Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2[CH:6]=[N:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1[Cl:20].BrC1N(COCC[Si](C)(C)C)C2C=NNC(=O)C=2C=1.[F:40][CH:41]([F:64])[O:42][C:43]1[CH:44]=[CH:45][C:46](B2OC(C)(C)C(C)(C)O2)=[C:47]2[C:52]=1[O:51][C:50]([CH3:54])([CH3:53])[CH:49]=[CH:48]2.C1(OC2C=C(B3OC(C)(C)C(C)(C)O3)C=CC=2OC(F)F)CC1>>[Cl:20][C:3]1[C:4]2[C:9](=[O:10])[NH:8][N:7]=[CH:6][C:5]=2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:2]=1[C:46]1[CH:45]=[CH:44][C:43]([O:42][CH:41]([F:40])[F:64])=[C:52]2[C:47]=1[CH:48]=[CH:49][C:50]([CH3:54])([CH3:53])[O:51]2
Reactant: C[Si](C)(C)CCOCn1c(Br)c(Cl)c2c(=O)[nH]ncc21
Reactant: CC1(C)C=Cc2c(B3OC(C)(C)C(C)(C)O3)ccc(OC(F)F)c2O1
Agent: CC1(C)OB(c2ccc(OC(F)F)c(OC3CC3)c2)OC1(C)C
Agent: C[Si](C)(C)CCOCn1c(Br)cc2c(=O)[nH]ncc21
Product: CC1(C)C=Cc2c(-c3c(Cl)c4c(=O)[nH]ncc4n3COCC[Si](C)(C)C)ccc(OC(F)F)c2O1
Yield: 69.8 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 1-(a) except for using 189 mg (0.500 mmol) of 2-bromo-3-chloro-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the following Reference example 16-(d) in place of 2-bromo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one, and using 352 mg (1.00 mmol) of 2-(8-difluoromethoxy-2,2-dimethyl-2H-chromen-5-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane obtained in the following Reference example 1-(i) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane, whereby 183 mg of the title compound was obtained as a pale yellowish foam. (Yield: 70%)
Reaction SMILES: C([O:8][C:9]1[C:27]([Cl:28])=[CH:26][C:12]([C:13]([NH:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)=[O:14])=[CH:11][C:10]=1[Cl:29])C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[Cl:28][C:27]1[CH:26]=[C:12]([CH:11]=[C:10]([Cl:29])[C:9]=1[OH:8])[C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=1)=[O:14]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(OCc3ccccc3)c(Cl)c2)cc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(O)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.3 %

Procedure:
A solution of methyl 4-(4-(benzyloxy)-3,5-dichlorobenzamido)benzoate (4) (8.8 g, 20.5 mmol) in DCM (500 mL) was cooled to 0° C. and treated dropwise with boron trichloride (20.5 mL, 20.5 mmol, 1 M in DCM). The mixture was then allowed to stir at RT for 12 h. The mixture was cooled in an ice bath then quenched by addition of water (150 mL). The resultant mixture was partitioned between EtOAc (200 mL) and H2O (100 mL). The aqueous phase was extracted with EtOAc (2×75 mL) and the combined organic phases washed successively with water (50 mL) and brine (50 mL), then dried over MgSO4 and filtered. The solvent was removed in vacuo. The residue was crystallised from isohexane/EtOAc to afford methyl 4-(3,5-dichloro-4-hydroxybenzamido)benzoate (5) (5.81 g, 84%): m/z 338 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 11.06 (1H, s), 10.52 (1H, s), 8.06 (2H, s), 8.00 (2H, d), 7.95 (2H, d), 3.88 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([N:17]([CH3:19])[CH3:18])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][N:17]([CH3:19])[CH3:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)C(=O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Agent: Cl
Product: CN(C)CC1(c2ccc(Cl)c(Cl)c2)CCCCC1

Procedure:
The title compound was synthesized from 1-(3,4-dichlorophenyl)-N,N-dimethylcyclohexanecarboxamide (71 mg, 0.24 mmol) using General Procedure E followed by HCl salt formation. The crude HCl salt was recrystallized from CH3CN (3 mL) to afford the product as an off-white solid. HPLC Rt=8.70 min; 1H NMR (400 mHz, MeOH-d4) 7.72 (d, J=2.44 Hz, 1H), 7.63 (d, J=8.55 Hz, 1H), 7.49 (dd, J=2.44, 8.55 Hz, 1 H), 3.47 (bs, 2H), 3.32 (s, 6H), 2.28-2.24 (bs, 2H), 1.81-1.39 (m, 8H); LCMS 9.79 min, (M+1)+ 286@10.0 min.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[N:8]([CH3:11])[CH:9]=[O:10].[CH3:12][C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][C:14]=1[CH2:24][O:25][C:26]1[CH:46]=[CH:45][C:29]([CH2:30][O:31]/[N:32]=[C:33](/[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)\[CH2:34][CH2:35]C(O)=O)=[CH:28][CH:27]=1>O1CCCC1>[CH3:11][NH:8][C:9](=[O:10])[CH2:35][CH2:34]/[C:33](=[N:32]\[O:31][CH2:30][C:29]1[CH:45]=[CH:46][C:26]([O:25][CH2:24][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:17][C:13]=2[CH3:12])=[CH:27][CH:28]=1)/[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccccc2)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CNC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Oxalyl chloride (0.156 ml) and N,N-dimethylformamide (catalytic amount) were added to a solution of E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid (700 mg) in tetrahydrofuran (10 ml) at room temperature, which was stirred at room temperature for 30 minutes and concentrated. The residue was dissolved in tetrahydrofuran (5 ml) and added dropwise to a mixture of a 40% aqueous methylamine (20 ml) and ethyl acetate (30 ml) at 0° C. After stirred at room temperature for 1 hour, water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain E-N-methyl-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutaneamide (466 mg, yield 65%) as colorless crystals. m.p. 141-142° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:37][O:38][C:39]1[CH:49]=[CH:48][C:47](/[CH:50]=[CH:51]\[C:52]2[CH:57]=[C:56]([O:58][CH3:59])[C:55]([O:60][CH3:61])=[C:54]([O:62][CH3:63])[CH:53]=2)=[CH:46][C:40]=1[O:41][CH2:42][C:43](O)=[O:44]>ClCCl.O>[F:15][C:2]([F:1])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH:11][C:43](=[O:44])[CH2:42][O:41][C:40]3[CH:46]=[C:47](/[CH:50]=[CH:51]\[C:52]4[CH:57]=[C:56]([O:58][CH3:59])[C:55]([O:60][CH3:61])=[C:54]([O:62][CH3:63])[CH:53]=4)[CH:48]=[CH:49][C:39]=3[O:38][CH3:37])[S:10][C:6]=2[CH:5]=1
Reactant: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)O
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)Nc1nc2ccc(OC(F)(F)F)cc2s1
Yield: 795.8 %

Procedure:
To a solution of 6-(trifluoromethoxy)-2-aminobenzothiazole (234 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetic acid (1) (374 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (8j) (470 mg, 80% yield)
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=2[N:13]=1)=[O:7])(=O)C.N>CO>[OH:4][CH2:5][C:6]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=2[N:13]=1)=[O:7]
Reactant: COc1ccc2nc(NC(=O)COC(C)=O)sc2c1
Agent: N
Solvent: CO
Product: COc1ccc2nc(NC(=O)CO)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
2-(Acetoxyacetylamino)-6-methoxybenzothiazole (13.0 g) prepared in Example 2 is dissolved in methanol (1000 ml) and thereto is added 28% aqueous ammonia (100 ml) and the mixture is stirred at room temperature for 1 hour. The solvent is distilled off and the resulting solids are washed with water, dried and recrystallized from ethanol to give the title compound (10.3 g) having the following physical properties.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:13])[NH:7]2.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=2)[CH2:26][CH2:25]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:12][C:9]1[CH:10]=[CH:11][C:2]([O:1][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)[CH2:26][CH2:25]2)=[C:3]2[C:8]=1[NH:7][C:6](=[O:13])[CH2:5][CH2:4]2
Reactant: Cc1ccc(O)c2c1NC(=O)CC2
Reactant: ClCCCN1CCN(Cc2ccc3ccccc3n2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Product: Cc1ccc(OCCCN2CCN(Cc3ccc4ccccc4n3)CC2)c2c1NC(=O)CC2
Temperature: 50 °C
Reaction time: 48 h
Yield: 17 %

Procedure:
After a mixture consisting of 5-hydroxy-8-methyl-1,2,3,4-tetrahydroquinolin-2-one (1.80 g, 10.2 mmol), tetra-n-butylammonium bromide (0.322 g, 1 mmol), potassium carbonate (4.146 g, 30 mmol), 1-(3-chloropropyl)-4-(2-quinolylmethyl)piperazine (3.67 g, 12.1 mmol) and N,N-dimethylformamide (40 ml) was stirred for 2 days at a bath temperature of 50° C. under an argon gas stream, the solvent was distilled off under reduced pressure. Water was added to the residue, followed by extraction with chloroform. The extract was washed with water and then dried over anhydrous magnesium sulfate. The extract was subjected to chromatography on a silica gel column (developer: chloroform/methanol=40/1) and then crystallized from ethyl acetate-n-hexane, whereby 0.773 g of the title compound was obtained as yellow leaflets (yield: 17.2%).
Reaction SMILES: O1CCCC1.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([OH:28])[C:14]2[C:15]3[CH:16]=[C:17]([CH3:27])[CH:18]=[CH:19][C:20]=3[C:21]([CH3:26])([CH3:25])[O:22][C:23]=2[CH:24]=1.[BH4-].[Na+]>O>[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([OH:28])[C:14]2[C@@H:15]3[CH:16]=[C:17]([CH3:27])[CH2:18][CH2:19][C@H:20]3[C:21]([CH3:26])([CH3:25])[O:22][C:23]=2[CH:24]=1
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)c1ccc(C)cc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Reaction time: 18 h

Procedure:
Five ml of tetrahydrofuran containing 38.75 mg of a cannabinol derivative having the formula ##STR4## were added to the activated-LPS effluent, and the mixture was incubated for 18 hours at 22° C. in the dark. Two ml of a solution of 4.5 mg/ml NaBH4 in H2O were added, and the mixture was incubated for 30 minutes at room temperature. Unconjugated THC derivative was removed by dialysis for 2 days against frequent changes of water and for 2 days against 0.1M acetic acid, pH 3.5, to yield a THC-LPS conjugate.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[NH:11][C:10]1=[O:19].[CH2:28]([NH:30][C:31](=[O:38])[C@@H:32]1[CH2:36][CH:35]([F:37])[CH2:34][NH:33]1)[CH3:29].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Cl:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:19])[C:9]2([N:33]1[CH2:34][CH:35]([F:37])[CH2:36][C@H:32]1[C:31]([NH:30][CH2:28][CH3:29])=[O:38])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CCNC(=O)[C@@H]1CC(F)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCNC(=O)[C@@H]1CC(F)CN1C1(c2ccccc2OC)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 18.5 h

Procedure:
1.0 mL of triethylamine was added under ice cooling to a 15 mL chloroform solution of 1.02 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 530 mg of the compound obtained in step 8-2, after which the reaction mixture was stirred for 18.5 hours at room temperature. 20 mL of a 5% potassium carbonate aqueous solution was poured into the reaction solution under stirring, and extraction was performed with chloroform (20 mL×2). The combined organic layer was washed with saturated brine and dried with sodium sulfate, then the drying agent was filtered off and the solvent was distilled off under reduced pressure. The residue thus obtained was separated and purified by column chromatography (silica gel 60, mobile phase: ethyl acetate/acetone=98/2; v/v) to obtain two kinds of diastereoisomer of the titled compound in amounts of 708 mg (isomer A: colorless, amorphous) and 501 mg (isomer B: colorless, amorphous).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:28]1([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[C:1]1([NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:31]3[CH2:32][CH2:33][N:28]([C:34]4[CH:43]=[CH:42][C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[N:35]=4)[CH2:29][CH2:30]3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccccc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: O=C(Nc1ccccc1)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2b from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(phenyl)-amide and 2-(piperazin-1-yl)-quinoline.
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)=[CH:23][CH:22]=1>>[C:1]1([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH:29]4[CH2:30][CH2:31][N:32]([C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]4)=[CH:25][CH:26]=3)=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NCc1ccccc1)c1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(=O)NCc4ccccc4)cc3)cc2)CC1
Yield: 14.6 %

Procedure:
The title compound (7.1 mg, 15%) was prepared from (4-{[(phenylmethyl)amino]carbonyl}phenyl)boronic acid (25.5 mg, 0.1 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (Example 9, Step 2, 36 mg, 0.10 mmol) in a manner similar to Example 9, Step 3. LRMS (ESI), m/z 487 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][OH:12].[CH3:13][C:14]([O-])(C)[CH3:15].[K+].C(Br)C=C>C1COCC1.C(OCC)(=O)C>[CH2:15]([O:12][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[NH2:1])[CH:14]=[CH2:13]
Reactant: CC(C)(C)[O-]
Reactant: Nc1cc([N+](=O)[O-])ccc1CO
Agent: [K+]
Solvent: C=CCBr
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOCc1ccc([N+](=O)[O-])cc1N
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of 2-amino-4-nitrobenzenemethanol (14.3 g, 85 mmol) in dry THF (350 mL) at 0° C. under an argon atmosphere, is treated dropwise over 35 min with a solution of potassium tert-butylate in THF (Fluka; 85 mL of 1.0 M). The mixture is stirred at 0° C. for 15 min and then treated dropwise over 50 min with a solution of allylbromide (7.9 mL, 94 mmol) in dry THF (80 mL) at 0° C. and then stirred at 20° C. for 90 min. The mixture is diluted with ethyl acetate (800 mL). The resulting solution is washed with saturated aqueous ammonium chloride (3×400 mL), dried (MgSO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent 50% ethyl acetate in hexane, to give the title compound as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[N:10]=1)=[O:8].[CH3:22][CH2:23][O-:24].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:24][CH2:23][CH3:22])[N:10]=1)=[O:8]
Reactant: CC[O-]
Reactant: COc1ccc(OC)c(CNC(=O)c2cccc(Br)n2)c1
Agent: [Na+]
Solvent: CCO
Product: CCOc1cccc(C(=O)NCc2cc(OC)ccc2OC)n1
Temperature: 150 °C
Yield: 69.5 %

Procedure:
A mixture of bromide from Example 156A (35 mg, 0.1 mmol) and NaOEt (21% w/w ethanol soulution, 56 μL, 0.15 mmol) in ethanol (500 μL) was heated in a microwave oven at 150° C. for 10 minutes. It was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel column using ethyl acetate:hexane (1:1) to provide the titled compound (22 mg, 70%). MS (ESI(+)) m/e 317 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.89 (t, J=6.4 Hz, 1H), 7.89-7.84 (m, 1H), 7.63-7.60 (m, 1H), 7.02-6.74 (m, 4H), 4.46 (d, J=6.4 Hz, 2H), 4.45 (q, J=7.1 Hz, 2H), 3.80 (s, 3H), 3.65 (s, 3H), 1.35 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: C1CCNCC1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2CCCCC2)c(C)c1
Yield: 96.3 %

Procedure:
BINAP (0.67 g; 1.1 mmol; 0.05 eq.) and palladium acetate (0.24 g; 1.1 mmol; 0.05 eq.) were added to a suspension methyl 4-bromo-3-methylbenzoate (5 g; 21.8 mmol; 1 eq.), Cs2CO3 (10.65 g; 32.7 mmol; 1.5 eq.) and piperidine (2.2 g; 26 mmol; 1.2 eq.) in dioxane (100 mL) and the reaction mixture was refluxed for 15 hours. After filtration through a pad of CELITE, the solution was concentrated in vacuo and the residue purified by column chromatography (petroleum ether/ethyl acetate, 80/20) to afford the title compound (4.9 g, 96%) as a brown solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH2:32]([O:39][C:40]1[CH:41]=[C:42]([C:46]2[N:51]=[CH:50][C:49]([OH:52])=[CH:48][N:47]=2)[CH:43]=[CH:44][CH:45]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[CH2:53](O)[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60]>O1CCCC1>[CH2:32]([O:39][C:40]1[CH:41]=[C:42]([C:46]2[N:47]=[CH:48][C:49]([O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])=[CH:50][N:51]=2)[CH:43]=[CH:44][CH:45]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Oc1cnc(-c2cccc(OCc3ccccc3)c2)nc1
Reactant: CCCCCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1cnc(-c2cccc(OCc3ccccc3)c2)nc1
Yield: 77.6 %

Procedure:
5.52 g (21.05 mmol) of triphenylphosphine and 3.67 g (21.05 mmol) of diethyl azodicarboxylate are stirred at 0° C. for 30 minutes in 100 ml of tetrahydrofuran. 3.90 g (14.03 mmol) of 2-(3-benzyloxyphenyl)-5-hydroxypyrimidine and 2.74 g (21.05 mmol) of 1-octanol are subsequently added, and the resultant solution is stirred at room temperature for 18 hours. Evaporation to dryness and purification by chromatography (silica gel/dichloromethane) give 4.25 g of 2-(3-benzyloxyphenyl)-5-octyloxypyrimidine. ##STR29## Removal of the benzyl protecting group by hydrogenation analogously to Example 1 gives 2-(3-hydroxyphenyl)-5-octyloxypyrimidine. ##STR30## 2-(3-Hydroxyphenyl)-5-octyloxypyrimidine is reacted with methanol analogously to Example 1 to give 2-(3-methoxyphenyl)-5-octyloxypyrimidine. ##STR31## The compound has the phase sequence: X43 I
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:32].Br[C:34]1[CH:44]=[CH:43][CH:42]=[C:41]([N:45]2[CH:54]=[CH:53][C:52]3[C:47](=[CH:48][CH:49]=[C:50]([N:55]([CH3:57])[CH3:56])[CH:51]=3)[C:46]2=[O:58])[C:35]=1[CH2:36][O:37][C:38](=[O:40])[CH3:39].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:57][N:55]([CH3:56])[C:50]1[CH:51]=[C:52]2[C:47](=[CH:48][CH:49]=1)[C:46](=[O:58])[N:45]([C:41]1[CH:42]=[CH:43][CH:44]=[C:34]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)=[O:25])=[CH:20][N:19]=4)[C:3](=[O:32])[N:2]([CH3:1])[CH:7]=3)[C:35]=1[CH2:36][O:37][C:38](=[O:40])[CH3:39])[CH:54]=[CH:53]2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: CC(=O)OCc1c(Br)cccc1-n1ccc2cc(N(C)C)ccc2c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)c2)cccc1-n1ccc2cc(N(C)C)ccc2c1=O
Temperature: 100 °C
Yield: 52.6 %

Procedure:
To 1-Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (43 mg, 0.097 mmol), Acetic acid 2-bromo-6-(6-dimethylamino-1-oxo-1H-isoquinolin-2-yl)-benzyl ester (40 mg, 0.097 mmol), potassium phosphate (41 mg, 0.19 mmol), 2-(dicyclohexylphoshphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (2.7 mg, 0.0057 mmol), and bis(dibenzylidineacetone)palladium(0) (1.6 mg, 0.0028 mmol) was added 4 mL of degassed 1:3 water/n-butanol. The headspace of the vessel was evacuated and backfilled with argon 4 times. This was heated at 100° C. for 110 minutes. This was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 2 to 5% methanol/dichloromethane) to yield Acetic acid 2-(6-dimethylamino-1-oxo-1H-isoquinolin-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzyl ester (33 mg, 0.051 mmol). MS (ESI) 649.2 (M+H)+.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH:15]=[C:14]([C:16]4[CH:17]=[N:18][C:19]5[N:20]([C:22]([C:25]6([C:28]7[CH:29]=[C:30]8[C:35](=[CH:36][CH:37]=7)[N:34]=[CH:33][CH:32]=[CH:31]8)[CH2:27][CH2:26]6)=[CH:23][N:24]=5)N=4)[CH:13]=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1.O1C2(CCC(O)CC2)OC[CH2:39]1>>[N:34]1[C:35]2[C:30](=[CH:29][C:28]([C:25]3([C:22]4[N:20]5[CH:39]=[C:16]([C:14]6[CH:13]=[N:12][N:11]([CH:8]7[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]7)[CH:15]=6)[CH:17]=[N:18][C:19]5=[N:24][CH:23]=4)[CH2:26][CH2:27]3)=[CH:37][CH:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: c1cnc2ccc(C3(c4cnc5ncc(-c6cnn(C7CCC8(CC7)OCCO8)c6)nn45)CC3)cc2c1
Reactant: OC1CCC2(CC1)OCCO2
Product: O=C1CCC(n2cc(-c3cnc4ncc(C5(c6ccc7ncccc7c6)CC5)n4c3)cn2)CC1
Temperature: 100 °C

Procedure:
The crude reaction mixture containing 6-(1-{2-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-4-yl]imidazo[1,2-b][1,2,4]triazin-7-yl}cyclopropyl)quinoline (˜30 mg, 0.07 mmol), prepared using a procedure analogous to that described for the synthesis of Example 88 starting from 1,4-dioxaspiro[4.5]decan-8-ol, was concentrated and treated directly with AcOH (1 mL), water (100 μL) and heated to 100° C. for 1 h to afford the desired product, which was purified by RP-HPLC. LCMS: (M+H)=449.2.