Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][S:11][C:5]=2[N:4]([CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:3]1=[O:16].[CH3:17][N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[CH:27]=[O:28]>>[CH:13]1([CH2:12][N:4]2[C:5]3[S:11][C:10]([CH:27]([OH:28])[C:19]4[N:18]([CH3:17])[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[N:20]=4)=[CH:9][C:6]=3[C:7](=[O:8])[N:2]([CH3:1])[C:3]2=[O:16])[CH2:14][CH2:15]1
Reactant: Cn1c(=O)c2ccsc2n(CC2CC2)c1=O
Reactant: Cn1c(C=O)nc2ccccc21
Product: Cn1c(=O)c2cc(C(O)c3nc4ccccc4n3C)sc2n(CC2CC2)c1=O

Procedure:
The title compound was prepared from 3-Methyl-1-(cyclopropylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (Example 32 step a) and 1-methylbenzimidazole-2-carboxaldehyde following the method of Example 1 step d.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[N:10]1[C:4]2[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([C:25]3[CH:26]=[C:27]([CH:31]=[CH:32][C:24]=3[CH3:23])[C:28]([OH:30])=[O:29])[C:3]=2[CH:13]=[CH:12][C:11]1=[O:14]
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CSc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CSc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
The solution of 4-chloro-8-(2,6-difluorophenyl)-2-(methylthio) pyrido[2,3-d]pyrimidin-7(8H)-one (1.70 g, 5.00 mmol) in DME (150 mL) and H2O (50 mL), in a pressure flask (500 mL, Chemglass), was added 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa borolan-2-yl)benzoic acid (1.97 g, 7.50 mmol) and K2CO3 (4.15 g, 30.0 mmol). The resulting mixture was degassed with Argon for 5 minutes, mixed with Pd(PPh3)4 (0.232 g, 0.20 mmol) and heated with a preheated oil bath (160° C.) under vigorous stirring for 30 minutes. The reaction mixture was filtered through celite, concentrated under vaccum to remove DME. It was then mixed with EtOAc (200 mL) and AcOH (2.5 mL), and shaked. The layers were separated. The organic layer was collected, further washed with brine (70 mL), dried over Na2SO4, filtered, concentrated and purified via a flash chromatography (load column with DCM, mobile phase EtOAc/Hexane) to afford the title compound as a white solid 2.15 g (98%). LC-MS (ES) m/z 440 (M+H)+; 1H-NMR (MeOD) δ 2.27 (s, 3 H), 2.31 (s, 3 H), 6.71 (d, J=9.6 Hz, 1 H), 7.28 (t, J=8.2 Hz, 2 H), 7.57 (d, J=8.4 Hz, 1 H), 7.64 (m, 2 H), 8.00 (d, J=1.6 Hz, 1 H), 8.14 (dd, J1=7.6 Hz, J2=1.6 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.S(=O)(=O)(O)O.C([O-])([O-])=O.[Na+].[Na+].[CH2:24](O)[CH3:25]>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][C:9]([O:11][CH2:24][CH3:25])=[O:10])[CH:7]=1
Reactant: CCO
Reactant: Nc1ccc(F)c(CC(=O)O)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Cc1cc(N)ccc1F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(5-amino-2-fluorophenyl)acetic acid (6.13 g, 36.2 mmol) in ethanol (15 mL) was added conc. sulfuric acid (2 mL) dropwise. The reaction mixture was stirred under N2 at 80° C. for 1 hr. After the reaction mixture was cooled to RT and neutralized with aqueous Na2CO3 to pH 7-8, the aqueous solution was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine, dried over Na2SO4 and evaporated under vacuum to afford ethyl 2-(5-amino-2-fluorophenyl)acetate as a yellow oil which was used for the next step without further purification (6.13 g, 95%).
Reaction SMILES: N([O-])=[O:2].[Na+].N[C:6]1[C:11]([CH3:12])=[CH:10][C:9]([Br:13])=[CH:8][N:7]=1>O.S(=O)(=O)(O)O>[Br:13][C:9]1[CH:10]=[C:11]([CH3:12])[C:6]([OH:2])=[N:7][CH:8]=1
Reactant: Cc1cc(Br)cnc1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)cnc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.7 %

Procedure:
Sodium nitrite (5.0 g, 72.5 mmol) in water (10 mL) was added dropwise to a cooled (0° C.) mixture of 2-amino-5-bromo-3-methylpyridine (5.0 g, 26.7 mmol; Lancaster) in 2.6 M sulfuric acid (70 mL). The mixture was allowed to warm to ambient temperature, stir for 1.5 hours, filtered, and the filtercake was washed with cold water and air dried. The precipitate was dissolved in dichloromethane (100 mL), dried (MgSO4), and concentrated to provide the title compound as a solid (4.2 g, 84%). MS (DCI/NH3) m/z 348 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CC(=O)c1cnc(OCC(F)(F)F)c(Cl)c1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1cnc(OCC(F)(F)F)c(Cl)c1
Yield: 57 %

Procedure:
The title compound is prepared in 57% yield (0.65 g, white solid) from 1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.8 g, 3.15 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: C(OC([N:8]1[CH2:25][CH2:24][C@@H:11]2[N:12]([CH3:23])[C:13]3[C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:16]=[CH:17][C:18]=3[C@H:10]2[CH:9]1Br)=O)(C)(C)C.[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:29]=1[NH2:30]>>[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:29]=1[NH:30][C:16]1[CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[C:13]2[N:12]([CH3:23])[C@H:11]3[CH2:24][CH2:25][NH:8][CH2:9][C@H:10]3[C:18]=2[CH:17]=1
Reactant: Nc1c(F)cccc1F
Reactant: CN1c2c(cccc2C(F)(F)F)[C@H]2C(Br)N(C(=O)OC(C)(C)C)CC[C@@H]21
Product: CN1c2c(cc(Nc3c(F)cccc3F)cc2C(F)(F)F)[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general coupling procedure as a yellow solid (12 mg, 31%) from (4aS,9bR)-bromo-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 45, 41 mg, 0.095 mmol) and 2,6-difluoroaniline (39 mg, 0.30 mmol). MS (APCI): 384 (base, M+H).
Reaction SMILES: [CH:1]([C:3]1[N:12]=[CH:11][C:10]([CH:13]=[CH2:14])=[CH:9][C:4]=1[C:5]([O:7]C)=O)=[CH2:2].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>CC(N(C)C)=O>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:22]2[CH2:2][CH2:1][C:3]3[N:12]=[CH:11][C:10]([CH:13]=[CH2:14])=[CH:9][C:4]=3[C:5]2=[O:7])=[CH:19][CH:18]=1
Reactant: COc1ccc(CN)cc1
Reactant: C=Cc1cnc(C=C)c(C(=O)OC)c1
Solvent: CC(=O)N(C)C
Product: C=Cc1cnc2c(c1)C(=O)N(Cc1ccc(OC)cc1)CC2
Temperature: 150 °C
Yield: 91.5 %

Procedure:
Methyl 2,5-divinylnicotinate (2.1 g, 11.1 mmol) was combined with p-methoxybenzylamine (2 mL, 15 mmol) and dimethylacetamide (7 mL) and heated for 20 min in a microwave reactor at 150° C. The reaction mixture was concentrated and purified over silica gel (0-100% EtOAc/hexanes) using automated chromatography. The product containing fractions were combined and evaporated under reduced pressure to give the compound (2.99 g, 92%). LC-MS (M+H)=295.1.
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:6][N:5]1[CH2:17][C:18]([NH:20][C:21]1[C:26]([Cl:27])=[CH:25][C:24]([N+:28]([O-])=O)=[CH:23][C:22]=1[Cl:31])=[O:19])=[O:3].S1C=CC=C1>CO.[Pt]>[NH2:1][C:2]([CH:4]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:7][CH2:6][N:5]1[CH2:17][C:18]([NH:20][C:21]1[C:26]([Cl:27])=[CH:25][C:24]([NH2:28])=[CH:23][C:22]=1[Cl:31])=[O:19])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)Nc2c(Cl)cc([N+](=O)[O-])cc2Cl)C(C(N)=O)C1
Agent: [Pt]
Solvent: CO
Solvent: c1ccsc1
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)Nc2c(Cl)cc(N)cc2Cl)C(C(N)=O)C1
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
A solution of 2-(aminocarbonyl)-N-(4-nitro-2,6-dichlorophenyl)-4-(tert-butoxycarbonyl)-1-piperazineacetamide (1.0 g, 2.1 mmol) in 30 mL of methanol containing methanolic 4% thiophene (0.25 mL) and 5% platinum on charcoal catalyst (450 mg) was hydrogenated using a Parr apparatus at 50° C. and 25 psi for 30 minutes. After cooling and removal of catalyst by filtration, the solvent was removed from the filtrate in vacuo to yield III as an amorphous solid (0.88 g, 94% yield).
Reaction SMILES: Cl.[NH2:2][OH:3].[Br:4][C:5]1[N:6]=[CH:7][C:8]([NH:11][C:12](=[O:33])[C@@H:13]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[C:24]([Cl:32])[CH:23]=2)[CH2:14][CH:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)=[N:9][CH:10]=1>CO.N1C(C)=CC=CC=1C>[Br:4][C:5]1[N:6]=[CH:7][C:8]([NH:11][C:12](=[O:33])[C@@H:13]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[C:24]([Cl:32])[CH:23]=2)[CH2:14][CH:15]2[CH2:20][CH2:19][C:18](=[N:2][OH:3])[CH2:17][CH2:16]2)=[N:9][CH:10]=1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Reactant: NO
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: CO
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=NO)CC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
A solution of hydroxylamine hydrochloride (7.0 mg, 0.099 mmol) in methanol (0.2 mL) and 2,6-lutidine (0.2 mL) was treated with N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionamide (prepared as in Example 60, 34 mg, 0.066 mmol). The reaction mixture was stirred at 25° C. for 30 min and was then concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water (1×5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 65/35 hexanes/ethyl acetate to 2/3 hexanes/ethyl acetate) afforded the N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-hydroxyimino-cyclohexyl)-propionamide (30 mg, 85.8%) was a white foam: [α]23589=−21.43° (c=0.35, chloroform); EI-HRMS m/e calcd for C20H22BrClN4O4S (M+H)+ 529.0307, found 529.0314.
Reaction SMILES: [C:1](=[N:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:25](OC)(C)(C)C>O1CCCC1>[C:1](=[N:14][N:15]([C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[CH3:25])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Reactant: COC(C)(C)C
Solvent: CI
Solvent: C1CCOC1
Product: CN(N=C(c1ccccc1)c1ccccc1)c1ccc(Cl)cc1
Reaction time: 4 h
Yield: 96 %

Procedure:
N-Benzhydrylidene-N′-(4-chlorophenyl)hydrazine (0.2 g, 0.65 mmol, 1 eq.) and 3.2 mL of tetrahydrofuran are placed in a predried 20 mL round-bottomed flask under argon. The solution is cooled to a temperature in the region of −10° C. and 0.5 M potassium hexamethylbis-silylamide solution (1.43 mL, 1.1 eq.) is then added. The solution darkens, and is left to react at this temperature for 30 minutes, followed by addition of a solution of methyl iodide in methyl tert-butyl ether (0.49 mL, 1.5 eq.). The mixture is then allowed to return to a temperature in the region of 25° C. and is left stirring for 4 hours. After treatment with sodium hydrogen carbonate, the mixture is extracted with ethyl acetate. The organic extracts are combined, dried over magnesium sulfate and then concentrated to dryness under vacuum. The residual oil is purified by chromatography on silica gel, eluting with an ethyl acetate/heptane mixture (10/90 by volume). N′-Benzhydrylidene-N-(4-chlorophenyl)-N-methylhydrazine is obtained in a yield of 96% in the form of a yellow solid, which product is used directly in the following step.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([NH:21][NH2:22])=[O:20])=[CH:17][CH:16]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:22][NH:21][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: COc1ccc(C(=O)NN)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: COc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 82 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-methoxybenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave,347 mg of the title compound (82%) as a yellow solid in 99.9% purity by HPLC (Rt: 5.44, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]([CH3:19])([C:16](=[O:18])[CH3:17])[CH2:14][OH:15].N1C=CC=CC=1.Cl>C(Cl)(Cl)Cl>[CH3:12][C:13]([CH3:19])([C:16](=[O:18])[CH3:17])[CH2:14][O:15][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)C(C)(C)CO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)C(C)(C)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71 %

Procedure:
47.6 g (0.25 mol) of 4-toluenesulphonyl chloride were dissolved in 100 ml of chloroform, 35 g (0.3 mol) of 2,2-dimethyl-1-hydroxy-butan-3-one were added, and 40 ml (0.5 mol) of pyridine were added dropwise at 0° to 5° C. The reaction mixture was subsequently stirred at room temperature for 15 hours and poured onto 200 g of ice and 70 ml of concentrated hydrochloric acid and the organic phase was separated off, washed three times with 200 ml of water each time, dried over sodium sulphate and concentrated. The residue was taken up in 100 ml of petroleum ether, whereupon the end product crystallized out. 48 g (71% of theory) of 2,2-dimethyl-1-tosyloxy-butan-3-one were obtained as colorless crystals of melting point 49°-52° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(N(CC)CC)C.[Br:22][CH2:23][C:24](Br)=[O:25]>ClCCl>[CH2:3]([N:2]([CH3:1])[C:24](=[O:25])[CH2:23][Br:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C(Br)CBr
Reactant: CCCCCCCCCCCCNC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCN(C)C(=O)CBr
Reaction time: 16 h

Procedure:
To a solution of N-methyl-N-dodecylamine (2.5 ml) and triethylamine (1.4 ml) in dichloromethane (10 ml) was added with stirring and ice cooling a solution of bromoacetyl bromide (0.87 ml) in dichloromethane (10 ml). The cooling bath was removed after 30 min and the reaction stood for 16 h at ambient temperature. The mixture was washed with water and saturated sodium hydrogen carbonate, dried (K2CO3) and the solution purified by flash chromatography (silica, methanol-dichloromethane). Appropriate fractions were combined and evaporated to a pale yellow oil, yield 1.53 g (48%). 1H-NMR (CDCl3) δ0.8 (3H,t), 1.2 (18H,m), 1.5 (2H,m,), 2.88 and 2.99 (3H,2xs), 3.27 (2H,m), 3.77 and 3.79 (2H,s)); MS (APCI+) found (M+1)=320, 322, C15H30BrNO requires 319,321.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[C:32]([O:36][C:37]([N:39]1[CH2:42][CH2:41][C@@H:40]1[CH2:43][OH:44])=[O:38])([CH3:35])([CH3:34])[CH3:33].[O:45]([CH2:52][C@H:53]1[CH2:55][C@@H:54]1[C:56]1[CH:57]=[C:58](O)[CH:59]=[N:60][CH:61]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C1(C)C=CC=CC=1>[C:32]([O:36][C:37]([N:39]1[CH2:42][CH2:41][C@H:40]1[CH2:43][O:44][C:58]1[CH:59]=[N:60][CH:61]=[C:56]([C@H:54]2[CH2:55][C@@H:53]2[CH2:52][O:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:57]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1CO
Reactant: Oc1cncc([C@H]2C[C@@H]2COc2ccccc2)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@H]2C[C@@H]2COc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.9 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (253 mg, 1.00 mmol, 1.6 equiv.) was dissolved in 2 mL of toluene (dried with molecular sieve 3 Å) in a 10 mL round-bottom flask with a side neck. The flask was equipped with rubber septa and a magnetic stirrer. The atmosphere was exchanged with Ar (3 times), and the flask was cooled with an ice bath. Tributylphosphine (248 μL, 1.00 mmol, 1.6 equiv.) was added dropwise. The mixture was warmed to room temperature and was stirred for 10 min. The colorless solution formed was then transferred dropwise (via syringe) with ice cooling into a solution of 1-(tert-butoxycarbonyl)-2(R)-azetidinylmethanol (188 mg, 1.00 mmol, 1.6 equiv.) and 5-[(1S,2S)-2-(phenoxymethyl)cyclopropyl]-3-pyridinol (151 mg, 626 μmol) in a 25 mL round-bottom flask equipped with a magnetic stirrer and an Ar balloon. The resulting mixture was warmed to room temperature and stirred overnight. The reaction was quenched by addition of saturated NaHCO3 solution (10 mL). The product was extracted into EtOAc (3×20 mL). The combined organic phases were dried over Na2SO4 and concentrated. The residue was purified by CC on SiO2 (25×2.5 cm, EtOAc/hexanes 2:1) to give the crude product, which was further purified by preparative HPLC in two portions (Supelco Discovery C18, 250×21.2 mm, 5 μm particle size, UV detection at 270 nm, flow rate 12.5 mL/min, gradient from 20% to 100% CH3CN in water within 40 min, then 100% CH3CN for 20 min; tR 29.1-31.1 min) to give the title compound as a yellowish oil (231 mg, 90%). MS (EI) m/z 410 (M+, 0.1%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][Sn:9]([CH3:17])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=1>>[CH3:8][Sn:9]([CH3:17])([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=1
Reactant: Brc1ccccn1
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: C[Sn](C)(C)c1ccccn1
Product: CCOC(=O)Cc1ccc(-c2ccccn2)cc1

Procedure:
The older known synthesis as described in EP 1244641 B1 on page 21 starts from 2-bromopyridine. In step 1 the 2-trimethylstannanylpyridine is prepared in a 45 to 50% yield (of the theory). The 2-trimethylstannanylpyridine is subsequently reacted with ethyl (4-bromophenyl)acetate in order to obtain the ethyl (4-pyridin-2-ylphenyl)acetate in a 75% yield. In the third step the ethyl (4-pyridin-2-ylphenyl)acetate is saponified to the (4-pyridin-2-ylphenyl)acetic acid with about 95% yield of theory. Consequently, the state of the art synthesis as shown below
Reaction SMILES: [C:1]1([CH:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:8][C:9](=[O:23])[CH2:10][N:11]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([OH:21])[C:15]=3[O:14][CH2:13][C:12]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][C:38]([O:40][CH3:41])=[O:39].O>CN(C=O)C>[C:24]1([CH:7]([NH:8][C:9]([CH2:10][N:11]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]=3[O:14][CH2:13][C:12]2=[O:22])=[O:23])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)CBr
Reactant: O=C(CN1C(=O)COc2c(O)cccc21)NC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1OCC(=O)N2CC(=O)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
N-diphenylmethyl-2-(8-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)acetamide (735 mg) was dissolved in DMF (30 ml), and the resultant solution was stirred at room temperature. Potassium carbonate (785 mg) and methyl bromoacetate (0.35 ml) were added to the solution, and the mixture was stirred at room temperature for 18 hours. Water (25 ml) was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The resultant organic layer was washed with saturated saline, dried over sodium sulfate, and concentrated. The resultant residue was recrystallized from ethyl acetate/n-hexane to obtain the object compound (492 mg, yield 56%)
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:29])[N:22]=[C:23]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[N:16]2[N:15]=1)[CH3:6].ClCCl.C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O>[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:9]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:29])[N:22]=[C:23]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[N:16]2[N:15]=1)[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCOc1ccccc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc([N+](=O)[O-])cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
Using an ice-acetone bath, 48.6 ml of trifluoroacetic acid (TFA and 12.1 ml of 70% strength nitric acid are cooled to −10° C., 3.0 g (8.86 mmol) of the compound from example 25A, dissolved in 7 ml of TFA are added dropwise, and the mixture is stirred at 0° C. for 20 hours. The reaction solution is stirred into 400 ml of ice-water and 200 ml of dichloromethane and neutralized using about 200 ml of saturated sodium bicarbonate solution. The aqueous phase is separated off and extracted 3 times with dichloromethane, and the combined organic phases are dried and concentrated. The residue is chromatographed on silica gel using toluene with added ethyl acetate in a gradient from 11 to 60%.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>C(OCC)(=O)C.C1CCCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[C:29]([C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(Br)nc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nc2)CC1
Yield: 65.3 %

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.3.). Starting with 1.28 g (3.43 mmol) of 2-(ethyloxy)-2-oxoethyl 4-(6-bromo-3-pyridyl)-1-piperazinecarboxylate, obtained in step 7.4., 1.96 g (10.29 mmol) of 3-(trifluoromethyl)phenylboronic acid, 2.91 g (13.72 mmol) of hydrated potassium phosphate and 0.40 g (0.34 mmol) of tetrakis(triphenylphosphine)palladium, and after chromatography on silica gel, eluting with a mixture 35/65 of ethyl acetate and cyclohexane, 0.98 g of pure product is obtained in the form of an oil that crystallizes at room temperature.