Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1.[OH-].[Na+]>CO>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][CH:5]([CH2:4][C:3]([OH:17])=[O:2])[CH2:6]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)CC1CCN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
To a solution of 6.6 g (27.13 mmol ) of tert-butyl 3-(2-methoxy-2-oxoethyl)pyrrolidine-1-carboxylate in methanol (150 mL) was added 25 mL (50 mmol) of 2N aqueous NaOH dropwise and the mixture was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was acidified with 2N hydrochloric acid at 0° C. The organics were extracted with ethyl acetate (×3), washed with brine, dried over anhydrous Na2SO4, and filtered. Evaporation of the solvent gave 5.67 g of [1-(tert-butoxycarbonyl)-pyrrolidin-3-yl]acetic acid. The acid (5.64 g, 24.6 mmol) was converted to the title compound (4.2 g) in 3 steps using the procedure outlined in Example 6. 1H NMR (500 MHz, CDCl3) δ 3.64–3.53 (m, 3H), 3.32 (m, 1H), 3.20 (m, 1H), 2.59 (m, 1H), 2.21 (m, 1H), 1.81 (m 1H), 1.49 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([OH:11])=O)[O:4][N:3]=1.[NH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>>[OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([NH:12][CH2:13][CH2:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)=[O:11])[O:4][N:3]=1
Reactant: O=C(O)CCc1cc(O)no1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Product: CC(C)(C)OC(=O)N1CCC(CCNC(=O)CCc2cc(O)no2)CC1

Procedure:
The title compound was prepared from commercially available 3-(3-hydroxyisoxazol-5-yl)propanoic acid and tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate analogously to Example 21 (step 2);
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C.[O:35]1[CH2:40][CH2:39][CH:38]([CH2:41][NH2:42])[CH2:37][CH2:36]1>CN(C=O)C.ClCCl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:42][CH2:41][CH:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1O
Reactant: NCC1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1NCC1CCOCC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 86.1 %

Procedure:
7-(Benzyloxy)-3-nitroquinolin-4-ol (12.3 g, 41.6 mmol) was slurried in DMF (83 mL). Phosphorous oxychloride (4.2 mL, 45 mmol) was added in one portion and the mixture was heated at 100° C. for 5 minutes. The solution was allowed to cool to 40° C. and was then poured into ice water (total volume 400 mL) resulting in a tan precipitate. The precipitate was filtered and washed with water. After drying, the solid was dissolved in dichloromethane and the residual water was separated. The organic fraction was dried over anhydrous sodium sulfate and anhydrous magnesium sulfate (about a 50/50 mixture). The organic fraction was filtered into a reaction flask (total volume of organic with 7-(benzyloxy)-3-chloro-4-nitroquinoline is about 425 mL). The flask was cooled to 8° C. and triethylamine (11.6 mL, 83.0 mmol) was added. (Tetrahydro-2H-pyran-4-yl)methylamine (6.0 g, 52 mmol) in dichloromethane (50 mL) was added dropwise to the mixture. The cooling bath was removed and the reaction was stirred for 16 hours. Water (200 mL) was added followed by stirring for 30 minutes. The layers were separated and the organic fraction was sequentially washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Recrystallization from 2-propanol afforded 14.1 g of 7-(benzyloxy)-3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)quinolin-4-amine as a yellow powder.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:12]([O-])=[O:13].[Na+]>O>[N:12]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]([OH:11])=[O:10])=[O:13]
Reactant: O=N[O-]
Reactant: O=C(O)CNc1ccccc1
Agent: [Na+]
Solvent: O
Product: O=NN(CC(=O)O)c1ccccc1

Procedure:
The precursor N-nitrosophenylglycine was prepared according to the method described in Organic Syntheses, Coll. Vol. 5, p. 962 (1973); Vol. 45, p. 96 (1965). N-phenyl glycine (50 g) was dissolved in water (600 ml) with stirring, and the solution was cooled to below 0° C. in a salt/ice bath mixture. To this was slowly added a cooled solution of sodium nitrite (25 g) in water (150 ml) so that the temperature of the mixture never rose above 0° C. After addition was complete, the mixture was stirred below 0° C. for 40 minutes after which a red-brown solution was obtained with a small amount of brown solid residue. The residue was removed by filtering the solution under vacuum, and the clear liquid was decolorised by treating with charcoal (5 g) for 5 minutes. After filtering off the charcoal, the solution was cooled again and acidified with concentrated hydrochloric acid (50 ml), whereupon a slightly reddish-brown precipitate formed. The mixture was stirred for 10 minutes and then the precipitate was filtered off. This was allowed to dry in air to give a tan coloured powder (48 g).
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([CH2:11][C:12]([OH:14])=[O:13])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:15]C1C=CC=C([N+]([O-])=O)C=1Cl>>[Cl:15][C:2]1[C:7]2[N:8]([CH2:11][C:12]([OH:14])=[O:13])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: O=C(O)Cn1cnc2cccc(Br)c21
Product: O=C(O)Cn1cnc2cccc(Cl)c21

Procedure:
Alternatively, the title compound was synthesised according to the procedure described for the synthesis of (7-bromo-1H-benzimidazol-1-yl)acetic acid (parts A-D) starting from 1,2-dichloro-3-nitrobenzene. The new intermediates isolated were:
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([NH:19][C:20]([C:22]4[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=4[C:24]([OH:26])=[O:25])=[O:21])[CH:18]=[C:13]3[C:12]([C:31]3[S:35][CH:34]=[N:33][CH:32]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].C(O)(=O)C>CCO>[S:35]1[C:31]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[C:17]([NH:19][C:20]([C:22]4[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=4[C:24]([OH:26])=[O:25])=[O:21])[CH:18]=3)[NH:10][CH:11]=2)=[CH:32][N:33]=[CH:34]1
Reactant: O=C(O)c1ccccc1C(=O)Nc1cnc2c(c1)c(-c1cncs1)cn2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1C(=O)Nc1cnc2[nH]cc(-c3cncs3)c2c1
Yield: 26.6 %

Procedure:
Sulfonamide 44 (20 mg, 40 μmol), 10% aqueous NaOH solution (0.36 mL, 0.9 mmol) in EtOH (1.0 mL) was refluxed for 30 min. The mixture was cooled, concentrated, treated with glacial acetic acid (0.72 mL, 12 mmol), and concentrated again. The residue was separated by LCMS (column LUNA 10 μ C18(2) 00G-4253-V0 250×50 mm) using water—MeCN (0.11% AcOH) as eluent (in gradient; flow 80 mL/min) to afford 45 (3.88 mg, 27%). 1H NMR (400 MHz; CDCl3+3 drops of CD3OD) δ 7.36 (dd, J=7.5, 2.5 Hz, 1H), 7.57 (s, 2H), 7.78 (s, 1H), 8.02 (d, J=2.0 Hz, 1H), 8.15 (d, J=1.8 Hz, 1H), 8.20 (d, J=1.9 Hz, 1H), 8.39 (d, J=2.1 Hz, 1H), 8.50 (s, 1H); MS (ES) m/z 406.3 (MH++MeCN).
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[C:17]2[S:18][CH:19]=[CH:20][C:16]=2[CH:15]=[CH:14][CH:13]=1)[CH3:5])=[N+]=[N-].C(O)=O.NN>[Ni].C(O)C>[S:18]1[CH:19]=[CH:20][C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:11]3[CH:10]=[CH:9][N:8]=[CH:7][C:6]=3[CH:4]([NH2:1])[CH3:5])[C:17]1=2
Reactant: CC(N=[N+]=[N-])c1cnccc1-c1cccc2ccsc12
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O=CO
Product: CC(N)c1cnccc1-c1cccc2ccsc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
Add Raney Nickel (1.38 g, 2.35 mmol) into a solution of 3-(1-azido-ethyl)-4-benzo[b]thiophen-7-yl-pyridine (0.66 g, 2.35 mmol) in ethanol (10 mL), formic acid (1.08 g, 23.54 mmol), and hydrazine (754.4 mg, 23.54 mmol) in a 50-mL round bottom flask in an ice bath. Stir the mixture at RT for 1 h and filter the Raney Nickel. Dilute the filtrate with ammonium hydroxide. Extract the product into chloroform. Wash the organic phase with water, dry over sodium sulfate, and concentrate to give the title compound as a brown oil (0.6 g, 100%). MS (ES) m/z 255 [M+1]+.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:36])=[CH:31][CH:30]=1>>[C:24]([C:10]1[C:9]([CH:7]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[CH:33][CH:34]=2)[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][N:15]=2)[N:11]=1)([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1nn(-c2ccc(C(F)(F)F)cn2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: CC(C)(C)c1nn(-c2ccc(C(F)(F)F)cn2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 15.5 %

Procedure:
Using cyclohexyl{3-tert-butyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.53 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.32 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.12 g, 15%) was obtained as a white solid.
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][N:16]1[C:21](=[O:22])[C:20]2[C:23]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:24]=3[S:25][C:19]=2[N:18]=[C:17]1[CH3:31]>>[C:1]12([CH2:11][C:12]([NH:15][N:16]3[C:21](=[O:22])[C:20]4[C:23]5[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:24]=5[S:25][C:19]=4[N:18]=[C:17]3[CH3:31])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Cc1nc2sc3c(c2c(=O)n1N)CCCCC3
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: Cc1nc2sc3c(c2c(=O)n1NC(=O)CC12CC4CC(CC(C4)C1)C2)CCCCC3

Procedure:
1-Adamantaneacetyl chloride and 3-amino-2-methyl-3,5,6,7,8,9-hexahydro-4H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-one (Matrix) were processed using the method described in Example 42C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.49-1.76 (m, 15 H) 1.78-1.89 (m, 2 H) 1.91-2.00 (m, 3 H) 2.08 (d, J=15.0 Hz, 1 H) 2.16 (d, J=15.0 Hz, 1 H) 2.34 (s, 3 H) 2.84 (s, 2 H) 3.11-3.29 (m, 3 H) 10.76 (s, 1 H); MS (ESI+) m/z 426 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].[O:14]=[N+:15]=[O:16]>CC#N>[C:1]([C:5]1[CH:6]=[C:7]([N+:15]([O-:16])=[O:14])[C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]=O
Reactant: CC(C)(C)c1ccc(O)c(C=O)c1
Solvent: CC#N
Product: CC(C)(C)c1cc(C=O)c(O)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
To a solution of 15.0 g (84.2 mmol) of 5-tert-Butyl-2-hydroxy-benzaldehyde in MeCN at −30° C. was added 14.5 g (109.4 mmol) of nitronium tetrafluoborate. The temperature was allowed to climb slowly to −12° C. ove 1 h. The mixture was partitioned between sat'd NaHCO3 and EtOAc. The organic layer was washed with water and brine then dried over MgSO4. After filtration and evaporation, 5-tert-butyl-2-hydroxy-3-nitro-benzaldehyde was obtained as yellow solid. To a portion of this material (6.27 g, 28.1 mmol) in 40 mL of DMF was added 19.4 g of K2CO3 in two batches. To this slurry was added 6.12 mL (98.3 mmol) of MeI. The mixture was stirred overnight, filtered, and diluted with EtOAc. This mixture was washed with water, and the wash was then extracted with EtOAc (3×150 mL). The extracts were washed with water and brine, then dried over MgSO4, filtered, and concentrated. Chromatography (5% EtOAc in hexanes) provided 5.38 g of 5-tert-butyl-2-methoxy-3-nitro-benzaldehyde as an off-white solid.
Reaction SMILES: [F:1][C:2]1[C:15]2[N:14]=[CH:13][C:12]3[NH:11][CH:10]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8](=[O:21])[C:7]=3[C:6]=2[CH:5]=[CH:4][C:3]=1[F:22].[C:23](=O)([O-])[O-].[K+].[K+].CI>CS(C)=O>[F:1][C:2]1[C:15]2[N:14]=[CH:13][C:12]3[N:11]([CH3:23])[CH:10]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8](=[O:21])[C:7]=3[C:6]=2[CH:5]=[CH:4][C:3]=1[F:22]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c[nH]c2cnc3c(F)c(F)ccc3c2c1=O
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C)c2cnc3c(F)c(F)ccc3c2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 69.6 %

Procedure:
A suspension of 35 g of ethyl 7,8-difluoro-1-oxo-1,4-dihydrobenzo[f][1,7]-naphthyridine-2-carboxylate and 31.8 g of potassium carbonate in 350 cm3 of dimethyl sulphoxide was heated, with stirring, at a temperature of 90° C. for 3 hours. After cooling to 50° C., 65 g of methyl iodide were added; the mixture was heated at 90° C. for 3 hours. After cooling to 20° C., the insoluble material was dewatered, washed 4 times with 100 cm3 of water, 3 times with 100 cm3 of ethanol, and twice with 100 cm3 of diethyl ether. 25.5 g of ethyl 7,8-difluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate was obtained in the form of white crystals, which melted at 320° C.
Reaction SMILES: CS(C)=O.Cl.Cl.[NH2:7][CH:8]1[CH2:11][NH:10][CH2:9]1.[NH2:12][C:13]1[C:18]([F:19])=[C:17]([F:20])[N:16]=[C:15]([N:21]2[C:30]3[C:25](=[CH:26][C:27]([F:33])=[C:28](F)[C:29]=3[Cl:31])[C:24](=[O:34])[C:23]([C:35]([OH:37])=[O:36])=[CH:22]2)[C:14]=1[F:38]>C(N(CC)CC)C>[NH2:7][CH:8]1[CH2:11][N:10]([C:28]2[C:29]([Cl:31])=[C:30]3[C:25]([C:24](=[O:34])[C:23]([C:35]([OH:37])=[O:36])=[CH:22][N:21]3[C:15]3[C:14]([F:38])=[C:13]([NH2:12])[C:18]([F:19])=[C:17]([F:20])[N:16]=3)=[CH:26][C:27]=2[F:33])[CH2:9]1
Reactant: NC1CNC1
Reactant: Nc1c(F)c(F)nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Nc1c(F)c(F)nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c1F
Yield: 50.2 %

Procedure:
To 1 ml dimethylsulfoxide solution of 70 mg of 3-aminoazetidine dihydrochloride and 250 mg of triethylamine at 80° C. was added 150 mg of 1-(4-amino-3,5,6-trifluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid with stirring, and the mixture was stirred at 80° C. for 1 hour. The reaction solution was allowed to cool and decanted with diethylether. Ethanol was added to the residue to disperse the solid content, and the solid content was collected by filtration, washed with ethanol, and dried to obtain 85 mg of the title compound as a pale yellow powder.
Reaction SMILES: [C:1]([O:9][C:10]1([CH2:13][CH2:14][O:15]C2CCCCO2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[C:1]([O:9][C:10]1([CH2:13][CH2:14][OH:15])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC1(CCOC2CCCCO2)CC1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: O=C(OC1(CCO)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)cyclopropyl benzoate (690 mg, 2.38 mmol) in 20 mL of MeOH was added PPTS (896 mg, 3.57 mmol, Aldrich) at rt. The reaction mixture was stirred at rt overnight, then concentrated and purified by a silica gel column chromatography (4:1 (v/v) petroleum ether/EtOAc) to the title compound as light yellow oil (320 mg, 65%).
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][C:8]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7][CH2:6]1)=O.[C:16]([O:20][C:21](=[O:35])[CH2:22][CH2:23][N:24]([CH2:28][C:29]1[S:30][C:31]([CH3:34])=[CH:32][CH:33]=1)[C:25]([NH2:27])=[S:26])([CH3:19])([CH3:18])[CH3:17]>CO>[C:16]([O:20][C:21](=[O:35])[CH2:22][CH2:23][N:24]([CH2:28][C:29]1[S:30][C:31]([CH3:34])=[CH:32][CH:33]=1)[C:25]1[S:26][CH:2]=[C:3]([CH:5]2[CH2:10][CH2:9][C:8]3([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:7][CH2:6]2)[N:27]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(CBr)C1CCC2(CCCCC2)CC1
Reactant: Cc1ccc(CN(CCC(=O)OC(C)(C)C)C(N)=S)s1
Solvent: CO
Product: Cc1ccc(CN(CCC(=O)OC(C)(C)C)c2nc(C3CCC4(CCCCC4)CC3)cs2)s1

Procedure:
2-bromo-1-spiro[5.5]undec-3-yl-ethanone (200 mg, 0.7 mmol) in MeOH (2 mL) was treated with 3-[1-(5-methyl-thiophen-2-ylmethyl)-thioureido]-propionic acid tert-butyl ester (250 mg, 0.8 mmol) following a method analogous to General Procedure C to produce 3-[(5-methyl-thiophen-2-ylmethyl)-(4-spiro[5.5]undec-3-yl-thiazol-2-yl)-amino]-propionic acid tert-butyl ester after workup and purification (45 mg). This propionate ester derivative (45 mg, 0.09 mmol) was hydrolyzed using NaOH (0.5 mL of 2.0N aq solution in 1 mL of 1:1:MeOH:THF) following a method analogous to General Procedure G1 to produce 3-[(5-methyl-thiophen-2-ylmethyl)-(4-spiro[5.5]undec-3-yl-thiazol-2-yl)-amino]-propionic acid after workup (15 mg, 33% yield). LC-MS m/z: 433 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 6.80 (d, 1H), 6.59 (d, 1H), 6.11 (s, 1H), 4.60 (s, 2H), 3.75 (t, 2H), 2.71 (t, 2H), 2.51 (m, 1H), 2.43 (s, 3H), 1.82 (m, 2H), 1.71 (m, 2H), 1.50 (m, 2H), 1.3-1.5 (m, 7H), 1.27-1.13 (m, 5H). Sodium salt of the title compound could be prepared from the title compound following a method analogous to General Procedure H.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][CH:23]=[C:22]([C:25]([OH:27])=O)[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3][CH2:2]1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:25]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[C:9]5[O:13][CH2:12][O:11][C:10]=5[CH:14]=[CH:15][C:7]=4[O:6][CH2:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)[C:17]=3[NH:24][CH:23]=2)=[O:27])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CCC4)ccc4c3OCO4)ncnc12
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CCC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclobutylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A68) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][C:44]=1[O:45][CH3:46])[CH2:41][NH:40][CH2:39][CH2:38]2>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:40]1[CH2:39][CH2:38][C:37]2[C:42](=[CH:43][C:44]([O:45][CH3:46])=[C:35]([O:34][CH3:33])[CH:36]=2)[CH2:41]1)=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: COc1cc2c(cc1OC)CNCC2
Product: COc1cc2c(cc1OC)CN(C(=O)[C@@H]1C[C@H](NCc3ccc(F)cc3F)CN1Cc1ccccc1)CC2
Yield: 5 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline instead of 2-piperazin-1-yl-benzonitrile, to the title compound (3.5 mg, 5.0%) as light yellow oil. MS m/e=522.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Al](C)C.[CH3:20][O:21][C:22](=[O:43])[CH2:23][C@H:24]([NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].C(=O)=O.CC(C)=O.[F-].[Na+].O>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:36]([N:35]([CH2:14][C@H:13]([OH:15])[CH2:12][O:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])[C@@H:24]([CH2:23][C:22]([O:21][CH3:20])=[O:43])[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: COC(=O)C[C@H](NCc1ccccc1)C(=O)OCc1ccccc1
Agent: C[Al](C)C
Agent: O=C=O
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)C[C@@H](C(=O)OCc1ccccc1)N(Cc1ccccc1)C[C@H](O)COS(=O)(=O)c1ccc(C)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 91.8 %

Procedure:
To a solution of (2S)-(+)-glycidyl tosylate (23.0 g, 0.101 mol) in 500 mL of methylene chloride was added 2.00 M of trimethylaluminum in toluene (50.4 mL) at −78 Celsius, under an atmosphere of nitrogen. After stirred at −78 Celsius for 10 min, to the mixture was added a solution of (S)-2-benzylamino-succinic acid 1-benzyl ester 4-methyl ester (30.0 g, 0.0916 mol) in 150 mL of methylene chloride. The resulting reaction mixture was stirred at −78 Celsius for 30 min. The dry ice-acetone bath was changed to an ice-water bath to warm the mixture up to 0 Celsius. The mixture was stirred at 0 Celsius for 30 min. To the reaction mixture was added sodium fluoride (16.2 g, 0.385 mol) followed by water (10.4 mL, 0.577 mol) at 0 Celsius. The resulting suspension was rapidly stirred for 1 h at 0 Celsius and filtered through a short column of celite and the column was subsequently washed with 600 mL of methylene chloride. The combined filtrates were dried over sodium sulfate, concentrated to dry and purified by column purification (eluting with 0 to 20% EtOAc in hexane) to yield the titled compound (46.7 g, 91.7%). MS (ESI): (M+H)+=556.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH:29]([CH2:32]OS(C)(=O)=O)[CH2:28]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:32][CH:29]2[CH2:30][CH2:31][NH:27][CH2:28]2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: CS(=O)(=O)OCC1CCNC1
Product: O=C(c1cn(CC2CCNC2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with methanesulfonic acid pyrrolidin-3-ylmethyl ester (described in WO 9742189) gave the title compound. ES-MS m/e (%): 450.2(M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A solution of 4-hydroxy-3-nitro-benzoic acid methyl ester (30 g, 152 mmol) in acetone (1000 mL) was charged into a 2 L reactor and treated with K2CO3 (31.5 g, 228 mol) and benzyl bromide (52 g, 36.1 mL, 304 mmol). The mixture was mechanically stirred at heated at reflux for 16 hours under a light argon flux. After cooling to room temperature the solvent was evaporated. The residue was taken up in ethyl acetate/water and the two phases were separated. The aqueous phase was extracted three times with ethyl acetate (total solvent volume: 1.5 L, total water volume 1 L). The combined organic phases were dried over sodium sulfate and evaporated. 4-Benzyloxy-3-nitro-benzoic acid methyl ester thus obtained was used crude in the following reaction.