Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][NH:11][C:10](=O)[C:9]=3[CH:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:22])=O.[OH-].[Na+]>C(#N)C>[Cl:22][CH:10]1[C:9]2[CH:8]=[CH:7][N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:14]=2[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][NH:11]1
Reactant: COC(=O)c1c[nH]c(=O)c2ccn(C3CCCC3)c12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: COC(=O)C1=CNC(Cl)c2ccn(C3CCCC3)c21
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (1.83 g) obtained in Step D of Example 29 in acetonitrile (20 mL) was added phosphoryl chloride (4 mL), and the mixture was stirred at 80° C. for 4 hr. To the reaction mixture was added 8N aqueous sodium hydroxide solution at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.37 g).
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].O[CH:6]1[C:15]2[C:10](=[C:11]([F:22])[CH:12]=[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:14]=2[Cl:16])[S:9][CH2:8][CH2:7]1>S(=O)(=O)(O)O>[F:1][CH2:2][CH2:3][O:4][CH:6]1[C:15]2[C:10](=[C:11]([F:22])[CH:12]=[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:14]=2[Cl:16])[S:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)c1cc(F)c2c(c1Cl)C(O)CCS2
Reactant: OCCF
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(F)c2c(c1Cl)C(OCCF)CCS2
Yield: 79 %

Procedure:
5 ml of 2-fluoroethanol and 3 drops of concentrated sulfuric acid were added to 2.4 g (8.2 mmol) of 4-hydroxy-5-chloro-6-ethoxycarbonyl-8-flurothiochroman (corresponding to compound of the formula (IX)), and the mixture was refluxed under heat for 5 hours. After allowed to cool, the reaction mixture was poured into an ice bath, and extracted with ethyl acetate twice. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 2.2 g (yield 79%) of 4-(2-fluoroethoxy)-5-chloro-6-ethoxycarbonyl-8-fluorothiochroman (corresponding to compound of the formula (X)).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([NH:5][C@@H:6]([CH2:10][CH3:11])[C:7]([OH:9])=O)=[O:4].O.O[N:16]1[C:20]2C=[CH:22][CH:23]=[CH:24][C:19]=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.C(N)CCC#C>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:20]([NH:16][C:7](=[O:9])[C@@H:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:13])[F:12])[CH2:10][CH3:11])[CH2:19][CH2:24][C:23]#[CH:22]
Reactant: On1nnc2ccccc21
Reactant: CC[C@H](NC(=O)C(F)(F)F)C(=O)O
Agent: C#CCCCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C#CCCCNC(=O)[C@H](CC)NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A 500 mL round bottom flask was charged with 2-(S)-(2,2,2-trifluoroacetylamino)-butyric acid (5.0 g, 0.025 mol), 1-hydroxybenzotriazole hydrate (4.5 g, 0.033 mol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (6.4 g, 0.033 mol), 4-(dimethylamino)pyridine (0.02 g, 0.163 mmol), and dimethylformamide (95 mL). To the resulting mixture was then added triethylamine (10.6 mL, 0.076 mol) and pent-4-yn-1-amine (2.7 g, 0.033 mol). The resulting mixture was stirred at room temperature for 22 h, then concentrated in vacuo to yield a residue which was purified via flash silica gel chromatography (Analogix IF-280, SF65-400 g column, gradient 90:10-40:60 Heptane:EtOAc) to yield (S)—N-(pent-4-ynyl)-2-(2,2,2-trifluoroacetamido)butanamide. 1H NMR (300 MHz, CDCl3) δ4.46-4.53 (m, 1H), 3.32-3.48 (m, 2H), 2.23-2.29 (m, 2H), 2.00 (s, 1H), 1.86-1.98 (m, 2H), 1.71-1.83 (m, 2H), and 0.91-0.98 (m, 3H).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][C:5]1[C:6](=[O:22])[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH3:21])[CH2:8][CH2:9][CH:10]=1.[Li+].[OH-]>C(O)(C(F)(F)F)=O>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:7]1[CH2:8][CH2:9][CH:10]=[C:5]([CH2:4][C:3]([OH:23])=[O:2])[C:6]1=[O:22]
Reactant: COC(=O)CC1=CCCN(Cc2ccc(OC)cc2OC)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2CCC=C(CC(=O)O)C2=O)c(OC)c1

Procedure:
[1-(2,4-dimethoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-acetic acid methyl ester (o) prepared by the Step 2 of Example 26 dissolved in TFA was reacted with LiOH to give [1-(2,4-dimethoxy-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-acetic acid (q1).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.C[N:23]([CH3:26])C=O>COC1C=CC=CC=1CN.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:23][CH2:26][C:11]4[CH:10]=[CH:9][CH:14]=[CH:13][C:12]=4[O:15][CH3:16])=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Agent: COc1ccccc1CN
Solvent: CCO
Product: COc1ccccc1CNC[C@@H](O)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 2-methoxybenzylamine in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=423.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([CH3:13])=[C:11]([CH3:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[N:8]2.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>O>[N:19]1([CH2:2][C:3]2[C:12]([CH3:13])=[C:11]([CH3:14])[CH:10]=[C:9]3[C:4]=2[N:5]=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[N:8]3)[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: COc1nc2cc(C)c(C)c(CCl)c2nc1OC
Reactant: c1c[nH]cn1
Solvent: O
Product: COc1nc2cc(C)c(C)c(Cn3ccnc3)c2nc1OC
Temperature: 110 °C
Yield: 62.5 %

Procedure:
A mixture of 5-chloromethyl-2,3-dimethoxy-6,7-dimethylquinoxaline (Preparation 3) (60 mg, 0.22 mmol) and imidazole (1.0 g, 14.7 mmol) was heated at 110° C. for 30 minutes, cooled and diluted with water. The resulting suspension was sonicated for 5 minutes at 20° C. and the solid filtered off. The solid was washed with water, and then hexane, affording 5-(imidazol-1-ylmethyl)-2,3-dimethoxy-6,7-dimethyl-quinoxaline (41 mg, 61%) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:4][C:5]([Br:18])=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8](OCC)=[O:9].O.[NH2:26][NH2:27]>C(O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:27][NH:26][C:13](=[O:14])[C:6]=2[C:5]([Br:18])=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1c(Br)nc(-c2ccccc2)c(N)c1C(=O)OCC
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1c(-c2ccccc2)nc(Br)c2c(=O)[nH][nH]c(=O)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a mixture of 1 ml of ethanol and 2 ml of hydrazine monohydrate was dissolved 90 mg of 3-amino-6-bromo-4,5-diethoxycarbonyl-2-phenylpyridine, and the mixture was stirred for 2 hours at room temperature. After the solvent was distilled off, the resulting crystals were collected by filtration with ethanol. Water was added to the crystals, and the mixture was neutralized with 1N hydrochloric acid, the resulting crystals were collected by filtration. The crystals were dissolved in a small volume of methanol. After mixing the methanol solution with silica gel, purification by silica gel column chromatography (eluent:ethyl acetate→ethylacetate/methanol 1:1) was conducted, followed by collection by filtration.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10]C)=[O:9])[CH3:3].[ClH:18]>>[ClH:18].[CH3:3][N:2]([CH2:4][C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9])[CH3:1]
Reactant: COC(=O)c1cccc(CN(C)C)c1[N+](=O)[O-]
Agent: Cl
Product: CN(C)Cc1cccc(C(=O)O)c1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h

Procedure:
The mixture of methyl 3-dimethylaminomethyl-2-nitrobenzoate (0.72 g) and 6M hydrochloric acid was stirred at 100° C. overnight. After cooling the mixture to room temperature, the precipitated crystals were filtered out, washed with diethylether and dried under reduced pressure to obtain 3-dimethylaminomethyl-2-nitrobenzoic acid hydrochloride.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[C:8]([OH:10])[C:7]([NH2:11])=[CH:6][C:4]=1[OH:5].[C:12]1([C:18](Cl)(Cl)Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:18]2[O:5][C:4]3[CH:6]=[C:7]4[N:11]=[C:18]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)[O:10][C:8]4=[CH:9][C:3]=3[N:2]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cc(O)c(N)cc1O
Reactant: ClC(Cl)(Cl)c1ccccc1
Agent: Cl
Product: c1ccc(-c2nc3cc4oc(-c5ccccc5)nc4cc3o2)cc1
Temperature: 190 °C

Procedure:
In the apparatus described in Example 13, 5.9 g of 2,5-diaminohydroquinone hydrochloride (28 m moles) were placed and at 180° C, 7.6 g of benzotrichloride (39 m moles) were added drop by drop. After 3 hours of heating at 190° C, the mixture was cooled and ground with mortar and pestle. The reaction product was extracted twice with 150 ml of xylene and passed through an aluminum oxide column heated at 125° C. The product was 4.5 g of crude XXII (74% of the theory). After two recrystallizations from xylene the melting point was 319°-323° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[O:13][C:12](=[O:14])[NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[N:18]=1.C([O-])([O-])=O.[K+].[K+].N#N>[Cu]I.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[O:13][C:12](=[O:14])[N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[N:18]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(c2cccc(Cl)c2)CCNC(=O)O1
Reactant: Brc1cccc(N2CCCCC2)n1
Agent: [Cu]I
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC1(c2cccc(Cl)c2)CCN(c2cccc(N3CCCCC3)n2)C(=O)O1
Temperature: 130 °C
Yield: 43.2 %

Procedure:
A mixture of 6-(3-chlorophenyl)-6-methyl-1,3-oxazinan-2-one (28 mg, 0.12 mmol), 2-bromo-6-piperidinopyridine (33 mg, 0.14 mmol), CuI (7 mg, 0.037 mmol), powdered K2CO3 (19 mg, 0.14 mmol) and CH2Cl2 (0.25 mL) was heated to 130 C under a stream of N2 such that the CH2Cl2 evaporated. The vessel was sealed and the mixture was heated at 130° C. for 1 h under N2. The residue was dissolved in MeCN (0.5 mL) and DMSO (0.5 mL) and purified by prep HPLC to afford 6-(3-chlorophenyl)-6-methyl-3-(6-(piperidin-1-yl)pyridin-2-yl)-1,3-oxazinan-2-one (20 mg) as a brown oil. LC-MS Method 1, tR=2.08 min, m/z=386, 388. 1H NMR (CDCl3) 1.62 (6H), 1.73 (s, 3H), 2.35 (m, 1H), 2.48 (m, 1H), 3.43 (5H), 4.11 (m, 1H), 6.50 (d, 1H), 7.20-7.60 (6H).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:16]2[CH:20]=[CH:19][N:18](COCC[Si](C)(C)C)[N:17]=2)=[C:6]2[CH2:11][CH2:10][N:9]([CH:12]([CH3:14])[CH3:13])[C:8](=[O:15])[C:7]=12.Cl>CO>[CH3:1][S:2][C:3]1[S:4][C:5]([C:16]2[CH:20]=[CH:19][NH:18][N:17]=2)=[C:6]2[CH2:11][CH2:10][N:9]([CH:12]([CH3:14])[CH3:13])[C:8](=[O:15])[C:7]=12
Reactant: CSc1sc(-c2ccn(COCC[Si](C)(C)C)n2)c2c1C(=O)N(C(C)C)CC2
Agent: Cl
Solvent: CO
Product: CSc1sc(-c2cc[nH]n2)c2c1C(=O)N(C(C)C)CC2
Temperature: 80 °C

Procedure:
To a solution of 3-(methylsulfanyl)-5-(propan-2-yl)-1-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)-6,7-dihydrothieno[3,4-c]pyridin-4(5H)-one (45 mg, 0.10 mmol) in MeOH (26 μL) at rt was added 4M HCl in MeOH (26 μL, 0.10 mmol). The solution was heated at 80° C. for 1 h. The resulting mixture was concentrated and purified by Gilson reverse phase chromatography to afford the title compound. 1H NMR (400 MHz, ppm, CDCl3) 7.60 (d, J=2.4 Hz, 1 H); 6.38 (d, J=2.4 Hz, 1 H); 5.00 (sep, J=6.8 Hz, 1 H); 3.40 (t, J=6.4 Hz, 2 H); 3.03 (t, J=6.4 Hz, 21-1); 2.60 (s, 3 H); 1.20 (s, 3 H); 1.18 (s, 3 H). HRMS (ES+) m/z 308.0884 [(M+H)+; calcd for C14H17N3OS2: 308.0886].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])=[N:6][CH:7]=1.Br[CH2:14][CH2:15]Br>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([S:9]([CH3:12])(=[O:11])=[O:10])[CH2:15][CH2:14]2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cc1ccc(Br)cn1
Reactant: BrCCBr
Product: CS(=O)(=O)C1(c2ccc(Br)cn2)CC1
Yield: 19 %

Procedure:
The title compound was prepared from 5-bromo-2-methanesulfonylmethyl-pyridine and 1,2-dibromoethane following a procedure analogous to that described in Step 3 for Intermediate 4. Yield: 19% of theory; LC (method 3): tR=2.52 min; Mass spectrum (ESI+): m/z=276/278 (Br) [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:42][O:43][C@H:44]([CH3:54])[C@H:45]([NH:52][CH3:53])[CH2:46][N:47]1[CH2:50][CH:49]([OH:51])[CH2:48]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:52]([C@@H:45]([C@H:44]([O:43][CH3:42])[CH3:54])[CH2:46][N:47]2[CH2:48][CH:49]([OH:51])[CH2:50]2)[CH3:53])=[O:8])=[CH:9][CH:10]=1
Reactant: CN[C@H](CN1CC(O)C1)[C@@H](C)OC
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CO[C@H](C)[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
To 4-chlorobenzoic acid (65.7 mg, 0.42 mmol) and DIPEA (0.365 mL, 2.10 mmol) in DCM (0.7 mL) was TBTU (148 mg, 0.46 mmol) added 1-((2R,3R)-3-Methoxy-2-(methylamino)butyl)azetidin-3-ol (Compound B2.2) (79 mg, 0.42 mmol) in DCM (0.7 mL) was added and the resultant mixture stirred at rt for 2 h. NaHCO3 was added and the stirring continued for 30 min. The layers were separated and the organic phase concentrated under reduced pressure. The residue was dissolved in THF/MeOH/water (3:1:1) and a small amount of NaOH (3.8M) was added. The resultant mixture was stirred for 30 min. The mixture was diluted with water and the organic solvent was removed. The water layer was extracted with DCM. The combined organic layers were filtered through a phase separator and concentrated. The residue was purified by preparative HPLC to give the title compound (39 mg, 28%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 0.92, 1.08, 2.34-2.40, 2.52-2.59, 2.63, 2.69, 2.70-2.76, 2.77, 3.18-3.23, 3.34-3.39, 3.44-3.48, 3.48-3.54, 4.04-4.10, 4.11-4.16, 4.40, 5.16-5.24, 7.31, 7.40, 7.43-7.50. Total of protons in spectrum: 22. Ratio major:minor:3:2. HRMS (M+H)+: calculated 327.1475. found 327.1476.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([N:9]([O:25][SiH:26]([CH3:28])[CH3:27])[C:10]2[CH:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[Br:24])[N:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:34][C:35]#[N:36]>>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([N:9]([O:25][SiH:26]([CH3:27])[CH3:28])[C:10]2[CH:15]=[C:14]([N:16]([CH2:34][C:35]#[N:36])[C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[Br:24])[N:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCBr
Reactant: Cc1ccc(Nc2cc(N(O[SiH](C)C)c3ccc(C(C)(C)C)cc3)ncn2)c(Br)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(N(CC#N)c2cc(N(O[SiH](C)C)c3ccc(C(C)(C)C)cc3)ncn2)c(Br)c1
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
To a solution of 4-(4-tertbutyldimethylsilyloxyanilino)-6-(2-bromo-4-methylanilino)pyrimidine (Reference Example 3, 396 mg) in tetrahydrofuiran (1 ml) under nitrogen atmosphere was added portion wise sodium hydride (60% dispersion in mineral oil, 58 mg). The solution was stirred for 30 minutes. Bromoacetonitrile (131 mg) was added and the reaction stirred for a further 1 hour. The solvent was evaporated and the residue purified by column chromatography eluting with DCM:MeOH:concentrated ammonia; 97.8:2:0.2 to give the title compound (158 mg, 37%) as a solid. M/z 524 (MH+).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]([C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH2:5][CH:6]([C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: N#Cc1ccc(C(CCN=[N+]=[N-])n2ccnc2)cc1
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccc(C(CCN)n2ccnc2)cc1
Reaction time: 16 h

Procedure:
The 4-(3-azido-1-imidazol-1-yl-propyl)-benzonitrile (490 mg, 1.9 mmol) was suspended in methanol (20 mL) and placed under argon. 10% Palladium on Carbon catalyst was carefully added under argon and the solution was evacuated under vacuum to bubbling and then purged with argon 3 times. The suspension was evacuated again and then a balloon filled with hydrogen was opened to the reaction. The reaction was left under hydrogen at room pressure for 16 hours. The reaction was evacuated again to bubbling and purged with argon. The catalyst was filtered off through a bed of celite under argon. The supernatant was concentrated in vacuo to give the desired product.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[C:1]([CH2:3][C:4]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: Nc1ccccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: N#CCC(=O)Nc1ccccn1
Reaction time: 4 h

Procedure:
Cyanoacetic acid (4.5 g) and 5.0 g of 2-aminopyridine, each in acetonitrile, were combined, and the suspension (150 ml) treated rapidly with a solution of 12.0 g of dicyclohexylcarbodiimide (DCCI) in 60 ml of acetonitrile. After stirring 4 hrs. and filtering, the filtrate was evaporated and the residue triturated with ether to give 2-(cyanoacetylamino)pyridine, m.p. 159°-161°. Recrystallization from ethyl acetate raised melting point to 162°-3°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[CH:5][C:4]=1[N:18]=[CH:19][N:20]([CH3:22])[CH3:21])#[N:2].Br[CH2:24][CH2:25][O:26][C:27]([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:27]([O:26][CH2:25][CH2:24][N:14]1[CH2:15][CH2:16][CH2:17][C@@H:13]1[CH2:12][O:11][C:6]1[C:7]([O:9][CH3:10])=[CH:8][C:3]([C:1]#[N:2])=[C:4]([N:18]=[CH:19][N:20]([CH3:21])[CH3:22])[CH:5]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1OC[C@H]1CCCN1
Reactant: CC(C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C#N)c(N=CN(C)C)cc1OC[C@H]1CCCN1CCOC(C)(C)C
Yield: 55.6 %

Procedure:
N′-(2-cyano-4-methoxy-5-[(2R)-pyrrolidin-2-ylmethoxy]phenyl)-N,N-dimethylimidoformamide (1.23 g, 4.06 mmol) in dimethylformamide (13 ml) was reacted with 2-(2-bromoethoxy)-2-methylpropane (809 mg, 4.47 mmol) in the presence of potassium carbonate (842 mg, 6.1 mmol) at 50° C. for 5 hours. The solvent was then evaporated, and the residue purified by chromatography on silica gel, eluting with dichloromethane:methanol (98:2) then (95:5), to yield N′-(5-{[(2R)-1-(2-tert-butoxyethyl)pyrrolidin-2-yl]methoxy}-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide (908 mg, 56% yield):
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].[CH3:12]I.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5](=[O:8])[N:6]([CH3:12])[CH:7]=1
Reactant: Cc1cc(O)ncc1Br
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(=O)n(C)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To a solution of 5-bromo-4-methylpyridin-2-ol (1.12 g, 6.0 mmol) in anhydrous THF (20 mL) was added NaH (288.0 mg, 12.0 mmol) and the reaction mixture was stirred at 0° C. for 30 min. Then, methyl iodide (1.7 g, 12.0 mmol) was added and stirred at room temperature for 3 h. Saturated NH4Cl (100 mL) was added and the resulting mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (PE:EA=10:1 to 2:1) to give the title compound (1.0 g, 83.3%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 7.44 (s, 1H), 6.94 (s, 1H), 3.51 (s, 3H), 2.24 (s, 3H). LCMS (M+H)+ 1202.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3=[CH:12][CH2:13][CH2:14][CH2:15][C:9]3=[C:8]([CH3:16])[C:7]([CH3:18])(O)[C:6]=2[CH:19]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([CH3:16])=[C:7]([CH3:18])[C:6]=2[CH:19]=1
Reactant: CC1=C2CCCC=C2Oc2ccc(Br)cc2C1(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC1=C(C)c2cc(Br)ccc2Oc2ccccc21

Procedure:
319 g (1 mol) of 8-bromo-10,11-dimethyl-dihydrodibenz[b,f]oxepin-10-ol (crude product) and 1.5 g of p-toluenesulfonic acid are heated in a distillation apparatus under 11 mm Hg for 1 hour at an external temperature of 180° and for 5 hours at an external temperature of 200°, water being eliminated. The distillation receiver is then changed and the 2-bromo-10,11-dimethyldibenz[b,f]oxepine formed is then distilled under a high vacuum; boiling point 142°-148°/0.01 mm Hg. The pale yellow distillate is dissolved in 300 ml of acetonitrile and the solution is cooled to 0°, whereupon the product crystallises out; melting point 117°-119°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C(=C(OC)C=CC=2)[O:40][C:39]=1C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([O:40][CH3:39])[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: COc1cccc2c(=O)c(I)c(-c3ccccc3)oc12
Product: COc1cccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Yield: 98 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-8-methoxy-2-phenyl-chromen-4-one was reacted to give the title compound as a white solid (73 mg, 98%). LCMS (Method B): RT=4.84 min, [M+H]+=498.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#N)=[C:7]([F:13])[CH:6]=1)[CH:2]=[CH2:3].[H-].C([Al+]CC(C)C)C(C)C.C1C[O:27]CC1>>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:27])=[C:7]([F:13])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C1CCOC1
Reactant: C=CCOc1ccc(C#N)c(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: C=CCOc1ccc(C=O)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product from Example 53A (6.42 g, 36.5 mmoles) in anhydrous THF (50 mL) was treated with diisobutylaluminum hydride (DIBAL) (37.0 mL, 37.0 mmoles, 1.0M in hexanes) dropwise at −78° C. After 30 minutes, an additional portion of DIBAL (37.0 mL) was added dropwise. After an additional 30 minutes, the acetone/dry ice bath was removed, and the reaction mixture was warmed to 0° C. After an additional 30 minutes, the reaction was carefully quenched with saturated NH4Cl. The mixture was diluted with diethyl ether (200 mL) and saturated sodium potassium tartrate (250 mL) and stirred vigorously for 2.0 hours. The two phases were separated, and the organic phase was washed with brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure to provide the title compound with no further purification. MS (DCI) m/z 181 (M+H)+.