Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:8]([CH2:20][CH3:21])[C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:19])[O:16]2)=[CH:11][CH:10]=1)[CH3:7].CN(C)[CH:24]=[O:25]>>[CH2:20]([N:8]([CH2:6][CH3:7])[C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([CH:24]=[O:25])[C:15](=[O:19])[O:16]2)=[CH:11][CH:10]=1)[CH3:21]
Reactant: CN(C)C=O
Reactant: CCN(CC)c1ccc2ccc(=O)oc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CC)c1ccc2cc(C=O)c(=O)oc2c1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 86.5 %

Procedure:
20 g of dimethylformamide are added dropwise to 40 g of phosphorus oxychloride at 20° - 50° C. The mixture is stirred for 45 minutes at 50° C whilst excluding moisture. A suspension of 42 g of 7-diethylamino-coumarin in 50 g of dimethylformamide is then added, the mixture is warmed to 60° C for 2 hours and poured out onto 400 g of ice water, and the whole is stirred for 2 hours. The crystalline precipitate is filtered off, thoroughly washed with water and dried in vacuo at 70° C. 41 g of 7-diethylamino-coumarin-3-aldehyde are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH:10]2[N:4]([N:5]=[C:6]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[C:7]3[CH:15]=[C:14]4[O:16][CH2:17][O:18][C:13]4=[CH:12][C:8]=3[CH2:9]2)[C:3]1=[O:28].O.NN.C(O)C>CO.[Ni]>[NH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:6]2[C:7]3[CH:15]=[C:14]4[O:16][CH2:17][O:18][C:13]4=[CH:12][C:8]=3[CH2:9][CH:10]3[CH2:11][N:2]([CH3:1])[C:3](=[O:28])[N:4]3[N:5]=2)=[CH:24][CH:23]=1
Reactant: CN1CC2Cc3cc4c(cc3C(c3ccc([N+](=O)[O-])cc3)=NN2C1=O)OCO4
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CO
Product: CN1CC2Cc3cc4c(cc3C(c3ccc(N)cc3)=NN2C1=O)OCO4
Yield: 71.4 %

Procedure:
0.38 g (1.0 mmol) of the nitro compound of Example 3 is reduced in 20 ml of methanol with RaNi and hydrazine hydrate analogously to Example 2. After boiling with ethanol, 0.25 g (71%) of the title compound of ethanol with a melting point of 280-289° C. (decomposition) is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.Br[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18].Cl>[Cl-].[Cl-].[Zn+2].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.C1COCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18]
Reactant: Brc1ccccn1
Reactant: O=Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=Cc1cccc(-c2ccccn2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 38.2 %

Procedure:
To a THF solution (8 mL) of 2-bromopyridine (1.30 g, 8.23 mmol) at −78° C. was added 1.6 M n-BuLi in hexanes (5.3 mL, 8.48 mmol). The resulting dark red solution was stirred at −78° C. for 10 min, and a solution of 0.5 M ZnCl2 in THF (18 mL, 9.0 mmol) was added giving a light brown slurry. After warming to room temperature, 3-bromobenzaldehyde (0.816 mL, 7.0 mmol) and Pd(PPh3)4 (0.242 g, 0.21 mmol) were added, and the mixture was stirred for 18 h at room temperature under argon. The reaction mixture was poured into 1 N HCl (30 mL) and washed with diethyl ether. The aqueous layer was neutralized with NaHCO3 and extracted with diethyl ether. The solvent was removed in vacuo to give the crude product as an oil. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane gave 0.49 g (38%) of the desired 3-(2-pyridinyl)benzaldehyde product as a colorless oil. GCMS: m/z=183 [M+].
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][N:16]=1)[C:10]([O:12][CH3:13])=[O:11])(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[C:6]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][N:16]=1)[C:10]([O:12][CH3:13])=[O:11])#[CH:5]
Reactant: COC(=O)c1ccnc(C#C[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#Cc1cc(C(=O)OC)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-((trimethylsilyl)ethynyl)isonicotinate (I125) (8.00 g, 34.2 mmol) in THF (150 mL) was added TBAF (1.0 M in THF) (51.4 mL, 51.4 mmol) at 0° C. The resulting solution was allowed to warm to room temperature at which stirring was continued for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with 10% NaHCO3 (50 mL). The organic layer was dried (MgSO4) and evaporated under reduced pressure to give a dark brown/black residue. The residue was adsorbed onto silica gel and purified by chromatography (SiO2, 0-20% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I126) (4.5 g, 81%) as a yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.73 (dd, J=5.1, 0.9 Hz, 1H), 8.01 (dd, J=1.5, 0.9 Hz, 1H), 7.80 (dd, J=5.1, 1.6 Hz, 1H), 3.95 (s, 3H), 3.22 (s, 1H).
Reaction SMILES: C1([O:7][C:8](=O)[C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]([C:22](=[O:31])[C:23]4[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=4[F:30])=[C:19]([NH2:21])[N:20]=3)=[CH:11][C:10]=2[OH:32])C=CC=CC=1.[C:34]1([NH:40][CH2:41][CH2:42][NH2:43])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[NH2:21][C:19]1[N:20]=[C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:43][CH2:42][CH2:41][NH:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:7])=[C:10]([OH:32])[CH:11]=2)[S:17][C:18]=1[C:22](=[O:31])[C:23]1[C:24]([F:30])=[CH:25][CH:26]=[CH:27][C:28]=1[F:29]
Reactant: NCCNc1ccccc1
Reactant: Nc1nc(Nc2ccc(C(=O)Oc3ccccc3)c(O)c2)sc1C(=O)c1c(F)cccc1F
Solvent: CN(C)C=O
Product: Nc1nc(Nc2ccc(C(=O)NCCNc3ccccc3)c(O)c2)sc1C(=O)c1c(F)cccc1F

Procedure:
A solution of 4-[4-amino-5-(2,6-difluoro-benzoyl)-thiazol-2-ylamino]-2-hydroxy-benzoic acid phenyl ester (16) and N-phenyl-ethylene-diamine (5 eq) in DMF was heated at 70° C. for 1 hour. DMF was removed under reduced pressure and the solution of resultant residue in ethyl acetate was washed with saturated aqueous NaHCO3 solution, brine, dried with MgSO4, filtered and concentrated. The product was purified by HPLC.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.Br[CH:11]([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(=O)(O)[O-].[Na+]>CN(C=O)C>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:11]([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:5]=1
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: Oc1cccnc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1cccnc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62 %

Procedure:
To a suspension of 1.20 g of sodium hydride (60% oil dispersion; 30.0 mmol) in 10 mL of dry DMF at room temperature were added dropwise 2.85 g of 3-hydroxypyridine (30 mmol) in 10 mL of dry DMF, maintaining the temperature below 40° C., and the mixture was stirred at room temperature for 90 min. Under ice-cooling, 6.28 g of tert-butyl 2-bromopropionate (30 mmol) in 10 mL of dry DMF were slowly added dropwise, maintaining the inner temperature within 5 to 10° C., and then the mixture was warmed to room temperature with stirring for 4 hours. After neutralizing with saturated sodium bicarbonate aq., the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine, dried and evaporated. The residue was purified by column chromatography on silica gel (eluent: n-hexane:ethyl acetate=2:1) to give 4.15 g of tert-butyl 2-(pyridin-3-yl)oxypropionate (Yield: 62%) as a brown oil.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]([F:20])([F:19])[CH2:17][OH:18]>CCN(CC)CC>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:2]([O:18][CH2:17][C:16]([F:20])([F:19])[F:15])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: OCC(F)(F)F
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)O)c1
Temperature: 120 °C

Procedure:
A mixture of 2.13 mmol 2-chloro-5-methanesulfonyl-benzoic acid, 0.64 mmol Cu(I)Br in 5 ml NEt3 and 25 ml 2,2,2-trifluoro-ethanol was heated to 120° C. for 16 h in a sealed tube. The volatiles were removed under vacuum and the residue was taken up in 70 ml 1N HCl. Extraction with ethyl acetate drying of the combined organic fractions and evaporation yielded a residue which was purified by reversed phase preparative HPLC eluting with an acetonitrile/water gradient. Evaporation of the product fractions yielded the title compound. MS (m/e): 297.0 (M−H, 100%)
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].Cl.Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1.CCN(C(C)C)C(C)C>CC#N>[C:6]([O:5][C:3](=[O:4])[CH2:2][NH:1][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNc1ncccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 102.9 %

Procedure:
To a suspension of H-Gly-OtBu.HCl (1.57 g) in MeCN (35 mL) was added 2-chloro-3-nitropyridine (1.5 g) and DIPEA (4.01 mL). The resulting yellow solution was heated up to 80° C. for 14 h. The reaction mixture was evaporated to dryness. The residue was taken up in DCM, washed with water and brine and the aq. phases were extracted with DCM. The combined org. layers were dried (MgSO4), filtrated off and evaporated in vacuo to afford 2.44 g of yellow solid. LC-MS (C): tR=0.81 min; [M+H]+: 254.27
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[NH2:6][CH2:7][CH2:8][CH3:9]>CO>[CH2:7]([N:6]([CH2:3][CH2:2][C:1]([NH2:5])=[O:4])[CH2:3][CH2:2][C:1]([NH2:5])=[O:4])[CH2:8][CH3:9]
Reactant: CCCN
Reactant: C=CC(N)=O
Solvent: CO
Product: CCCN(CCC(N)=O)CCC(N)=O
Temperature: 80 °C
Yield: 97590.4 %

Procedure:
A mixture of 118.6 g (1.67 mol) of acrylamide and 49.3 g (0.83 mmol) of 1-aminopropane in 250 ml of methanol was heated at 80° C. for 1 hour. The solvent was evaporated and the solid crystallized from ethanol. There was obtained 162.3 g (0.81 mol, 97%) of 3,3'-(propylimino)bispropanamide as a white solid; mp 101°-101.5° C.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][S:21]([C:24]4[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=4[F:31])(=[O:23])=[O:22])[CH:15]=3)[C:11]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[C:8]2[S:9][CH:10]=1)=[O:5])C.[NH3:38]>CO>[F:31][C:25]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=1[S:21]([NH:20][C:16]1[CH:15]=[C:14]([C:12]2[C:11]([C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)=[C:8]3[S:9][CH:10]=[C:6]([C:4]([NH2:38])=[O:5])[N:7]3[N:13]=2)[CH:19]=[CH:18][CH:17]=1)(=[O:23])=[O:22]
Reactant: CCOC(=O)c1csc2c(-c3ccncc3)c(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3)nn12
Reactant: N
Solvent: CO
Product: NC(=O)c1csc2c(-c3ccncc3)c(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3)nn12
Reaction time: 18 h
Yield: 93 %

Procedure:
6-[3-(2,5-Difluoro-benzenesulfonylamino)-phenyl]-7-pyridin-4-yl-pyrazolo[5,1-b]thiazole-3-carboxylic acid ethyl ester (30 mg, 0.055 mmol) was suspended a 7 N ammonia solution in methanol (1 mL) at 0° C. and stirred at this temperature for 18 hours. The mixture was evaporated to dryness and taken up with DCM and evaporated to dryness three times. The beige solid was dried under vacuum at room temperature to give 26 mg (93%) of 6-[3-(2,5-difluoro-benzenesulfonylamino)-phenyl]-7-pyridin-4-yl-pyrazolo[5,1-b]thiazole-3-carboxylic acid amide.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1C1C=CC=C[NH+]=1.[Cr](Cl)([O-])(=O)=O.C([O-])(=O)C.[Na+].[CH3:28][C:29]12[CH:37]([CH:38]([CH3:50])[CH2:39][CH2:40][CH2:41][C:42]3([CH3:49])[CH2:46][O:45][C:44]([CH3:48])([CH3:47])[O:43]3)[CH2:36][CH2:35][CH:34]1[CH:33]([OH:51])[CH2:32][CH2:31][CH2:30]2.CC(O)C>C(Cl)Cl.O>[CH3:28][C:29]12[CH:37]([CH:38]([CH3:50])[CH2:39][CH2:40][CH2:41][C:42]3([CH3:49])[CH2:46][O:45][C:44]([CH3:48])([CH3:47])[O:43]3)[CH2:36][CH2:35][CH:34]1[C:33](=[O:51])[CH2:32][CH2:31][CH2:30]2
Reactant: CC(CCCC1(C)COC(C)(C)O1)C1CCC2C(O)CCCC12C
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: ClCCl
Product: CC(CCCC1(C)COC(C)(C)O1)C1CCC2C(=O)CCCC21C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a suspension of 1.720 g of 2,2'-bipyridinium chlorochromate and 0.860 g of anhydrous sodium acetate in 10 ml of methylene chloride, was added a solution of 0.500 g of [IR-[1β(R*,S*),3aα,4β,7aβ]]-octahydro-7a-methyl-1-[1-methyl-4 -(2,2,4-trimethyl-1,3-dioxolan-4-yl) butyl]-1H-inden-4-ol in 5 ml of methylene chloride and the mixture obtained stirred at room temperature for 2 hours. Additional 0.800 g of 2,2'-bipyridinium chlorochromate was then added and the stirring continued for an additional 2.5 hours. After this time, 1 ml of 2-propanol was introduced and 15 minutes later, the mixture diluted with water and extracted with ether. The combined organic phases were dried, evaporated and the residue purified by fast filtration through silica (eluent: hexane-ethyl acetate, 3:1) to give 0.446 g (90% yield) of pure [1R-(1R*,S*)-1β,3aα,7aβ] -octahydro-7a-methyl-1-[1-methyl-4-(2,2, 4-trimethyl-1,3-dioxolan-4-yl)-butyl]-4H-inden-4-one.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[C:13](=[C:15]([C:19]([O:21]C)=O)[CH:16]=[CH:17][CH:18]=3)[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH3:23]>>[OH:11][C:12]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:13]=1[N:14]=[C:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[NH:23][C:19]2=[O:21]
Reactant: N
Reactant: COC(=O)c1cccc2oc(-c3ccc([N+](=O)[O-])cc3)nc12
Product: O=c1[nH]c(-c2ccc([N+](=O)[O-])cc2)nc2c(O)cccc12
Reaction time: 20 h

Procedure:
Methyl 2-(4-nitrophenyl)benzoxazole-4-carboxylate (0.20 g) obtained as described in Example 19 (2nd stage) was dissolved in liquid ammonia (30 ml) and sealed in an autoclave. The reaction mixture was left at 55° C., 20 bar for 20 hours. Under these conditions, the expected 2-(4-nitrophenyl)benzoxazole derivative apparently rearranged to give the corresponding quinazolinone derivative. Once the reaction was complete the ammonia was removed and the resulting solid recrystallised from boiling ethyl acetate and petrol (84%).
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.C(Cl)Cl.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(N(CC)CC)C>[CH3:23][S:24]([O:1][CH2:2][C:3]#[C:4][CH:5]1[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=2[CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2)(=[O:26])=[O:25]
Reactant: OCC#CC1c2ccccc2C=Cc2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC#CC1c2ccccc2C=Cc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
This preparation illustrates methods according to step 3 of the process for preparing the compounds of formula A. In this preparation a solution containing 0.25 g. of 5-(3-hydroxy-prop-1-ynyl)-5H-dibenzo[a,d]cycloheptene in 25 ml. of anhydrous methylene chloride containing 0.25 ml. of triethylamine is stirred and cooled to maintain the temperature between 0°C and -10°C and 0.15 ml. of methanesulfonyl chloride is added. Cooling is then discontinued and the temperature of the mixture allowed to rise, with stirring, for 15 minutes. The solution is then poured into ice water, resulting in a two-phase organic-aqueous mixture. The organic layer is separated and washed successively with ice cold 1Normal aqueous hydrochloric acid, water, and saturated brine, and then dried over sodium sulfate and evaporated under vacuum yielding 5-(3-methanesulfonyloxyprop-1-ynyl)-5H-dibenzo[a,d] cycloheptene which is of sufficient purity to be used directly as starting material for subsequent examples.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2C(=O)C3=CC=CC=C3C2=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
A mixture of N-[2-[1-tert-butoxycarbonylpiperidin-4-yl]ethyl]phthalimide (1.0 g) and hydrazine hydrate (0.16 ml) in ethanol (10 ml) was refluxed for 1 hour. After cooling to room temperature, the mixture was evaporated. The residue was chromatographed on alumina eluting with chloroform and the fractions containing the object product were collected and evaporated to give 2-[1-tert-butoxycarbonylpiperidin-4-yl]ethylamine (0.4 g) as an oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[O:4][CH:5]=[CH:6][C:7]=1[C:8](OCC)=[O:9].[H-].C([Al+]CC(C)C)C(C)C.[K].[Na]>C1(C)C=CC=CC=1>[F:14][C:2]([F:1])([F:13])[C:3]1[O:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9]
Reactant: CCOC(=O)c1ccoc1C(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [K]
Solvent: Cc1ccccc1
Product: OCc1ccoc1C(F)(F)F
Temperature: -60 °C
Yield: 100.2 %

Procedure:
20 g of the product of Stage B were cooled to -60° C. in 200 ml of toluene, 160 ml of diisobutylaluminium hydride were added dropwise. The mixture was stirred for 1 and a half hours at -60° C. and was then poured into sodium potassium double tartrate and extracted with methylene chloride. The solvent was evaporated and the residue was chromatographed on silica (eluent: 7/3 hexane/ethyl acetate) to obtain 16 g of the expected product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[C:15](Cl)(=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CN(C1C=CC=CN=1)C.Cl>ClCCl.C(N(CC)CC)C>[C:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2)(=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CCCCCCCCC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
6-hydroxy-2-naphthoic acid (3.0 g) and triethylamine (2.4 g) were dissolved in 30 ml of dichloromethane. Nonanoyl chloride (4.0 g) and dimethylaminopyridine (0.2 g) were added to the solution, and the mixture was stirred at room temperature for about 20 hours. Dilute hydrochloric acid was added, and the organic layer was separated in a separating funnel. The solvent was removed by evaporation, and the residue was dried after washing with n-hexane to give 4.5 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([CH:12]2[CH2:14][CH2:13]2)[N:6]=1)=[O:4].Br[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:9][CH:8]=[C:7]([CH:12]2[CH2:14][CH2:13]2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(C2CC2)cnc1N
Reactant: Brc1cccnc1
Product: COC(=O)c1nc(C2CC2)cnc1Nc1cccnc1

Procedure:
The product was obtained starting from 3-amino-6-cyclopropylpyrazine-2-carboxylic acid methyl ester (200 mg, 1.04 mmol; intermediate A-10, step 2) and 3-bromopyridine (142 μl, 1.45 mmol) according to the method described in example A-1, step 2 as yellow solid (192 mg, 68%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:3]=1.C([Li])CCC.[CH:28](N1CCOCC1)=[O:29].Cl>O1CCCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:28]=[O:29])=[CH:3][C:4]=1[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1
Reactant: COc1ccc(Br)cc1COCc1ccc(C(F)(F)F)cc1
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C=O)cc1COCc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1.4 g of 4-bromo-1-methoxy-2-({[4-(trifluoromethyl)benzyl]oxy}methyl)benzene was dissolved in 15 ml tetrahydrofuran and cooled at −78° C., and 3.0 ml n-butyl lithium (1.5 M solution in pentane) was added. After stirring the reaction mixture at −78° C. for 30 minutes, 0.45 ml N-formyl morpholine was added, and the mixture was stirred at −78° C. for 1 hour. 1N hydrochloric acid was added to the reaction solution, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (3:1), 0.42 g of 4-methoxy-3-({[4-(trifluoromethyl)benzyl]oxy}methyl)benzaldehyde was obtained.
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1>CC(N(C)C)=O.CO.[Cu]>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([O:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(Br)cc1
Reactant: Cc1ccc(O)cn1
Agent: [Cu]
Agent: [K]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: COc1ccc(Oc2ccc(C)nc2)cc1

Procedure:
4 g of a potassium salt of 5-hydroxy-2-methylpyridine was suspended in 10 ml of dimethylacetamide, and 5.1 g of p-methoxybromobenzene and 450 mg of a copper powder were added to the suspension, followed by allowing the mixture to react in a nitrogen stream at 140° C. for 14 hours. The reaction mixture was diluted with 50 ml of methanol and filtered, and the filtrate was immediately dried to a solid. 100 ml of ethyl acetate was added to the residue, and the mixture was washed with 50 ml of an aqueous sodium hydroxide solution at pH 9. The ethyl acetate layer was washed with water, dried with anhydrous sodium sulfate and immediately dried to obtain 3.9 g of oily 5-(p-methoxyphenoxy)-2-methylpyridine.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[S:14][C:15]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:19]=[C:18]([O:28][CH3:29])[C:16]=2[N:17]=1)=[S:11])(=O)C1C=CC=CC=1.C1COCC1.C[O-].[Na+]>CO>[CH3:29][O:28][C:18]1[C:16]2[N:17]=[C:13]([NH:12][C:10]([NH2:9])=[S:11])[S:14][C:15]=2[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=S)NC(=O)c3ccccc3)nc12
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2ccccc2)c2sc(NC(N)=S)nc12
Reaction time: 72 h
Yield: 86.9 %

Procedure:
To a solution of 1-benzoyl-3-(4-methoxy-7-phenyl-benzothiazol-2-yl)-thiourea (1.3 g, 3.1 mmol) in methanol (20 ml)/THF (40 ml) was added NaOMe (250 mg, 4.6 mmol) and the mixture stirrd for 72 h at r.t. After evaporation of the solvents water (100 ml) was added with stirring followed by aceticacid (1 ml) which caused a solid to precipitate. This solid was collected and on a glass sinter, washed with water (100 ml), followed by EtOAc (30 ml) then finally cyclohexane (30 ml). After drying the title compound was obtained as a white solid (850 mg, 87% yield), MS: m/e=316.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:5][C@H:6]1[CH2:11][C@@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][N:7]1C(OC)=O.Br>>[F:25][C:23]1[CH:22]=[C:4]([CH:3]=[C:2]([F:1])[CH:24]=1)[CH2:5][C@H:6]1[CH2:11][C@@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][NH:7]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)cc(F)c1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](Cc3cc(F)cc(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
(2R,4S)-Methyl 2-(3,5-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.645 g, 1.83 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 14.43 mL, 82.38 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx III, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(3,5-difluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (153 mg, 28%). 1H NMR (600 MHz, dmso) δ 1.01-1.11 (m, 1H), 1.26-1.38 (m, 1H), 1.68-1.78 (m, 2H), 2.41-2.77 (m, 5H), 2.91-2.99 (m, 1H), 5.67 (s, 1H), 6.92 (d, 2H), 6.99 (s, 1H). HRMS Calculated for [C15H16F2N2O2+H]+: 295.1258. Found: 295.1249