Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:21]([O-])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1>C(OCC)(=O)C.[Pd]>[NH2:21][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[C:2]([F:1])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2F)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N)cc2F)C1

Procedure:
3-Fluoro-4-(3(R)-(t-butoxycarbonyl)aminopyrrolidin-1-yl)nitrobenzene (32.7 g, 0.101 M) was dissolved in ethyl acetate (500 ml) treated with palladium catalyst (10% on carbon, 7.5 g) and hydrogenated at atmospheric pressure until the theoretical uptake of gas. After filtration through celite and evaporation, the required product was obtained as a red gum of sufficient quality for use without purification (29.85 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+]>O.CO.[Pd]>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1ccc2ccccc2n1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: c1ccc2nc(-c3ccc4ccccc4n3)ccc2c1
Temperature: 82.5 °C
Reaction time: 24 h
Yield: 43.4 %

Procedure:
5.00 g of 2-chloroquinoline and 1.80 g of sodium hydroxide are dissolved in a mixture of 20 ml of water and 16 ml of methanol. Following the addition of 1.5 g of palladium (10% by weight on activated carbon) as catalyst, the mixture is stirred for 24 h at 80-85° C. at 0.1 MPa. Then, following cooling, the catalyst and the precipitated product are filtered off. Extraction of the catalyst gives 1.7 g of 2,2′-biquinoline (43% yield). According to 1H NMR, the crude product has a purity of about 98%. CAS Registry Number: 119-91-5.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]2([CH3:15])[CH3:14])=[CH:6][C:5]=1[CH2:18][CH3:19])[CH3:3].[ClH:20].C[CH:22]([NH2:37])[C:23]1C=[CH:27][C:26](CCC2C=CC=CC=2)=[CH:25][CH:24]=1>>[ClH:20].[CH2:18]([C:5]1[CH:6]=[C:7]2[C:12]([C:11]([CH3:15])([CH3:14])[CH2:10][CH2:9][C:8]2([CH3:17])[CH3:16])=[CH:13][C:4]=1[CH:2]([N:1]=[C:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:37]1)[CH3:3])[CH3:19]
Reactant: CCc1cc2c(cc1C(C)N)C(C)(C)CCC2(C)C
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Agent: Cl
Product: CCc1cc2c(cc1C(C)N=C1CCCCCN1)C(C)(C)CCC2(C)C

Procedure:
Following essentially the same procedure described in Example IV above and substituting 7-(α-aminoethyl)-6-ethyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene for the α-methyl-ρ-phenethylbenzylamine hydrochloride above, results in the formation of 2-[1-(7-ethyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl)ethylimino]hexahydro-1H-azepine hydrochloride, having a M.P. of 246.5°-7.5° C. (dec.)
Reaction SMILES: O[C@@:2]1([C:16]2[S:17][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=4)[N:22]=3)=[CH:19][N:20]=2)[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2.[N-:39]=[N+:40]=[N-:41].[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:39]([C:2]1([C:16]2[S:17][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=4)[N:22]=3)=[CH:19][N:20]=2)[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2)=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc2c(c1)CCC[C@@]2(O)c1ncc(-c2cc(C)cc(Nc3cc(C(F)(F)F)ccn3)n2)s1
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)CCCC2(N=[N+]=[N-])c1ncc(-c2cc(C)cc(Nc3cc(C(F)(F)F)ccn3)n2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of (S)-methyl 5-hydroxy-5-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (100 mg, 0.185 mmol) and sodium azide (36.1 mg, 0.555 mmol) in DCM (2 mL) at rt was added TFA (0.016 mL, 0.203 mmol) dropwise and the mixture was stirred at rt for 16 h, after which time the reaction was heated to 40° C. for 5 days. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude methyl 5-azido-5-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate as a brown oil, which was used as such for the following transformation. MS ESI calcd for C27H22F3N7O2S [M+H]+ 566, found 566.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[F:11])#[N:2].[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:17]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][C:4]=1[F:11])#[N:2]
Reactant: N#Cc1ccc(C=O)cc1F
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1ccc(C#N)c(F)c1

Procedure:
A solution of the product from Step A (970 mg, 6.5 mmol) and (carbethoxymethylene)triphenylphosphorane (2.3 g, 6.5 mmol) was heated at reflux in 50 mL of toluene overnight. The reaction was concentrated in vacuo, triturated with ether, and filtered. The filtrate was concentrated in vacuo, and purified by flash column chromatography on silica gel (15% EtOAc/hexane) to yield the desired product as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]([CH3:39])O[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].CN.[CH3:42][NH:43]C=O.O>C(O)(=O)C>[OH2:23].[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]([CH3:39])[N:43]([CH3:42])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CNC=O
Reactant: CCCc1nc2c(C)cc(-c3coc(C)n3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: CN
Solvent: CC(=O)O
Solvent: O
Product: CCCc1nc2c(C)cc(-c3cn(C)c(C)n3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
A mixture of 1.5 g (3 mMol) of tert.butyl 4'-[(2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate, 10 ml of 40% N-methylamine solution and 15 ml of N-methylformamide is heated for 10 hours to 200° C. in an autoclave. After cooling, the contents of the autoclave are stirred with about 40 ml of water, this suspension is adjusted to pH 6.5 with glacial acetic acid, then the crude product precipitated is suction filtered and dissolved in 1N sodium hydroxide solution. This solution is washed successively with 25 ml of acetic acid and diethylether, then adjusted to pH 6 with 20% citric acid. The product precipitated is suction filtered, washed with about 30 ml of water and dried, then triturated with diethylether and dried in a high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]3([C@H:18]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[N:11]([CH3:27])[C:10]2=[O:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:29]([C:31]1[S:35][CH:34]=[C:33]([C:36]([OH:38])=[O:37])[CH:32]=1)=O.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:23]([C:22]1[CH:21]=[CH:20][C:19]([C@H:18]2[C@:12]3([N:11]([CH3:27])[C:10](=[O:28])[N:9]([C:4]4[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:13]3=[O:14])[CH2:15][N:16]([CH2:29][C:31]3[S:35][CH:34]=[C:33]([C:36]([OH:38])=[O:37])[CH:32]=3)[CH2:17]2)=[CH:26][CH:25]=1)#[N:24]
Reactant: O=Cc1cc(C(=O)O)cs1
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CNC[C@H]2c1ccc(C#N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CN(Cc1cc(C(=O)O)cs1)C[C@H]2c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 75 %

Procedure:
To a solution of 4-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile (0.1 g, 0.24 mmol) (Example 15a) in 1,2-DCE (4 mL) were sequentially added 5-Formyl-3-thiophenecarboxylic acid (0.045 g, 0.29 mmol) and sodium sulfate (150 mgs) under a nitrogen atmosphere at room temperature. The contents were stirred at room temperature for twenty hours and sodium triacetoxyborohydride (0.075 g, 0.336 mmol) was added. The reaction was allowed to continue at room temperature for six hours and quenched by the addition of water (15 m]L). DCM (15 mL) was added, and sulfurdioxide gas was bubbled through the reaction mixture for ten minutes and the contents transferred into a separating funnel. The organic layer was separated, washed with brine (2×20 μL), dried over sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography using DCM and MeOH to yield 0.1 g of the titled compound. Retention time: 3.09 min. YMC S5 Combiscreen 4.6×50 mm (4 minute gradient). Solvent A=10% MeOH, 90% water and 0.2% phosphoric acid. Solvent B=90% MeOH, 10% water and 0.2% phosphoric acid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:19][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=3)[CH2:11][C@@H:6]2[CH2:5][CH2:4]1.C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(Cl)Cl>[CH:2]([C@H:3]1[CH2:19][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=3)[CH2:11][C@@H:6]2[CH2:5][CH2:4]1)=[O:1]
Reactant: OC[C@@H]1CC[C@H]2CN(c3ncc(F)cn3)CCN2C1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=C[C@@H]1CC[C@H]2CN(c3ncc(F)cn3)CCN2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
A mixture of 3.75 g (14.1 mmol) of (7R,9aS)-7-hydroxymethyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Preparation 5), 2.48 g (21.2 mmol) of N-methylmorpholine-N-oxide, 5.0 g of 4 Å molecular sieves, 0.495 g (1.41 mmol) of tetrapropylammonium per-ruthenate, and 375 mL of methylene chloride was stirred at ambient temperature for 2 h. The reaction was quenched with saturated sodium thiosulfate and filtered through Celite. The filtrate was washed with brine, dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 95:5 chloroform:methanol gave 2.27 g (61%) of (7R,9aS)-7-formyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6]([C:8]1[C:13](=[O:14])[CH:12]=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:9]=1)=O)C.[C:25]1([NH:31]N)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)(=O)C>[C:25]1([N:31]2[C:6]([C:8]3[C:13](=[O:14])[CH:12]=[CH:11][N:10]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=4)[N:9]=3)=[N:5][CH:4]=[N:2]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN(C)C=NC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ncnn1-c1ccccc1
Temperature: 120 °C
Yield: 93.9 %

Procedure:
A solution of N-[(dimethylamino)methylidene]-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide (0.119 g, 0.35 mmol) in acetic acid (5.0 mL) was treated with phenyl hydrazine (0.070 mL, 0.71 mmol). The resulting solution was heated under microwave heating conditions at 120° C. for 10 min. After that time the reaction was cooled to room temperature and the crude product purified by flash column chromatography (silica gel, ethyl acetate to 85:15 ethyl acetate/methanol) to give a colorless solid that was recrystallized from ethyl acetate/hexanes to give 0.126 g (46%) of 3-(1-phenyl-1H-1,2,4-triazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as colorless crystals.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:30]1[CH2:31][CH2:32][CH:27]([NH:26][C:3]([C:5]2[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:28][CH2:29]1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)nn1C
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NC2CCOCC2)n(C)n1
Yield: 37 %

Procedure:
As described for example 81c, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (73 mg, 0.21 mmol) was converted, using 4-aminotetrahydropyran instead of morpholine, to the title compound (32 mg, 37%) which was obtained as a white solid. MS: m/e=416.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][NH:17][C:16](=[O:20])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:23][N:24]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[N:25]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][N:17]([CH2:23][N:24]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[N:25]4)[C:16](=[O:20])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=c1nc(N2CCC(O)(c3ccc(F)cc3)CC2)nc[nH]1
Reactant: FC(F)(F)c1ccn(CCl)n1
Product: O=c1nc(N2CCC(O)(c3ccc(F)cc3)CC2)ncn1Cn1ccc(C(F)(F)F)n1
Yield: 30.5 %

Procedure:
4-[4-(4-Fluorophenyl)-4-hydroxypiperidin-1-yl]-1,3,5-triazin-2(1H)-one (426 mg, 1.18 mmol) synthesized in Reference Synthesis Example 14 and 1-(chloromethyl)-3-(trifluoromethyl)-1H-pyrazole (219 mg, 1.18 mmol) were used to obtain the title compound (158 mg, yield 30%) by synthesis in a similar manner to Reference Synthesis Example 8.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl[C:9]([N:11]1[CH2:16][CH:15]([CH2:17][CH3:18])[O:14][C:13]2[CH:19]=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33])=[N:27][CH:28]=3)[CH:21]=[CH:22][C:12]1=2)=[O:10].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:17]([CH:15]1[O:14][C:13]2[CH:19]=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33])=[N:27][CH:28]=3)[CH:21]=[CH:22][C:12]=2[N:11]([C:9](=[O:10])[NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:16]1)[CH3:18]
Reactant: CCC1CN(C(=O)Cl)c2ccc(-c3ccc(OCC(C)(C)C(=O)OC)nc3)cc2O1
Reactant: CCCCCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCNC(=O)N1CC(CC)Oc2cc(-c3ccc(OCC(C)(C)C(=O)OC)nc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
n-Hexylamine (23.0 μL, 0.173 mmol) was added dropwise to a solution of methyl 3-(5-(4-(chlorocarbonyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyridin-2-yloxy)-2,2-dimethylpropanoate B-11 (50.0 mg, 0.115 mmol) and N-ethyl-N,N-diisopropylamine (40.2 μL, 0.231 mmol) in anhydrous methylene chloride (1.10 mL) at 0° C. under an atmosphere of argon. The reaction mixture was slowly warmed to room temperature and stirred for 8 h, then sequentially diluted with methylene chloride (30 mL), quenched with an aqueous pH 7 phosphate buffer solution (15 mL) and decanted. The aqueous layer was extracted with methylene chloride (3×30 mL); the combined extracts were successively washed with an aqueous pH 7 phosphate buffer solution (20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. Crude methyl 3-(5-(2-ethyl-4-(hexylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyridin-2-yloxy)-2,2-dimethylpropanoate B-12 (55.2 mg, Yield=96%) was obtained as a light tan solid and was used for the next step without further purification. MS (ESI) [M+1]+ 498.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:34]1[CH2:41][CH2:40][CH2:39][C@@H:35]1[C:36]([NH2:38])=[O:37]>>[OH:32][C:29]([CH3:31])([CH3:30])[CH2:28][C@@:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:18][C:17](=[O:33])[N:16]([C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:6]=[N:7][C:2]([N:34]4[CH2:41][CH2:40][CH2:39][C@@H:35]4[C:36]([NH2:38])=[O:37])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[CH3:15])[CH2:21][CH2:20]1
Reactant: C[C@@H](c1ccc(-c2ccc(Cl)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: NC(=O)[C@H]1CCCN1
Product: C[C@@H](c1ccc(-c2ccc(N3CCC[C@@H]3C(N)=O)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 26 %

Procedure:
The title compound was prepared from 3-{(S)-1-[4-(6-chloro-pyridazin-3-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one and D-prolinamide following a procedure analogous to that described in Example 53. Yield: 26% of theory; Mass spectrum (ESI+): m/z=544 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]1([O-:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+].N>>[CH:14]1[CH:15]=[CH:16][C:11]([O:17][C:2]2[C:3]([N+:8]([O-:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: [O-]c1ccccc1
Agent: N
Agent: [Na+]
Product: O=[N+]([O-])c1ccccc1Oc1ccccc1
Reaction time: 15 h
Yield: 93.9 %

Procedure:
A steel autoclave was filled with 157.6 g of o-chloronitrobenzene and 116.1 g of sodium phenolate. At room temperature, 150 g of liquid ammonia were pumped into the vessel, the mixture was heated to 600 with stirring for 15 hours and subsequently cooled. Removal of the ammonia by distillation and workup of the distillation residue gave 202 g of 2-nitrodiphenyl ether (94% of the theoretical yield), 98.5% pure.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:32])[CH2:18][CH:19]2[CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]([O:29]C)=[O:28])[C:21](=[O:31])[CH2:20]2)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-:33].[Li+].Cl>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:32])[CH2:18][CH:19]([CH2:24][C:23]([NH:22][CH2:26][C:27]([OH:29])=[O:28])=[O:25])[CH2:20][C:21]([OH:33])=[O:31])[CH2:15][CH2:16]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)CN1C(=O)CC(CC(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)CC1=O
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)CC(CC(=O)O)CC(=O)NCC(=O)O)CC1
Yield: 108.5 %

Procedure:
To a stirred solution of methyl (4-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}-2,6-dioxopiperidin-1-yl)acetate (Example 72, 0.463 g, 1.04 mmol) in THF (5 mL) stirring at 0° C. was added 1 M lithium hydroxide solution (5 mL, 5 mmol). After 3 h the reaction mixture was acidified with 1 M hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to provide 5-[4-(2-tert-butylphenyl)piperazin-1-yl]-3-{2-[(carboxymethyl)amino]-2-oxoethyl}-5-oxopentanoic acid (0.505 g, quant) as a pale brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][C:5]2([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C.[CH3:25][Si:26]([CH2:29][CH2:30][O:31][CH2:32]Cl)([CH3:28])[CH3:27]>C(Cl)Cl>[CH3:12][O:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([CH3:15])([CH3:14])[CH2:6][C:7]2=[O:13])=[CH:3][C:2]=1[O:1][CH2:32][O:31][CH2:30][CH2:29][Si:26]([CH3:28])([CH3:27])[CH3:25]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1cc2c(cc1O)C(C)(C)CC2=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OCOCC[Si](C)(C)C)C(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a solution of 5-hydroxy-6-methoxy-3,3-dimethyl-indan-1-one (40.0 g, 0.194 mol, see preparation in J. Chem. Soc. Perkin Trans. I 1982, p2013-2017) in CH2Cl2 (400 mL) were added diisopropylethylamine (35.5 mL, 0.204 mol) and SEMCl (34.9 mL, 0.198 mol). The reaction mixture was stirred at room temperature for 3 hours and concentrated. The residue was purified by flash chromatography eluted with EtOAc/hexane (2:8) to give 60.5 g (93%) of the desired product as brown oil. MS (DCI/NH3) m/z: 337.1 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 0.00 (s, 9H) 0.96 (t, J=8.10 Hz, 2H) 1.39 (s, 6H) 2.56 (s, 2H) 3.83 (t, J=8.10 Hz, 2H) 3.90 (s, 3H) 5.39 (s, 2H) 7.15 (s, 1H) 7.20 (s, 1H).
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([Cl:30])=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)[N:9]=1)(=O)C.[ClH:31]>CO>[ClH:30].[ClH:31].[ClH:30].[NH2:4][C:5]1[S:6][C:7]([Cl:30])=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:13][CH2:12]2)[N:9]=1
Reactant: CC(=O)Nc1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)c(Cl)s1
Agent: Cl
Solvent: CO
Product: Nc1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)c(Cl)s1

Procedure:
A mixture of 2-acetamido-4-(4-benzhydrylpiperazin-1-ylmethyl)-5-chlorothiazole (5.4 g), methanol (50 ml) and conc. hydrochloric acid (12.5 ml) was refluxed under heating for 6 hours. After concentration of the reaction mixture, the resultant crystals were recrystallized from methanol to obtain white crystals (1.3 g) of 2-amino-4-(4-benzhydrylpiperazin-1-ylmethyl)-5-chlorothiazole trihydrochloride, mp 210°-250° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>>[O:13]1[CH2:14][CH2:15][N:10]([C:2]2[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=2)[CH2:11][CH2:12]1
Reactant: O=c1[nH]cc(Br)c(=O)[nH]1
Reactant: C1COCCN1
Product: O=c1[nH]cc(N2CCOCC2)c(=O)[nH]1
Yield: 76 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 10 (Step1), starting from 5-bromouracil (0.10 g, 052 mmol) and 20 equivalents of morpholine. The crude was purified by precipitation in acidic water (10 mL, pH 5) to afford the title compound (0.08 g, 76%) as white, powder. 1H NMR (400 MHz, DMSO-d6): δ 2.74-2.84 (m, 4H), 3.64 (t, J=4.6 Hz, 4H), 6.72 (s, 1H), 10.47 (s, 1H), 11.05 (s, 1H).
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[F:18][C:19]1[C:24]([C:25]2[NH:29][CH:28]=[C:27]([CH2:30][N:31]([CH3:39])[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:26]=2)=[CH:23][CH:22]=[CH:21][N:20]=1.[S:40]1[CH:44]=[CH:43][N:42]=[C:41]1[S:45](Cl)(=[O:47])=[O:46]>O1CCCC1.O>[F:18][C:19]1[C:24]([C:25]2[N:29]([S:45]([C:41]3[S:40][CH:44]=[CH:43][N:42]=3)(=[O:47])=[O:46])[CH:28]=[C:27]([CH2:30][N:31]([CH3:39])[C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])[CH:26]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: O=S(=O)(Cl)c1nccs1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2nccs2)c1)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a suspension of sodium hydride (60% in oil, 31 mg) in tetrahydrofuran (4 mL) were added dropwise 15-crown-5 (0.16 mL), a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (183 mg) in tetrahydrofuran (1 mL) and 1,3-thiazole-2-sulfonyl chloride (160 mg) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→ethyl acetate) to give the title compound as a pale-yellow oil (yield 168 mg, 62%).