Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C@@H:9]([C@@H:11]2[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[O:12]2)[CH3:10])[N:5]=[C:4]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:3]=1.[CH3:27][CH:28]1[CH2:31][N:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH2:29]1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:16][C:13]1([CH3:17])[O:12][C@H:11]([C@H:9]([O:8][C:6]2[N:5]=[C:4]([S:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:3]=[C:2]([NH:35][S:32]([N:30]3[CH2:31][CH:28]([CH3:27])[CH2:29]3)(=[O:34])=[O:33])[CH:7]=2)[CH3:10])[CH2:15][O:14]1
Reactant: C[C@@H](Oc1cc(Cl)nc(SCc2ccc(F)cc2)n1)[C@@H]1COC(C)(C)O1
Reactant: CC1CN(S(N)(=O)=O)C1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC1CN(S(=O)(=O)Nc2cc(O[C@H](C)[C@@H]3COC(C)(C)O3)nc(SCc3ccc(F)cc3)n2)C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
A solution of the sub-title product of step (iii) (94 g) dissolved in dioxane (700 mL) was treated with 3-methylazetidine-1-sulfonamide (Intermediate B) (42.5 g), potassium carbonate (65.1 g), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (11.2 g) and tris(dibenzylideneacetone)dipalladium(0) (10.8 g) under nitrogen. The resulting mixture was stirred at 100° C. for 60 minutes. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL). The organics were dried over magnesium sulfate, filtered and evaporated in vacuo to afford crude product. The crude product was purified by flash silica chromatography with elution 30% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the sub-title product (98 g) as a red oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][C@H:4]1[F:36].[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:40])[CH2:38][CH3:39])[C@H:4]([F:36])[CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:33][CH2:34]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)[C@H](F)C1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@H]1F

Procedure:
Starting from N-[(1S*,3R*,4S*)-4-amino-3-fluorocyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f72) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[CH:11]=[C:10]([C:17]([O:19]C(C)(C)C)=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[CH:11]=[C:10]([C:17]([OH:19])=[O:18])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc3nccn23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cc(C(=O)O)cc3nccn23)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 5-(4-methylphenyl)imidazo[1,2-a]pyridine-7-carboxylate (40 mg, 0.13 mmol) in dichloromethane (0.65 mL) was added trifluoroacetic acid (0.65 mL). The mixture was stirred at ambient temperature. After 1.5 h, the mixture was concentrated. The crude product was purified by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.025% trifluoroacetic acid) gave the mixture of the title compound and the impurities. The mixture was carried onto the next step: LC-MS [H+1]=253.1.
Reaction SMILES: [CH2:1]([C:3](=[CH:7][CH2:8][O:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([O:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[CH2:11]1)[C:4]([OH:6])=[O:5])[CH3:2].[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH2:1]([CH:3]([CH2:7][CH2:8][O:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([O:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[CH2:11]1)[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCC(=CCO[C@@H]1CCC[C@H](OCc2nc(-c3ccc(F)cc3)oc2C)C1)C(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(CCO[C@@H]1CCC[C@H](OCc2nc(-c3ccc(F)cc3)oc2C)C1)C(=O)O

Procedure:
0.3 g of the 2-ethyl-4-{(1R,3S)-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]-cyclohexyloxy}but-2-enoic acid is dissolved in a solvent mixture of 2 ml of ethyl acetate and 1 ml of methanol, and 0.05 g of palladium (10% on carbon) is added. The mixture is then hydrogenated at a hydrogen pressure of 1 bar for 3 h. After removal of the palladium by filtration, the solvent mixture is removed under reduced pressure and the residue is recrystallized from acetonitrile. This gives 0.25 g of 2-ethyl-4-{(1R,3S)-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]-cyclohexyloxy}butanoic acid as a white solid. C23H30FNO5 (419.49), MS (ESI): 420 (M+H+)
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([C:21]([N:23]([CH3:29])[CH2:24][C:25]([O:27]C)=[O:26])=[O:22])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>O1CCOCC1.O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([C:21]([N:23]([CH3:29])[CH2:24][C:25]([OH:27])=[O:26])=[O:22])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN(CC(=O)O)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
A solution of methyl 2-[[(5-{(1R)-4-cyclohexyl-1-[2-(hydroxyamino)-2-oxoethyl]butyl}-1,2,4-oxadiazol-3-yl)carbonyl](methyl)amino]acetate (Preparation 40) (180 mg, 0.44 mmol) in 1,4-dioxane (4 ml) was cooled to 0° C. and treated with lithium hydroxide monohydrate (42 mg, 1 mmol). The mixture was stirred for 1 hour being allowed to warm to room temperature over this time. The mixture was then treated with hydrochloric acid (2M), diluted with water and extracted with ethyl acetate (×2). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by HPLCb to afford the title compound as a white foam (95 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([S:22](C)=O)[N:14]=[C:13]2[CH2:25][CH2:26][CH3:27])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([SH:22])[N:14]=[C:13]2[CH2:25][CH2:26][CH3:27])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CCCc1nc(S(C)=O)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCc1nc(S)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
800 mg of the product obtained in Stage 5 above is introduced into 16 ml of methylene chloride and 0.54 ml of trifluoroacetic anhydride is added. Agitation is carried out for 30 minutes, followed by evaporation to dryness and the residue is taken up in 10 ml of methanol and 4 ml of triethylamine. After agitation for 30 minutes, extraction is carried out with chloroform, the extracts are washed with a saturated solution of ammonium chloride, dried and evaporated to dryness. In this way 720 mg of expected product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C:7](=[CH2:9])[CH2:6][N:5]1C(OCC1C=CC=CC=1)=O.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][CH:7]([CH3:9])[CH2:6][NH:5]1
Reactant: [H][H]
Reactant: C=C1C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1CC(C)CN1
Yield: 99.9 %

Procedure:
(S)-1-Benzyloxycarbonyl-4-methylideneproline methyl ester (1.80 g (6.5 mmol), prepared as described in 1)) was dissolved in methanol (50 ml). The resulting solution was stirred at room temperature in an atmosphere of hydrogen in the presence of 10% palladium on charcoal (180 mg) for 2 hours. At the end of this time, the reaction mixture was filtered to remove the catalyst and the filtrate was concentrated by evaporation under reduced pressure, to give the title compound (0.93 g) as a pale yellow oil (yield quantitative).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11](F)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(F)cc1OC
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(N2CCN(C)CC2)cc1OC
Yield: 66.3 %

Procedure:
Methyl 2-methoxy-4-fluoro-benzoate (1.6 gr, 9.7 mmol), K2CO3 (1.3 gr, 9.7 mmol) and N-methyl piperazine (1.3 mL, 11.7 mmol) were heated at 100° C. in DMSO (5 mL) for 20 hours. Reaction mixture was diluted with DCM and washed with water. Organic phase was dried over sodium sulfate and evaporated to dryness. Column chromatography purification on silica gel using dichloromethane/methanol 95:5 as the eluant, afforded 1.7 g (yield 66%) of the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:6]
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of 3-iodobenzoic acid (9.92 g, 40.00 mmol, 1.00 equiv) in DMF (100 mL), 1-(bromomethyl)benzene (6.84 g, 40.00 mmol, 1.00 equiv), potassium carbonate (11.04 g, 80.00 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at room temperature. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was diluted with 50 mL of water and extracted with 2×50 mL of ethyl acetate. The combined organic layers were washed with 2×50 mL of sodium chloride, dried over anhydrous sodium sulfate and concentrated under vacuum to give 13.1 g (97%) of benzyl 3-iodobenzoate as light brown oil
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][NH:21][C:15]=2[CH:14]=1.CC1(C)C(C)(C)OB([C:31]2[CH:40]=[CH:39][C:34]3[C:35](=[O:38])[O:36][CH2:37][C:33]=3[CH:32]=2)O1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:31]3[CH:40]=[CH:39][C:34]4[C:35](=[O:38])[O:36][CH2:37][C:33]=4[CH:32]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(I)c3cn2)c1Cl
Reactant: CC1(C)OB(c2ccc3c(c2)COC3=O)OC1(C)C
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4ccc5c(c4)COC5=O)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-benzofuran-1(3H)-one. LCMS (M+H)+: 456.0/458.0.
Reaction SMILES: [C:1]([OH:10])(=O)[CH:2]([CH:4]([C:6](O)=[O:7])[OH:5])[OH:3].[CH3:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH2:29]>C1(C)C=CC=CC=1>[CH2:28]([N:29]1[C:6](=[O:7])[CH:4]([OH:5])[CH:2]([OH:3])[C:1]1=[O:10])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]/[CH:20]=[CH:19]\[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Solvent: Cc1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCCN1C(=O)C(O)C(O)C1=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Tartaric acid (150 parts) is added to 173 parts of toluene and the mixture is heated with stirring to 100° C. Armeen O (281 parts) is added slowly and in small portions while the system is kept under nitrogen purge. After the addition of the Armeen O is completed the contents are heated to 130° C. at which temperature the water formed is removed by azeotroping, and collected. The temperature is then raised to 160° C., after no more water is collected and kept at about 160° C. for one hour under nitrogen purge to remove the toluene. The liquid residue is then filtered through diatomaceous earth to yield the desired N-oleyltartarimide. Analysis shows nitrogen content of 3.42% and hydroxyl content of 8.33%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][C:13]2=[O:20])([O-:9])=[O:8].[CH2:21]([O:23][C:24](=[O:27])[CH2:25]Br)[CH3:22]>CC(C)=O>[CH2:21]([O:23][C:24](=[O:27])[CH2:25][N:14]1[C:13](=[O:20])[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=2)[C:15]1=[O:19])[CH3:22]
Reactant: O=C1NC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 611.2 %

Procedure:
Potassium carbonate (57.8 g) was added to a solution mixture of 5-nitro-isoindole-1,3-dione (26.2 g) and bromo-acetic acid ethyl ester (25.1 g) in acetone (500 ml). The resulting mixture was refluxed overnight (18 h). After cooling, reaction mixture was filtered and rinsed with ethyl acetate. Filtrate was concentrated and the residue was triturated with ether (200 ml). Solid was collected and rinsed with ether. Dried in vacuo to give the title compound 231.9 g. 1H NMR (200 MHz, CDCl3) δ 8.69 (m, 2H), 8.07 (d, J=8.2 Hz, 1H), 4.48 (s, 2H), 4.24 (q, J=7.0 Hz, 2H), 1.30 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:9])[C:6](Cl)=[O:7])(=[O:3])[CH3:2].[Cl:10][C:11]1[CH:12]=[C:13]2[C:19]3([CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:18][N:17]([C:24]([NH:26][C:27]3[S:28][C:29]([Cl:32])=[CH:30][N:31]=3)=[O:25])[C:14]2=[CH:15][CH:16]=1>>[C:1]([O:4][C@H:5]([CH3:9])[C:6]([N:21]1[CH2:22][CH2:23][C:19]2([C:13]3[C:14](=[CH:15][CH:16]=[C:11]([Cl:10])[CH:12]=3)[N:17]([C:24](=[O:25])[NH:26][C:27]3[S:28][C:29]([Cl:32])=[CH:30][N:31]=3)[CH2:18]2)[CH2:20]1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)C(=O)Cl
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Cl)ccc21
Product: CC(=O)O[C@H](C)C(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Step 1 of Example 17, with the exceptions that (R)-2-acetoxypropionic acid chloride was used instead of acetoxyacetic acid chloride, and that 5-chloro-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide was used instead of 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide.
Reaction SMILES: C(OC([N:8]1[CH2:17][C@:16]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)([CH3:18])[N:15]([CH2:27][C:28]([OH:30])=[O:29])[C:14](=[O:31])[C:9]21[CH2:13][CH2:12][CH2:11][CH2:10]2)=O)(C)(C)C.OS(O)(=O)=O.[CH3:37]O>>[F:25][C:23]1[CH:24]=[C:19]([C@@:16]2([CH3:18])[N:15]([CH2:27][C:28]([O:30][CH3:37])=[O:29])[C:14](=[O:31])[C:9]3([CH2:10][CH2:11][CH2:12][CH2:13]3)[NH:8][CH2:17]2)[CH:20]=[C:21]([F:26])[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@](C)(c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)C12CCCC2
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CN1C(=O)C2(CCCC2)NC[C@@]1(C)c1cc(F)cc(F)c1

Procedure:
A mixture of [(8R)-6-(tert-butoxycarbonyl)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]acetic acid (4.41 g, 10.1 mmol, described in Intermediate 21) and conc. H2SO4 (3.0 mL) in MeOH (100 mL) was heated at reflux for 24 h. The reaction mixture was concentrated in vacuo to a volume of about 30 mL, poured into saturated aqueous NaHCO3 (150 mL), and extracted with EtOAc (2×200 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound. MS: m/z=353 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][C:13](=O)[CH3:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][NH:17]C=O.CN.Cl>O.C(O)=O>[ClH:1].[CH3:16][NH:17][CH:13]([CH3:14])[CH2:12][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(=O)CC1(c2ccc(Cl)cc2)CCC1
Reactant: CNC=O
Agent: CN
Agent: Cl
Solvent: O=CO
Solvent: O
Product: CNC(C)CC1(c2ccc(Cl)cc2)CCC1

Procedure:
The ketone prepared as described above (5.4 g) was mixed with N-methylformamide (18 ml), 98% formic acid (4 ml) and 25% aqueous methylamine (0.6 ml) and the mixture heated under reflux for sixteen hours. The mixture was poured into water and extracted with dichloromethane. The extract was washed, dried and evaporated to give a residue which was heated under reflux with concentrated hydrochloric acid (10 ml) for six hours. The mixture was evaporated to dryness and the residue dried by repeated addition and vacuum evaporation of an industrial methylated spirit/toluene mixture. The solid residue was recrystallised from propan-2-ol to give N-methyl-2-[1-(4-chlorophenyl)-cyclobutyl]-1-methylethylamine hydrochloride (m.p. 193°-194° C.) (Formula I R1, R2 =H; R3 =Me; R4 =H; R5 =4-Cl; R6 =H; R7 =Me; R8 =H).
Reaction SMILES: Cl.Cl.[C@H]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([Cl:43])=[CH:40][CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][C@@H:55]([N:57]2[CH2:62][CH2:61][CH:60]([OH:63])[CH2:59][CH2:58]2)C)CC1>>[OH:63][CH:60]1[CH2:61][CH2:62][N:57]([C@@H:55]([CH3:54])[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([Cl:43])=[CH:40][CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[CH2:58][CH2:59]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cccc(Cl)c34)cccc2[nH]1
Agent: Cl
Product: C[C@@H](CN1CCC(NC(=O)c2cc3c(OCc4coc5cccc(Cl)c45)cccc3[nH]2)CC1)N1CCC(O)CC1

Procedure:
This compound is synthesized from 4-(4-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (118, see example 76) and amine 50 analogously to the method described in example 1.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].C(OC1C=CC=CC=1C(=O)NC1SC=C(S(C)=O)N=1)(=O)C.[C:28]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38](=[O:47])[NH:39][C:40]1[S:41][C:42]([S:45][CH3:46])=[CH:43][N:44]=1)(=[O:30])[CH3:29]>>[C:28]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38](=[O:47])[NH:39][C:40]1[S:41][C:42]([S:45]([CH3:46])=[O:1])=[CH:43][N:44]=1)(=[O:30])[CH3:29]
Reactant: O=S([O-])OO
Reactant: CSc1cnc(NC(=O)c2ccccc2OC(C)=O)s1
Agent: CC(=O)Oc1ccccc1C(=O)Nc1nc(S(C)=O)cs1
Agent: [K+]
Product: CC(=O)Oc1ccccc1C(=O)Nc1ncc(S(C)=O)s1

Procedure:
Using the Oxone® procedure as described in section 1.5.1.7 for the synthesis of compound (1), 518 (1.1 g, 3.57 mmol), affords 11 as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:11](Cl)(=O)C>CO>[O:1]=[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][NH:3]1
Reactant: O=C(O)c1ccnc(O)c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1cc[nH]c(=O)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 2-hydroxypyridine-4-carboxylic acid (5.0 g) in MeOH (50 ml) was added acetyl chloride (26 ml) dropwise at 0° C. over 15 min. The reaction mixture was slowly warmed to room temperature, and stirred for 20 h. The reaction mixture was concentrated in vacuo, and diluted with EtOAc and water. The organic layer was washed with saturated NaHCO3 solution, concentrated in vacuo, and purified by column chromatography (MeOH/DCM) to afford the title compound (3.5 g) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([CH:20]3[O:25][CH2:24][CH2:23][NH:22][CH2:21]3)=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH:33]=O)=[CH:28][CH:27]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([CH:20]3[O:25][CH2:24][CH2:23][N:22]([CH2:33][CH2:32][C:29]4[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=4)[CH2:21]3)=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C(=O)C2CNCCO2)CC1
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C(=O)C2CN(CCc3ccccc3)CCO2)CC1

Procedure:
To a stirred solution of N-(3,4-dichlorophenyl)-4-(morpholin-2-ylcarbonyl)piperazine-1-carboxamide (350 mg) in dichloromethane (10 ml) under an argon atmosphere was added phenacetaldehyde (0.16 mL) then NaBH(OAc)3 (383 mg) and the reaction was stirred for 3.5 h. The solvent was then removed under reduced pressure and dissolved in dichloromethane (40 ml) and 1M NaOH (20 ml). The organic layer was separated, dried (MgSO4) and evaporated. Purification by column chromatography 3-7% MeOH:DCM afforded the title compound (170 mg) as a white foam.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[O:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]2[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=2[CH:30]=[O:31])[CH2:23]1.CC(=CC)C.Cl>C(O)(C)(C)C>[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[O:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]2[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=2[C:30]([OH:6])=[O:31])[CH2:23]1
Reactant: O=P([O-])(O)O
Reactant: O=Cc1ccccc1N1CCCC(COc2nc3ccccc3s2)C1
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Product: O=C(O)c1ccccc1N1CCCC(COc2nc3ccccc3s2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.9 %

Procedure:
An aqueous solution (1 mL) of sodium chlorite (7.46 mg, 0.0660 mmol) and sodium dihydrogen phosphate (6.89 mg, 0.0574 mmol) was added to a solution of 2-[3-[(benzothiazol-2-yl)oxymethyl]piperidin-1-yl]benzaldehyde (10.1 mg, 0.0287 mmol) and 2-methyl-2-butene (0.00912 mL, 0.0861 mmol) in tert-butanol (3 mL). The mixture was stirred at room temperature for 5 hours. Subsequently, 2 mol/L hydrochloric acid was added to make the mixture acidic. The mixture was then extracted with ethyl acetate and washed with brine. The washed product was dried over magnesium sulfate and the solvent was evaporated. The resulting residue was air-dried to give 7.50 mg (71%) of the desired compound as a colorless powder.