Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][CH2:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:14].C(N(CC)CC)C>C(O)C>[N+:8]([C:7]1[C:2]([NH:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:14])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: NCC(O)c1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccnc1NCC(O)c1ccccc1
Yield: 5.3 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (20.0 g, 0.13 mole), 2-amino-1-phenylethanol (20.74 g, 0.15 mole), and triethylamine (17.5ml, 0.13 mole) in 200 ml of absolute ethanol was heated to reflux for 11/2 hours. The reaction mixture was filtered and evaporated to dryness. The residue was partitioned between water and methylene chloride (2×). The methylene chloride layers were combined and extracted with water. The methylene chloride layers were dried, filtered, and evaporated to a solid (30.8 g, 94.5%). A 2.4-g sample was recrystallized from methanol and water to give a yellow solid, which was collected by filtration, washed with water, and dried under high vacuum overnight to give 1.8 g of the compound, mp 101°-103° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C@H:13]([OH:16])[CH2:14][OH:15].N1C=CC=CC=1.[C:23](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C@H:13]([OH:16])[CH2:14][O:15][C:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc2ccccc2c(Cl)c1[C@H](O)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc2ccccc2c(Cl)c1[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 24 h

Procedure:
A suspension of (S)-1-(1-chloro-3-methylnaphthalen-2-yl)ethane-1,2-diol (6.70 grams, 28.2 mmol) and CH2Cl2 (67 mL) was treated with pyridine (4.78 mL, 59.2 mmol) at 23° C. Trityl chloride (8.28 g, 29.6 mmol) was added and the reaction was stirred for 24 h. The reaction was washed with 1.0 M aq CuSO4 monohydrate (3×50 mL), H2O (2×50 mL), and brine (50 mL). The final organic layer was dried over Na2SO4, filtered, and concentrated. The residue was treated with benzene and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give (S)-1-(1-chloro-3-methylnaphthalen-2-yl)-2-(trityloxy)ethanol. 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J=8.2 Hz, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.53-7.44 (m, 2H), 7.51 (s, 1H), 7.43-7.40 (m, 6H), 7.30-7.20 (m, 9H), 5.93-5.77 (m, broad, 1H), 3.59 (dd, J=9.4, 9.0 Hz, 1H), 3.52 (dd, J=9.4, 5.0 Hz, 1H), 2.85 (d, broad, J=4.3 Hz, 1H), 2.52 (s, 3H).
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:21][C:22]1[C:23]([CH:32]2[CH2:34][O:33]2)=[CH:24][C:25]([O:30][CH3:31])=[C:26]([CH:29]=1)[C:27]#[N:28]>>[OH:33][CH:32]([C:23]1[C:22]([CH3:21])=[CH:29][C:26]([C:27]#[N:28])=[C:25]([O:30][CH3:31])[CH:24]=1)[CH2:34][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[C:10]2[CH:19]=[CH:18][C:13]3[C:14](=[O:17])[O:15][CH2:16][C:12]=3[C:11]=2[CH3:20])[CH2:5][CH2:6]1
Reactant: Cc1c(C(O)CN2CCNCC2)ccc2c1COC2=O
Reactant: COc1cc(C2CO2)c(C)cc1C#N
Product: COc1cc(C(O)CN2CCN(CC(O)c3ccc4c(c3C)COC4=O)CC2)c(C)cc1C#N

Procedure:
4-(1-hydroxy-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-5-methyl-2-(methyloxy)benzonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLES 2C and 28˜29 starting from 5-(1-hydroxy-2-piperazin-1-ylethyl)-4-methyl-2-benzofuran-1(3H)-one and 5-methyl-2-(methyloxy)-4-oxiran-2-ylbenzonitrile. LC/MS (M+1)+=466.02.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].Br.[NH2:23][C:24]1[C:29]([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[C:36](=[O:40])[NH:35][CH2:34][CH2:33]3)=[CH:28][C:27](Br)=[CH:26][N:25]=1>>[NH2:23][C:24]1[C:29]([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[C:36](=[O:40])[NH:35][CH2:34][CH2:33]3)=[CH:28][C:27]([C:9]2[CH:8]=[CH:7][C:6]([C:3]([N:2]([CH3:1])[CH3:21])([CH3:4])[CH3:5])=[CH:11][CH:10]=2)=[CH:26][N:25]=1
Reactant: CN(C)C(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Nc1ncc(Br)cc1-c1ccc2c(c1)CCNC2=O
Agent: Br
Product: CN(C)C(C)(C)c1ccc(-c2cnc(N)c(-c3ccc4c(c3)CCNC4=O)c2)cc1
Yield: 11.3 %

Procedure:
General Method C was applied to N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-amine (109 mg, 0.38 mmol) and 6-(2-amino-5-bromopyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one hydrobromide (125 mg, 0.31 mmol) to afford 6-(2-amino-5-(4-(2-(dimethylamino)propan-2-yl)phenyl)pyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (14 mg, 11% yield) as a white solid after purification by flash chromatography. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.32 (s, 1H), 7.81-8.11 (m, 2H), 7.37-7.79 (m, 7H), 5.87 (s, 2H), 3.41 (m, 2H), 2.85-3.10 (m, 2H), 2.11 (s, 6H), 1.30 (s, 6 H); MS (EI) m/z=401.5 [M+1]+.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25]>>[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH:25][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: NCc1cccc(Br)c1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: Brc1cccc(CNc2nccc(-n3cnc4ccccc43)n2)c1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 3-bromobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 380.2, 382.2 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.58 (s, 1H); 8.44 (d, J=5.3 Hz, 1H); 8.01 (br s, 1H); 7.85 (m, 1H); 7.58 (s, 1H); 7.45 (d, J=7.5 Hz, 1H); 6.87 (d, J=5.5 Hz, 1H); 5.83 (br s, 1H); 4.74 (d, J=6.1 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[CH:32]=[C:31]([CH2:33][N:34]([C@@H](C)CO)[CH3:35])[S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].N[C@H:44]([CH3:47])[CH2:45]O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:44]1([CH2:47][N:34]([CH2:33][C:31]2[S:30][CH:29]=[C:28]([C:25]3[CH:26]=[C:27]4[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=3)[NH:21][CH:20]=[C:19]4[CH:16]3[CH2:17][CH2:18][N:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])[CH2:14][CH2:15]3)[CH:32]=2)[CH3:35])[CH2:2][CH2:45]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)[C@@H](C)CO)c4)cc23)CC1
Reactant: C[C@@H](N)CO
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)CC5CC5)c4)cc23)CC1
Yield: 14.7 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide trifluoroacetate (salt), substituting (cyclopropylmethyl)amine (1.20 mmol) for (2R)-2-amino-1-propanol to afford 6.2 mg of the title compound (14.7%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH3:12]>[Cu]I>[NH2:12][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: N
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: [Cu]I
Product: Nc1nc(Cl)ccc1C(=O)O
Temperature: 115 °C
Yield: 72 %

Procedure:
2,6-Dichloronicotinic acid (0.38 g, 2 mmol) and copper (I) iodide (720 mg, 3.8 mmol) were added to liquid ammonia (approx. 20 mL) in a sealed tube at −78° C., which was heated for 25 hours (oil bath temperature: 115° C.). The oil bath temperature was raised to 125° C. followed by additionally heating for 14 hours 30 minutes. The reaction mixture was allowed to return to room temperature followed by distilling off the ammonia. The insoluble material that precipitated following addition of methanol was filtered out and the filtrate was concentrated to obtain the title compound (0.25 g, 1.45 mmol, 72%) as a solid.
Reaction SMILES: C(B(CC)[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)C.FC(F)(F)S(O[C:18]1[C@:19]2([CH2:36][CH2:35][C@H:34]3[C@@H:24]([CH2:25][CH:26]=[C:27]4[C@:32]3([CH3:33])[CH2:31][CH2:30][CH:29]=[CH:28]4)[C@@H:21]2[CH2:22][CH:23]=1)[CH3:20])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:18]2[C@:19]3([CH2:36][CH2:35][C@H:34]4[C@@H:24]([CH2:25][CH:26]=[C:27]5[C@:32]4([CH3:33])[CH2:31][CH2:30][CH:29]=[CH:28]5)[C@@H:21]3[CH2:22][CH:23]=2)[CH3:20])[CH:5]=1
Reactant: CCB(CC)c1cccnc1
Reactant: C[C@]12CCC=CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(OS(=O)(=O)C(F)(F)F)=CC[C@@H]12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@]12CCC=CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Yield: 83.9 %

Procedure:
The method followed that described in Example 1, using in step (b) diethyl(3-pyridyl)borane (0.88g, 6.0 mmol), androsta-3,5,16-trien-17-yl trifluoromethanesulphonate (2.01g, 5.0 mmol), prepared in step (a), THF (25 ml), bis(triphenylphosphine)palladium(II) chloride (35 mg, 0.05 mmol), and aqueous sodium carbonate (2M, 10 ml). Chromatography, on elution with dichloromethane, afforded the title compound (1.39 g, 84%) which crystallised from hexane, m.p. 110°-112° C. 1H-NMR (CDCl3) inter alia δ 1.02(3H,s,19-CH3), 1.07(3H,s,18-CH3), 5.44(1H,m,6-H), 5.61(1H,m,3-H), 5.95(1H,dm, J 9.8 Hz, 4-H), 6.01(1H,m, 16-H), 7.23(1H,m,Py 5-H), 7.66(1H,m,Py 4-H), 8.46(1H,m,Py 6-hr), 8.63(1H,m,Py 2-H); MS m/z 331 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].[NH3:12]>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:12])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: N
Solvent: CCO
Product: NCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 65 %

Procedure:
3-Nitrobenzyl bromide (10 g, 46.3 mmol) was dissolved in ethanol (200 ml) and stirred at room temperature A solution of conc.NH3 (aq) (200 ml) in ethanol (300 ml) was added dropwise to the reaction over 30 minutes. The reaction was stirred for 18 h at room temperature before evaporating to dryness. Water (350 ml) was added to the residue and the solution was washed with EtOAc (2×200 ml). The aqueous layer was basified with 1M NaOH and extracted with EtOAc (2×200 ml). The organic extracts of the basic layer were combined, dried (Na2SO4) and evaporated to dryness. The product was obtained as an orange oil (4.6 g, 65% yield). LCMS purity 100%, m/z 153 [M++H]+.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.[CH:25]([N:28]1[CH2:33][CH2:32][CH:31]([SH:34])[CH2:30][CH2:29]1)([CH3:27])[CH3:26].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>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:20]([N:15]1[C:14]([C:8]2[N:7]=[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([S:34][CH:31]5[CH2:32][CH2:33][N:28]([CH:25]([CH3:27])[CH3:26])[CH2:29][CH2:30]5)[CH:24]=[CH:23][C:5]=43)[CH:9]=2)=[N:18][C:17]([CH3:19])=[N:16]1)([CH3:22])[CH3:21]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Reactant: CC(C)N1CCC(S)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(SC4CCN(C(C)C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 120 °C
Yield: 70.5 %

Procedure:
A mixture of 8-bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (150 mg, 0.386 mmol), 1-isopropylpiperidine-4-thiol (92 mg, 0.579 mmol), Pd2(dba)3 (18 mg, 5 mol %), XantPhos (23 mg, 10 mol %) and DIPEA (0.27 mL, 1.54 mmol) in dioxane (4 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. After cooling to RT, the crude mixture was diluted with DCM (75 mL) and purified by column chromatography (Si-PCC, gradient 0-6% 2N NH3/MeOH in DCM followed by C18, gradient 20-50% MeOH in 0.5% TFA/H2O). The product containing fractions were combined and concentrated in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The basic fractions were concentrated under reduced pressure affording 2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-(1-isopropylpiperidin-4-ylsulfanyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene as a colorless solid (127 mg, 70%). LCMS: RT 3.00 min [M+H]+ 467.1
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:19]=[C:18]([N:20]([CH3:22])[CH3:21])[CH:17]=[CH:16][C:4]=1[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=O.[CH2:24]([N:26]([CH2:34][CH3:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)[CH3:25].C(OC(=O)C)(=O)C>>[CH3:1][N:2]([CH3:23])[C:3]1[CH:19]=[C:18]([N:20]([CH3:22])[CH3:21])[CH:17]=[CH:16][C:4]=1[C:5]1([C:30]2[CH:31]=[CH:32][C:27]([N:26]([CH2:24][CH3:25])[CH2:34][CH3:35])=[CH:28][C:29]=2[CH3:33])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=[O:11])[O:10]1
Reactant: CN(C)c1ccc(C(=O)c2ccccc2C(=O)O)c(N(C)C)c1
Reactant: CCN(CC)c1cccc(C)c1
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccccc32)c(C)c1

Procedure:
Condensation of 2-(2,4-bis(dimethylamino)benzoyl)-benzoic acid and N,N-diethyl-m-toluidine in the presence of acetic anhydride also afforded 3-(2,4-bis(dimethylamino)-phenyl-3-(2-methyl-4-(diethylamino)phenyl)phthalide.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][C:6](=[O:8])[O:5][C:3]1=[O:4].[C:10]([C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:34])[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[CH:17]=[CH:18][CH:19]=1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[CH:15]=[C:16]([NH:20][C:21]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:6](=[O:8])[CH2:7][C:2]([CH3:9])([CH3:1])[C:3]([OH:5])=[O:4])[CH2:30][CH2:29]3)=[CH:24][CH:23]=2)=[O:34])[CH:17]=[CH:18][CH:19]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)cc2)c1
Product: CC(C)(CC(=O)N1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cc2)CC1)C(=O)O

Procedure:
4-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperazin-1-yl}-2,2-dimethyl-4-oxo-butyric acid was prepared from 2,2-dimethylsuccinic anhydride and N-(3-tert-butyl-phenyl)-4-piperazin-1-yl-benzamide. HRMS m/z calcd for C27H35N3O4 [M+H]+: 466.2701. Found: 466.2698.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)O1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]3[CH:28]=[N:29][NH:30][CH:31]=3)=[CH:3][CH:4]=2)[CH2:9][CH2:10][NH2:11])=[CH:13][CH:14]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: NCCC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Product: NCCC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propylamine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-B3) Rt 2.54 [M+H]+ 312.04. 1H NMR (Me-d3-OD) δ 2.39 (2H, m), 2.84 (2H, t), 4.06 (1H, t), 7.27-7.33 (6H, m), 7.54 (2H, d), 7.91 (2H, s).
Reaction SMILES: C(C1CCC2C(=C(C(=O)C)C=CC=2[C:14]#[N:15])C1=O)(=O)C.[C:20]([NH:23][CH:24]1[CH2:33][CH2:32][C:31]2[C:26](=[C:27]([NH:34]C(=O)C)[CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:38])(=[O:22])[CH3:21]>>[C:20]([NH:23][CH:24]1[CH2:33][CH2:32][C:31]2[C:26](=[C:27]([NH2:34])[CH:28]=[CH:29][C:30]=2[C:14]#[N:15])[C:25]1=[O:38])(=[O:22])[CH3:21]
Reactant: CC(=O)Nc1cccc2c1C(=O)C(NC(C)=O)CC2
Reactant: CC(=O)c1ccc(C#N)c2c1C(=O)C(C(C)=O)CC2
Product: CC(=O)NC1CCc2c(C#N)ccc(N)c2C1=O

Procedure:
The reaction was carried out in the same manner as in Example 1-(4), except that 250 mg of the compound prepared in (1) above was used instead of 2,8-diacetylamino-1-tetralone of Example 1-(4), and post-treated to produce 182 mg of the title compound.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:36])[C@@H:15]([O:33][CH2:34][CH3:35])[C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][C:19]=1[F:32])[OH:17])C1C=CC=CC=1.[CH3:37][O-:38].[Na+]>CO>[CH3:37][O:38][C:14](=[O:36])[C@@H:15]([O:33][CH2:34][CH3:35])[C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:20][C:19]=1[F:32])[OH:17]
Reactant: C[O-]
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCc2ccccc2)cc1F
Agent: [Na+]
Solvent: CO
Product: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(OCc2ccccc2)cc1F

Procedure:
In analogy to the procedure described in example 17 b], (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-fluoro-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one was treated with sodium methoxide in methanol to give (2S,3R)-3-(4-benzyloxy-2-fluoro-phenyl)-2-ethoxy-3-hydroxy-propionic acid methyl ester as colorless liquid. According to 1H-NMR spectroscopy, one single diastereomer was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][O:12][CH2:11]2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[O:23][CH:24]=2)[N:3]=1.Cl.[CH3:33][O:34][C:35](=[O:39])[CH2:36][NH:37][CH3:38].C(N(CC)CC)C>C1COCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[O:23][CH:24]=[C:20]([CH2:19][S:18][C:4]3[N:3]=[C:2]([N:37]([CH3:38])[CH2:36][C:35]([O:34][CH3:33])=[O:39])[C:7]([C:8]#[N:9])=[C:6]([CH:10]4[CH2:15][CH2:14][CH2:13][O:12][CH2:11]4)[C:5]=3[C:16]#[N:17])[N:21]=2)=[CH:26][CH:27]=1
Reactant: N#Cc1c(Cl)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1C1CCCOC1
Reactant: CNCC(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CN(C)c1nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c(C2CCCOC2)c1C#N
Temperature: 25 °C
Reaction time: 10 h

Procedure:
239 mg (0.42 mmol) of the compound from Example 43A are dissolved in 6 ml of dry THF, and 116 mg (0.83 mmol) of sarcosine methyl ester hydrochloride and 126 mg (1.25 mmol) of triethylamine are then added in succession. The reaction mixture is stirred at RT for 10 h. The solvent is then removed on a rotary evaporator and the residue is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5, 15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].[CH:16]([C:18]([CH3:20])=[O:19])=[CH2:17].CC(OC)(C)C>O>[CH3:12][O:11][C:9](=[O:10])[CH:8]([CH2:17][CH2:16][C:18](=[O:19])[CH3:20])[C:7]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CC(=O)OC
Reactant: C=CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)C(CCC(C)=O)C(=O)OC
Temperature: 15 °C

Procedure:
Potassium carbonate (5.62 kg), dimethyl malonate (54.8 kg) and acetonitirile (90 kg) were charged to the reaction vessel and stirred together at 15° C. Methyl vinyl ketone (28.5 kg) was pumped into the vessel over 2 hours at below 25° C. The slurry was stirred at 18-20° C. for 2 hours. MTBE (132 kg) was charged to the vessel to dilute the reaction mixture followed by water (114 kg). The mixture was stirred for five minutes then the layers were allowed to separate and the aqueous layer run off. More water (57 kg) was charged to the vessel, the reaction mixture stirred for another 5 minutes, the layers allowed to separate, and again the aqueous layer run off. The organic layer was concentrated under reduced pressure until most of the solvent had been removed (volume approx 80 L) affording 76 kg of A-1 as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[N:4][C:3]=1[OH:9].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1=COCCC1
Reactant: Oc1nncc(Cl)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
4,5-Dichloro-3-hydroxypyridazine (3000 g, 18.18 moles), dihydropyran (1943 g, 23.08 mole), p-toluenesulfonic acid monohydrate (283 g, 1.49 moles) and 16 L of tetrahydrofuran were added to a 50 L round bottomed flask equipped with a heating mantle, reflux condenser and a mechanical stirrer. The mixture was stirred at reflux for 29 h. Additional dihydropyran was added at 6 h (1328 g, 15.79 mol) and at 21 h (780 g, 9.25 moles). The reaction mixture was allowed to cool to room temperature overnight. The mixture was concentrated in vacuo to an oily residue. The residue was taken up in 16 L of ethyl acetate and washed with 2N NaOH (2×6 L). The organic solution was dried (MgSO4) and concentrated in vacuo to give 4,5-dichloro-2-(tetrahydro-2H-pyran-2-yl)-3(2H)-pyridazinone which was a black oily solid which was used without further purification in the next step. The product was purified by filtration through silica gel with ethyl acetate followed by evaporation and recrystallization from ethyl acetate/cyclohexane to give a white solid, mp=74°-76° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31][CH2:32][CH2:33][O:34][C:35]3[CH:40]=[CH:39][C:38](C4C(C#N)=CSC=4)=[CH:37][CH:36]=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[O:48]1[CH2:53][CH2:52][N:51](C2C=CC(O)=CC=2)[CH2:50][CH2:49]1>>[S:1]1[C:5]2[CH:4]=[CH:9][CH:8]=[CH:7][C:6]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31][CH2:32][CH2:33][O:34][C:35]3[CH:40]=[CH:39][C:38]([N:51]4[CH2:52][CH2:53][O:48][CH2:49][CH2:50]4)=[CH:37][CH:36]=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Reactant: Oc1ccc(N2CCOCC2)cc1
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CCCOc3ccc(N4CCOCC4)cc3)s1)CC2

Procedure:
The title compound was prepared in a similar manner to the synthesis of compound 51 by substituting compound 51A with 4-morpholinophenol in step 2 of Example 51: 1H NMR (DMSO-d6): δ 7.96 (d, J=7.67 Hz, 1H), 7.72 (d, J=7.98 Hz, 1H), 7.60 (d, J=7.06 Hz, 1H), 7.27-7.42 (m, 4H), 6.88 (d, J=8.9 Hz, 2H), 6.75-6.79 (m, 2H), 4.76 (s, 2H), 3.85 (t, J=6.29 Hz, 2H), 3.64-3.68 (m, 6H), 3.07-3.11 (m, 2H), 2.95-2.98 (m, 6H), 1.87-1.94 (m, 2H). ESI (+)/MS: 656 (M+H)+.