Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]=3[C:29]([F:32])([F:31])[F:30])[O:15][N:14]=2)=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].CN1CCOCC1.CN(C(O[N:48]1N=[N:55][C:50]2C=CC=N[C:49]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:49]([CH2:50][NH:55][C:3](=[O:4])[C:2]([OH:1])([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:19]=3[C:29]([F:32])([F:31])[F:30])[O:15][N:14]=2)=[CH:9][CH:8]=1)[CH3:6])#[N:48]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(O)(C(=O)O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(O)(C(=O)NCC#N)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 20.16 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid (Int-XV, (30 mg, 0.067 mmol), 4-methylmorpholine (27.3 mg, 0.269 mmol), and HATU (33.3 mg, 0.088 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=30.21 min) to provide (R/S)-N-(cyanomethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanamide (7 mg, 0.014 mmol, 20.16% yield): LCMS=484.0 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.81 (1 H, t, J=5.83 Hz), 8.11-8.23 (2 H, m), 7.51-7.92 (7 H, m), 4.04-4.23 (2 H, m), 1.81 (3 H, s); HPLC peak RT=10.0 min (Method A).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([N:12]3[CH2:15][CH:14]([NH:16][CH2:17][CH2:18][O:19]S(C)(=O)=O)[CH2:13]3)[CH:6]=[CH:5][C:4]=2[C:3]=1[C:24]([NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:25].C(CN)O>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([N:12]3[CH2:15][CH:14]([NH:16][CH2:17][CH2:18][OH:19])[CH2:13]3)[CH:6]=[CH:5][C:4]=2[C:3]=1[C:24]([NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:25]
Reactant: CS(=O)(=O)OCCNC1CN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1
Solvent: NCCO
Product: O=C(NCC1CCCCC1)c1c(Cl)ccc2nc(N3CC(NCCO)C3)ccc12
Yield: 35.6 %

Procedure:
Prepared according to the method of example 33(b), using 6-chloro-N-(cyclohexylmethyl)-2-[3-[[2-[(methylsulfonyl)oxy]ethyl]amino]-1-azetidinyl]-5-quinolinecarboxamide (Example 55(a)) (0.10 g) and ethanolamine (0.3 mL) to afford the title compound (0.03 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]2[S:13][C:12]([C:14]([F:17])([F:16])[F:15])=[N:11][CH:10]=2)[C:6](=[O:18])[N:5]=[C:4](SC)[N:3]=1.Cl.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH:34]=2)=[CH:25][CH:24]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:34][CH2:33][N:32]([C:4]3[N:3]=[C:2]([CH3:1])[N:7]([CH2:8][C:9]4[S:13][C:12]([C:14]([F:17])([F:16])[F:15])=[N:11][CH:10]=4)[C:6](=[O:18])[N:5]=3)[CH2:31][CH:30]=2)=[CH:25][CH:24]=1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Reactant: CSc1nc(C)n(Cc2cnc(C(F)(F)F)s2)c(=O)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nc(N2CC=C(c3ccc(F)cc3)CC2)nc(=O)n1Cc1cnc(C(F)(F)F)s1
Yield: 61.5 %

Procedure:
To a 1,4-dioxane solution (500 μL) of 6-methyl-4-(methylthio)-1-{[2-(trifluoromethyl)thiazol-5-yl]methyl}-1,3,5-triazin-2(1H)-one (38.7 mg, 0.120 mmol) synthesized in Reference Synthesis Example 374, 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (30.8 mg, 0.144 mmol) and N,N-diisopropylethylamine (41.1 μL, 0.240 mmol) were added and the resultant mixture was stirred under reflux by heating for 1 day. After the completion of the reaction, the reaction solution was purified by silica gel column chromatography (hexane/ethyl acetate=1/1→0/1) to obtain the title compound (33.3 mg, yield: 61%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH2:10][CH:11]([OH:13])[CH3:12])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:9][CH2:10][CH:11]([CH3:12])[O:13][C:6]=2[N:7]=1
Reactant: CC(O)COc1c(Cl)nc(Cl)nc1N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1COc2c(nc(Cl)nc2N2CCOCC2)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(2,4-dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-propan-2-ol (148 mg, 0.48 mmol) in THF (8 mL) was added sodium hydride (58 mg, 1.44 mmol, 60% dispersion in mineral oil) and the resulting mixture stirred at RT for 4 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo affording 2-Chloro-7-methyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine as an off-white solid (139 mg, quantitative). LCMS: RT=2.94 min, [M+H]+=272/274.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][N:9]([C:18](=[O:28])[CH:19]=[C:20]1[C:24](=[O:25])[O:23][C:22](C)(C)[O:21]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]>CO>[CH3:22][O:23][C:24](=[O:25])[C:20]([OH:21])=[CH:19][C:18](=[O:28])[N:9]([O:8][CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:29])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)cc1)OCC(=O)OC(C)(C)C
Yield: 69 %

Procedure:
[[2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetyl]-(4-fluorobenzyl)-aminooxy]-acetic acid tert-butyl ester was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as a clear oil (69% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.50 (9H, s, t-Bu), 3.92 (3H, s, OCH3), 4.35 (2H, s, CH2), 4.94 (2H, s, CH2), 6.55 (1H, s, CH), 7.05 (2H, m, aromatics), 7.39 (2H, m, aromatics), 13.35 (1H, broad s, OH). HRMS (ES+) calculated for C18H23FNO7, [M+H]+: 384.145856. found: 384.146214.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]3[NH:14][CH:15]=[C:16]([C:17]#[N:18])[C:11]3=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:19]([C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([F:33])[CH:32]=1)[C:29](=[O:34])[N:28]([C:35]1[C:43]3[CH2:42][O:41]B(O)[C:39]=3[CH:38]=[CH:37][CH:36]=1)[N:27]=[CH:26]2)([CH3:22])([CH3:21])[CH3:20].ClCCCl.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CCOC(C)=O>[C:19]([C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([F:33])[CH:32]=1)[C:29](=[O:34])[N:28]([C:35]1[C:43]([CH2:42][OH:41])=[C:39]([N:14]3[C:12]4=[N:13][C:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[CH:9][CH:10]=[C:11]4[C:16]([C:17]#[N:18])=[CH:15]3)[CH:38]=[CH:37][CH:36]=1)[N:27]=[CH:26]2)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc4c3COB4O)ncc2c1
Reactant: CN1CCN(c2ccc3c(C#N)c[nH]c3n2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CN1CCN(c2ccc3c(C#N)cn(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)c3n2)CC1
Temperature: 45 °C
Reaction time: 48 h
Yield: 16.7 %

Procedure:
In a 25 mL round-bottomed flask, 6-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (110 mg, 456 μmol), 6-tert-butyl-8-fluoro-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)phthalazin-1(2H)-one (177 mg, 501 μmol, Eq: 1.10) and copper acetate (112 mg) were combined with 1,2-dichloroethane (3.03 ml) to give a blue suspension. Pyridine (72.1 mg, 73.7 μl, 912 μmol, Eq: 2) was added. The reaction mixture was heated to 45° C. and stirred for 2 d. The reaction mixture was poured into 20 mL EtOAc and extracted with sat NH4Cl (3×20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 5% to 10% MeOH in DCM) to give 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-6-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (43 mg, 17%) of off white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][CH3:23])=[O:21])[CH:15]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11]([CH3:12])=[O:32])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][CH3:23])=[O:21])[CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(SC)sc3c2Cl)ccn1
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2Cl)ccn1
Reaction time: 0.62 h

Procedure:
To the solution of 4-(7-chloro-2-(methylthio)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (64 mg, 0.175 mmol, 1.0 eq) in 5 mL of DCM was added MCPBA (33 mg, 0.192 mmol, 1.1 eq) at 0° C. and reaction stirred for 30-45 min. Thereafter, it was quenched with water (10 mL) and aqueous phase extracted with ethyl acetate (25 mL×5), combined organic layers dried over sodium sulfate, filtered and condensed under reduced pressure to yield crude product which was sufficiently pure and was carried to next step without further purification. LC/MS (m/z) [382.0] (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:28])([F:27])[C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH2:25][NH2:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][N:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:26][CH2:25][C:19]1([C:16]2[CH:17]=[N:18][C:13]([C:12]([F:28])([F:27])[F:11])=[N:14][CH:15]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:6]
Reactant: NCC1(c2cnc(C(F)(F)F)nc2)CCOCC1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(NCC1(c2cnc(C(F)(F)F)nc2)CCOCC1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and (4-(2-(trifluoromethyl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine. LCMS (MH+): m/z=400.1, tR (minutes, Method F)=2.15
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:10][C:7]2([CH2:9][CH2:8]2)[C:6]2(OCC[O:11]2)[CH2:5]1.Cl>CC(C)=O>[OH:1][CH2:2][CH2:3][N:4]1[CH2:5][C:6](=[O:11])[C:7]2([CH2:8][CH2:9]2)[CH2:10]1
Reactant: OCCN1CC2(CC2)C2(C1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CN(CCO)CC12CC2

Procedure:
The above product from Example 1 (100 mg) was mixed with 1N HCl (4 ml) and acetone (20 ml). The reaction was refluxed overnight and evaporated. The solution was basified with 2N NaOH and extracted with EtOAc. The combined organic layer was washed with H2O followed by brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography to give title compound. Mass: (M+1), 156
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]([NH:13][C:14]3[CH:35]=[CH:34][C:17]([CH2:18][N:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C:21]([CH2:28][C:29]([O:31]CC)=[O:30])=[N:20]4)=[CH:16][CH:15]=3)=[O:12])[CH:9]=[CH:10][C:2]1=2.O.[OH-].[Li+].O.Cl>O1CCCC1>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]([NH:13][C:14]3[CH:35]=[CH:34][C:17]([CH2:18][N:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C:21]([CH2:28][C:29]([OH:31])=[O:30])=[N:20]4)=[CH:16][CH:15]=3)=[O:12])[CH:9]=[CH:10][C:2]1=2
Reactant: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4c(c3)OCCO4)cc2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1nn(Cc2ccc(NC(=O)c3ccc4c(c3)OCCO4)cc2)c2ccccc12
Yield: 98.6 %

Procedure:
Ethyl 2-[1-[4-(2,3-dihydrobenzo[b][1,4]dioxin-6-carboxamido)benzyl]-1H-indazol-3-yl]acetate (260 mg, 0.551 mmol) was dissolved in tetrahydrofuran (20 mL), and in an ice bath, 10 mL aqueous solution dissolving lithium hydroxide monohydrate (70 mg, 1.67 mmol) was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, and adjusted to pH≈3-4 with diluted hydrochloric acid. A solid precipitated, which was filtered and dried to obtain a white solid 241 mg, at a yield of 98.5%.
Reaction SMILES: OO.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[N:8][C:9]=1[Cl:10].[OH:14]S([O-])=O.[Na+]>FC(F)(F)C(O)=O>[Cl:3][C:4]1[C:9]([Cl:10])=[N+:8]([O-:14])[C:7]([C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(Cl)c(Cl)n1
Reactant: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(Cl)c(Cl)[n+]1[O-]
Reaction time: 1 h

Procedure:
50% Hydrogen peroxide (38 g, 0.35 mol) was carefully added to a mechanically stirred mixture of trifluoroacetic acid (350 mL) and 5,6-dichloropyridine-2-carboxylic acid (56.4 g, 0.29 mol) at 79° C. After one hour, the reaction mixture was poured into 1 L of saturated aqueous NaHSO3, stirring vigorously and cooling in an ice bath. The precipitate was collected and dried to provide 5,6-dichloropyridine-2-carboxylic acid-N-oxide (62.9 g, 0.30 mol), mp 160° C.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].C([O-])(=O)C.[NH4+:25]>CS(C)=O>[C:12]1([C:11]2[C:10]3[CH:9]=[CH:8][S:7][C:6]=3[NH:5][C:3](=[O:4])[N:25]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [NH4+]
Reactant: O=C(c1ccccc1)c1ccsc1NC(=O)C(Cl)(Cl)Cl
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: O=c1nc(-c2ccccc2)c2ccsc2[nH]1
Temperature: 95 °C

Procedure:
To a solution of 2.0 g of 2-trichloroacetamido-3-benzoylthiophene in 18 ml of dimethylsulfoxide was added 0.89 g of ammonium acetate. The mixture was heated at 95° C for 2 hours, and poured into ice water, and extracted with chloroform. The chloroform layer was washed with water, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was chromatographed on 60 g of silica gel, using methanol as an eluent to obtain 4-phenyl-1,2-dihydrothieno(2,3-d)-pyrimidin-2-one as crystals. Recrystallized from chloroform-acetone, the crystals having a melting point of 247.5°- 249° C. were obtained.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:23])[CH2:15][CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18])[CH3:12].C([O-])(=O)C.[Na+]>C(O)C>[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]1[C:17]([CH3:18])=[N:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:10])=[CH:3][CH:4]=2)[C:20]=1[CH3:21])[CH3:12]
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Reactant: Cc1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cc1c(C)nn(-c2ccc(C)cc2)c1C
Yield: 89 %

Procedure:
8.0 grams p-tolylhydrazine-hydrochloride, 9.3 grams 3,3-diacetyl-propionic acid-ethyl ester, 4.1 grams anhydrous sodium acetate and 70 milliliters ethanol were mixed and the mixture was heated to the boiling temperature under reflux for 1.5 hour. The reaction mixture was worked up as described in Example (3a). After distillation, 12.1 grams 3,5-dimethyl-1-(p-tolyl)-pyrazol-4-acetic acid-ethyl ester were obtained as a viscous oil having a Kp0.001 of 145°-146° C., representing a yield of 89%. For analysis, the product was redistilled resulting in an n20D 1.5455.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[Br:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([NH2:24])=[C:19]([O:25][CH3:26])[CH:18]=1>ClCCl>[Br:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([NH:24][C:2]2[N:6]([CH3:7])[C:5]3[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=[CH:11][C:4]=3[N:3]=2)=[C:19]([O:25][CH3:26])[CH:18]=1
Reactant: COC(=O)c1cccc2nc(Cl)n(C)c12
Reactant: COc1cc(Br)cc(C)c1N
Solvent: ClCCl
Product: COC(=O)c1cccc2nc(Nc3c(C)cc(Br)cc3OC)n(C)c12
Temperature: 100 °C
Yield: 13.2 %

Procedure:
A mixture of 1.50 g (6.68 mmol) of methyl 2-chloro-1-methyl-1H-benzimidazole-7-carboxylate and 2.89 g (13.4 mmol) of 4-bromo-2-methoxy-6-methylphenylamine was heated at 100° C. for five days. The cooled reaction was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate, water and brine. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The thus obtained residue was purified via flash chromatography eluting with 100% dichloromethane to elute the residual 4-bromo-2-methoxy-6-methylphenylamine and 30% ethyl acetate/hexanes to give 356 mg (13%) of the title compound.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[C:25]1([NH:35]N)[C:34]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=2[CH:28]=[CH:27][N:26]=1.C1(N)C2CCCCC=2C=CN=1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:35]([C:25]4[C:34]5[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=5[CH:28]=[CH:27][N:26]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: NNc1nccc2c1CCCC2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Agent: Cl[Sn]Cl
Agent: Nc1nccc2c1CCCC2
Agent: O=N[O-]
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3nccc4c3CCCC4)n2)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and (5,6,7,8-tetrahydro-isoquinolin-1-yl)-hydrazine (prepared from the commercial 5,6,7,8-tetrahydro-isoquinolin-1-ylamine using sodium nitrite and tin(II) chloride in analogy to that described in J. Med. Chem. 2003, 46, 4676-4686) according to example 43 gave the desired product. MS: M=448.0 (M+H)+
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:21]4[C:16]3=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][CH:10]=2)O1.[Br:29][C:30]1[CH:31]=[CH:32][C:33](I)=[N:34][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+].O>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.CCOC(C)=O.C1COCC1>[Br:29][C:30]1[CH:31]=[CH:32][C:33]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:22]4[C:27]3=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:11][CH:10]=2)=[N:34][CH:35]=1
Reactant: CC1(C)OB(c2ccc(-n3c4ccccc4c4ccccc43)cc2)OC1(C)C
Reactant: Brc1ccc(I)nc1
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: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1ccc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)nc1
Yield: 90.4 %

Procedure:
Following the procedure for 1, 5 (4.84 g, 13.1 mmol), 5-bromo-2-iodopyridine (3.72 g, 13.1 mmol), tetrakis(triphenylphosphine)palladium(0) (0.757 g, 0.655 mmol), Na2CO3 (4.97 g, 46.9 mmol), H2O (45 mL) and THF (75 mL) yielded 6 (4.73 g, 90% yield) as a colorless solid after flash chromatography (SiO2, 1:1 hexanes-dichloromethane) and subsequent trituration with EtOAc.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([C:13]2[CH:14]=[N:15][C:16]([O:19]C)=[CH:17][CH:18]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl>O1CCOCC1>[Cl:8][C:6]1[CH:5]=[C:4](/[CH:9]=[CH:10]/[C:11]([C:13]2[CH:18]=[CH:17][C:16](=[O:19])[NH:15][CH:14]=2)=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COc1ccc(C(=O)/C=C/c2cc(Cl)cc(Cl)c2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(/C=C/c1cc(Cl)cc(Cl)c1)c1ccc(=O)[nH]c1

Procedure:
In analogy to example 162, step 2, (E)-3-(3,5-dichlorophenyl)-1-(6-methoxypyridin-3-yl)prop-2-en-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as a colourless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[C:41]([F:43])[CH:42]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[C:15]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:16]=[CH:17][CH:18]=3)[CH2:13][N:12]2C(OC(C)(C)C)=O)[O:9][C:8](=[O:39])[NH:7]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:43][C:41]1[CH:40]=[C:4]([CH:3]=[C:2]([F:1])[CH:42]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[C:15]([O:21][Si:22]([CH:29]([CH3:30])[CH3:31])([CH:23]([CH3:24])[CH3:25])[CH:26]([CH3:27])[CH3:28])[CH:16]=[CH:17][CH:18]=3)[CH2:13][NH:12]2)[O:9][C:8](=[O:39])[NH:7]1
Reactant: CC(C)[Si](Oc1cccc2c1CN(C(=O)OC(C)(C)C)[C@@H]([C@H]1OC(=O)N[C@H]1Cc1cc(F)cc(F)c1)C2)(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[Si](Oc1cccc2c1CN[C@@H]([C@H]1OC(=O)N[C@H]1Cc1cc(F)cc(F)c1)C2)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (R)-tert-butyl 3-((4S,5S)-4-(3,5-difluorobenzyl)-2-oxooxazolidin-5-yl)-8-(triisopropylsilyloxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Step F (11), 470 mg) in CH2Cl2 (20 mL) was treated with TFA (5 mL). This reaction mixture was stirred at rt for 3 h. The mixture was then concentrated in vacuo. Ethyl acetate (10 mL) was added and removed and toluene (10 mL) was added and removed twice to give the title compound: 1H NMR (CDCl3, 500 MHz) δ 1.10 (18H, m), 1.30 (3H, m), 2.61-2.66 (2H, m), 3.08 (1H, dd, J=5, 15 Hz), 3.18 (1H, m), 3.36 (1H, m), 3.79 (1H, d, J=20 Hz), 4.05-4.09 (1H, m), 4.14 (1H, d, J=20 Hz), 4.39 (1H, m), 5.54 (1H, s), 6.64 (1H, d, J=5 Hz), 6.69-6.72 (2H, m), 6.78 (2H, m), 7.01 (1H, m). MS (ESI) (M+H)+ 517.11.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:37])[C@@H:15]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:16][C:17]2[N:18]=[N:19][N:20](CC3C=CC=CC=3)[CH:21]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]>CO.[OH-].[OH-].[Pd+2]>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:37])[C@@H:15]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:16][C:17]2[N:18]=[N:19][NH:20][CH:21]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](Cc2cn(Cc3ccccc3)nn2)NC(=O)OC(C)(C)C)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](Cc2c[nH]nn2)NC(=O)OC(C)(C)C)CC1

Procedure:
Debenzylation of 4-[(S)-3-(1-Benzyl-1H-[1,2,3]triazol-4-yl)-2-tert-butoxycarbonylamino-propionyl]-piperazine-1-carboxylic acid butyl ester (1.14 g) was performed using the H-Cube® (Thales Nanotechnology). Parameters were chosen as follows: 0.05 M solution in MeOH, Pd(OH)2/C, 60° C., 30 bar. Yield: 739 mg colorless foam.
Reaction SMILES: F[C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7]C)=[O:5].[OH:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][C:20]2=[O:25].CC1NC2C(C=1)=CC(O)=CC=2>>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:2]=1[O:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][C:20]2=[O:25]
Reactant: CCOC(=O)c1ccc(F)cc1F
Reactant: O=C1NCCc2c(O)cccc21
Agent: Cc1cc2cc(O)ccc2[nH]1
Product: COC(=O)c1ccc(F)cc1Oc1cccc2c1CCNC2=O

Procedure:
The title compound was prepared by substituting methyl 2,4-difluorobenzoate for ethyl 2,4-difluorobenzoate and 5-hydroxy-3,4-dihydro-2H-isoquinolin-1-one for 2-methyl-5-indolol in EXAMPLE 3A, except here the heating was at 130° C.
Reaction SMILES: [CH3:1][C@H:2]([OH:7])[CH2:3][C@@H:4]([OH:6])[CH3:5].[CH3:8][O:9][P:10](OC)OC>>[CH3:8][O:9][P:10]1[O:7][C@@H:2]([CH3:1])[CH2:3][C@H:4]([CH3:5])[O:6]1
Reactant: COP(OC)OC
Reactant: C[C@H](O)C[C@H](C)O
Product: COP1O[C@@H](C)C[C@H](C)O1
Temperature: 100 °C

Procedure:
10 g of (+)-(2S,4S)pentane-2,4-diol and 13.6 g of trimethylphosphite were mixed, and heated at 100° C. on an oil bath. After completion of distilling methanol off, the residue is distilled under reduced pressure to obtain colorless transparent 2-methoxy-(4S,6S)-4,6-dimethyl-1,3,2-dioxaphosphorinane. bp: 70°-72° C./15 mmHg.