Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][O:28]2)=[O:24])[C:5]1=[O:32].C(N(C(C)C)CC)(C)C.[C:42](OC(=O)C)(=[O:44])[CH3:43]>CN(C=O)C>[C:42]([NH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][O:28]2)=[O:24])[C:5]1=[O:32])(=[O:44])[CH3:43]
Reactant: NCCn1c(=O)c(C(=O)NCC2CCCO2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)NCCn1c(=O)c(C(=O)NCC2CCCO2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-N-(tetrahydro-2-furanylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.057 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (3 mL) under nitrogen was treated with acetic anhydride (0.06 mL, 0.63 mmol) at 40° C. The reaction was concentrated in vacuo and the resulting residue was treated with 1 N NaHSO4, filtered, washed with water, and dried in vacuo to provide the title compound as a pale yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (ddd, J=15.28, 11.80, 7.14 Hz, 1 H), 1.67 (s, 3 H), 1.79-1.89 (m, 2 H), 1.90-2.00 (m, 1 H), 3.26-3.31 (m, 2 H), 3.33-3.40 (m, 1 H), 3.56 (ddd, J=13.91, 5.95, 4.30 Hz, 1 H), 3.64-3.71 (m, 1 H), 3.76-3.84 (m, 1 H), 3.96-4.04 (m, 1 H), 4.15 (s, 2 H), 4.27 (t, J=6.77 Hz, 2 H), 7.11-7.17 (m, 2 H), 7.38-7.44 (m, 2 H), 8.03 (t, J=5.85 Hz, 1 H), 8.19 (d, J=1.46 Hz, 1 H), 8.56 (d, J=1.46 Hz, 1 H), 10.42 (t, J=5.58 Hz, 1 H); ES+ MS: 483 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=[CH:3]1.[Cl:18][C:19]1[C:27]2[NH:26]N=[CH:24][C:23]=2[C:22]2[CH2:28][N:29]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:30](=[O:37])[C@H:31]([CH2:33][C:34]([OH:36])=O)[CH2:32][C:21]=2[CH:20]=1.[CH:43]1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]2[CH2:32][C@@H:31]([CH2:33][C:34]([N:14]3[CH2:15][CH2:16][CH:11]([C:8]4[C:7](=[O:17])[NH:6][C:5]5[CH:4]=[CH:3][N:2]([CH3:1])[C:10]=5[CH:9]=4)[CH2:12][CH2:13]3)=[O:36])[C:30](=[O:37])[N:29]([CH2:38][C:39]([CH3:42])([CH3:40])[CH3:41])[CH2:28][C:22]2=[C:23]2[C:27]=1[NH:26][CH:43]=[CH:24]2
Reactant: On1nnc2ccccc21
Reactant: Cn1ccc2[nH]c(=O)c(C3CCNCC3)cc21
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)O)C1=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc2[nH]c(=O)c(C3CCN(C(=O)C[C@@H]4Cc5cc(Cl)c6[nH]ccc6c5CN(CC(C)(C)C)C4=O)CC3)cc21
Temperature: 25 °C

Procedure:
To a mixture of 1-methyl-6-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridin-5(4H)-one (41 mg, 0.177 mmol), (S)-2-(4-chloro-9-neopentyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (64.5 mg, 0.177 mmol), HOBT (26.3 mg, 0.195 mmol) and EDC (37.4 mg, 0.195 mmol) in DMF (2 mL) was added diisopropylethylamine (108 μl, 0.620 mmol) at rt. The resulting mixture was stirred at rt over night, most of the solvent was removed under N2, the residue was purified on reverse phase PrepHPLC to afford a grey gum which was triturated with Et2O (2 mL), filtered and washed with Et2O (2×0.5 mL) to afford the expected product, (S)-7-chloro-4-(2-(4-(1-methyl-5-oxo-4,5-dihydro-1H-pyrrolo [3,2-b]pyridin-6-yl)piperidin-1-yl)-2-oxoethyl)-2-neopentyl-1,2,4,5-tetrahydroazepino[3,4-e]indol-3(8H)-one (32 mg grey solid. Mass spec: 577.30 (MH+) calc. for C31H37ClN6O3 576.26.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][CH:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].[BH4-].[Na+].[C:30](O)(=O)[CH3:31]>>[CH2:30]([N:22]1[C:10]2[C:11](=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=[C:13]3[C:15]([F:16])([F:17])[F:18])[O:19][CH2:20][CH:21]1[CH2:23][C:24]([F:25])([F:26])[F:27])[CH3:31]
Reactant: CC(=O)O
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)NC(CC(F)(F)F)CO3
Agent: [BH4-]
Agent: [Na+]
Product: CCN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OCC1CC(F)(F)F

Procedure:
This compound was prepared by General Method 5 (EXAMPLE 1) from (±)-3,4-dihydro-8-isopropoxy-3-(2,2,2-trifluoroethyl)-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (0.019 g, 0.05 mmol) and NaBH4 (0.5 pellets, >0.5 mmol) in 2 mL glacial acetic acid to afford (±)-4-ethyl-3,4-dihydro-8-isopropoxy-3-(2,2,2-trifluoroethyl)-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline, of sufficient purity as to be used directly in the next reaction.
Reaction SMILES: [Na].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)#[N:3].[CH2:11]([O:14][CH2:15]Cl)[C:12]#[CH:13]>C(C(C)=O)C>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:15][O:14][CH2:11][C:12]#[CH:13])=[CH:6][CH:5]=1)#[N:3]
Reactant: N#Cc1ccc(O)cc1
Reactant: C#CCOCCl
Agent: [Na]
Solvent: CCC(C)=O
Product: C#CCOCOc1ccc(C#N)cc1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A sodium salt of p-cyanophenol(14.1 g) was dissolved in methyl ethyl ketone (20 ml), and chloromethyl 2-propynyl ether (Intermediate I-a) (10.6g, 0.1 mol) prepared in example 1 was added dropwise to the solution with stirring at room temperature. The reaction mixture was stirred for further 2 hours and the solvent was then evaporated off. The residue was extracted with toluene (30 ml) and the organic layer was washed with distilled water (20 g). The solvent was then evaporated off to obtain a crude reaction product (18.7 g). This was recrystallized from hexane (60 ml) to obtain 1-cyano-4-[(2-propynyloxy)methoxy]benzene (Intermediate II-i) (15.0 g, 79.7% yield). Its chemical purity by HPLC was 99.0%.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([NH:51][C:32]([N:12]2[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][C:7]=2[O:35][CH2:36][CH3:37])=[O:33])[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
In a manner analogous to the method described in example 3, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was reacted with 4-amino-piperidine-1-carboxylic acid tert-butyl ester (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C39H50Cl2N5O4 [(M+H)+] 722.3235, observed 722.3235.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][NH:4][CH2:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:7].[C:15]([O:19][C:20](=[O:33])[NH:21][CH2:22][CH2:23][CH:24]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)[CH3:25])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20](=[O:33])[NH:21][CH2:22][CH2:23][CH:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH:7][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][NH:4][CH2:3][CH:2]([CH3:14])[CH3:1])[CH2:28][CH2:27]1)[CH3:25])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(CCNC(=O)OC(C)(C)C)N1CCC(=O)CC1
Reactant: CC(C)CNC[C@H](N)c1ccccc1
Product: CC(C)CNC[C@H](NC1CCN(C(C)CCNC(=O)OC(C)(C)C)CC1)c1ccccc1
Yield: 58.2 %

Procedure:
Using general procedure A, (R) —N2-(2-methylpropyl)-1-phenyl-ethane-1,2-diamine (350 mg, 1.82 mmol) and [3-(4-oxo-piperidin-1-yl)-butyl]-carbamic acid tert-butyl ester (493 mg, 1.83 mmol) afforded {3-[4-((R)-2-(2-methylpropyl)amino-1-phenyl-ethylamino)-piperidin-1-yl]-butyl}-carbamic acid tert-butyl ester (473 mg, 58%).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5](C=O)[CH2:6]2)#[N:2].[CH3:12][OH:13]>[Co]>[C:1]([CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH2:5][CH:6]2[CH:12]=[O:13])#[N:2]
Reactant: N#CC1CC2CC(C=O)C1C2
Reactant: CO
Agent: [Co]
Product: N#CC1CC2CC1CC2C=O

Procedure:
89.5 g (0.6 mol) of 2-Cyano-5-formyl bicyclo[2.2.1]heptane and 2-cyano-6-formyl bicyclo[2.2.1]heptane which had been obtained in Example 1, methanol (89.5 g) and 4.5 g (as dried mass) of Raney cobalt catalyst (cobalt 94 mass %, aluminum 3.5 mass %, manganese 2.1 mass %) obtained by developing a cobalt-aluminum alloy containing manganese were added in a stainless steel autoclave of electromagnetic stirring having an inner volume of 0.5 liter, and ammonia gas (24.5 g, 1.44 mol) was blown in the autoclave.
Reaction SMILES: [Mg:1].[Br-:2].[CH:3]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[CH2:4]>O1CCCC1>[CH:3]([C:5]1[CH:10]=[C:9]([Mg:1][Br:2])[CH:8]=[CH:7][CH:6]=1)=[CH2:4]
Reactant: [Br-]
Reactant: C=Cc1ccccc1
Reactant: [Mg]
Solvent: C1CCOC1
Product: C=Cc1cccc([Mg]Br)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a 2 liter three-neck flask equipped with a 500 ml dropping funnel, a reflux condenser, and a stirrer was added 28 g (1.15 mole) of metallic magnesium and it was dried sufficiently by supplying dry nitrogen gas. After that, 50 ml of tetrahydrofuran which had been dried with a molecular sieve 5 A, was dropped into the flask and the contents were stirred vigorously. A solution of 183 g (1.0 mole) of 3-vinylbenzene bromide in 500 ml of dry tetrahydrofuran was dropped little by little over 2 hours. The temperature was maintained at about 80° C. and, after the dropping of the solution, the stirring was continued for further 1 hour as it stands. Thereby obtaining a Grignard reagent (3-vinylphenylmagnesium bromide: formula VII).
Reaction SMILES: [C:1]1([C@@H:7]([NH:10][C:11]([CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=O)[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([C:13]1[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:17])[O:18][C:11]=1[NH:10][C@H:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:8][CH3:9])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC[C@H](NC(=O)Cc1ccccc1C(=O)O)c1ccccc1
Product: CC[C@H](Nc1oc(=O)c2ccccc2c1C(C)=O)c1ccccc1

Procedure:
A mixture of 2-[((S)-1-phenyl-propylcarbamoyl)-methyl]-benzoic acid (10 g), acetic anhydride (50 ml), and N,N-dimethylaminopyridine (100 mg) was heated at gentle reflux (Tmax=+124° C.) for 7 min and evaporated in vacuo at +50° C. to give the title compound as a yellow-brown solid (11.1 g, purity 98% by NMR). LC-MS (m/z) 322.3 (MH+); tR=1.72. 1H NMR (500 MHz, DMSO-d6): 0.89 (t, J=7.2 Hz, 3H), 1.86-1.97 (m, 2H), 2.56 (s, 3H), 4.95 (q, J=7.1 Hz, 1H, CH—NH), 7.26 (t, J=7.5 Hz, 1H), 7.29 (unres. m, 1H), 7.36-7.41 (unres m., 3H), 7.71 (t, J=7.5 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.98 (d, J=7.8 Hz, 1H), 11.53 (d, J=7.6 Hz, 1H, NH). 13C APT NMR (125 MHz, DMSO-d6, δ(DMSO-d6)=39.87 ppm): 10.68 (CH3), 30.0 (CH2), 31.57 (CH3), 57.01 (CH), 92.44 (C), 114.88 (C), 124.2 (CH), (CH), 124.26 (CH), 126.65 (CH), 127.8 (CH), 129.05 (CH), 129.93 (CH), 135.71 (CH), 138.68 (C), 141.86 (C), 158.51 (C), 160.55 (C), 194.82 (C, MeCO).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C(O)CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH:21]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22]1>C(O)(C)C.CCOC(C)=O.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)[CH2:22]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: C1CCN(C2CCNC2)CC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: OCCO
Product: Brc1ccc(N2CCC(N3CCCCC3)C2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
283 mg (1.00 mmol) 4-bromo-iodobenzene, 10 mg (0.05 mmol) CuI, 124 mg (2.00 mmol) ethyleneglycol and 424 mg (2.00 mmol) potassium phosphate are added to a reaction vessel, which is evacuated and rinsed with argon several times. Then 154 mg (1.00 mmol) 1-pyrrolidin-3-yl-piperidine in 1 mL isopropanol are added and the reaction is shaken for 15 h at 80° C. The reaction solution is diluted with EtOAc and extracted twice with 5% ammonia solution. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac.
Reaction SMILES: [N:1]1([S:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1C(=O)N([Br:26])C(=O)C1>C(Cl)Cl>[Br:26][C:16]1[CH:17]=[C:12]([CH2:11][CH2:10][S:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)(=[O:9])=[O:8])[CH:13]=[CH:14][C:15]=1[NH2:18]
Reactant: Nc1ccc(CCS(=O)(=O)N2CCOCC2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Nc1ccc(CCS(=O)(=O)N2CCOCC2)cc1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A solution of 103 mg (0.381 mmol) of 4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamine (as prepared in the previous step) in CH2Cl2 (15 mL) was cooled to 0° C. and treated portionwise with 67.8 mg (0.381 mmol) of solid NBS. The mixture was stirred at 0° C. for 15 min, diluted with CH2Cl2 (30 mL) and washed with saturated aqueous NaHCO3 (1×20 mL). The organic layers were dried (MgSO4) and concentrated in vacuo to afford 133 mg (100%) of the title compound as a tan solid: Mass spectrum (ESI, m/z): Calcd. for C12H17N2O3SBr, 349.0/351.0 (M+H). found 348.7/350.8.
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)=[CH:13][C:12]=1[CH3:24]>>[CH3:7][O:6][C:3]([CH:19]1[C:20](=[O:23])[CH2:21][CH2:22][N:17]([C:14]2[CH:15]=[N:16][C:11]([O:10][CH3:9])=[C:12]([CH3:24])[CH:13]=2)[CH2:18]1)=[O:8]
Reactant: COC(=O)OC
Reactant: COc1ncc(N2CCC(=O)CC2)cc1C
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1CN(c2cnc(OC)c(C)c2)CCC1=O
Temperature: 90 °C
Yield: 77.2 %

Procedure:
To a stirred suspension of sodium hydride (60%, 153 mg, 6.36 mmol) in dimethyl carbonate (3.82 mL, 45.4 mmol) at room temperature was slowly added 6′-methoxy-5′-methyl-2,3,5,6-tetrahydro-[1,3′]bipyridinyl-4-one (1 g, 4.54 mmol). The reaction mixture was heated to reflux (90° C.) for 1 h and then cooled to room temperature. The mixture was partitioned between CH2Cl2 and water and a solution of 1N HCl was added cautiously. The aqueous layer was separated and washed with an addition portion of CH2Cl2. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the crude product, which was purified by flash-chromatography on silica gel (heptane/ethylacetate 3/1) to afford 6′-methoxy-5′-methyl-4-oxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-3-carboxylic acid methyl ester (975 mg, yield 77%) as a white solid. 1H-NMR (400 MHz, DMSO, 298K) (mixture of keto and enol tautomers observed) δ ppm 2.12 (s, 6H) 2.36-2.69 (m, 4H) 3.26-3.96 (m, 20H) 7.34-7.77 (m, 4H) 11.84 (s, 1H). LCMS: [M+H]+=279.1, Rt(3)=1.51 min (tautomer 1) and 1.70 min (tautomer 2).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=C[C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14](NC4C=CC=C(O)C=4)[N:13]=3)=[CH:4][C:3]=2O1.CC1OC(C)=CC=1CN.[Cl:36]C1N=C(Cl)C(F)=CN=1>>[Cl:36][C:14]1[N:13]=[C:12]([NH:11][CH2:5][C:4]2[CH:3]=[C:8]([CH3:7])[O:9][C:10]=2[CH3:1])[C:17]([F:18])=[CH:16][N:15]=1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cc1cc(CN)c(C)o1
Product: Cc1cc(CNc2nc(Cl)ncc2F)c(C)o1

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of (2,5-dimethyl-3-furyl)methylamine (188 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) gave 2-chloro-N4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-4-pyrimidineamine. The reaction of 2-chloro-N4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-4-pyrimidineamine and 3-aminophenol (200 mg, 1.83 mmol) gave N4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (50 mg, 51%). 1H NMR (CDCl3): δ 2.22 (s, 3H), 2.23 (s, 3H), 4.39 (d, J=5.1 Hz, 2H), 5.24 (br, 1H), 5.90 (s, 1H), 6.52 (d, J=6.6 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 7.13 (t, J=8.1 Hz, 1H), 7.29 (s, 1H), 7.71 (m, 2H); 19F NMR (282 MHz, CDCl3): δ −167.84; LCMS: ret. time: 19.83 min.; purity: 96.32%; MS (m/e): 329.05 (MH+).
Reaction SMILES: COC1C2C(=C(OC)C=CC=2)C(OC)=CC=1C([CH:19]1[CH2:25][CH2:24][C:23]2([C:27]3([CH3:32])OCC[O:28]3)[CH2:26][CH:20]1[C:21](=[O:33])[O:22]2)=O.Cl.[CH3:35][OH:36]>>[CH3:35][O:36][C:21]([CH:20]1[CH2:26][C:23]([C:27](=[O:28])[CH3:32])([OH:22])[CH2:24][CH2:25][CH2:19]1)=[O:33]
Reactant: CO
Reactant: COc1c(C(=O)C2CCC3(C4(C)OCCO4)CC2C(=O)O3)cc(OC)c2c(OC)cccc12
Agent: Cl
Product: COC(=O)C1CCCC(O)(C(C)=O)C1

Procedure:
1.6 g of 2-(1,4,5-trimethoxy-2-naphthylcarbonyl)-5-(2-methyl-dioxolan-2-yl)-6-oxa-bicyclo[3,2,1]octan-7-one, prepared as described in Example 4, was dissolved in methanol and treated at room temperature for 1 hour with a 1N solution of hydrogen chloride in anhydrous methanol. After evaporating off the solvent, there was obtained in almost quantitative yield 1.5 g of 1-1,4,5-trimethoxy-3-naphthylcarbonyl)-2-methoxycarbonyl-4-acetyl-4-hydroxy-cyclohexane (X, R=OCH3). m/z 444 (M+.); IR (film): 3460 cm-1 (OH), 1730 cm-1 (C=O ester, 1710 cm-1 (C=O ketone) and 1665 cm-1 (C=O benzylic ketone). PMR (CDCl3): inter alia 2.3 (s, CH3CO), 3.75-4.05 (s, four OCH3), 6.8 (s, aromatic H) and 6.85-8.0 (m, three aromatic H). 1.5 g of this compound was dissolved in 15 mo of trifluoroacetic acid and refluxed with 1.4 ml of pyridine-borane complex. After removal of the solvent, the residue was treated with a 10% aqueous solution of sodium hydroxide. After mild acidification the free acid was extracted with ethyl acetate. The solvent was evaporated off and the residue was directly treated with an ethereal solution of phenyldiazomethane to give the title product. This was purified by chromatography: m/z 508 (M+.); PMR (CDCl3): inter alia 1.25 (d, CH3 --CH), 3.70-3.95 (s, three OCH3), 5.15 (d, CH2Ph) and 6.4-8.1 (m, nine aromatic H).
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20].N12CCN(CC1)CC2.O>CN(C)C=O>[CH:11]1([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:7][CH:6]=2)=[O:10])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(Nc1ccc(O)nc1)C1CCCCC1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)Oc1ccc(NC(=O)C2CCCCC2)cn1)c1ccccc1
Yield: 70.7 %

Procedure:
A solution of cyclohexanecarboxylic acid (6-hydroxy-pyridin-3-yl)-amide (0.66 g, 3.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.51 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.34 g, 3.00 mmol) in dimethylformamide (20 ml) was stirred at room temperature for 18 hours. Water was added and the precipitates were collected by suction. The solids were dissolved in dichloromethane and the solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was crystallised from ethyl acetate:heptane yielding the title compound (0.75 g, 71% yield) as a slightly coloured solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6](/[Br:11])\[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([OH:14])=[O:13].[C:16]([C@@H:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)#[N:17]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6](/[Br:11])\[C:7](=[O:10])[O:8][CH3:9])[C@H:3]1[C:12]([O:14][C@H:18]([C:16]#[N:17])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:20]=1)=[O:13]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: COC(=O)/C(Br)=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Solvent: ClC(Cl)Cl
Product: COC(=O)/C(Br)=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Example 1, the product of Step B and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(E)-[2-bromo-3-oxo-3-methoxy-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+9.5°±2.5° (c=0.3% in chloroform).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH2:9]([O:16][C:17]([Cl:19])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)=O.CO>C(Cl)Cl>[ClH:19].[CH2:9]([O:16][C:17]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH2:1])[CH2:4][CH2:5]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C=O
Solvent: CO
Solvent: ClCCl
Product: Cl
Product: NCC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
To a solution of 4-aminomethyl piperidine (7.19 g) in anhydrous methylene chloride (80 ml), there was dropwise added a solution of benzyloxycarbonyl chloride (3.0 ml) in anhydrous methylene chloride (25 ml) under a nitrogen gas atmosphere while cooling with dry ice-methanol. After the completion of the dropwise addition, the resulting mixture was stirred while cooling with dry ice-methanol for 20 minutes and then stirred at room temperature for additional 2 hours. The reaction solution was concentrated under reduced pressure and ether and a citric acid solution were added to the resulting residue. The resulting aqueous phase was washed twice with ether. After addition of chloroform to the aqueous phase, sodium carbonate was added thereto at room temperature with stirring to make the aqueous phase basic. Separately, the resulting organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting oily product was dissolved in ether and a 4N hydrogen chloride solution in ethyl acetate (10 ml) was added to the ether solution with ice cooling. The resulting precipitates were filtered off to thus give the title compound (Reference Compound 4-1, 1.86 g) in the form of crystals.
Reaction SMILES: [C:1]([NH2:5])(C)(C)C.C=[O:7].O.[C:9]1([CH3:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[O:7]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:15]=[CH:1][NH:5]1
Reactant: C=O
Reactant: CC(C)(C)N
Reactant: Cc1ccccc1
Solvent: O
Product: C1=Cc2ccccc2ON1
Temperature: 25 °C
Yield: 78 %

Procedure:
A 500 mL three-neck round-bottom flask with a stir-bar was charged with tert-butylamine (14.6 g, 200 mmole), paraformaldehyde (15.0 g, 500 mmole), siloxane-bridged-bisphenol (26.8 g, 0.1 mol, prepared by the procedure described in Example 10), and toluene (200 mL) were placed into a 500 mL. The flask was connected to a Dean-Stark trap and condenser and the reaction mixture was heated to reflux for 4.0 hours while stirring. A total of 7.2 ml (400 mmol) of water was collected. The reaction mixture was allowed to cool to room temperature and passed through a thin layer of silica gel. The toluene was removed by rotary evaporation and the residue was sparged with nitrogen gas for five hours at 60° C. The final product was a fairly mobile, clear, red liquid. The yield was 78% of theory.