Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([O:15]CC3C=CC=CC=3)[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]>CCOC(C)=O.CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(OCc3ccccc3)cc2o1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc2ccc(O)cc2o1
Reaction time: 12 h
Yield: 70.1 %

Procedure:
To a solution of 6-benzyloxy-benzofuran-2-carboxylic acid ethyl ester (8.1 g, 27 mmol) in EtOAc/EtOH (3/1, 130 mL) was added Pd/C (0.8 g). The reaction mixture was shaken in a Parr Shaker under H2 (50 psi, 12 h). The reaction mixture was filtered (Celite®), washed with EtOAC (400 mL) and EtOH (100 mL). The filtrate was concentrated and the resulting residue was purified by silica gel flash chromatography using EtOAc:hexanes (0-50%) to provide the title compound as colorless solid (3.9 g, 70%). MS (ESI): mass calcd. for C11H10O4, 206.1.0; m/z found, 207.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.50 (d, J=8.6, 1H), 7.46 (d, J=0.8, 1H), 7.25-7.23 (m, 1H), 6.90 (dd, J=8.5, 2.2, 1H), 6.12 (s, 1H), 4.57-4.30 (m, 2H), 1.49-1.31 (m, 3H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[N+:20]([O-])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.C(O)(=O)C.[Zn]>[NH2:20][C:19]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]=1[NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(NCc2ccccc2)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1ccc(N)c(NCc2ccccc2)c1
Reaction time: 1 h
Yield: 106.5 %

Procedure:
To a stirring solution of ethyl 3-(benzylamino)-4-nitrobenzoate (1.52 g, 5 mmol) in ethanol (50 mL) and acetic acid (7 mL) was added zinc dust (2.3 g, 35 mmol). After 1 hr at room temperature, the solids were filtered and the remaining solution was concentrated. The resulting residue was diluted with ethyl acetate (200 mL) and washed with dilute aq. NaHCO3 (1×100 mL), then the organic layer was dried (MgSO4), filtered and then concentrated to provide 1.44 g (˜100%) of crude ethyl 4-amino-3-(benzylamino)benzoate as an orange/brown oil. This material was used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:16]=[C:15]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][N:12]3S(C2C=CC=CC=2)(=O)=O)=[N:5][N:4]=1.C1(C[OH:42])CCCCC1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[NH:21]1[C:22]2[C:18](=[C:17]([C:15]3[CH:14]=[C:13]4[C:9]([CH:10]=[N:11][NH:12]4)=[C:8]([C:6]4[O:7][C:3]([CH2:2][OH:42])=[N:4][N:5]=4)[CH:16]=3)[CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(-c3cccc4[nH]ccc34)cc21
Reactant: OCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: OCc1nnc(-c2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)o1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 29.6 %

Procedure:
4-[5-(Chloromethyl)-1,3,4-oxadiazol-2-yl]-6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazole (25 mg, 0.051 mmol), cyclohexylmethanol (17.48 mg, 0.153 mmol) and potassium carbonate (21.16 mg, 0.153 mmol) were placed in N-methyl-2-pyrrolidone (1 ml) and the mixture heated under microwave irradiation at 100° C. for 20 mins. Additional cyclohexylmethanol (17.48 mg, 0.153 mmol) was added and the mixture heated at 110° C. for 20 mins, followed by 110° C. for a further 20 mins. The solvent was removed and the residue purified by Mass Directed Automated Preparative HPLC to give the title compound as a white solid (5 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.Cl.[CH:13]12[NH:20][CH:17]([CH2:18][CH2:19]1)[CH2:16][O:15][CH2:14]2.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:20]2[CH:13]3[CH2:19][CH2:18][CH:17]2[CH2:16][O:15][CH2:14]3)[N:3]=1
Reactant: C1CC2COCC1N2
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc(N2C3CCC2COC3)c2nc[nH]c2n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 89.4 %

Procedure:
A mixture of 2,6-dichloro-9H-purine (527 Mg, 2.79 mmol), 3-Oxa-8-aza-bicyclo[3.2.1]octane hydrochloride (500 mg, 3.34 mmol) and DIPEA (1.2 mL, 6.98 mmol) in IMS (15 mL) were heated at 80° C. for 3 h then stirred at r.t. for 18 h. The resulting precipitate was collected by filtration and washed with further IMS. The resulting solid was dried in vacuo affording the title compound (663 mg, 90%). 1H NMR (CDCl3, 400 MHz): δ 8.14 (1 H, s), 5.60 (1 H, brd s), 4.80 (1 H, brd s), 3.66 (4 H, brd s), 2.00 (4 H, s)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]3[CH2:14][CH2:13]3)[CH2:10][CH2:9][C:8]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH3:32])[CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:20][CH:19]=3)=[O:16])=[CH:7][C:6]=2[CH:33]=1.B([O-])([O-])O[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH3:49])=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH2:46]([O:45][CH2:44][CH2:43][O:42][C:39]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH:12]4[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]([C:15]([NH:17][C:18]4[CH:19]=[CH:20][C:21]([CH2:24][N:25]([CH3:32])[CH:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[CH:22][CH:23]=4)=[O:16])=[CH:7][C:6]=3[CH:33]=2)=[CH:41][CH:40]=1)[CH2:47][CH2:48][CH3:49]
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3N(C3CC3)CC2)cc1)C1CCOCC1
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: Cc1ccccc1
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
A mixture of 7-bromo-1-cyclopropyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.45 g), 4-(2-butoxyethoxy)phenyl borate (0.23 g), 1M potassium carbonate solution (1.5 ml), ethanol (1.5 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.05 g), and the mixture was refluxed for 3 hours under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized to give 7-[4-(2-butoxyethoxy)phenyl]-1-cyclopropyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 31) (0.25 g) as pale yellow crystals.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:17]=[C:16]([C:18](Cl)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][NH:22][CH:23]([CH2:25][CH3:26])[CH3:24]>C(Cl)Cl>[CH3:21][N:22]([CH:23]([CH3:24])[CH2:25][CH3:26])[C:18]([C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:17]=1)=[O:19]
Reactant: O=C(Cl)c1cc(-c2ccccc2)nc2ccccc12
Reactant: CCC(C)NC
Agent: Cl
Solvent: ClCCl
Product: CCC(C)N(C)C(=O)c1cc(-c2ccccc2)nc2ccccc12

Procedure:
The procedure of Example 42 is followed using 2-phenylquinoline-4-carboxylic acid chloride hydrochloride (10.7 g) and N-methylbut-2-ylamine (10.5 g) in methylene chloride (75 ml) as the starting materials.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[S:14](=[O:16])(=[O:15])[CH2:13][CH2:12][C:10]3=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[NH2:23].O.[Cl-].[NH4+]>C(O)(C)C>[OH:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]4[S:14](=[O:16])(=[O:15])[CH2:13][CH2:12][C:10]4=3)[N:5]=[CH:4][C:3]=2[C:17]#[N:18])[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1
Reactant: COc1cc(N)cc(O)c1
Reactant: N#Cc1cnc2ccc3c(c2c1Cl)CCS3(=O)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: COc1cc(O)cc(Nc2c(C#N)cnc3ccc4c(c23)CCS4(=O)=O)c1
Yield: 22.8 %

Procedure:
65 mg (0.23 mmol) of 9-chloro-1,2-dihydrothieno[3,2-f]quinoline-8-carbonitrile 3,3-dioxide are refluxed together with 39 mg (1.2 eq., 0.28 mmol) of 3-hydroxy-5-methoxyaniline in 2 ml of isopropanol for 2 hours. After the reaction is complete, the crude product is mixed with water and sat. ammonium chloride solution, extracted 3× with dichloromethane/methanol, washed 1× with sat. sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. Final purification of the compound took place by chromatography. 20 mg (22%) of the desired product were obtained.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][NH:15][C:16]([C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23]([C@@H:25]3[CH2:29][C@@H:28](OS(C)(=O)=O)[CH2:27][N:26]3[C:35](=[O:56])[CH2:36][C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:24])=[O:17])[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:57]=[N+:58]=[N-:59].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:57]([C@@H:28]1[CH2:27][N:26]([C:35](=[O:56])[CH2:36][C:37]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:25]([C:23]([N:19]2[CH2:20][CH2:21][CH2:22][CH:18]2[C:16]([NH:15][CH2:14][C@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:9]2)=[O:17])=[O:24])[CH2:29]1)=[N+:58]=[N-:59]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)N2CCCC2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 85 °C
Reaction time: 10 h
Yield: 81.3 %

Procedure:
To a solution of 33 mg of (2R)-N-{((3R)-1-cyclohexylmethyl-3-piperidyl)methyl}-1-{(2S,4R)-4-(methylsulfonyloxy)-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxamide in 1 ml of N,N-dimethylformamide, 8.3 mg of sodium azide was added at room temperature, followed by 10 hours' stirring at 85° C. under heating. The reaction liquid was diluted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resultant residue was purified by means of a preparative thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), chloroform/methanol/28% aqueous ammonia=100/10/1) to provide 25 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[C:14]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1>>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:23]1[CH2:24][CH2:25][N:20]([C:14]2[C:13]([CH3:12])=[CH:18][C:17]([CH3:19])=[CH:16][N:15]=2)[CH2:21][CH2:22]1)=[O:6]
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(Cl)cc1Br
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3Br)CC2)c(C)c1
Yield: 98.7 %

Procedure:
Using 2-bromo-4-chlorobenzoic acid (2.09 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine (1.7 g) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (3.58 g) was obtained.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:3]=1[C:4]([OH:6])=[O:5].NC(N)=[S:20].O.[OH-].[Na+]>Cl.C(O)(=O)C>[SH:20][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NC(N)=S
Reactant: O=C(O)c1c(-c2ccc(Cl)cc2)ccnc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1c(-c2ccc(Cl)cc2)ccnc1S
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 73.9 g (0.24 mol) of 2-bromo-4-(4-clorophenyl)nicotinic acid and 22.0 g (0.29 mol) of thiourea in 100 ml of 5% HCl and 150 ml of acetic acid was stirred at 100° C. for 2 hours. The mixture was poured into water and 400 ml of 50% sodium hydroxide was added to the resultant mixture, and the mixture was stirred at room temperature for 30 minutes. The mixture was then acidified with 20% HCl, and the crystal thus precipitated was filtrated out and washed with water. The washed crystal was then dried to obtain a crude crystal of 2-mercapto-4-(4-chlorophenyl)nicotinic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1O.C(N(CC)CC)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH3:46][O:47][C:48](=[O:60])[N:49]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]#[CH:59])=[CH:54][CH:53]=1)[CH3:50]>C(#N)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[C:59]#[C:58][C:55]1[CH:56]=[CH:57][C:52]([CH2:51][N:49]([C:48]([O:47][CH3:46])=[O:60])[CH3:50])=[CH:53][CH:54]=1
Reactant: C#Cc1ccc(CN(C)C(=O)OC)cc1
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(F)cc([N+](=O)[O-])c1C#Cc1ccc(CN(C)C(=O)OC)cc1
Temperature: -8 °C
Reaction time: 2 h
Yield: 156.8 %

Procedure:
The nitro compound 8 (47.87 g, 0.223 mol) was dissolved in acetonitrile (240 ml) and cooled to −8° C. Triethylamine (33.8 g, 0.334 mol) was added. A clear dark solution was formed. Triflic anhydride (69.17 g, 0.245 mol) was added slowly and the reaction temperature was maintained at −10° C. 10 minutes after addition was complete, TLC analysis indicate the completion of triflate formation. Cooling bath was removed. Alkyne 5 (47.46 g, 0.234 mol) was added. The solution was degassed 3 times by evacuating the flask and backfilling it with nitrogen. The solution was then transferred into an addition funnel. Into a separate reaction flask was added acetonitrile (240 ml) and triethylamine (22.5 g, 0.223 mol). The solution was degassed 3 times by exposing the reaction flask to vacuum and nitrogen alternatively. Dichlorobis(triphenylphosphine) palladium (II) (3.13 g, 0.0045 mol) was added to the solution and the solution was degassed again 3 times. This solution was heated to 65° C. under protection of nitrogen. Once the temperature reached 65° C., one quarter of the solution of alkyne 5 and triflate in addition funnel was quickly added to the reaction flask. The remaining solution in addition funnel was added over 30 minutes at 65° C. After the addition was complete, the reaction solution was stirred at 65° C. for 2 hours. HPLC analysis indicated the reaction was complete. Reaction mixture was cooled to room temperature. Solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (500 ml) and washed with water (300 ml). The aqueous phase was separated and back extracted with ethyl acetate (200 ml). The combined organic solution was washed with water (200 ml). It was then concentrated to dryness to provide a dark oil residue (140 g). This crude product was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 2.87 (d, br, 3H), 3.755 (s, 3H), 4.011 (s, 3H), 4.50 (s, br, 2H), 7.21 (s, br, 2H), 7.55 (d, 2H, J=9 Hz), 7.80 (dd, 1H, J=2.7 Hz and J=7.2 Hz), 7.86 (dd, 1H, J=2.7 Hz and J=8.1 Hz).
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:19]O>>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc([N+](=O)[O-])c1F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
2-Fluoro-3-nitrobenzoic acid (75 g) was dissolved in 300 ml of methanol, and then 20 ml of concentrated H2SO4 was added. The mixture was stirred at 70° C. overnight and cooled to rt, the resulting solid was filtered and washed with water (3×200 ml), to the filtered was added water (400 ml), the resulting precipitate was filtered and washed with water (2×100 ml) to afford another batch of product. The solid were combined and dried under vacuum to afford the title compound was obtained as a light yellow solid (78 g, 96%).
Reaction SMILES: [CH3:1][C:2]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:16][CH:15]=2)[C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([CH3:10])=[C:4]2[N:3]=1.[CH3:28][C:29]([CH3:31])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[CH3:1][C:2]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([CH:29]([CH3:31])[CH3:28])[CH2:26][CH2:27]3)=[CH:16][CH:15]=2)[C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([CH3:10])=[C:4]2[N:3]=1
Reactant: CC(C)=O
Reactant: Cc1cc(C)c2nc(C)n(Cc3ccc(NCC4CCNCC4)cc3)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: Cc1cc(C)c2nc(C)n(Cc3ccc(NCC4CCN(C(C)C)CC4)cc3)c2n1
Reaction time: 0.33 h
Yield: 52.6 %

Procedure:
A solution of Compound 157 (0.350 g, 0.97 mmol) in 1,2-dichloroethane was added with acetone (0.106 mL, 1.46 mmol) followed by stirring for 20 minutes. The mixture was added with sodium triacetoxyborohydride (0.616 g, 2.91 mmol) followed by stirring at room temperature overnight. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution and extracted with dichloromethane three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:2 mol/L ammonia-methanol solution=19:1). The obtained crystals were recrystallized from ethanol-diisopropyl ether to obtain Compound 161 (0.205 g, 0.51 mmol, 52%).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH:15]=[CH:14][O:13][C:12]([OH:16])=[C:11]1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH:25]([C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=1)[CH3:26]>CS(C)=O>[CH2:3]([N:10]1[CH2:15][CH2:14][O:13][C@@H:12]([O:16][CH2:26][CH2:25][C:27]2[CH:28]=[C:29]([C:37]([F:38])([F:40])[F:39])[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=2)[C@@H:11]1[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OC1=C(c2ccc(F)cc2)N(Cc2ccccc2)C=CO1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Fc1ccc([C@H]2[C@H](OCCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)OCCN2Cc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
3.76 g of sodium hydride and 300 ml of dimethylsulfoxide (DMSO) were charged into a clean and dry 4neck round bottom flask under nitrogen atmosphere, followed by heating to about 70° C. and was stirred for about 2 hours. Resultant reaction solution was cooled to about 30° C. and a solution of 30 g of (±)-N-benzyl-3-(4-fluorophenyl)-1,4-oxazin-2-ol of Formula VIII dissolved in 60 ml of dimethyl sulfoxide, a solution of 50 g of 1-(1-bromoethyl) 3,5-bis-trifluoromethyl-benzene of Formula VII dissolved in 60 ml of dimethylsulfoxide were charged followed by stirring for about 3 hours. After completion of the reaction, the reaction mass was quenched with 450 ml of precooled water and 300 ml of toluene. Organic and aqueous phases were separated and the aqueous phase was extracted with 2×300 ml of toluene. Combined organic layer was washed with 3×300 ml of water followed by drying the organic layer over 100 g of anhydrous sodium sulphate and the organic layer was distilled completely at about 60° C. under vacuum to afford 40 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:23]=[CH:22][N:13]3[C:14](=[O:21])[C:15]([C:18](O)=[O:19])=[CH:16][N:17]=[C:12]3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C([Cl:27])=O>CN(C=O)C.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:23]=[CH:22][N:13]3[C:14](=[O:21])[C:15]([C:18]([Cl:27])=[O:19])=[CH:16][N:17]=[C:12]3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc2cc(C#Cc3cccc(F)c3)ccn2c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnc2cc(C#Cc3cccc(F)c3)ccn2c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 8-((3-fluorophenyl)ethynyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (50 mg, 0.162 mmol, 1 equiv) and 1 drop DMF in dichloromethane was added oxalyl dichloride (1 mL) dropwise. The reaction mixture was stirred at room temperature for 3 h and concentrated to give the desired product, which was directly used for the next step.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].C/[C:12](=[CH:17]\[CH2:18][CH2:19]/[C:20](/C)=[CH:21]/[CH2:22][O:23]C1CCCCO1)/[CH2:13][CH2:14][CH:15]=O.CC(=CC)C>O.C(O)(C)(C)C>[C:22]([OH:23])(=[O:6])[CH2:21][CH2:20][CH:19]=[CH:18][CH2:17][CH2:12][CH:13]=[CH:14][CH3:15]
Reactant: C/C(=C\CC/C(C)=C/COC1CCCCO1)CCC=O
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC=CCCC=CCCC(=O)O

Procedure:
A.a) A solution of 105 g of 80% sodium chlorite and 100 g of sodium dihydrogen phosphate in 1 l of water is added within 30 min. to 50 g of (4E,8E)-(RS)-4,8-dimethyl-10-(tetrahydro-pyran-2-yloxy)-deca-4,8-dienal in 1.5 l of tert-butanol and 1.5 1 of 2-methyl-2-butene. After 2 1/2 hrs. at room temperature the mixture is concentrated and the residue is taken up in methylene chloride, washed with ice-water and 10% potassium hydrogen sulphate solution and dried. 46.5 g of (4E,8E)-(RS)-4,8-dimethyl-10-(tetrahydro-pyran-2-yloxy])-deca-4,8-dienoic acid are obtained. The acid obtained is dissolved in 590 ml of methylene chloride and treated at 0° C. with 14.9 ml of N-allyl-methyl-amine, 32.0 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and 1.88 g of dimethylaminopyridine. After 3 hrs. at room temperature and working up with methylene chloride/10% potassium hydrogen sulphate and subsequently saturated sodium hydrogen carbonate solution the organic phase is dried and concentrated. 52.3 g of crude (4E,8E)-(RS)-4,8-dimethyl-1 0-(tetrahydro-pyran-2-yloxy)-deca-4,8-dienoic acid allyl-methylamide are obtained.