1-Acetyl-5-acetoxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethyl-propanamide (7.5 g) was dissolved in EtOH (70 ml) and a solution of NaOH (8.3 g) in water (20 ml) was added, which was followed by refluxing for 10 hr. EtoH was evaporated under reduced pressure and CHCl3 (200 ml) was added. After washing with water, the mixture was dried over anhydrous sodium sulfate and CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3/MeOH=1/0−10/1) to give 3.0 g of N-(5-hydroxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.