Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:32])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][N:14]=[C:13]([N:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]=3[CH:31]=2)[CH:7]=1.[Br:33]N1C(=O)CCC1=O>C(#N)C>[Br:33][C:4]1[C:5]([OH:32])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][N:14]=[C:13]([N:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[C:12]=3[CH:31]=2)[CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1noc2ccc(-c3cc(Cl)ccc3O)cc12
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1noc2ccc(-c3cc(Cl)cc(Br)c3O)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a solution of di-tert-butyl [5-(5-chloro-2-hydroxyphenyl)-1,2-benzoxazol-3-yl]imidodicarbonate (2.00 g, 4.34 mmol) in acetonitrile (45 mL) was added N-bromosuccinimide (0.811 g, 4.56 mmol). The mixture was stirred at ambient temperature for 0.5 h and concentrated in vacuo. The residue was purified by column chromatography eluting with a 5-15% gradient of ethyl acetate in hexanes) to afford di-tert-butyl [5-(3-bromo-5-chloro-2-hydroxyphenyl)-1,2-benzoxazol-3-yl]imidodicarbonate as an orange solid in 35% yield (0.83 g): 1H NMR (300 MHz, DMSO-d6) δ 9.55 (s, 1H), 7.95-7.93 (m, 1H), 7.89-7.86 (m, 2H), 7.69 (d, J=2.6 Hz, 1H), 7.38 (d, J=2.6 Hz, 1H), 1.39 (s, 18H); MS (ES−) m/z 536.9 (M−1), 538.9 (M−1), 540.9 (M−1).
Reaction SMILES: O[C:2]1[N:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[NH:5][C:4]([O:18][CH3:19])(O)[CH:3]=1.C(N(CC)C1C=CC=CC=1)C.O=P(Cl)(Cl)[Cl:33]>>[Cl:33][C:2]1[CH:3]=[C:4]([O:18][CH3:19])[N:5]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[N:7]=1
Reactant: COC1(O)C=C(O)N=C(c2nc(C(F)(F)F)cs2)N1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: COc1cc(Cl)nc(-c2nc(C(F)(F)F)cs2)n1
Temperature: 110 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a stirred solution of compound 289 (2.38 g, 1 eq.) in POCl3 (7.2 mL) was added N,N-diethylaniline (2.17 g, 1.7 eq.). The mixture was stirred at 110° C. for 16 hrs. The reaction was cooled down to room temperature and poured dropwise into an ice/water mixture. The aqueous solution was extracted with DCM. Organics were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography to yield compound 290 as an orange solid in 45% yield. MS (ESI, EI+): m/z=296 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][C:8]=1[O:16][CH3:17])=O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[CH3:17][O:16][C:8]1[C:7]2[N:6]=[C:4]([CH2:3][O:2][CH3:1])[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: COCC(=O)Nc1c(OC)cccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCc1nc2c(OC)cccc2[nH]1
Temperature: 25 °C
Yield: 31.9 %

Procedure:
[step 2] 2-Methoxy-N-(2-methoxy-6-nitrophenyl)acetamide (5.4 g, 22.5 mmol) obtained in step 1 was dissolved in ethanol (45 mL), tin (II) chloride.2 hydrate (24.4 g, 108 mmol) was added, and the mixture was stirred with heating under reflux for 1 hr. After cooling to room temperature, 4 mol/L aqueous sodium hydroxide solution was added to the mixture. The mixture was filtered through celite, and the solution was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained brown oil (3.7 g) was suspended in diisopropyl ether (30 mL) and isopropyl alcohol (3 mL), and stirred at room temperature for 1 hr. The suspension was suction filtered, and the obtained solid was dried under reduced pressure to give 4-methoxy-2-(methoxymethyl)-1H-benzo[d]imidazole (1.38 g, 32%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10](OCC)=[O:11].CC(C)=O.C(=O)=O.CC(C[AlH]CC(C)C)C>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][OH:11]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: OCc1cc2ccccc2[nH]1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
In a 50-mL round-bottom flask, a total of 2.28 g (12 mmol) of ethyl 2-indolecarboxylate was dissolved in 15 mL of dry THF under N2. The solution was cooled to -78° C. (acetone-dry ice bath) and 24 mL (24 mmol) of 1.0M DIBAL in THF was added over a period of 1 h. The mixture was stirred for 2 h at -78° C., quenched with 10 mL of 1N HCl, then allowed to warm to room temperature. The reaction mixture was then extracted with ether (4×100 mL) and the ether layer was washed with 1N HCL (2×100 mL), dried over MgSO4, filtered, and evaporated in vacuo. The product was purified by flash chromatography (1:1 ethyl acetate:petroleum ether). Yield: 1.76 g (99%). 1H NMR (CDCl3): δ1.86 (t, 1H, J=6, OH), 4.82 (d, 2H, J=6), 6.40 (s, 1H), 7.0-7.3 (m, 2H), 7.34 (d, 1H, J=7.8), 7.58 (d, 1H, J=7.8), 8.36 (br s, 1H) MS (EI): m/z 147 (M+).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]2[CH2:26][CH2:25][CH:24]3[CH:19]([CH:20]=[CH:21][CH2:22][CH2:23]3)[S:18]2)=[CH:12][CH:11]=1.[CH:27](OCC)=[O:28].[Cl-].[NH4+]>C1COCC1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[S:18][CH:19]3[CH:24]([CH2:25][C:26]=2[CH:27]=[O:28])[CH2:23][CH2:22][CH:21]=[CH:20]3)=[CH:14][CH:15]=1
Reactant: Clc1ccc(N=C2CCC3CCC=CC3S2)cc1
Reactant: CCOC=O
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=CC1=C(Nc2ccc(Cl)cc2)SC2C=CCCC2C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
3.0 ml of lithium diisopropyl amide (1.5 mol/l of THF/cyclohexane solution) was dropped into 20 ml of anhydrous THF solution including 0.84 g of (4-chlorophenyl)-(3,4,4a,5,6,8a-hexahydro-thiochromene-2-ylidene)-amine under nitrogen atmosphere at −78° C. After stirring at −78° C. for 30 minutes, 2 ml of THF solution including 0.34 g of ethyl formate was dropped into the resulting solution. The solution was stirred at room temperature for one additional hour, and added with saturated ammonium chloride aqueous solution, extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain crude 2-(4-chloro-phenylamino)-4a,5,6,8a-tetrahydro-4H-thiochromene-3-carbaldehyde.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9]Br)([CH3:4])([CH3:3])[CH3:2].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH:20]=1)[CH:18]=[O:19].C([O-])([O-])=O.[K+].[K+]>>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:21][C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:20][C:17]=1[CH:18]=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)NCCOc1ccc(Cl)cc1C=O
Yield: 71.2 %

Procedure:
In a manner similar to the method described in Example 227a, (2-bromo-ethyl)-carbamic acid tert-butyl ester (10 g, 44.8 mmol) was reacted with 5-chloro-2-hydroxy-benzaldehyde (7 g, 44.8 mmol), K2CO3 (18.6 g, 134 mmol) and KI (1.48 g, 8.96 mmol) to give title compound as oil (9.56 g)
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[Cl:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][N:57]1[CH2:62][CH2:61][CH:60]([NH2:63])[CH2:59][CH2:58]1>>[Cl:31][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:22]=1[NH:21][C:19]1[N:18]=[CH:17][C:8]2[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[C:7]=2[N:20]=1)[C:26]([NH:63][CH:60]1[CH2:61][CH2:62][N:57]([CH3:56])[CH2:58][CH2:59]1)=[O:28]
Reactant: CN1CCC(N)CC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3Cl)ncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(Cl)c2)CC1

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-chlorobenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-1.77 (m, 15 H) 2.23 (s, 3 H) 2.84 (m, 2 H) 3.96-4.07 (t, J=12 Hz, 2 H) 4.66 (m, 1 H) 7.80 (dd, J=8.5, 1.9 Hz, 1 H) 8.00 (d, J=1.8 Hz, 1 H) 8.08 (d, J=8.6 Hz, 1 H) 8.19-8.33 (m, 2 H) 8.58 (s, 1 H). [M+H] calc'd for C26H32ClF2N7O2, 548; found 548.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[F:12].[Si:13]([O:20][CH2:21][C:22]([CH3:36])([CH3:35])[CH2:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][C:25]=1[C:31]([F:34])([F:33])[F:32])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(N(C(C)C)C(C)C)C.O.N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([CH2:23][C:22]([CH3:35])([CH3:36])[CH2:21][O:20][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])=[C:25]([C:31]([F:34])([F:32])[F:33])[CH:26]=2)=[O:11])=[CH:4][C:3]=1[F:12]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Cc1ccc(N)cc1C(F)(F)F
Reactant: O=C(O)Cc1ccc(Br)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)Cc1ccc(NC(=O)Cc2ccc(Br)c(F)c2)cc1C(F)(F)F
Yield: 61.4 %

Procedure:
A solution of 2-(4-bromo-3-fluorophenyl)acetic acid (50 mg, 0.215 mmol), 4-(3-((tert-butyl dimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)aniline (78 mg, 0.215 mmol), N-ethyl-N-isopropylpropan-2-amine (83 mg, 0.644 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (49.3 mg, 0.322 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (61.7 mg, 0.322 mmol) in DCM (20 mL) was stirred at 20° C. for 16 h. The mixture was washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=3/1) to yield 2-(4-bromo-3-fluorophenyl)-N-(4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)acetamide (80 mg, 0.132 mmol, 61.4% yield): 1H NMR (400 MHz, CD3OD) δ 7.83 (d, J=2.0 Hz, 1H), 7.61 (d, J=6.6 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.15 (dd, J=9.7, 1.8 Hz, 1H), 7.01 (d, J=6.8 Hz, 1H), 3.62 (s, 2H), 2.70 (s, 2H), 2.07 (s, 2H), 0.86 (s, 9H), 0.76-0.69 (m, 6H), 0.05-0.02 (m, 6H); ES-LCMS m/z 576.0 (M+H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([C:13]1[CH:41]=[CH:40][C:16]2[N:17]([CH2:21][CH2:22][O:23][C:24]3[CH:39]=[CH:38][C:27]([CH2:28][CH:29]([C:34]([O:36][CH3:37])=[O:35])[C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=3)[C:18](=[O:20])[S:19][C:15]=2[CH:14]=1)=O>CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:13]1[CH:41]=[CH:40][C:16]2[N:17]([CH2:21][CH2:22][O:23][C:24]3[CH:39]=[CH:38][C:27]([CH2:28][CH:29]([C:34]([O:36][CH3:37])=[O:35])[C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=3)[C:18](=[O:20])[S:19][C:15]=2[CH:14]=1
Reactant: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccc5ccccc5c4)ccc32)cc1)C(=O)OC
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(Cc4ccc5ccccc5c4)ccc32)cc1)C(=O)OC

Procedure:
The procedure is as in Example 48, starting from the compound obtained in Example 60. The recrystallisation solvent is methanol.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.[NH:21]1[CH2:26][CH2:25][C:24]2([C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27]2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>>[C:8]1([C:5]2[N:4]=[N:3][C:2]([N:21]3[CH2:26][CH2:25][C:24]4([C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=[CH:27]4)[CH2:23][CH2:22]3)=[CH:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Reactant: Clc1ccc(-c2ccccc2)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: C1=CC2(CCN(c3ccc(-c4ccccc4)nn3)CC2)c2ccccc21

Procedure:
The object product (54 mg, 27%) was obtained in the same manner as in Example 1 and using 3-chloro-6-phenylpyridazine (114 mg), spiro[indene-1,4′-piperidine] trifluoroacetate (210 mg) and potassium carbonate (130 mg).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH2:5]([O:12][NH:13][CH:14]([C:16]1[CH:20]=[CH:19][N:18]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])[CH:17]=1)[CH3:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>CCOCC>[CH3:1][NH:2][C:3]([N:13]([CH:14]([C:16]1[CH:20]=[CH:19][N:18]([C:21]2[C:22]([CH3:28])=[CH:23][CH:24]=[CH:25][C:26]=2[CH3:27])[CH:17]=1)[CH3:15])[O:12][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:4]
Reactant: CN=C=O
Reactant: Cc1cccc(C)c1-n1ccc(C(C)NOCc2ccccc2)c1
Solvent: CCOCC
Solvent: O
Product: CNC(=O)N(OCc1ccccc1)C(C)c1ccn(-c2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methyl isocyanate (5 ml) is added to a solution of 2.1 g of N-benzyloxy-1-[1-(2,6-dimethylphenyl)-1H-pyrrol-3-yl]-ethylamine in 200 ml of ether and the solution is stirred at room temperature for 24 hours. Excess water is added and the mixture is stirred for 3 hours. The organic layer is separated, washed with brine, dried over magnesium sulfate and evaporated to dryness to yield N-(N'-methylcarbamoyl)-N-benzyloxy-1-[1-(2,6-dimethylphenyl)-1H-pyrrol-3-yl]-ethylamine.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([N:9]2[N:19]=[C:18]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:10]2=[O:11])[CH2:5][CH2:4][CH2:3]1.[C:28]([OH:31])(=[O:30])[CH3:29]>>[CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([N:9]2[N:19]=[C:18]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:10]2=[O:11])[CH2:5][CH2:4][CH2:3]1.[C:28]([O-:31])(=[O:30])[CH3:29]
Reactant: CC(=O)O
Agent: CN1CCCC(n2nc(Cc3ccc(Cl)cc3)c3ccccc3c2=O)CC1
Product: CC(=O)[O-]

Procedure:
The pH value of the emulsion is 5.2, the molar ratio azelastine : acetic acid is 1:1.25.
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])/[CH:2]=[CH:3]/[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].CCN(CC)CC.Br[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>CN(C=O)C.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22](/[C:3](/[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:2]\[C:1]([O:11][CH2:12][CH3:13])=[O:10])[CH:23]=1
Reactant: Brc1cccnc1
Reactant: CCOC(=O)/C=C/CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C(/CC(=O)OCC)c1cccnc1
Temperature: 40 °C
Yield: 87.1 %

Procedure:
To a solution of 15 mL (85.6 mmol) of diethyl (2E)-pent-2-enedioate in 5 mL of anhydrous DMF are added, under a stream of argon, 0.62 g (2.8 mmol) of Pd(OAc)2, 1.7 g (5.56 mmol) of P(OTol)3 and 5.5 mL (39.7 mmol) of Et3N, the medium is then heated to 40° C. and 4 mL (39.75 mmol) of 3-bromopyridine are added. The medium is then heated for 24 hours at 90° C., and then taken up in 100 mL of EtOAc, washed with 100 mL of water, dried over Na2SO4, concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 10% EtOAc. 9.12 g of diethyl (2Z)-3-(pyridin-3-yl)pent-2-enedioate are obtained in the form of a yellow wax.
Reaction SMILES: C1(S([C:10]2[CH:25]=[CH:24][C:13]3[N:14]([C:18](=O)[CH2:19][CH2:20][NH:21][CH3:22])[CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)(=O)=O)C=CC=CC=1.B.Cl.Cl.[C:29]1([S:35](C2C=CC3N(CCCNC)CCOC=3C=2)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OCC)C.C1COCC1>[C:29]1([S:35]([C:25]2[CH:10]=[CH:11][C:12]3[O:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][NH:21][CH3:22])[C:13]=3[CH:24]=2)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CNCCC(=O)N1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: CNCCCN1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNCCCN1CCOc2ccc(S(=O)(=O)c3ccccc3)cc21
Temperature: 0 °C

Procedure:
To 1 mL of freshly distilled THF was added 1-(7-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-3-methylamino-propan-1-one (0.075 g, 0.210 mmol) and the resulting solution was cooled to 0° C. Borane:THF complex (0.315 mL of a 1 M solution, 0.315 mmol) was added dropwise over 2 minutes, during which offgassing was observed. The solution was warmed to reflux for 6 hours with stirring and then cooled to room temperature. Ethanolic hydrogen chloride (0.750 mL of a 2N solution, 1.5 mmol) was added dropwise accompanied by vigorous offgassing. The reaction mixture was refluxed for 2 hours at which time a white solid was observed in the solution. To the reaction mixture was added 2 mL diethyl ether and the solid was filtered and dried overnight under reduced pressure to give 0.045 g. of [3-(7-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propyl]-methyl-amine hydrochloride as a fluffy white solid. MS: 347 (M+H)+, mp: 188.3-193.2° C. (as hydrochloride salt).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12]C)=[CH:7]2.B(Br)(Br)Br.ClC(Cl)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([OH:12])=[CH:7]2
Reactant: COc1cnc2c(Cl)ccnc2c1
Agent: BrB(Br)Br
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: Oc1cnc2c(Cl)ccnc2c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A pressure-resistant vial was charged with 8-chloro-3-methoxy-1,5-naphthyridine (1200 mg, 6166 mmol), boron tribromide (6412 μl, 67825 μmol) and dichloroethane (10277 μl, 6166 μmol). The vessel was sealed and the mixture was stirred at 60° C. for 16 h. The reaction mixture was carefully diluted with DCM, and the solids were filtered.
Reaction SMILES: [OH:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:23]=[C:22]([C:24]([NH:26][CH:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])=[O:25])[O:21][N:20]=2)=[CH:15][CH:14]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>>[OH:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:23]=[C:22]([C:24]([NH:26][CH:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])=[O:25])[O:21][N:20]=2)=[CH:15][CH:14]=1)=[O:5]
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: COC(=O)C(NC(=O)c1cc(-c2ccc(N)cc2)no1)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)[C@H](O)c3ccccc3)cc2)no1)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
To (R)-2-hydroxy-2-phenylacetic acid (200 mg), methyl 2-(3-(4-aminophenyl) isoxazole-5-carboxamido)-3-methylbutanoate (417 mg), in N,N′-Dimethyl formamide (5 ml), DCC (406 mg) and HOBT (177 mg) were added and stirred at RT for 16 hours. The reaction mixture was filtered and concentrated to obtain brown oil which was purified by column chromatography (silica gel, EtOAc—CHCl3) to obtain pale brown solid which was crystallized from DCM-Petroleum ether to yield 235 mg (39%) of the title compound as off white solid. MS (ES+): m/z 452 (M+1); 1H NMR (DMSO-d6; 300 MHz): δ 10.19 (s, 1H), 9.2 (d, 1H), 7.88 (d, 4H), 7.69 (s, 1H), 7.54 (m, 2H), 7.39-7.27 (m, 3H), 6.51 (d, 1H), 5.13 (d, 1H), 4.3 (m, 1H), 3.67 (s, 3H), 2.24 (m, 1H), 0.96 (d, 6H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[N:7][C:6]=2[CH:5]=[CH:4][N:3]=1.C[Si](Cl)(C)C.[I-:34].[Na+].[OH-].[Na+]>C(#N)CC>[I:34][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[N:7][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: [I-]
Reactant: COc1ccccc1-c1nc2ccnc(Cl)c2c(=O)n1CCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCC#N
Product: COc1ccccc1-c1nc2ccnc(I)c2c(=O)n1CCc1ccccc1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A mixture of 5-chloro-2-(2-methoxy-phenyl)-3-phenethyl-3H-pyrido[4,3-d]pyrimidin-4-one (300 mg, 0.766 mmol), trimethylsilyl chloride (0.097 mL, 0.766 mmol) and sodium iodide (344 mg, 2.297 mmol, 3 equiv.) in propionitrile (7.66 mL) was heated to reflux under nitrogen in the dark for 4 hours. TLC showed no starting material remaining. The reaction mixture was cooled to ambient temperature and poured into 1N NaOH (30 mL). The resulting suspension was extracted with ethyl acetate (3×20 mL), the combined extracts were washed with water, brine and dried, filtered and concentrated in vacuo to give a brown oil. The crude product was purified by column chromatography using 10% ethyl acetate in dichloromethane to provide 235 mg (64%) of product.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([S:15][CH2:16][CH2:17][C:18](OC)=O)[CH:8]=[N:9][C:10]=1[O:11][CH2:12][O:13][CH3:14].[K].[O-]CCCC.BrC[C:30]1C=C[CH:33]=[C:32]([F:36])[CH:31]=1>C1COCC1>[F:36][C:32]1[CH:33]=[C:17]([CH:18]=[CH:30][CH:31]=1)[CH2:16][S:15][C:7]1[CH:6]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:10]([O:11][CH2:12][O:13][CH3:14])=[N:9][CH:8]=1
Reactant: Fc1cccc(CBr)c1
Reactant: COCOc1cc(SCCC(=O)OC)cnc1OCOC
Agent: CCCC[O-]
Agent: [K]
Solvent: C1CCOC1
Product: COCOc1cc(SCc2cccc(F)c2)cnc1OCOC
Temperature: -45 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a solution of methyl 3-{[5,6-bis(methoxymethoxy)pyridin-3-yl]sulfanyl}propanoate (Intermediate 42; 1 g, 3.15 mmol) in THF (17 ml) at −45° C. was added potassium ten-butoxide (0.389 g, 3.47 mmol). After stirring at −45° C. temperature for 1 hour, 1-(bromomethyl)-3-fluorobenzene (0.715 g, 3.78 mmol) was added and the reaction mixture stirred for 3 hours. Upon warming to room temperature the reaction mixture was partitioned between dichloromethane and water. The aqueous phase was re-extracted and the combined organic extracts were washed with brine, dried and concentrated in vacuo. The crude product was purified by column chromatography (SiO2; 0-50% ethyl acetate/petrol) to yield 5-[(3-fluorobenzyl)sulfanyl]-2,3-bis(methoxymethoxy)pyridine (690 mg, 64%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[N:18]=[C:17](S(C)(=O)=O)[N:16]=1>C1COCC1.[NH4+].[Cl-].CCOC(C)=O>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[N:18]=[C:17]([O:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[N:16]=1
Reactant: CS(=O)(=O)c1nc(Cl)cc(Cl)n1
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Oc2nc(Cl)cc(Cl)n2)cc1
Reaction time: 3 h
Yield: 95.3 %

Procedure:
_A solution of 4-acetamidophenol (666 mg, 4.40 mmol) in anhydrous THF (40 ml), stirring at ambient temperature, was treated with a 60% dispersion of sodium hydride in mineral oil (176 mg, 4.40 mmol). The reaction mixture was then allowed to stir for 30 minutes at ambient temperature before 4,6-dichloro-2-methanesulfonyl-pyrimidine (1.0 g, 4.40 mmol) was added. The reaction was then allowed to stir for a further 3 hours before the reaction was diluted with saturated aqueous NH4Cl and EtOAc. The organic layer was separated, washed with saturated aqueous NaCl and dried over sodium sulfate then concentrated in vacuo. The residue was purified by column chromatography (Silica Gel, MeOH:CH2Cl2, 5:95) yield the title compound 1.25 g, (95%) as a solid. 1H-NMR (400 MHz, DMSO-d6): δ 2.06 (3H, s), 7.18 (2H, d, J=8.5 Hz), 7.62 (2H, d, J=8.5 Hz), 10.05 (1H, s), LC-MS: ES+=298.16, ES-=296.18).