Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]1[CH:5]=C(C=C[C:11]=1C)C=O)C.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:5]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=[O:18])[CH:4]=[CH2:11]
Reactant: COc1ccc(C=O)cc1O
Reactant: CCOc1cc(C=O)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(C=O)ccc1OC

Procedure:
The title compound was prepared analogously to 3-ethoxy-4-methyl-benzaldehyde (intermediate E10) by reaction of 3-hydroxy-4-methoxy-benzaldehyde with alkylbromide in DMF using K2CO3 as base (see also A. W. White, R. Almassy, A. H. Calvert, N. J. Curtin, R. J. Griffin, Z. Hostomsky, K. Maegley, D. R. Newell, S. Srinivasan and B. T. Golding J. Med. Chem. 2000, 43, 4084-4097).
Reaction SMILES: [Br-].[Mg+2].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br-].[CH2:11]([N:18]1[CH2:25][C@H:24]2[C:26](=[O:27])[C@H:20]([CH2:21][O:22][CH2:23]2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.[OH-].[Na+]>C(OCC)(=O)C>[CH2:11]([N:18]1[CH2:19][CH:20]2[C:26]([C:7]3[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=3)([OH:27])[CH:24]([CH2:23][O:22][CH2:21]2)[CH2:25]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Fc1ccccc1
Reactant: O=C1[C@@H]2COC[C@H]1CN(Cc1ccccc1)C2
Agent: [Br-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: OC1(c2ccc(F)cc2)C2COCC1CN(Cc1ccccc1)C2
Yield: 23.8 %

Procedure:
To 4-fluorobenzene magnesium bromide (2M diethyl ether solution) (5.0 mL, 10.0 mmol), (1R,5S)-7-benzyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-one (462 mg, 2.00 mmol) was added dropwise at 0° C. and the resultant mixture was stirred at room temperature for 1 minute. After completion of the reaction, water and 1 M sodium hydroxide aqueous solution were added to the reaction solution and extraction from the resultant reaction mixture with ethyl acetate was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel (amino-based) column chromatography (hexane/ethyl acetate=5/1) to obtain the title compound (156 mg, yield 24%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[C:12]([CH3:13])=[CH:11][S:10][C:9]=1[C:14](OC)=[O:15].Cl>C1COCC1>[Cl:7][C:8]1[C:12]([CH3:13])=[CH:11][S:10][C:9]=1[CH2:14][OH:15]
Reactant: COC(=O)c1scc(C)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1csc(CO)c1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92.4 %

Procedure:
Lithium aluminum hydride (1.35 g) was added to a THF (50 ml) solution of methyl 3-chloro-4-methylthiophene-2-carboxylate (3.40 g) at 0° C., followed by stirring at 0° C. for 20 minutes. An 1M aqueous hydrochloric acid solution was added to the reaction solution and the whole was stirred at room temperature for 1 hour. The solution was filtered and, after ethyl acetate was added, the organic layer was separated. Furthermore, the organic layer washed with brine and, after drying over anhydrous sodium sulfate and filtration, the solvent was removed by evaporation under reduced pressure. The resulting crude product was purified by column chromatography (hexane:ethyl acetate=4:1) to obtain 2.68 g of (3-chloro-4-methyl-2-thienyl)methanol (pale yellow oil).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].Cl[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:9]=1[O:16][CH3:17]>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:9]=1[O:16][CH3:17]
Reactant: COc1c(F)cc(F)cc1CCl
Reactant: OCCCCl
Product: COc1c(F)cc(F)cc1COCCCCl

Procedure:
In an analogous manner to that described in (8) 1-chloromethyl-3,5-difluoro-2-methoxy-benzene was reacted with 1-chloro-3-propanol to yield 1-(3-chloro-propoxymethyl)-3,5-difluoro-2-methoxy-benzene as a colorless liquid; MS: 250 (M)+.
Reaction SMILES: C1(C)C=CC(S([Cl:10])(=O)=O)=CC=1.[N:12]1([CH:18](O)[CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[Cl:10][CH2:19][CH2:18][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(O)N1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: ClCCN1CCCCC1
Reaction time: 12 h

Procedure:
Into a 50 mL round bottom flask is placed 6.40 g (33.6 mmol) of p-toluenesulfonyl chloride and 25 mL of methylene chloride. The resulting solution is cooled with an ice bath as 4.00 g (31.0 mmol) of 1-piperidinoethanol in 6 mL of methylene chloride is added dropwise. After the addition is complete, the ice bath is removed and the resulting slurry is stirred for about 12 hours. The reaction mixture is concentrated on a rotary evaporator to yield a solid residue which may then be used as in Preparation 4 below.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.[H-].[Na+].F[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.[Cl-].[NH4+]>CN(C)C=O>[F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][N:6]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH:7]=1
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: N#Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2cc(C(F)(F)F)cn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a 0° C. solution of 4-(trifluoromethyl)-1H-pyrazole (1 g, 7 mmol) in N,N-dimethylformamide (10 mL) was added 60 wt % sodium hydride (132 mg, 3.31 mmol). The mixture was stirred at 0° C. for 30 minutes. 4-fluorobenzonitrile (979 mg, 8.08 mmol) was added and the reaction was heated to 80° C. overnight. Saturated ammonium chloride was added and the mixture extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave 4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (1.2 g, 72%). 1H NMR (400 MHz, CD3OD, δ): 8.84 (s, 1H), 7.96 (s, 1H), 7.95 (d, 2H), 7.78 (d, 2H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:67][CH:68]1[CH2:73][CH2:72][O:71][CH2:70][CH2:69]1>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:67][CH:68]5[CH2:73][CH2:72][O:71][CH2:70][CH2:69]5)=[O:28])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCOCC1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(C(=O)NC2CCOCC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
To a mixture of 0.05 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-benzoic acid (I-169), 0.06 g (0.16 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.06 mL (0.32 mmole) of diisopropylethylamine. After stirring at room temperature for 30 minutes 0.03 g (0.32 mmole) of 4-aminotetrahydropyran was added. The mixture was stirred at room temperature for 18 hours, then diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with 1M sodium hydroxide solution then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate to give 0.035 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(tetrahydropyran-4-yl)-benzamide (I-173).
Reaction SMILES: C([NH:4][CH:5]1[CH2:8][N:7]([C:9]2[C:10]([F:33])=[CH:11][C:12]3[C:13]([CH:32]=2)=[N:14][C:15]2[N:16]([N:28](C=O)[CH3:29])[CH:17]=[C:18]([C:23]([O:25]CC)=[O:24])[C:19](=[O:22])[C:20]=2[CH:21]=3)[CH2:6]1)(=O)C.[OH-].[K+]>>[NH2:4][CH:5]1[CH2:8][N:7]([C:9]2[C:10]([F:33])=[CH:11][C:12]3[C:13]([CH:32]=2)=[N:14][C:15]2[N:16]([NH:28][CH3:29])[CH:17]=[C:18]([C:23]([OH:25])=[O:24])[C:19](=[O:22])[C:20]=2[CH:21]=3)[CH2:6]1
Reactant: CCOC(=O)c1cn(N(C)C=O)c2nc3cc(N4CC(NC(C)=O)C4)c(F)cc3cc2c1=O
Agent: [K+]
Agent: [OH-]
Product: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CC(N)C4)cc3nc21
Temperature: 100 °C
Reaction time: 24 h
Yield: 74.3 %

Procedure:
A suspension of 1.8 g of 8-(3-acetylamino-1-azetidinyl)-3-ethoxycarbonyl-7-fluoro-1-(N-formyl-N-methylamino)-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine in 40 cm3 of N aqueous potassium hydroxide is heated with stirring to a temperature in the region of 100° C. for 24 hours. After cooling to approximately 70° C., some slight insoluble matter is removed by filtration. At the same temperature, 40 cm3 of N methanesulphonic acid are added to the filtrate, and the precipitate formed is drained and washed with 3 times 20 cm3 of water at approximately 70° C. After recrystallization in 100 cm3 of dimethylformamide, 1.05 g of 8-(3-amino-1-azetidinyl)-7-fluoro-1-methylamino-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 315°-318° C.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[N:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[N:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=1)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Cc1ccnc(N)n1
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2nccc(C)n2)c1=O
Temperature: 50 °C
Reaction time: 120 h
Yield: 11.3 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 2-amino-4-methylpyrimidine (46 mg, 0.417 mmol) was added. The resulting mixture was stirred at 50° C. during five days. The solvent was evaporated and the residue purified by column chromatography (silica gel, hexane/ethyl acetate 2:1) to yield the title compound (11 mg, 11.3% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:23]1[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Cl:29][C:26]1[CH:25]=[N:24][C:23]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([CH:10]3[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]3)=[CH:15][C:16]=2[F:21])=[N:28][CH:27]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)c(F)c2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Nc3ncc(Cl)cn3)c(F)c2)C1
Temperature: 120 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
(RS)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (60 mg), 2,5-dichloropyrimidine (30.2 mg, CAS 22536-67-0) and cesium carbonate (99 mg) were combined with dioxane (2 ml) to give a yellow suspension. The mixture was degassed by bubbling argon into the mixture for several minutes. Xantphos (7.03 mg) and tris(dibenzylideneacetone)dipalladium chloroform complex (6.29 mg) were then added. The reaction mixture was then capped and stirred at 120° C. for 2 hours. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 80% EtOAc in hexanes) to afford tert-butyl (RS)-2-(4-(5-chloropyrimidin-2-ylamino)-3-fluorophenyl)morpholine-4-carboxylate (26 mg, 31%) as a colourless amorphous solid. MS (ISP): 411.3 ([{37Cl}M+H]+), 409.2 ([{35Cl}M+H]+), 355.3 ([{37Cl}M+H—C4H8]+), 353.3 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: CS(O[C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:15]2[CH:20]=[CH:19][C:18](OS(C)(=O)=O)=[CH:17][CH:16]=2)([CH3:14])[CH3:13])=[CH:8][CH:7]=1)(=O)=O.C(N(CC)CC)C>C(OCC)(=O)C.[Pd]>[C:9]1([C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:14])[CH3:13])[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(c1ccc(OS(C)(=O)=O)cc1)c1ccc(OS(C)(=O)=O)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(c1ccccc1)c1ccccc1
Yield: 84 %

Procedure:
0.5 mol of Compound A were stirred at 40° C. and under 20 bar of H2 in 3,000 ml of ethyl acetate with the addition of 27 g of palladium/carbon (5% Pd) and 1 mol of triethylamine; during the course of the reaction a further 15 g of Pd/C were added in total. After distillation, 84% of Compound B was obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])#[N:8].[Cl-].[OH:19][NH3+:20]>CO>[OH:19][NH:20][C:7]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])=[NH:8]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: [NH3+]O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: N=C(NO)c1cccc(C(=O)O)c1

Procedure:
1382 g (10.0 mol) of potassium carbonate are added in portions with stirring to a suspension, held at 30° C., of 500 g (3.40 mol) of 3-cyanobenzoic acid in 8 l of methanol. 695 g (10.0 mol) of hydroxylammonium chloride are subsequently added in small portions at an internal temperature of 40-45° C. The reaction mixture is then heated at the boil for 15 hours. The reaction mixture is evaporated in vacuo, and the residue is dissolved in water and acidified using 37% aqueous hydrochloric acid. The resultant precipitate is filtered off with suction, washed with water and dried in vacuo: 3-(N-hydroxycarbamimidoyl)benzoic acid as colourless crystals;
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[CH:2]=[CH2:3].O.O.Cl[Sn]Cl.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:16]=1[NH2:17])[C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1ccc([N+](=O)[O-])c(OCC=C)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCOC(=O)c1ccc(N)c(OCC=C)c1
Yield: 92.5 %

Procedure:
The crude ester (10 g, 38 mM) was dissolved in ethanol (20 ml) and added to a stirred suspension of SnCl2.2H2O (42.9 g, 0.19M) in ethanol (60 ml) under argon at ambient temperature. The mixture was heated to reflux for 30 minutes, cooled and poured onto ice. After making basic to pH 8 with an aqueous solution of sodium bicarbonate, the mixture was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO4 and evaporated to give allyl 3-allyloxy-4-aminobenzoate (8.2 g).
Reaction SMILES: [F:1][H-]F.[K+].CCCC[N+](CCCC)(CCCC)CCCC.F.F.[F-].[CH2:25]([O:32][CH2:33][C:34]12[O:40][CH:39]1[CH2:38][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36][CH2:35]2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)(Cl)Cl>[CH2:25]([O:32][CH2:33][C:34]1([OH:40])[CH2:35][CH2:36][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:38][CH:39]1[F:1])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: F[H-]F
Reactant: CC(C)(C)OC(=O)N1CCC2(COCc3ccccc3)OC2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: F
Agent: [F-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(O)(COCc2ccccc2)C(F)C1
Temperature: 120 °C
Reaction time: 48 h
Yield: 66.3 %

Procedure:
Potassium bifluoride (1.22 g) and tetrabutylammonium dihydrogentrifluoride (472 mg) were added to tert-butyl 6-[(benzyloxy) methyl]-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (2.50 g), followed by heating and stirring at 120° C. for 2 days. The reaction was diluted with chloroform and filtered through Celite. The residue obtained by concentration of the solvent under reduced pressure was purified by silica gel column chromatography (EtOAc/hexane) to obtain tert-butyl 4-[(benzyloxy)methyl]-3-fluoro-4-hydroxypiperidine-1-carboxylate (1.76 g).
Reaction SMILES: [CH:1]([C:3]1([CH3:16])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)=O.[C:17](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[C:1]([C:3]1([CH3:16])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[CH:17]
Reactant: CC1(C=O)CCCN(C(=O)OC(C)(C)C)C1
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#CC1(C)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
To a stirred solution of tert-butyl 3-formyl-3-methylpiperidine-1-carboxylate (2.10 g, 9.25 mmol) in methanol (40 mL) was added potassium carbonate (2.76 g, 20.00 mmol). The mixture was treated with dimethyl 1-diazo-2-oxopropylphosphonate (2.11 g, 11.00 mmol), and the resulting mixture was allowed to stir at room temperature. After 2 h, the mixture was concentrated, diluted with water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (6% ethyl acetate/petroleum ether elute) to afford 1.50 g (73%) of tert-butyl 3-ethynyl-3-methylpiperidine-1-carboxylate as a pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([OH:15])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].CS(O[CH:21]([CH2:25][O:26][CH3:27])[CH2:22][O:23][CH3:24])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].S([O-])(=O)(=O)C>CN(C=O)C.C(Cl)Cl.O>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:15][CH:21]([CH2:25][O:26][CH3:27])[CH2:22][O:23][CH3:24])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC(COC)OS(C)(=O)=O
Reactant: COC(=O)c1cc(O)cc(C(C)(C)C)c1
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCC(COC)Oc1cc(C(=O)OC)cc(C(C)(C)C)c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 60.3 %

Procedure:
Methyl 3-tert-butyl-5-hydroxybenzoate (O6.043; 2.28 g) and 2-methoxy-l-methoxymethyl-ethyl methanesulfonate (2.93 g) were dissolved in DMF (50 ml), and cesium carbonate (4.82 g) was added. After stirring at 50° C. for 6 h, the mixture was left to stand overnight. After stirring at 50° C. for 4 further hours, one further eq. of cesium carbonate and one further eq. of the mesylate were added, and the mixture was stirred at 50° C. for a further 4 h and left to stand overnight. Then the mixture was stirred at 50° C. for a further 8 h and left to stand for 6 days, and then a further 0.5 eq. of cesium carbonate and mesylate was added. After stirring at 50° C. for a further 8 h, the mixture was left to stand for 5 days, then the DMF was drawn off and the residue was taken up with DCM/water. The DCM phase was removed and concentrated. The residue was purified using silica gel (120 g cartridge, n-heptane/MTB ether gradient 0-50% within 60 min). 2.05 g of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:12][C:11](=[O:13])[NH:10][N:9]=2)[N:5]=[C:4]([O:14][C@H:15]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]2)[CH:3]=1.C(O)(C(F)(F)F)=O>>[CH3:1][C:2]1[CH:3]=[C:4]([O:14][C@H:15]2[CH2:19][CH2:18][NH:17][CH2:16]2)[N:5]=[C:6]([C:8]2[NH:12][C:11](=[O:13])[NH:10][N:9]=2)[CH:7]=1
Reactant: Cc1cc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)nc(-c2n[nH]c(=O)[nH]2)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(O[C@H]2CCNC2)nc(-c2n[nH]c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.4 %

Procedure:
A mixture of (S)-tert-butyl 3-((4-methyl-6-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-2-yl)oxy)pyrrolidine-1-carboxylate (700 mg, 1.937 mmol) and TFA (3 mL, 38.9 mmol) was stirred at RT for 1 hour. The solvent was removed in vacuo and the crude product purified by preparative HPLC eluting with a gradient 5-40% ACN in water (acid mode). The product-containing fractions were collected and evaporated in vacuo to give the title compound (12 mg, 2%).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:35])[C@@H:16]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:25]([O:33][CH3:34])[CH:24]=2)[CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:10]1)(C)(C)C.O1CCCC1.O>Cl.C(O)(=O)C>[CH:18]1([CH2:17][C@H:16]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:25]([O:33][CH3:34])[CH:24]=2)[C:15]([NH:14][C:11]2[CH:12]=[CH:13][N:9]([CH2:8][CH2:7][OH:6])[N:10]=2)=[O:35])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COc1cc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)n2)ccc1S(C)(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1cc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCO)n2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
In a round bottom flask was placed (R)—N-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2-(4-methanesulfonyl-3-methoxy-phenyl)-propionamide (14 mg, 0.03 mmol), tetrahydrofuran (2 mL), water (0.5 mL) and acetic acid (2 mL). It was stirred at 25° C. for 2 h and after this time concentrated hydrochloric acid (2 drops) was added and the reaction was complete in 20 min. The reaction was worked up and then purified on a Biotage Flash chromatography system (12M column, silica gel, 10% methanol/ethyl acetate) to afford (R)-3-cyclopentyl-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-2-(4-methanesulfonyl-3-methoxy-phenyl)-propionamide (4 mg, 31%): [α]30589=−40.0° (c=0.10, methanol); ES-HRMS m/e calcd for C21H29N3O5S (M+H)+ 436.1901, observed 436.1902; 1H NMR (300 MHz, DMSO-d6) δ 1.13 (m, 2H, CH2), 1.36-1.83 (m, 8H, 4×CH2), 2.13 (m, 1H, CH), 3.20 (s, 3H, SO2CH3), 3.66 (m, 2 H, OCH2), 3.86 (m, 1H, ArCHCO), 3.95 (s, 3H, OCH3), 3.99 (t, J=5.7 Hz, 2 H, NCH2), 4.83 (t, J=5.3 Hz, 1H, OH), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.14 (dd, Jm=1.2 Hz, Jo=8.2 Hz, 1H, Ar), 7.27 (d, Jm=1.2 Hz, 1H, Ar), 7.53 (d, J=2.2 Hz, 1H, Ar), 7.73 (d, Jo=8.2 Hz, 1H, Ar), 10.72 (s, 1H, NH).
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3](O)=[O:4].CN(C=O)C.C(Cl)(=O)C([Cl:27])=O>C(Cl)Cl>[C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([Cl:27])=[O:4])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of CBZ-L-Pro-OH (0.62 g, 2.49 mmol) and a drop of DMF in methylene chloride (10 ml) under argon was added oxalyl chloride (0.26 ml; 2.99 mmol) which resulted in a vigorous evolution of gas. After the evolution of gas ceased, the reaction was stirred for an additional 30 minutes. The reaction was then concentrated to give, as a light yellow oil, N-carbobenzoxy-L-prolyl chloride (CBZ-L-Pro-Cl).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13](O)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:25]>O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13](=[O:14])[NH2:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1(COCc1ccccc1)C(=O)O
Reactant: N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1(COCc1ccccc1)C(N)=O

Procedure:
This material was prepared in analogy to example 1 and 2, step A, using 2-benzyloxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.426 g, see example 12, step A) and ammonia solution (320 μL of a 25% solution in water) to give the desired (rac)-2-benzyloxymethyl-2-carbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g, MS (ES+): 335.3 (MH+)) as a yellow oil.