Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5](/[CH:6]=[N:7]/[C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][O:11][C:12]3=[O:17])=[CH:4][CH:3]=1.[CH:20]([C:22]1[CH:32]=[CH:31][C:25]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[CH:24][CH:23]=1)=O.[O-:33][CH2:34][CH3:35].[Na+].O>C(OCC)(=O)CC.CCOC(C)=O>[CH3:29][N:28]([CH3:30])[C:26]([C:25]1[CH:31]=[CH:32][C:22]([CH:20]2[C:34](=[O:33])[C:35]3[C:13]([C:12]([O:11][CH2:10][CH3:9])=[O:17])=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][CH:6]2[C:5]2[CH:18]=[CH:19][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:23][CH:24]=1)=[O:27]
Reactant: CC[O-]
Reactant: CN(C)C(=O)c1ccc(C=O)cc1
Reactant: O=C1OCc2c(/N=C/c3ccc(F)cc3)cccc21
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOC(=O)CC
Solvent: O
Product: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C(=O)N(C)C)cc1)C(c1ccc(F)cc1)N2
Temperature: 30 °C
Yield: 44 %

Procedure:
Sodium (115 mg, 5 mmol) was added to EtOH (10 mL) to afford sodium ethoxide. (E)-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one (500 mg, 1.96 mmol) and 4-formyl-N,N-dimethylbenzamide (382 mg, 2.16 mmol) were dissolved in ethyl propionate (10 mL), and the sodium ethoxide solution was added dropwise to the mixture at 0° C., then the mixture were heated to 30° C. for 1 h. To the reaction mixture was added water and EtOAc, the organic phase was separated, washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and then concentrated to afford the crude product. The crude product was purified by flash chromatography (MeOH:DCM 1:25) to give the title compound (400 mg, yield 44%). LC-MS (ESI) m/z: 461 (M+1)+
Reaction SMILES: [CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:28](O)=[O:29])[CH:25]=4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.B.CO>O1CCCC1.Cl.O1CCOCC1>[CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([N:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH2:28][OH:29])[CH:25]=4)[CH2:20]3)=[O:18])=[CH:14][CH:15]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CC1CCCC1)Nc1ccc(NC(=O)N2Cc3ccc(C(=O)O)cc3C2)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CO
Product: O=C(CC1CCCC1)Nc1ccc(NC(=O)N2Cc3ccc(CO)cc3C2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a stirring suspension of 2-(4-(2-cyclopentylacetamido)phenylcarbamoyl)isoindoline-5-carboxylic acid (18 mg, 0.044 mmol) in tetrahydrofuran was added 1M borane in tetrahydrofuran (0.18 mL, 0.18 mml) dropwise. The mixture was heated at 60° C. for 1 hour. The reaction was cooled to room temperature and treated with several drops of 4M HCl-dioxane and methanol and then the clear solution was stirred at room temperature for 2 hours. The reaction was concentrated and purified by reverse-phase HPLC to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.69 (s, 1H), 8.26 (s, 1H), 7.45 (s, 4H), 7.28-7.32 (m, 2H), 7.22-7.26 (m, 1H), 5.18-5.22 (m, 1H), 4.72-4.73 (bs, 4H), 4.50-4.53 (bs, 2H), 2.17-2.32 (m, 3H), 1.70-1.80 (m, 2H), 1.44-1.67 (m, 4H), 1.13-1.24 (m, 2H); MS (ESI(+)) m/e 394 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[C:11]([O:17][CH3:18])(=[O:16])[CH2:12][C:13]([CH3:15])=O.[NH2:19][C:20]1[CH2:24][CH2:23][C:22](=[O:25])[CH:21]=1>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:12]([C:11]([O:17][CH3:18])=[O:16])=[C:13]([CH3:15])[NH:19][C:20]3[CH2:24][CH2:23][C:22](=[O:25])[C:21]2=3)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: NC1=CC(=O)CC1
Solvent: CO
Product: COC(=O)C1=C(C)NC2=C(C(=O)CC2)C1c1ccc(F)c(Br)c1
Temperature: 25 °C
Yield: 40.2 %

Procedure:
3-Bromo-4-fluorobenzaldehyde (3.045 g, 15 mmol), methyl acetoacetate (2.09 g, 18 mmol) and 3-aminocyclopent-2-enone (1.45 g, 15 mmol) were heated to 65° C. in methyl alcohol for 5 days. The reaction was allowed to cool to ambient temperature and the white precipitate collected, washed with methyl alcohol and dried to provide 2.29 g of the title compound. Flash chromatography (5% methyl alcohol/methylene chloride) of the filtrate provided an additional 1.46 g of the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8]CC)=O)=[CH:2]1.O.[NH2:12][NH2:13]>C(O)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:12][NH2:13])=[O:8])=[CH:2]1
Reactant: NN
Reactant: CCOC(=O)c1ccoc1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccoc1
Reaction time: 6 h

Procedure:
Ethyl 3-furancarboxylate (7.0 g) and hydrazine monohydrate (4.8 ml) in ethanol (10 ml) were heated at reflux while stirring for 6 hours. The solvent was evaporated under reduced pressure, and the thus-precipitated crystals were recrystallized from ethanol, thereby giving 3.2 g of the desire compound.
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.Cl>C(Cl)Cl.O1CCOCC1.CCOC(C)=O>[F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[C:18]([F:21])([F:19])[F:20])[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)[C@H](F)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(O[C@@H]2CCNC[C@H]2F)c(C(F)(F)F)c1
Reaction time: 3 h
Yield: 95 %

Procedure:
A solution of tert-butyl (3R,4R)-3-fluoro-4-(4-nitro-2-(trifluoromethyl)phenoxy)piperidine-1-carboxylate (1.6 g, 1.0 eq, 3.9 mmol) in CH2Cl2 (10 mL) was cooled to 0° C. while stirring. 4N HCl in dioxane (10 mL) was added to the above solution and stirred at 0° C. for 30 minutes and brought to room temperature for 3 hours. The volatiles were removed under vacuum to leave a crude solid. The crude mixture was dissolved in EtOAc (100 mL) and partitioned with 1N aqueous NaOH solution (50 mL). Organic layers were separated and the aqueous layer was washed with EtOAc (50 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to give the desired product in 95% yield.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=[O:16])=[CH:7]1)C.[OH-].[Na+].O>O1CCOCC1>[CH:15]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:5][C:4]([OH:17])=[O:3])[CH:7]=1)=[O:16]
Reactant: CCOC(=O)Cn1cc(C=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1cn(CC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 73.5 %

Procedure:
(3-Formylindol-1-yl)acetic acid ethyl ester (15.9 g 69 mmol) was dissolved in 1,4-dioxane (100 mL) and 1N sodium hydroxide (10 mL) was added and the resulting mixture was stirred at room temperature for 4 days. Water (500 mL) was added and the mixture was washed with diethyl ether (150 mL). The aqueous phase was acidified with 5N hydrochloric acid and extracted with ethyl acetate (250+150 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford 10.3 g (73%) of (3-formylindol-1-yl)acetic acid as a solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH2:10][C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=1)(=[O:24])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH:10]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C:4](=[N:3][O:2][CH3:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:33][CH:32]=1)(=[O:24])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCCCC(=O)CC(=NOC)C(=O)OCC
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(=O)C(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=NOC)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.7 %

Procedure:
A mixture of 50 mg (0.218 mmol) of ethyl 2-methoxyimino-4-oxooctanoate (from Step A), 83 mg (0.218 mmol) of [2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl bromide (from Step E), 36 mg (0.262 mmol) of freshly pulverized anhydrous potassium carbonate, and 0.6 mL of dry DMF was stirred vigorously for 24 hours at room temperature at which time the starting material was all consumed [TLC (5:1 hexane/EtOAc)]. The mixture was partitioned between 10 mL of EtOAc and 10 mL of 0.2N HCl. The EtOAc layer was then washed with 3×10 mL H2O, 1×5 mL brine, and dried briefly over anhydrous sodium sulfate. The filtrate, obtained from filtration over sintered glass, was concentrated to dryness and the resulting residue was flash chromatographed over 20 mL silica gel (column packed using hexane, sample introduced as a solution in CH2Cl2) eluting with 20/1 hexane/ethyl acetate, to give 83 mg (71%) of the desired product as an oil, homogeneous by TLC. Rf =0.35 in 5:1 hexane/EtOAc. 1H NMR (200 MHz, CDCl3, ppm)=δ0.88 (t, J=7.2 Hz, 3H), 1.00 (s, 9H), 1.31 (m, 5H), 1.52 (m, 2H), 2.32 (t, J=7.0 Hz, 2H), 3.03 (m, 1H), 3.40 (m, 1H), 3.61 (s, 1H), 4.04 (s, 3H), 4.25 (m, 3H), 7.16-7.52 (m, 7H), 8.15 (m, 1H), Mass spectrum: FAB (m/e) 531 (M+1)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](O)=O.CCN(C(C)C)C(C)C.CN(C(O[N:27]1[N:35]=[N:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N1C=CC=CC=1C(NN)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:60])=CC=1>C(Cl)Cl.CC(=O)OCC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:60][C:28]([C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][N:34]=2)=[N:27][N:35]=1
Reactant: O=C(O)c1ccccn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NNC(=O)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: c1ccc(-c2nnc(-c3ccccn3)s2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3 %

Procedure:
To a solution of the appropriate pyridine-carboxylic acid (1 eq.) and DIPEA (3 eq.) in DCM (20 mL/mmol), TBTU (1 eq.) is added. The mixture is stirred for 5 min before the appropriate pyridine-carboxylic acid hydrazide (1 eq.) is added. The mixture is stirred at rt for 1 h before it is diluted with DCM, washed with water, dried over MgSO4, filtered and concentrated. The remaining residue is dissolved in THF, Lawesson's reagent (2 eq.) is added and the mixture is stirred at 110° C. for 6 min under microwave irradiation. The mixture is diluted with EA, washed with sat. aq. NaHCO3, and concentrated. The crude product is purified by chromatography on prep. TLC plates or by prep. HPLC to give the desired 2,5-dipyridyl-[1,3,4]thiadiazole in 3-44% yield.
Reaction SMILES: C([N:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH2:4][C:5]([OH:7])=[O:6])C.O.[OH-].[Li+].Cl>C1COCC1.O>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([NH:3][CH2:4][C:5]([OH:7])=[O:6])=[CH:13][CH:12]=1
Reactant: CCN(CC(=O)O)c1ccc(OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(NCC(=O)O)cc1
Reaction time: 15 h
Yield: 50.7 %

Procedure:
To a solution of 19.59 g (108 mmol) of ethyl N-(4-methoxyphenyl)glycine in 100 mL of THF under N2 was added 5.44 g (130 mmol) of lithium hydroxide monohydrate in 25 mL water. After 15 hours, the mixture was reduced to ½ the original volume in vacuo and then acidified with concentrated hydrochloric acid to ph 3 and a precipitate formed. The solid was collected and washed with 100 mL water, then dried in vacuo to give 9.92 g (51%) of the desired compound as a off-white solid. 1H NMR (CDCl3): δ 6.68 (d, J=8.8, 2H); 6.49 (d, J=8.8, 2H); 3.73 (s, 2H); 3.64 (s, 3H); 2.49 (br s, 2H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:8])=[C:5]([OH:20])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:28]([CH3:32])[C:29](=[O:31])[CH3:30].O>CN(C=O)C.C(Cl)Cl>[ClH:19].[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:13][CH3:14])[CH2:15][CH3:16])=[O:8])=[C:5]([O:20][CH:28]([CH3:32])[C:29](=[O:31])[CH3:30])[CH:4]=1
Reactant: CC(=O)C(C)Cl
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC(C)C(C)=O
Reaction time: 3 h
Yield: 119 %

Procedure:
To a stirred suspension of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (1.94 g, 6 mmoles) and potassium carbonate (4.16 g, 30 mmoles) in DMF (10 ml) was added 3-chloro-2-butanone (0.95 g, 8.9 mmoles) and the mixture stirred for 3 hours, followed by pouring into water and extraction with methylene chloride. The extract was washed well with water, dried and concentrated in vacuo. The residue was dissolved in 1-propanol and treated with 2N HCl followed by concentration to give an oily residue. This was crystallized from acetone and the product recrystallized from 2-propanol to give 1.4 g of the title compound mp 98° C. as the hemihydrate.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([OH:16])=O)=[CH:13][C:8]=2[N:7]=[CH:6]1)#[N:2].C1C=CC2N(O)N=NC=2C=1.Cl.CC[N:30]([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32].CCN=C=NCCCN(C)C.Cl.CN([CH:52]=[O:53])C>>[OH:53][CH:52]1[CH2:35][CH:34]2[N:30]([C:14]([C:12]3[CH:11]=[CH:10][C:9]4[N:5]([CH2:4][CH2:3][C:1]#[N:2])[CH:6]=[N:7][C:8]=4[CH:13]=3)=[O:16])[CH:31]([CH2:32][CH2:36]2)[CH2:33]1
Reactant: N#CCCn1cnc2cc(C(=O)O)ccc21
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: N#CCCn1cnc2cc(C(=O)N3C4CCC3CC(O)C4)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 67 %

Procedure:
To a solution of 1-(2-cyanoethyl)-1H-benzoimidazole-5-carboxylic acid (0.25 g, 1.16 mmol) in DMF (2.5 mL) was added with stirring HOBt (0.17 g, 1.27 mmol) followed by exo-nortropinol hydrochloride (0.21 g, 1.27 mmol), DIPEA (0.45 g, 3.48 mmol). EDCl.HCl was then added and it was stirred at room temperature for 12 h. The solvent was then evaporated and to the residue diluted with water (5 mL) and extracted with CH2Cl2. The organic phase was washed with brine solution, dried (Na2SO4) and the solvent evaporated. The residue was purified by preparative HPLC which afforded 0.26 g (67%) of 3-[5-(3-Hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-benzoimidazol-1-yl]-propionitrile. MS-ESI m/z 325 (M+1).
Reaction SMILES: CC1(C)C[O:35][C:5]2([CH2:9][C@@H:8]([CH2:10][C@H:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32][CH3:33])=[C:28]([CH3:34])[CH:27]=3)[C:12](N([C@H](C)[C@H](O)C3C=CC=CC=3)C)=[O:13])[CH2:7][CH2:6]2)OC1.S(=O)(=O)(O)[OH:39]>O1CCOCC1.O>[CH3:34][C:28]1[CH:27]=[C:26]([C@@H:11]([CH2:10][C@H:8]2[CH2:7][CH2:6][C:5](=[O:35])[CH2:9]2)[C:12]([OH:39])=[O:13])[CH:31]=[CH:30][C:29]=1[S:32][CH3:33]
Reactant: CSc1ccc([C@@H](C[C@H]2CCC3(C2)OCC(C)(C)CO3)C(=O)N(C)[C@H](C)[C@H](O)c2ccccc2)cc1C
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: CSc1ccc([C@@H](C[C@H]2CCC(=O)C2)C(=O)O)cc1C
Temperature: 110 °C
Yield: 90 %

Procedure:
A solution of (R)-3-((R)-8,8-dimethyl-6,10-dioxa-spiro[4.5]dec-2-yl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-2-(3-methyl-4-methylsulfanyl-phenyl)-propionamide (1.35 g, 2.57 mmol) in dioxane (14 mL) was treated with a 9 N aqueous sulfuric acid solution (8 mL). The resulting solution was then heated at 110° C. for 16 h. The reaction was then cooled and diluted with water (150 mL) and extracted with a chloroform/methanol solution (3:2, 2×50 mL) and then combined the organic extracts and concentrated. The resulting residue was then dissolved in acetonitrile and concentrated with silica gel (3 g) and purified on Biotage Flash chromatography system (40 L column, silica gel, 60% ethyl acetate/hexanes) to afford (R)-2-(3-methyl-4-methylsulfanyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionic acid (674 mg, 90%) as a pale yellow gum: [α]28958−115.4° (c=0.35, methanol); ES-HRMS m/e calcd for C16H20O3S (M+Na)+ 315.1025, observed 315.1025; 1H NMR (300 MHz, DMSO-d6) δ 1.46 (m, 1H, CH), 1.76-2.32 (m, 8H, 4×CH2), 2.22 (s, 3H, ArCH3), 2.44 (s, 3H, SCH3), 3.48 (m, 1H, ArCHCO), 7.14 (m, 3H, Ar), 12.31 (s, 1H, CO2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH3:2]>C(O)C.[Pt]=O>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)Cc1ccncc1
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)CC1CCNCC1
Reaction time: 4 h

Procedure:
Ethyl-4-pyridylacetate (5 g) is dissolved in ethanol (30 mL), treated with platinum oxide catalyst (30 mg) and hydrogenated on a Parr apparatus for 4 hr. The catalyst is filtered off and the ethyl-4-piperidinylacetate is isolated by removal of the solvent under vacuum. This material is then dissolved in acetonitrile (50 mL) and treated with 4-chlorobenzyl chloride (4.9 g) and sodium carbonate (10 g). The resulting mixture is heated in methanol (30 mL) and treated with a solution of lithium hydroxide (2 g) in water (10 mL). The mixture is allowed to stand overnight. Addition of 47.6 mL of 1 N HCI solution followed by concentration and extraction of the residue with chloroform provides the desired 1-(4-chlorobenzyl)-4-piperidylacetic acid. A portion of this material (1 g) is dissolved in methylene chloride and treated with 1,1′-carbonyldiimidazole (0.65 g) and allowed to stand overnight. This solution is then treated with 2-methylindoline (0.5 g). After 2 h the resulting mixture is washed 3 times with water dried and concentrated. Purification by column chromatography on silica gel provides 1.2 g of the desired 2-(1-[4-chlorobenzyl]piperidin-4-yl)-1-(2-methylindolin-1-yl)-1-ethanone (Compound 1). The dihydrochloride salt is subsequently prepared (Compound 1a).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[O:28][CH2:29][CH2:30][O:31]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][NH:51][C:52](=[O:54])[CH3:53])=[C:45](O)[CH:44]=1>>[C:52]([NH:51][CH2:50][CH2:49][C:46]1[CH:45]=[CH:44][C:43]([F:42])=[CH:48][C:47]=1[O:31][CH2:30][CH2:29][O:28][CH:16]1[CH:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17]1)(=[O:54])[CH3:53]
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCc3ccccc3)cc2)cc1
Reactant: CC(=O)NCCc1ccc(F)cc1O
Product: CC(=O)NCCc1ccc(F)cc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCc2ccccc2)cc1

Procedure:
Analogously to Method G, 6.7 g of tert-butyl 4-(4-benzyloxyphenyl)-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate and 4.54 g of N-[2-(4-fluoro-2-hydroxyphenyl)ethyl]acetamide (Example 112b) are reacted. The title compound is obtained as a yellowish oil. Rf=0.16 (2:1 EtOAc-heptane); Rt=5.44.
Reaction SMILES: [CH3:1][CH:2]([Si:4]([CH:7]([CH3:9])[CH3:8])([Cl:6])Cl)[CH3:3].[CH2:10]([OH:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:8][CH:7]([Si:4]([CH:2]([CH3:1])[CH3:3])([O:18][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[Cl:6])[CH3:9]
Reactant: CC(C)[Si](Cl)(Cl)C(C)C
Reactant: CCCCCCCCO
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCCO[Si](Cl)(C(C)C)C(C)C
Temperature: -5 °C
Reaction time: 8 h

Procedure:
Alternatively, di(2-propyl)octyloxychlorosilane was prepared as follows. To a 1000 ml three-neck round-bottom flask fitted with a stirrer, drying tube, thermometer and dropping funnel was added di(2-propyl)dichlorosilane (28.3 g, 153 mmol) and dry toluene (200 ml). The reaction mixture was then stirred and cooled to -5° C. A solution of dry octanol (10.0 g, 76 mmole) and dry pyridine (6.5 g, 82 mmole) in dry toluene (100 ml) was added dropwise for 60 minutes. The reaction mixture was suspended overnight at room temperature, filtered under a "nitrogen blanket" and fractionated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH:19]=[O:20])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.O.[BH4-].[Na+]>O1CCCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(C=O)cc2C(=O)N(C)c2ccc(Cl)nc21
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN1c2ncc(CO)cc2C(=O)N(C)c2ccc(Cl)nc21
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a solution of 2-chloro-5,11-dihydro-11-ethyl-8-formyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.5822 g, 1.84 mmol) in tetrahydrofuran (20 mL) was added water (0.1 mL) followed by sodium borohydride (0.0695 g, 1.84 mmol). The mixture was stirred for 0.5 hour then diluted with brine (20 mL) and extracted with dichloromethane (3×30 mL). The combined organics were dried, concentrated and the residue was purified by flash chromatography (gradient hexanes to ethyl acetate to yield the title compound (0.52 g, 89%), m.p. 166°-168° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:37])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[CH:20]([C:29]([OH:31])=O)[NH:19][CH:18]3[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:62][C:63]1[CH:72]=[CH:71][C:66]([C:67]([O:69][CH3:70])=[O:68])=[CH:65][C:64]=1[O:73][CH3:74]>>[CH3:70][O:69][C:67](=[O:68])[C:66]1[CH:71]=[CH:72][C:63]([NH:62][C:29]([C@@H:20]2[NH:19][C@@H:18]([CH2:32][C:33]([CH3:36])([CH3:34])[CH3:35])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:37])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[O:31])=[C:64]([O:73][CH3:74])[CH:65]=1
Reactant: COC(=O)c1ccc(N)c(OC)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2)c(OC)c1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 63 (0.28 g, 0.5 mmol), was reacted with diisopropylethylamine (0.38 mL, 2.25 mmol), diphenylphosphinic chloride (0.36 mL, 1.9 mmol), then reacted with methyl 4-amino-3-methoxy-benzoate (Ark Pharm) (0.09 g, 0.5 mmol) to give rac-4-{[(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methoxy-benzoic acid methyl ester as a white solid (Yield, 102 mg, 33%). MS (H+), 610.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9](S)=[CH:8][C:4]=1[C:5]([OH:7])=O.[Na].C(O[S:18]([O-])(=O)=O)C.Cl.CCO[CH2:26][CH3:27]>O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([CH2:26][CH3:27])=[CH:8][C:4]=1[C:5]([OH:7])=[S:18]
Reactant: CCOS(=O)(=O)[O-]
Reactant: COc1cc(N)c(S)cc1C(=O)O
Reactant: CCOCC
Agent: Cl
Agent: [Na]
Solvent: O
Product: CCc1cc(C(O)=S)c(OC)cc1N
Yield: 88 %

Procedure:
159 g of 2-methoxy-4-amino-5-mercaptobenzoic acid, 355 cm3 of water and 160 cm3 of 30% sodium hydroxyde solution are placed in a flask fitted with a condenser. The mixture is heated until the solid dissolves, then 123 g of ethylsulfate is added. The mixture is heated to reflux, treated with 10 cm3 of 30% sodium hydroxyde solution, then heated to reflux for 1 hour. After cooling, 800 cm3 of water is added and the solution is filtered. The precipitate obtained by adding 100 cm3 of concentrated hydrochloric acid in the presence of ether is drained, washed with water and dried. 162 g of 2-methoxy-4-amino-5-ethylthio benzoic acid is obtained (yield=88%).