Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([CH2:27][CH2:28][CH2:29][CH3:30])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16](=[CH:22][CH:23]=O)[CH:15]=2)=[C:8]([O:25][CH3:26])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:31]([C:33]1[C:34](=[C:49]([C:52]#[N:53])[C:50]#[N:51])[O:35][C:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:39]([F:42])([F:41])[F:40])[C:37]=1[CH3:38])#[N:32]>>[CH2:27]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH2:19][C:18]([CH3:20])([CH3:21])[CH2:17][C:16](=[CH:22][CH:23]=[CH:38][C:37]3[C:36]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:39]([F:42])([F:40])[F:41])[O:35][C:34](=[C:49]([C:52]#[N:53])[C:50]#[N:51])[C:33]=3[C:31]#[N:32])[CH:15]=2)=[C:8]([O:25][CH3:26])[CH:7]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCN(CCCC)c1ccc(C=CC2=CC(=CC=O)CC(C)(C)C2)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Product: CCCCN(CCCC)c1ccc(C=CC2=CC(=CC=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)CC(C)(C)C2)c(OC)c1
Temperature: 50 °C
Yield: 76 %

Procedure:
207 mg (0.51 mmol) of [3-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]-5,5-dimethyl-2-cyclohexenylidene]acetaldehyde and 175 mg (0.56 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile were dissolved, and the mixture was stirred with heating at 50° C. for 3 hours. The precipitate was separated by filtration and washed with ethanol. The residue was purified by silica gel column chromatography to give 274 mg of a dark brown crystal (yield: 76.8%; mp: 164-166° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[S:12][C:13]([CH3:16])=[N:14][N:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[CH2:48][CH2:47][N:46]3[C:39](=[CH:40][C:41]4[CH2:42][C:43]([CH3:50])([CH3:49])[CH2:44][C:45]=43)[C:38]2=[O:51])=[N:24][CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1)(=[O:19])[CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[CH2:48][CH2:47][N:46]3[C:39](=[CH:40][C:41]4[CH2:42][C:43]([CH3:50])([CH3:49])[CH2:44][C:45]=43)[C:38]2=[O:51])=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[S:12][C:13]([CH3:16])=[N:14][N:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cc1nnc(Nc2cc(Br)cn(C)c2=O)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3nnc(C)s3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 90 °C
Yield: 27.9 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 267a (150 mg, 0.50 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (640 mg, 1.5 mmol), PdCl2(dppf) (37 mg, 0.050 mmol), K3PO4 (212 mg, 1.0 mmol), sodium acetate (82 mg, 1.0 mmol), acetonitrile (10 mL), and water (0.2 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 267b (80 mg, 28%) as yellow solid. MS-ESI: [M+H]+ 574.2
Reaction SMILES: [CH2:1]([C@:3]1([CH2:29][CH2:30][CH2:31][CH2:32][B:33]2[O:37][C:36]([CH3:39])([CH3:38])[C:35]([CH3:41])([CH3:40])[O:34]2)[C:8](=[O:9])[O:7][C@@H:6](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)[N:4]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:2].C(=O)=O.N.[Li]>CC#N.C1COCC1>[C:25]([O:24][C:22]([NH:4][C@@:3]([CH2:1][CH3:2])([CH2:29][CH2:30][CH2:31][CH2:32][B:33]1[O:34][C:35]([CH3:41])([CH3:40])[C:36]([CH3:39])([CH3:38])[O:37]1)[C:8]([O:7][CH3:6])=[O:9])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC[C@]1(CCCCB2OC(C)(C)C(C)(C)O2)C(=O)O[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Agent: N
Agent: O=C=O
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC[C@@](CCCCB1OC(C)(C)C(C)(C)O1)(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
A three-necked round-bottomed flask equipped with nitrogen inlet tube and dry ice condenser was charged with (3S,5R,6S)-tert-butyl 3-ethyl-2-oxo-5,6-diphenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)morpholine-4-carboxylate (0.57 g, 1.01 mmol) and THF (1 mL). After cooling the condenser to −78° C. and the flask to −45° C. (CO2 (s), CH3CN), ammonia (50 mL) was condensed into the flask. Once complete, lithium metal (0.07 g, 10 mmol, small pieces) was carefully added over 10 min. After stirring an additional 1 h, the reaction mixture was carefully quenched with NH4Cl (s) until the solution became clear. The bath was removed and the ammonia was allowed to evaporate over night. The resulting residue was diluted with ethyl acetate and washed successively with 0.5N HCl and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was dissolved in 50% methanol in toluene (50 mL, 0.1 M) and treated with TMSCHN2 (2.0 M in hexanes) until the pale yellow color persisted. With TLC indicating the reaction complete, the excess TMSCHN2 was quenched with acetic acid until the solution became clear. The solution was concentrated, diluted with ethyl acetate and washed successively with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-60% ethyl acetate in heptane over 4 CV) gave (S)-methyl 2-(tert-butoxycarbonylamino)-2-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as colorless oil (0.283 g, 71%). Rf 0.88 (30% ethyl acetate in heptane); ESI-LCMS m/z calcd for C20H38BNO6: 399.3. found 400.3 (M+1)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:14][C:15]([N:17]1[CH2:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[CH3:30])[CH2:18]1)=[O:16])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1.C[Si]([N:35]=[C:36]=[O:37])(C)C>C1COCC1>[Cl:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:5]([N:4]([CH2:14][C:15]([N:17]1[CH2:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[CH3:30])[CH2:18]1)=[O:16])[CH2:3][CH2:2][NH:1][C:36]([NH2:35])=[O:37])=[O:13]
Reactant: Cc1c(Cl)cccc1N1CN(C(=O)CN(CCN)C(=O)c2cccc(Cl)c2)CC1=O
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1N1CN(C(=O)CN(CCNC(N)=O)C(=O)c2cccc(Cl)c2)CC1=O

Procedure:
A mixture of N-(2-Amino-ethyl)-3-chloro-N-{2-[3-(3-chloro-2-methyl-phenyl)-4-oxo-imidazolidin-1-yl]-2-oxo-ethyl}-benzamide (80 mg, 0.16 mmol, 1 eq), Trimethylsilyl isocyanate (0.027 ml, 0.19 mmol, 1.2 eq), in THF (1 ml) was stirred at room temperature overnight. It was purified with HPLC to give the desired product. LCMS observed for (M+H)+: 492.1
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:14][CH:13]2[CH2:12][NH:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[CH3:15]I>>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:14][CH:13]2[CH2:12][N:11]([CH3:15])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1
Reactant: CI
Reactant: Clc1cccc(C23CNCC2C3)c1
Agent: Cl
Product: CN1CC2CC2(c2cccc(Cl)c2)C1

Procedure:
By the method of Example 10, 1-(m-chlorophenyl)-N-methyl-1,2-cyclopropanedicarboximide, m.p. 72°-73° C., prepared from 1-(m-chlorophenyl)-1,2-cyclopropanedicarboximide (Example 6) and methyl iodide gives 1-(m-chlorophenyl)-3-methyl-3-azabicyclo[3.1.0]hexane hydrochloride as colorless crystals, m.p. 180°-182° C.
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[N:21]=[N:22][NH:23][CH:24]=3)=[C:9]([O:25]CC3C=CC=CC=3)[C:8]2=[O:33])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N2C=CC(CCCC3N=NNC=3)=C(O)C2=O)C=CC=CC=1>C1COCC1>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[N:21]=[N:22][NH:23][CH:24]=3)=[C:9]([OH:25])[C:8]2=[O:33])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1c(OCc2ccccc2)c(CCCCCCCc2c[nH]nn2)ccn1-c1ccccc1
Agent: O=c1c(O)c(CCCc2c[nH]nn2)ccn1-c1ccccc1
Solvent: C1CCOC1
Product: O=c1c(O)c(CCCCCCCc2c[nH]nn2)ccn1-c1ccccc1
Yield: 73.8 %

Procedure:
Reaction of 158f (0.22 g, 0.50 mmol) in anhydrous THF as described for synthesis of 159b gave 159f (0.13 g, 74%) of pure product. 1H NMR (400 MHz, DMSO) δ 8.91 (s, 1H), 8.57 (s, 1H), 7.82 (d, J=7.4 Hz, 2H), 7.42 (t, J=7.6 Hz, 2H), 7.31 (t, J=7.3 Hz, 1H), 7.09 (d, J=6.6 Hz, 1H), 6.64 (d, J=7.0 Hz, 1H), 6.04 (t, J=6.9 Hz, 1H), 4.36 (t, J=7.0 Hz, 2H), 3.86 (t, J=7.2 Hz, 2H), 1.83 (m, 2H), 1.61 (m, 2H), 1.26 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 158.80, 147.89, 147.00, 130.88, 129.05, 128.30, 127.12, 125.87, 119.83, 114.13, 107.10, 50.48, 50.05, 30.37, 29.20, 28.67, 26.46, 26.42. HRMS (FAB) calcd for C20H25N4O2 [M+H]+ 353.1977. found 353.1992.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:17]([OH:19])=O)=[N:10][C:11]=2[O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]([CH3:27])([CH3:26])[C:22]([NH:24][CH3:25])=[O:23]>>[CH3:26][C:21]([NH:20][C:17]([C:9]1[CH:8]=[CH:7][C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[C:11]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16]2)[N:10]=1)=[O:19])([C:22](=[O:23])[NH:24][CH3:25])[CH3:27]
Reactant: CNC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc(C2CCCC2)c(OCC2CC2)n1
Product: CNC(=O)C(C)(C)NC(=O)c1ccc(C2CCCC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 39 b) and 2-amino-N,2-dimethyl-propanamide (CAN 106914-07-2) as starting materials, MS (LC/MS): 360.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-])=O.NN>[Ni]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCC2
Agent: [Ni]
Agent: NN
Product: Nc1ccc2c(c1)NCCC2

Procedure:
reducing 7-nitro-1,2,3,4-tetrahydroquinoline in the presence of Raney nickel and hydrazine to obtain 7-amino-1,2,3,4-tetrahydroquinoline;
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([Cl:10])[CH:7]=[C:6](Cl)[N:5]=1.[OH:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[C:18]([CH:21]=1)[C:19]#[N:20]>CN(C)C=O>[Cl:3][C:4]1[N:5]=[C:6]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=3)=[C:18]([CH:21]=2)[C:19]#[N:20])[CH:7]=[C:8]([Cl:10])[N:9]=1
Reactant: N#Cc1cc(CO)ccc1Oc1cccc(C(F)(F)F)c1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(COc2cc(Cl)nc(Cl)n2)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.8 %

Procedure:
To a suspension of NaH (0.532 g, 13.30 mmol) in N, N-dimethylformamide (6 ml) was added 2,4,6-trichloropyrimidine (1.057 g, 5.76 mmol) at 0° C. The reaction mixture was stirred for 5 min at room temperature, and then dropwise was added to a solution of 5-(hydroxymethyl)-2-(3-(trifluoromethyl)phenoxy)benzonitrile (1.3 g, 4.43 mmol) in N, N-dimethylformamide (6 ml). The reaction mixture was stirred for another 1 h at room temperature. Then, the reaction mixture was quenched with water and the solution was purified with reverse phase column chromatography (120 g) using water/MeCN as eluent to afford 5-(((2,6-dichloropyrimidin-4-yl)oxy)methyl)-2-(3-(trifluoromethyl)phenoxy)benzonitrile (1.4 g, 3.18 mmol, 71.7% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[C:3]=1[F:11].[CH3:12][C:13](OC(C)=O)=[O:14]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:13](=[O:14])[CH3:12])=[C:3]([F:11])[C:4]=1[F:10])#[N:7]
Reactant: N#Cc1ccc(N)c(F)c1F
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C#N)c(F)c1F
Yield: 67 %

Procedure:
A mixture of 9.59 g of 4-amino-2,3-difluorobenzonitrile and 20 mL of Ac2O is heated for 1 hour on a steam bath. The red solution is cooled in an ice bath and the resulting faint pink crystals filtered off, washed with 2×10 mL of Et2O and air dried. In this manner there is obtained 8.26 g (67% yield) of 4'-cyano-2',3'-difluoroacetanilide, m.p. 175°-177° C. with the appropriate NMR and IR spectral data and an ion at 197 in the mass spectrum.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:22]=[CH:21][C:9]2[C:10](=O)[CH:11]=[C:12]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[O:13][C:8]=2[C:7]=1[CH2:23][CH2:24][CH3:25]>C(OCC)(=O)C.P(=O)(O)(O)O.[Pd]>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:22]=[CH:21][C:9]2[CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[O:13][C:8]=2[C:7]=1[CH2:23][CH2:24][CH3:25]
Reactant: CCCc1c(OCCCCl)ccc2c(=O)cc(CCC(=O)OC)oc12
Agent: [Pd]
Agent: O=P(O)(O)O
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCl)ccc2c1OC(CCC(=O)OC)CC2
Yield: 79 %

Procedure:
Methyl 7-(3-chloropropoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-propanoate (2.0 g, 5.35 mmol) was dissolved in a mixture of 25 ml ethyl acetate and 0.32 ml phosphoric acid and hydrogenated at 5 psi and 25° C. using 2 g of 5% Pd/C as catalyst. The product was dissolved in ethyl acetate, washed with 10% sodium carbonate solution, then washed once with water, dried over magnesium sulfate and filtered. The solvent was removed under vacuum to give the product as a colorless oil (1.5 gm, 90% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1([N:13]([O:26][CH2:27][C:28]#[CH:29])[C:14](=[O:25])[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)=O.C[O-].[Na+].Cl.[Cl-].[Na+]>CN(C)C=O>[OH:2][C:3]1[C:5]2([CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]2)[N:13]([O:26][CH2:27][C:28]#[CH:29])[C:14](=[O:25])[C:15]=1[C:16]1[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=1[CH3:22]
Reactant: C#CCON(C(=O)Cc1c(C)cc(C)cc1C)C1(C(=O)OC)CCN(OC)CC1
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Product: C#CCON1C(=O)C(c2c(C)cc(C)cc2C)=C(O)C12CCN(OC)CC2
Reaction time: 4 h

Procedure:
To a solution of 1-methoxy-4-{prop-2-ynyloxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylic acid methyl ester (150 mg, 0.41 mmol) in dimethylformamide (2 ml) at 0° C. was added sodium methoxide (33 mg, 0.62 mmol) in one portion and stirring continued at room temperature for 4 hours. The reaction mixture was poured on ice water, acidified to pH 5-6 with an aqueous HCl solution, saturated with sodium chloride and thoroughly extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/hexane 2:1). Yield: 14 mg of 4-hydroxy-8-methoxy-1-prop-2-ynyloxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (title compound P2ii.8) as a tan solid.
Reaction SMILES: [OH-].[K+].[O:3]1[CH2:6][C:5](=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4]1.[Br:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>O1CCOCC1.[Cl-].[Na+].O>[Br:13][C:14]1[CH:19]=[C:18]([C:5]2([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][O:3][CH2:4]2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C=C1COC1
Reactant: OB(O)c1cccc(Br)c1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CC1(c2cccc(Br)c2)COC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
To a solution of [Rh(cod)Cl]2 (171.3 mg, 0.3518 mmol) in 30 mL of dioxane was added aqueous KOH (6.097 mL of 1.5 M, 9.145 mmol) followed by ethyl 2-(oxetan-3-ylidene)acetate (1 g, 7.035 mmol) and a solution of (3-bromophenyl)boronic acid (2.119 g, 10.55 mmol) in 10 mL of dioxane. The reaction was stirred for 30 minutes at room temperature then further (3-bromophenyl)boronic acid (706 mg, 0.5 eq) was added and the reaction stirred overnight. Brine was added and the aqueous layer extracted twice with ethyl acetate. The combined organics were washed with brine and then dried, filtered and concentrated under reduced pressure. The crude product was purified on silica (Companion, 80 g) eluting with 1-20% EtOAc:Petrol ether to give ethyl 2-[3-(3-bromophenyl)oxetan-3-yl]acetate as a yellow oil (1.50 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.CC(N)[CH2:12][C:13]1[CH:18]=CC=CC=1.OP(O)(O)=O.[Br-].C1([Zn+])CC1.[OH-].[Na+]>>[Cl:1][C:2]1[N:7]=[C:6]([CH:18]2[CH2:13][CH2:12]2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(N)Cc1ccccc1
Agent: O=P(O)(O)O
Agent: [Br-]
Agent: [Na+]
Product: Fc1cnc(Cl)nc1C1CC1
Temperature: 70 °C
Yield: 2031.8 %

Procedure:
In a 20 mL glass microwave tube 2,4-dichloro-5-fluoropyrimidine (500 mg, 2.99 mmol) and Amphos (53.0 mg, 0.075 mmol) were treated with 0.5 M cyclopropylzinc(II) bromide (7786 μL, 3.89 mmol) via syringe under an atmosphere of argon. The solution was then heated in the microwave at 70° C. for 20 min. The mixture was treated with 1N NaOH and extracted with EtOAc (25 mL), dried over MgSO4, filtered and concentrated. Purification with flash chromatography (eluting with 100% DCM) afforded 2-chloro-4-cyclopropyl-5-fluoropyrimidine (263 mg, 51%) as a pale yellow viscous oil. MS (ESI, pos. ion) m/z: 173.0 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.21-8.28 (1H, m), 2.24-2.34 (1H, m), 1.27-1.34 (2H, m), 1.17-1.27 (2H, m).
Reaction SMILES: Cl.CO[C:4](=[NH:14])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[CH:15]([NH:17][NH2:18])=O>N1C=CC=CC=1>[N+:11]([C:8]1[CH:7]=[CH:6][C:5]([C:4]2[NH:18][N:17]=[CH:15][N:14]=2)=[CH:10][CH:9]=1)([O-:13])=[O:12]
Reactant: COC(=N)c1ccc([N+](=O)[O-])cc1
Reactant: NNC=O
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(-c2ncn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Nitro-benzimidic acid methyl ester hydrochloride (635 mg, 2.93 mmol) was suspended in pyridine (7 mL) and formic hydrazide (Aldrich, 178 mg, 2.95 mmol) was added and the mixture was stirred at rt for 1 hr. The solvent was removed and the residue was dissolved in toluene (10 mL) and the mixture was stirred at reflux for 1.5 hrs. the mixture was cooled and water was added. The organic layer was separated and dried over sodium sulfate. The solvent was removed and the residue was suspended in 25% EtOAc/Hexanes and the solid was filtered to give a solid. 510 mg.
Reaction SMILES: C([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6](C)[C:5]2[CH:16]=[CH:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19][C:4]1=2)C.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>C(OCC)(=O)C>[N:28]1([C:18]2[CH:17]=[CH:16][C:5]3[C:4]([N:19]=2)=[N:3][C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]=3)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCN1c2ncccc2C(=O)N(C)c2ccc(OS(=O)(=O)C(F)(F)F)nc21
Reactant: C1CCNC1
Solvent: CCOC(C)=O
Product: O=c1nc2ccc(N3CCCC3)nc2nc2ncccc12

Procedure:
5,11-Dihydro-11-ethyl-5-methyl-2-trifluoromethanesulfonyloxy-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.25 g) was dissolved in pyrrolidine (1 ml) and refluxed 30 min. The cooled solution was diluted with ethyl acetate, washed with water, and the organic phase was dried (anhydrous magnesium sulfate) and concentrated. The resulting oily residue was crystallized from ethyl acetate/hexane to provide 0.11 g of 5,11-dihydro-11-ethyl-5-methyl-2-n-(pyrrolidino-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one, m.p. 185°-188° C.
Reaction SMILES: [OH-].[K+].CS(C)=O.[CH:7]1[CH:12]=[C:11]([NH:13][C:14]2[N:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=[CH:9][CH:8]=1.[CH3:20][C:21]1[N:26]=[C:25]([CH2:27]Br)[CH:24]=[CH:23][CH:22]=1>O>[CH3:27][C:25]1[N:26]=[C:21]([CH2:20][N:13]([C:11]2[CH:12]=[CH:7][CH:8]=[CH:9][N:10]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:19]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cccc(CBr)n1
Reactant: c1ccc(Nc2ccccn2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc(CN(c2ccccn2)c2ccccn2)n1
Reaction time: 0.75 h

Procedure:
To a flask were added 0.6 g pulverized potassium hydroxide and 15 ml dimethylsulfoxide. After adding 1.4 g of 2,2′-dipyridylamine, the mixture was stirred under nitrogen for 45 minutes, when 1.5 g 6-methyl-2-(bromomethyl)pyridine was added. After stirring for 1 hour, 35 ml of water was added and the product was extracted with 60 ml of 50% ethyl acetate, 50% hexane. The organic layer was washed with 30 ml water and the solvent was removed. The residue was purified by silica gel chromatography using 48% ethyl acetate, 48% hexane, and 4% methanol resulting in 2.0 g of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7]([OH:9])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:37]1[C:41]2([CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH2:40][CH:39]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[NH:38]1.CCN(C(C)C)C(C)C>O.CN(C=O)C>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7]([N:38]1[C@H:39]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:40][C:41]2([CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH2:37]1)=[O:9])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CCOC(=O)C1CC2(CCOCC2)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H]1CC2(CCOCC2)CN1C(=O)[C@@H](NC(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
In a 50 ml round-bottomed flask, (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (813 mg, 4.64 mmol) was combined with DMF (10 ml) to give a colorless solution. HATU (1.76 g, 4.64 mmol) was added and stirred at room temperature for 10 min. Ethyl 8-oxa-2-azaspiro[4.5]decane-3-carboxylate (prepared according to the patent procedure described in WO 199808850) (900 mg, 4.22 mmol) and DIPEA (1.91 g, 2.58 ml, 14.8 mmol) were added and stirred overnight. It was diluted with H2O and extracted with EtOAc (2×100 ml). The organic layer was washed with brine and H2O, dried with MgSO4, filtered and concentrated in vacuo to afford (S)-ethyl 2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-8-oxa-2-azaspiro[4.5]decane-3-carboxylate as a viscous oil (1.3 g, 83.2%). ESI-LRMS m/e calcd for C18H30N2O6 [M+] 370. found 371 [M+H+].
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH2:32][CH2:31][CH2:30][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:29])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C1CCC(N=C=NC2CCCCC2)CC1>>[CH2:1]([NH:8][C:9]([N:11]1[CH2:32][CH2:31][CH2:30][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](=[O:29])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Product: O=C(COc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Yield: 53.8 %

Procedure:
(2S)-1-(N-Benzylaminocarbonyl-L-prolyl)-2-(1-hydroxy-2-phenoxyethyl)pyrrolidine (798 mg) was subjected to DMSO-DCC oxidation as in Example 1D), followed by recrystallization from ethyl acetate-hexane to give 427 mg of the title compound (See Table 6).