Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([N:12]1[CH2:19][C:18]2[C:14](=[N:15][NH:16][C:17]=2[NH:20][C:21](=[O:31])[C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=2)[C:13]1([CH3:33])[CH3:32])=[O:11].[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([N:12]1[CH2:19][C:18]2[C:17]([NH:20][C:21](=[O:31])[C:22]3[CH:23]=[CH:24][C:25]([C:26]([NH:41][CH:38]4[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]4)=[O:28])=[CH:29][CH:30]=3)=[N:16][NH:15][C:14]=2[C:13]1([CH3:32])[CH3:33])=[O:11]
Reactant: CN1CCC(N)CC1
Reactant: CC1(C)c2n[nH]c(NC(=O)c3ccc(C(=O)O)cc3)c2CN1C(=O)Nc1c(Cl)cccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CN1CCC(NC(=O)c2ccc(C(=O)Nc3n[nH]c4c3CN(C(=O)Nc3c(Cl)cccc3Cl)C4(C)C)cc2)CC1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
To a solution of N-[5-(2,6-Dichloro-phenylcarbamoyl)-6,6-dimethyl-2,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-terephthalamic acid (0.11 g, 0.22 mmol) N,N-diispropylethylamine (0.12 mL, 0.66 mmol) 1-Methyl-piperidin-4-ylamine (0.04 g, 0.34 mmol) in dry CH2Cl2 (20 mL), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.11 g, 0.34 mmol) was added. The reaction was stirred at room temperature over night, the solvent removed under reduced pressure, the residue dissolved in CH2Cl2 (40 mL) and washed with water (1×20 mL) then with saturated sodium hydrogencarbonate aqueous solution (1×20 mL). The organic phase was dried over sodium sulphate, the solvent evaporated in vacuo and the crude product purified by flash chromatography (CH2Cl2/MeOH/NH3 90/10/1) to afford 0.07 g (yield 55%) of the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=1[O:38][CH3:39].CN(C)C=O>O>[O:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=3[O:38][CH3:39])[CH2:7][CH2:6]2)=[N:9]1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCC(c2noc3ccccc23)CC1
Temperature: 75 °C
Yield: 94.7 %

Procedure:
A mixture of 3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4.3 g, 18 mmol), K2CO3 (5.5 g, 40 mmol), and 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (5.5 g, 18 mmol), and dimethylforrnamide (6t3 ml) was stirred and heated at 75° C. for 16 hours. The reaction was poured into water and was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4), and the solvent concentrated to afford 7.2 g of a beige solid. Recrystallization (twice) from ethyl alcohol yielded 3.3 g (43%) of 1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]bitoxyl]-3-methoxyphenyl]ethanone, m.p.=99°-101° C.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.Cl.[CH3:11][O:12][C:13](=[O:16])[CH2:14][NH2:15].C(N(CC)CC)C>CCOCC>[C:8]([C:3]1[C:2]([NH:15][CH2:14][C:13]([O:12][CH3:11])=[O:16])=[N:7][CH:6]=[CH:5][N:4]=1)#[N:9]
Reactant: N#Cc1nccnc1Cl
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)CNc1nccnc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
In 8 ml of ether there was dissolved chlorocyanopyrazine (0.42 g; 0.003 M) prepared in Step B above, after which there was added glycine methyl ester hydrochloride (378 mg; 0.003 M), followed by triethylamine (607 mg, 0.84 ml; 0.006 M). The reaction mixture was stirred at room temperature overnight. The resulting precipitate was filtered, washed twice with ether, and the filtrate concentrated under vacuum, then passed through a silica gel column and eluted with dichloromethane to give the title compound (130 mg).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:8][CH:7]=[C:6]([C:9]([O:11][CH2:12]C)=[O:10])[C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Br:3][C:4]1[N:8]([S:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:28])=[O:27])[CH:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1c[nH]c(Br)c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cn(S(=O)(=O)c2ccccc2)c(Br)c1-c1ccccc1
Yield: 93 %

Procedure:
Using sodium hydride (60% in oil, 281 mg), ethyl 5-bromo-4-phenyl-1H-pyrrole-3-carboxylate (1.70 g) and benzenesulfonyl chloride (0.9 mL), a procedure as in Reference Example 41 was performed to give the title compound as white crystals (yield 2.51 g, 93%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.C[O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH2:17]>>[OH:11][CH:9]([C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:10][NH:17][C@H:16]([C:15]([OH:19])=[O:14])[CH3:18]
Reactant: COC(=O)[C@H](C)N
Reactant: Fc1cc(F)cc(C2CO2)c1
Agent: Cl
Product: C[C@H](NCC(O)c1cc(F)cc(F)c1)C(=O)O

Procedure:
Following General Procedure EB and reacting 2-(3,5-difluorophenyl)-1,2-epoxyethane (Example ECl) and L-alanine methyl ester hydrochloride (Bachem), the title compound was isolated after flash chromatography with 3:1 to 1:1 (gradient) hexanes/ethyl acetate.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][NH2:16])(C)(C)C.[CH2:18](N(CC)CC)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][NH:7][C:6](=[O:5])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1CN
Reactant: CCN(CC)CC
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)NCc1ccccc1CN
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of tert-butyl[2-(aminomethyl)benzyl]carbamate (0.2 g, 0.93 mmol) and triethylamine (260 μL, 1.9 mmol) in DCM (10 mL) was added AC2O (0.285 g, 0.00279 mol) dropwise and the reaction stirred for 2 h at r.t. The reaction was concentrated, the residue dissolved in EtOAc (20 mL) then washed with saturated aq NaHCO3 (2×10 mL). The organic layer was dried (Na2SO4) and concentrated to give the crude product (0.25 g, 90%). To a solution of this in DCM (5 mL) was added 2 mL of 4M HCl/dioxane and the solution was stirred for 1 h. The reaction was concentrated to give the title compound (0.16 g, 95%) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[CH:10](O)=O>>[CH3:1][C:2]1[C:3]2[N:9]=[CH:10][NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=CO
Reactant: Cc1cccc(N)c1N
Product: Cc1cccc2[nH]cnc12
Temperature: 70 °C
Yield: 90 %

Procedure:
A mixture of 3-methyl-1,2-benzenediamine (11.9 g) and formic acid (150 mL) was heated at 70° C. for 15 minutes. The solvent was removed under reduced pressure and the residual oil was stirred with water (100 mL) and sodium hydroxide solution (65 mL of 4.0 N) was added until the solution was just basic. The precipitate was filtered off, washed with water, and air dried to give 11.6 g (90%) of 4-methyl-1H-benzimidazole, mp 141°-145° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.[C:27](OC(=O)C)(=[O:29])[CH3:28].CO>N1C=CC=CC=1>[C:27]([O:15][C:10]1[CH:11]=[C:12]2[C:7]3=[C:8]([C:16](=[O:26])[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][N:6]3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]2=3)[CH:9]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)Oc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (200 mg) obtained in Example 2 was suspended in pyridine (5 ml), and to the suspension was added acetic anhydride (0.14 ml), and the mixture was stirred at room temperature for 2 hours. A small amount of methanol was added dropwise to the reaction mixture, and the solvent was evaporated under reduced pressure. The residual crude crystals were washed with methanol and ether in succession to produce the title compound (100 mg; 46%).
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[CH:8]=[C:9]3[C:14](=[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=24)[N:13]=[CH:12][N:11]([C@H:21]2[CH2:26][CH2:25][O:24][CH2:23][C@@H:22]2[OH:27])[C:10]3=[O:28])=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:27][C@@H:22]1[C@@H:21]([N:11]2[C:10](=[O:28])[C:9]3[C:14](=[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]4=[C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:30][CH:29]=4)[CH:8]=3)[N:13]=[CH:12]2)[CH2:26][CH2:25][O:24][CH2:23]1
Reactant: O=c1c2cc(Cc3ccc(Cl)cc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Reactant: C1COCCN1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cc(Cc3ccc(N4CCOCC4)cc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Temperature: 65 °C

Procedure:
To a solution of 6-(4-chlorobenzyl)-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (0.100 g, 0.238 mmol) in 2 mL of DMF under an atmosphere of nitrogen was added morpholine (0.083 g, 0.95 mmol), bis(tri-tert-butylphosphine)palladium(0) (0.012 g, 0.024 mmol), cesium carbonate (0.232 g, 0.713 mmol), and 0.2 mL of water. The mixture was warmed to 65° C. for 5 min, flushed with nitrogen, and irradiated in a microwave reactor at 130° C. for 25 min. The reaction was cooled to rt and diluted with water and dichloromethane. The aqueous layer was reextracted with dichloromethane and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-4% methanol in dichloromethane to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 471.9 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 8.30 (s, 1H), 8.01-7.98 (m, 2H), 7.65-7.59 (m, 2H), 7.07 (d, J=8.7 Hz, 2H), 7.77 (d, J=8.7 Hz, 2H), 4.89-4.82 (m, 1H), 4.35 (s, 2H), 4.22-4.18 (m, 1H), 4.13-4.08 (m, 2H), 3.79 (t, J=4.8 Hz, 4H), 3.59-3.52 (m, 1H), 3.34-3.28 (m, 1H), 3.06 (t, J=4.8 Hz, 4H), 2.66 (br 5, 1H), 2.32-2.22 (m, 1H), 2.03-1.99 (m, 1H).
Reaction SMILES: C1CC[CH:4]([N:7]=C=NC2CCCCC2)CC1.[NH2:16][C@H:17]([C:25]([OH:27])=O)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(NC(=O)[O-])C1C=CC=CC=1.ON1C(=O)CCC1=O>C1COCC1>[CH3:4][NH:7][C:25](=[O:27])[C@H:17]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH2:16]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])NCc1ccccc1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: CNC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 16 h

Procedure:
DCC (3.02 g) was added to a solution of L-phenylalanine-N-benzylcarbamate (4.00 g) and N-hydroxysuccinimide (1.69 g) in dry THF (35 ml) at 0° C. The mixture was stirred at that temperature for 16 h and filtered through Celite. To the filtrate was added aqueous methylamine (40% aq., 5 ml) and the mixture was stirred at RT for 24 h. The reaction mixture was concentrated in vacuo and the crude material (6.01 g) was dissolved in ethanol (250 ml). A suspension of 10% palladium on carbon in H2O (ca 2 ml) was added to the ethanol solution in a bomb. The mixture was stirred in the presence of hydrogen at 724 kPa (105 psi) for 18 h. The solution was filtered through Celite and the filtrate was evaporated in vacuo. The residue was partioned between 1N hydrochloric acid (110 ml) and dichloromethane (50 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (50 ml). The aqueous layer was basified with 3N sodium hydroxide solution to pH ~14 and extracted with dichloromethane (3×50 ml). The latter extracts were combined, dried (Na2SO4), filtered and evaporated, to give the title compound as a colourless viscous oil which solidified under high vacuum (2.24 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][C:11]3[CH:20]=[C:19]([N:21]4[CH2:26][CH2:25][N:24]([CH2:27][C:28]5[CH2:33][C:32]([F:35])([F:34])[CH2:31][CH2:30][C:29]=5[C:36]5[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=5)[CH2:23][CH2:22]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C(N(CC)CC)C.[C:50](Cl)([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>ClCCl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:29]2[CH2:30][CH2:31][C:32]([F:34])([F:35])[CH2:33][C:28]=2[CH2:27][N:24]2[CH2:23][CH2:22][N:21]([C:19]3[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:10][C:5]4[CH:6]=[CH:7][CH:8]=[C:9]5[C:4]=4[CH:3]=[N:2][N:1]5[C:50]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)([C:63]4[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=4)[C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[CH:20]=3)[CH2:26][CH2:25]2)=[CH:37][CH:38]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(F)(F)C3)CC2)cc1Oc1cccc2[nH]ncc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC(F)(F)C3)CC2)cc1Oc1cccc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of EXAMPLE 521F (1.81 g) and triethylamine (0.85 mL) in dichloromethane (10 mL) was added trityl-chloride (1.06 g) and the reaction stirred at room temperature. After stirring for 16 hours the reaction was loaded onto silica gel (Reveleris 80 g) and eluted using a gradient of 0.1% to 1.5% methanol/dichloromethane over 40 minutes (flow=40 ml/min) to give the title compound.
Reaction SMILES: B([O-])=O.[Na+].[Cl:5][CH:6]([Cl:27])[C:7]([CH3:26])([CH3:25])[C:8](=[O:24])[CH:9]([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[N:10]1[CH:14]=[N:13][CH:12]=[N:11]1.C(O)(=O)C>CO>[Cl:27][CH:6]([Cl:5])[C:7]([CH3:25])([CH3:26])[CH:8]([OH:24])[CH:9]([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[N:10]1[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: CC(C)(C(=O)C(Oc1ccc(Cl)cc1Cl)n1cncn1)C(Cl)Cl
Agent: O=B[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C(Cl)Cl)C(O)C(Oc1ccc(Cl)cc1Cl)n1cncn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
1.5 g (0.04 mole) of sodium boranate are added in portions to a solution of 8 g (0.02 mole) of 4,4-dichloro-1-(2,4-dichlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one in 80 ml of methanol at 20°-30° C., while stirring. After two hours, the mixture is brought to pH 6 by addition of acetic acid. The solution is evaporated under reduced pressure, the residue is taken up in 200 ml of methylene chloride and the mixture is washed three times with 400 ml of water each time and dried over sodium sulphate. After evaporating the solution and removing the residual solvent by warming the residue at 50° C. under 0.01 bar for two hours, 6 g (75% of theory) of 4,4-dichloro-1-(2,4-dichlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol are obtained as a 3:1 mixture of the two diastereomers in the form of a highly viscous oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH2:9][O:10][CH2:11][CH2:12][C:13]([C:18]2[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:19]=2[F:25])([CH:15]([F:17])[F:16])[N:14]=1)([CH3:4])([CH3:3])[CH3:2]>CCCCCCC.C(O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH2:9][O:10][CH2:11][CH2:12][C@:13]([C:18]2[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:19]=2[F:25])([CH:15]([F:17])[F:16])[N:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1=NC(c2cc(N)ccc2F)(C(F)F)CCOC1
Solvent: CCCCCCC
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(N)ccc2F)(C(F)F)CCOC1
Yield: 50 %

Procedure:
Racemic [5-(5-amino-2-fluoro-phenyl)-5-difluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl]-carbamic acid tert-butyl ester (1.62 g, 4.04 mmol) was separated via a VWR prep HPLC System on a Chiralpak AD 20 um 4×50×100 (4×SMB columns) column; eluent: heptane/ethanol 70/30; flow=65 ml/min; UV detection at 220 nm. As a result, 754 mg of the desired title compound ((S)-isomer) was obtained as the first eluting isomer. Purity: >99.5% ee.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.O=P(Cl)(Cl)[Cl:9].O[C:13]1[CH:18]=[C:17]([CH3:19])[NH:16][C:15](=[O:20])[C:14]=1[C:21]#[N:22].[NH4+].[OH-]>C(Cl)(Cl)Cl>[Cl:9][C:13]1[CH:18]=[C:17]([CH3:19])[NH:16][C:15](=[O:20])[C:14]=1[C:21]#[N:22]
Reactant: Cc1cc(O)c(C#N)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)c(C#N)c(=O)[nH]1
Reaction time: 0.08 h
Yield: 36 %

Procedure:
Using a 100 ml round bottom with reflux condenser, PCl5 (6.7 g, 32 mmol), POCl3 (3.0 mL, 32 mmol) and 30 ml CHCl3 (dry) were stirred for 5 min (see: Heterocycles, vol. 60, No. 6, 2003, 1461-1468). Added 4-hydroxy-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (4 g, 26.6 mmol) and stirred for 2 h at 80° C. Quenched reaction while hot and poured into 1 L beaker with 100 “g” ice, 24 mL NH4OH, pH by paper was 8-9. Stirred 5 min and filtered. Washed solid with water. Suspended solid in ethanol and filtered and washed with ethanol. Gave: 4-chloro-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (1.7 g, 9.58 mmol, 40% yield) 1H NMR (400 MHz, DMSO-d6) δ ppm 12.85 (br. s., 1H) 6.53 (s, 1H) 2.28 (s, 3H) MS (ES) [M+H]+ 168.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15](Br)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[N:18][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)Br)CC1
Reactant: Nc1ccccn1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cnc3ccccn23)CC1

Procedure:
To a solution of 1.15 g of 1-tert-butoxycarbonyl-4-(1-bromo-formylmethyl)piperidine (from Step C) in 15 mL ethanol was added 388 mg of 2-aminopyridine. After refluxing for 18 h, the solvent was evaporated. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. Aqueous layer was extracted with ethyl acetate (3×). The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography with 50% ethyl acetate in hexanes, followed by 100% ethyl acetate to give the title compound as a solid. 1H NMR (500 MHz, CDCl3) δ 1.48 (s, 9H), 1.70 (m, 2H), 2.06 (d, J=13 Hz, 2H), 2.93–3.02 (m, 3H), 4.26 (br, 2H), 6.87 (t, J=6.8 Hz, 1H). 7.21(m, 1H), 7.44(s, 1H), 7.69(d, J=9.2 Hz,1H), 7.99 (d, J=6.9 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.BrCC1CCCCO1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2([C:40]3[C:31](=[CH:32][C:33]4[O:38][CH2:37][CH2:36][O:35][C:34]=4[CH:39]=3)[O:30][CH2:29]2)[C:21]1=[O:41]>>[S:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:3]1[CH2:2][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2([C:40]3[C:31](=[CH:32][C:33]4[O:38][CH2:37][CH2:36][O:35][C:34]=4[CH:39]=3)[O:30][CH2:29]2)[C:21]1=[O:41]
Reactant: BrCc1nc2ccccc2s1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2nc3ccccc3s2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)-1,3-benzothiazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-(1,3-benzothiazol-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (77%) as a colorless solid: mp 164-166° C.; 1H NMR (300 MHz, CDCl3) δ8.04 (d, J=8.1 Hz, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.54-7.46 (m, 1H), 7.43-7.35 (m, 1H), 7.24-7.17 (m, 2H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 6.97 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.41 (s, 1H), 5.53 (d, J=16.2 Hz, 1H), 5.24 (d, J=16.2 Hz, 1H), 4.97 (d, J=9.0 Hz, 1H), 4.69 (d, J=9.0 Hz, 1H), 4.24-4.11 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.2, 165.9, 155.3, 152.9, 144.7, 141.2, 138.3, 135.3, 132.1, 128.9, 126.3, 125.5, 124.0, 123.9, 123.2, 121.9, 120.8, 111.8, 109.2, 99.4, 64.5, 63.9, 58.0, 42.6; MS (ES+) m/z 442.8 (M+1).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:10]2[C:13]3[C:3]=1[CH2:4][CH:5]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[NH:22][C:21]4=[O:29])[CH2:16][CH2:15]1)[C:6]=3[CH:7]=[CH:8][CH:9]=2.O.C(OCC)(=O)C.[CH3:37][N:38](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[C:37]([C:2]1[CH:12]=[CH:11][C:10]2[C:13]3[C:3]=1[CH2:4][CH:5]([N:14]1[CH2:15][CH2:16][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[NH:22][C:21]4=[O:29])[CH2:18][CH2:19]1)[C:6]=3[CH:7]=[CH:8][CH:9]=2)#[N:38]
Reactant: CN(C)C=O
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C2Cc3c(Br)ccc4cccc2c34)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2cccc3c2c1CC3N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
1-[1-(3-Bromoacenaphthen-1-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one (1.25 g) was dissolved in N,N-dimethylformamide (16 ml), zinc cyanide (380 mg) and tetrakistriphenylphosphinepalladium (1.6 g) were added, and the mixture was stirred at 110° C. for 1 hr. After allowing to cool, water and ethyl acetate were poured into the reaction mixture, and the mixture was subjected to celite filtration. The filtrate was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, and recrystallized from acetone to give the title compound (1.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])/[CH:5]=[CH:6]/[CH:7]=[O:8])[CH3:2].[N+](C1C=CC=CC=1C(O)=O)([O-])=O.N1CCCC1.[OH:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[C:29]=1[CH:30]=O>CS(C)=O>[CH2:1]([O:3][C:4]([CH:5]1[C:6]([CH:7]=[O:8])=[CH:30][C:29]2[C:28](=[CH:35][CH:34]=[CH:33][C:32]=2[O:36][CH3:37])[O:27]1)=[O:9])[CH3:2]
Reactant: CCOC(=O)/C=C/C=O
Reactant: COc1cccc(O)c1C=O
Agent: O=C(O)c1ccccc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: C1CCNC1
Product: CCOC(=O)C1Oc2cccc(OC)c2C=C1C=O
Temperature: 25 °C
Reaction time: 78 h
Yield: 13.1 %

Procedure:
(E)-4-oxo-but-2-enoic acid ethyl ester (7.63 mL, 63.09 mmol), 2-nitro benzoic acid (1.77 g, 10.52 mmol), and pyrrolidine (0.87 mL, 10.52 mmol) were added simultaneously to a solution of commercially available 2-hydroxy-6-methoxy-benzaldehyde (8.0 g, 52.58 mmol) in dimethysulfoxide (50 mL) at 25° C. and the solution was stirred for 78 hours at 25° C. The reaction was quenched by the addition of water. The reaction mixture was then partitioned between water and ethyl acetate. The combined organics were washed with a saturated brine solution, dried over anhydrous sodium sulfate, filtered, rinsed and concentrated in vacuo. The residue obtained was purified on a silica gel flash column chromatography using ethyl acetate-hexanes as eluants, yielding 5-methoxy-3-formyl-2H-chromene-2-carboxylic acid ethyl ester as a solid (1.80 g, 51.9%).