Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:9][C:10]([NH:12][CH3:13])=[S:11])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][C:2]=1[CH3:8].C(OC(O[CH2:21][CH3:22])CCl)C.[OH-]>Cl>[C:1]1([N:9]=[C:10]2[N:12]([CH3:13])[CH:22]=[CH:21][S:11]2)[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][C:2]=1[CH3:8]
Reactant: CNC(=S)Nc1ccc(C)cc1C
Reactant: CCOC(CCl)OCC
Agent: Cl
Agent: [OH-]
Product: Cc1ccc(N=c2sccn2C)c(C)c1
Temperature: 25 °C

Procedure:
19.4 g (0.1 mole) of N-2,4-xylyl-N'-methyl-thiourea and 15.2 g (0.1 mole) of chloroacetaldehyde-diethylacetal in 150 ml of 2N aqueous hydrochloric acid are refluxed for 1 hour. The clear light-yellow solution is subsequently cooled to room temperature; it is rendered slightly alkaline with 30% aqueous medium hydroxide solution, and extracted with ether. The ether extract is washed with water, dried with sodium sulphate and filtered, and the ether is then distilled off. The oily residue is distilled; b.p. 132°-134° C/0.3 Torr; yield: 20.2 g = 92% of theory.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[F:29][CH:30]([F:40])[C:31]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1>>[F:40][CH:30]([F:29])[C:31]1[N:32]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:17][CH2:18]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1
Reactant: FC(F)c1nc2ccccc2[nH]1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-n4c(C(F)F)nc5ccccc54)nc(N4CCOCC4)c3n2)CC1

Procedure:
Following General Procedure D, 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 was reacted with 2-(difluoromethyl)-1H-benzo[d]imidazole to give 157. 1H NMR (400 MHz, DMSO) δ 8.43 (d, J=8.3 Hz, 1H), 8.23 (d, J=8.7 Hz, 1H), 8.00-7.72 (overlapping m, 3H), 7.51 (app t, J=7.7 Hz, 1H), 7.44 (app t, J=7.7 Hz, 1H), 4.56 (br s, 4H), 4.03 (s, 1H), 3.86 (br s, 4H), 3.74 (br s, 2H), 2.92 (d, J=10.6 Hz, 2H), 1.99 (t, J=11.3 Hz, 2H), 1.67 (d, J=11.8 Hz, 2H), 1.38-1.10 (overlapping m, 3H), 1.04 (s, 6H). LCMS: 538.3
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-])=O)=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][OH:19]>[Ni].CO>[NH2:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH2:3][CH2:2][OH:1])[C:5]([C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][OH:19])=[CH:6]2
Reactant: CC(C)(CCO)c1cc2cc([N+](=O)[O-])ccc2n1CCO
Agent: [Ni]
Solvent: CO
Product: CC(C)(CCO)c1cc2cc(N)ccc2n1CCO
Yield: 25.9 %

Procedure:
A solution of 3-[1-(2-hydroxy-ethyl)-5-nitro-1H-indol-2-yl]-3-methyl-butan-1-ol (300 Mg, 1.03 mmol) and Raney Nickel (200 mg, in CH3OH (30 mL) was stirred for 5 h at room temperature under a H2 atmosphere. The catalyst was filtered through a celite pad and the filtrate was evaporated under vacuum to give a residue, which was purified by preparative TLC to afford 3-[5-amino-1-(2-hydroxy-ethyl)-1H-indol-2-yl]-3-methyl-butan-1-ol (70 mg, 26%). 1H NMR (300 MHz, CDCl3) δ 7.07 (d, J=8.7 Hz, 1H), 6.83 (d, J=2.1 Hz, 1H), 6.62 (dd, J=2.1, 8.4 Hz, 1H), 6.15 (s, 1H), 4.47 (t, J=5.4 Hz, 2H), 4.07 (t, J=5.4 Hz, 2H), 3.68 (t, J=5.7 Hz, 2H), 2.16 (t, J=5.7 Hz, 2H), 4.00-3.91 (m, 4H), 2.76 (s, 2H), 1.61 (s, 6H), 1.42 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]1[CH2:30][NH:29][CH2:28][CH2:27][NH:26]1>N1C=CC=CC=1>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:29]4[CH2:28][CH2:27][NH:26][CH:25]([C:21]5[O:20][CH:24]=[CH:23][CH:22]=5)[CH2:30]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: c1coc(C2CNCCN2)c1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(c4ccco4)C3)c(F)cc2c1=O
Temperature: 25 °C
Yield: 23.5 %

Procedure:
A mixture of 843 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 2.28 g of 2-furanylpiperazine and 10 ml of pyridine was heated in a pressure bcttle for 24 hours, then cooled first to room temperature and then at 0° C. The pyridine was removed under reduced pressure and the residue purified by flash column chromatography using chloroform:methanol:water:triethylamine (95:5:.1:.1), giving 280 mg of the desired product, mp 176° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][C:4](=[S:13])[C:3]=1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)=O.[NH2:23]OS(O)(=O)=O.[OH-].[Li+]>CO>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4]1[S:13][N:23]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:3]=1[C:2]2=[O:1]
Reactant: Cc1ccc(C(=O)c2c(O)c3cc(C)ccc3[nH]c2=S)cc1
Reactant: NOS(=O)(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2nsc3[nH]c4ccc(C)cc4c(=O)c23)cc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 55.4 %

Procedure:
To a solution of 13 (80 mg, 0.259 mmol) in 25 mL of methanol was added a solution of hydroxylamine-O-sulfonic acid (102.6 mg, 0.907 mol) and lithium hydroxide (38.1 mg, 0.907 mmol) in 3 mL of methanol and the mixture was stirred at room temperature for 30 hours. The reaction mixture was concentrated under reduced pressure and applied to flash chromatography. Elution with heptane/EtOAc (3:1) gave 19 as a white solid (44 mg, 55%). mp: 330° C.;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][CH2:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.[BH3-]C#[N:31].[Na+]>CO>[NH2:31][CH:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:20][CH2:19][CH2:18][N:10]([C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:9])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: [BH3-]C#N
Reactant: C[C@@H](c1ccc(Br)cc1)N(CCCC(=O)c1ccccc1)C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CO
Product: C[C@@H](c1ccc(Br)cc1)N(CCCC(N)c1ccccc1)C(=O)OC(C)(C)C
Yield: 93 %

Procedure:
To a stirred solution of (S)-tert-butyl 1-(4-bromophenyl)ethyl(4-oxo-4-phenylbutyl)carbamate (193 mg, 0.43 mmol) and NH4OAc (670 mg, 8.6 mmol) in MeOH (15 mL) was added NaCNBH3 (270 mg, 4.3 mmol). The mixture was heated at reflux for 22 h and concentrated under reduced pressure. The residue was partitioned between 1 M aq NaOH (25 mL) and CH2Cl2 (2×50 mL). The combined CH2Cl2 layers were washed with brine (15 mL), dried over Na2SO4 and concentrated to afford tert-butyl 4-amino-4-phenylbutyl((1S)-1-(4-bromophenyl)ethyl)carbamate (179 mg, 93%) as an oil which was used without further purification. LC-MS Method 1 tR=1.57 min, m/z=449, 447.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[CH:17]([Br:21])[CH2:18][CH2:19]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH:17]([Br:21])[C:16]2=[O:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)C(Br)CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C1C(Br)CCN1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
6.1 g (14.3 mmol) (RS)—N-(4-benzyloxy-phenyl)-2,4-dibromo-butyramide and 0.1 g of Dowex 2×10 are suspended in 50 ml dichloromethane. 7 ml of a 50% aqueous sodium hydroxide solution is slowly added under vigorous stirring. The resulting reaction mixture is stirred overnight at RT, then poured into 25 ml of cold water. The organic phase is separated, dried and evaporated. The crude material is recrystallised from ethyl acetate to yield 1.72 g (35%) of a brownish solid. Mp=125–126° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([CH:12]([CH2:14][CH3:15])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:16]([CH2:18][CH3:19])[CH3:17])[CH:2]1[O:4][CH2:3]1.[NH3:20]>O>[OH:4][CH:2]([CH2:1][O:5][C:6]1[C:11]([CH:12]([CH2:14][CH3:15])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:16]([CH2:18][CH3:19])[CH3:17])[CH2:3][NH2:20]
Reactant: CCC(C)c1cccc(C(C)CC)c1OCC1CO1
Reactant: N
Solvent: O
Product: CCC(C)c1cccc(C(C)CC)c1OCC(O)CN
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A 2.5 liter autoclave is charged, at room temperature and under nitrogen blanketing, with 440 g (1.667 mol) of 2,6-bis(sec-butyl)phenyl glycidyl ether and 30.2 g of water. Then 698.5 g (41.08 mol) of ammonia gas is blown in under pressure over 5 minutes and the reaction mixture is thereafter heated to 80° C. over 2 hours. After 1 hour at 80° C., the reaction mixture is cooled to room temperature, the pressure in the system is removed and the reaction product is concentrated on a rotary evaporator at 80° C./13 mbar. Yield: 436.1 g (93% of theory) of a brownish liquid reaction product which is purified by flash distillation. The boiling point is 170° C./0.13 mbar and the amine content is 3.548 meq/g (=99.1% of theory).
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.[CH3:11][N:12]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21](C=O)[C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CO.C(OCC)C>[CH2:9]([O:8][CH:1]([O:5][CH2:6][CH3:7])[C:21]1[C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:11])[C:25]=2[CH:24]=[CH:23][CH:22]=1)[CH3:10]
Reactant: CCOC(OCC)OCC
Reactant: CN1c2ccccc2Sc2c(C=O)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCOC(OCC)c1cccc2c1Sc1ccccc1N2C
Temperature: 0 °C
Yield: 96.2 %

Procedure:
15.0 ml of triethyl orthoformate were added at room temperature to a solution of 4.90 g (20.3 mmol) of 10-methylphenothiazine-4-carbaldehyde and 50 mg of p-toluenesulphonic acid×1H2O in 15 ml of methanol. The reaction mixture was boiled at reflux for 45 minutes, cooled and poured into 30 g of ice, 30 ml of saturated aqueous sodium hydrogen carbonate solution and 100 ml of diethyl ether. The organic phase was washed with 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The residue was chromatographed on 300 g of silica gel with diethyl ether/hexane (1:4), whereupon, after crystallization from diethyl ether/hexane in a refrigerator, 6.16 g (96.2%) of 4-diethoxymethyl-10-methyl-phenothiazine were obtained as a white solid of m.p. 44.6°-46.2°.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[C@@H:10]([OH:11])[CH2:9][CH2:8][NH:7]1)=[O:5].CCN(C(C)C)C(C)C.[Cl:21][C:22]1[C:29]([CH3:30])=[C:28]([N:31]=[C:32]=[O:33])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>C(Cl)Cl>[CH3:2][O:3][C:4]([C@@H:6]1[C@@H:10]([OH:11])[CH2:9][CH2:8][N:7]1[C:32]([NH:31][C:28]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:21])[C:29]=1[CH3:30])=[O:33])=[O:5]
Reactant: Cc1c(N=C=O)ccc(C#N)c1Cl
Reactant: COC(=O)[C@H]1NCC[C@@H]1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1[C@@H](O)CCN1C(=O)Nc1ccc(C#N)c(Cl)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
A solution of ester 1A (500 mg, 2.75 mmol) in dry CH2Cl2 (10 mL) was cooled to 0° C., treated with Hunig's base (0.53 mL, 3.04 mmol) and stirred at 0° C. for 30 min. The solution was treated with isocyanate 23E (505 mg, 2.62 mmol), and the resulting suspension was stirred at rt for 3 h. The insoluble solids were filtered off and the filtrate was partitioned between aqueous NH4Cl (6.0 mL) and CH2Cl2 (3×60 mL). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue and insoluble solids were combined and chromatographed (silica gel; EtOAc/hexane gradient) to yield the title compound (177.2 mg, 75.3%) as a white solid, mp 189-191° C. HPLC: 1.72 min (retention time) (Conditions: YMC S-5 C-18 (4.6×50 mm), eluting with 0-100% B, 4 min gradient. (A=90% H2O-10% CH3CN-0.1% TFA and B=10% H2O-90% CH3CN-0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm). Chiral HPLC: retention time=22.2 min (100%); Conditions: AD (4.6×250 mm); Eluted with 20% isopropanol in heptane for 30 min at 1 mL/min. MS (ES) m/z 338 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[OH:20].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CS(C)=O.O>[Br:1][C:2]1[C:3]([O:20][C:14]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=2[F:12])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Oc1ccc(F)cc1F
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cnc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 100 °C
Yield: 67.8 %

Procedure:
5-bromo-6-chloronicotinic acid (3 g, 12.69 mmol), 2,4-difluorophenol (3.30 g, 25.4 mmol) and cesium carbonate (16.54 g, 50.8 mmol) were combined in DMSO (25.4 mL), heated at 100° C. for 6 hours, cooled, diluted with 150 mL of iced water and the pH was adjusted to pH 3 with 12M HCl. The resulting solid was collected by filtration, washed with cold water and dried to constant mass to afford the title compound (2.84 g, 64%).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=1)[CH:10]=[CH:9]2)=[C:2]=[O:3].[NH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1>C1(C)C=CC=CC=1>[S:27]1[CH:28]=[CH:29][N:30]=[C:26]1[NH:25][C:2]([NH:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:22])[F:23])[CH:15]=1)[CH:10]=[CH:9]2)=[O:3]
Reactant: O=C=Nc1cccc2ccc(-c3cccc(OC(F)(F)F)c3)nc12
Reactant: Nc1nccs1
Solvent: Cc1ccccc1
Product: O=C(Nc1nccs1)Nc1cccc2ccc(-c3cccc(OC(F)(F)F)c3)nc12
Temperature: 140 °C

Procedure:
To a mixture of 8-isocyanato-2-(3-(trifluoromethoxy)phenyl)quinoline (0.277 mmol) in toluene (5 mL) was added 2-aminothiazole (0.553 mmol, 55 mg). The mixture was concentrated to dryness, redissolved in pyridine and microwave heated (140° C.×10 min). The reaction mixture was diluted with CH2Cl2, washed with saturate aqueous NaHCO3, water, brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (0% to 100% ethyl acetate in pentane) afforded the desired product. MS (ESI) calcd for C20H13F3N4O2S (m/z): 430.07. found: 431 [M+1].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH:4]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:3]1=[O:19].[H][H]>CO.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH:4]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:3]1=[O:19]
Reactant: [H][H]
Reactant: CC(C)CC1C(=O)N(C)CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)CC1NCCN(C)C1=O

Procedure:
1-Methyl-3-(2-methylpropyl-4-(phenylmethyl)piperazinone (Example 47, 2.1 g.) is dissolved in methanol (200 ml.), 10% palladium charcoal (1.0 g.) is added and the product is hydrogenated (50 lb. initial hydrogen pressure until the uptake of hydrogen ceased. The solution is filtered and the methanol is removed under reduced pressure to give the title compound as an oil.
Reaction SMILES: O=P(Cl)(Cl)Cl.[F:6][C:7]([F:30])([F:29])[C:8]([N:10]1[CH2:28][CH2:27][C:13]2([C:18]3=[C:19]([CH3:22])[CH:20]=[CH:21][N:17]3[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=3[O:14]2)[CH2:12][CH2:11]1)=[O:9].[OH-].[Na+].CN([CH:36]=[O:37])C>>[CH3:22][C:19]1[CH:20]=[C:21]([CH:36]=[O:37])[N:17]2[C:18]=1[C:13]1([CH2:27][CH2:28][N:10]([C:8](=[O:9])[C:7]([F:6])([F:29])[F:30])[CH2:11][CH2:12]1)[O:14][C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]2=1
Reactant: Cc1ccn2c1C1(CCN(C(=O)C(F)(F)F)CC1)Oc1ccccc1-2
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C=O)n2c1C1(CCN(C(=O)C(F)(F)F)CC1)Oc1ccccc1-2
Reaction time: 0.5 h
Yield: 24 %

Procedure:
POCl3 (38 μL, 0.41 mmol) was added dropwise at 0° C. under N2 to DMF (32 μL, 0.41 mmol). The reaction was stirred for 30 min at this temperature and a white solid formed, to which was slowly added a solution of 2,2,2-trifluoro-1-(3′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl)ethanone (95 mg, 0.27 mmol) in dry DMF (0.7 mL). The reaction stirred for 4 h, poured onto ice, 0.8 ml of 1M NaOH was added and the product was extracted with dichloromethane (3×5 mL). The organic phases were combined, washed with brine, dried, filtered and concentrated and the residue was purified by silica-gel column chromatography eluting with 5-40% EtOAc in hexanes to yield 3-methyl-1′-(2,2,2-trifluoroacetyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde (25 mg, 24%). ESI-MS m/z calc. 378.1, found 379.3 (M+1)+; Retention time 1.83 minutes (3 min run).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH2:8][NH2:9])[CH:7]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH2:8][NH:9][C:11](=[O:13])[CH3:12])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1cc(Br)ccc1Cl
Solvent: Cc1ccccc1
Product: CC(=O)NCc1cc(Br)ccc1Cl
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-2-chlorobenzenemethanamine (i.e. the product of Step A) (600 mg, 2.72 mmol) in toluene (10 mL) at 0° C. was added acetic anhydride (0.55 mL, 5.45 mmol). The reaction mixture was stirred at 100° C. for 3 h. The reaction mixture was then extracted with ethyl acetate (3×), and the organic layers were combined, washed with water and brine and dried (Na2SO4). The solvent was evaporated to provide the title product (600 mg).
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:19][CH:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH:29]([O-])=O.[NH4+]>CO.[Pd]>[CH3:29][C:20]1[O:19][C:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:17][C:16]=1[CH2:15][CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:28][CH:27]=1
Reactant: c1ccc(COc2ccc(OCCc3coc(-c4ccccc4)n3)cc2)cc1
Reactant: O=C[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(O)cc1
Temperature: 25 °C
Yield: 67 %

Procedure:
4-[2-(4-Benzyloxyphenoxy)ethyl]-2-phenyloxazole (7.0 g, 18.8 mmol) was dissolved in methanol (150 mL) and treated with palladium on carbon (1.0 g, 10 mol %) and ammonium formate (20.0 g, 0.32 mol). The suspension was heated at reflux for 8 h and then cooled to ambient temperature. The resultant suspension was filtered through Celite with a methanol wash, and the filtrate was concentrated to provide a colorless oil (3.72 g, 70%). 1H NMR (250 MHz, CDCl3) δ 8.84 (s, 1H), 7.81-7.87 (m, 2H), 7.41-7.49 (m, 3H), 6.72 (d, 2H), 6.59 (d, 2H), 4.04 (t, 2H), 2.81 (t, 2H), 2.30 (s, 3H); MS(EI): 282 (M+H), 280 (M−H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][C:3]=1C.B([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)(O)O>>[OH:14][CH2:13][C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)=[CH:7][CH:6]=2)[N:12]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(-c2noc(CO)n2)ccc1Br
Product: O=C(O)c1ccc(-c2ccc(-c3noc(CO)n3)cc2)cc1

Procedure:
3-(4-Bromo-3-methylphenyl)-1,2,4-oxadiazol-5-ylmethanol (EP 0533268 A1) (1.0 g, 3.7 mmol) was reacted with 4-boronobenzoic acid using similar conditions to Description 11 to afford 4'-(5-hydroxymethyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid. This was dissolved in methanol (70 ml), treated with conc. sulphuric acid (2 ml) and heated under reflux for 4 hours. The solution was concentrated in vacuo and the residue basified with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to afford the title compound (0.76 g, 68%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[CH:28]([CH:30]4[CH2:32][CH2:31]4)[OH:29])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH:35]([C:37]1([C:43]([OH:45])=[O:44])[CH2:42][O:41][CH2:40][O:39][CH2:38]1)=[CH2:36].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O1CCOCC1.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]>[CH:30]1([CH:28]([OH:29])[C:27]([NH:26][C@@H:24]([CH3:25])[C:23]([N:19]2[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([NH:14][C@@H:12]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2](/[CH:36]=[CH:35]/[C:37]5([C:43]([OH:45])=[O:44])[CH2:42][O:41][CH2:40][O:39][CH2:38]5)=[CH:3][CH:4]=4)[N:9]=3)[CH3:13])=[O:16])[NH:18]2)=[O:34])=[O:33])[CH2:32][CH2:31]1
Reactant: C[C@H](NC(=O)C(O)C1CC1)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Reactant: C=CC1(C(=O)O)COCOC1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@H](NC(=O)C(O)C1CC1)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/C4(C(=O)O)COCOC4)cc3n2)N1
Temperature: 50 °C

Procedure:
A solution of (S)-1-[(S)-2-(2-cyclopropyl-2-hydroxy-acetylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (592 mg, 1.11 mmol), 5-vinyl[1,3]dioxane-5-carboxylic acid (176 mg, 1.11 mmol), triethylamine (343 mg, 472 μL, 3.39 mmol) and tri(o-tolyl)phosphine (67 mg, 0.22 mmol) in 1,4-dioxane (15 mL) was degassed with nitrogen for 5 minutes and then warmed to 50° C. under nitrogen with stirring. Tris(dibenzylideneacetone)dipalladium(0) (101 mg, 0.11 mmol) was added and the mixture was heated to reflux for 20 minutes and then allowed to cool to room temperature. The suspension was filtered through Celite and the filtrate evaporated to give crude 5-((E)-2-{2-[(R)-1-({(S)-1-[(S)-2-(2-cyclopropyl-2-hydroxy-acetylamino)-propionyl]-hexahydro-pyridazine-3-carbonyl}-amino)-ethyl]-quinolin-7-yl}-vinyl)-[1,3]dioxane-5-carboxylic acid.
Reaction SMILES: [CH2:1]([N:10]1[C:15](=[O:16])[C:14]([CH2:17]OS(C)(=O)=O)=[CH:13][C:12]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH3:30])[CH:24]=2)=[N:11]1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH2:1]([N:10]1[C:15](=[O:16])[C:14]([CH2:17][N:35]2[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]2)=[CH:13][C:12]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH3:30])[CH:24]=2)=[N:11]1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC=Cc3ccccc3)n2)ccc1F
Product: Cc1cc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC=Cc3ccccc3)n2)ccc1F
Yield: 80.1 %

Procedure:
Following the procedure of Example 1(10), 2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-methanesulonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 80.1%).