Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH:4]=[C:5]([CH3:8])[CH:6]=[CH2:7])([O-:3])=[O:2].[Na].[CH3:10][OH:11]>>[N+:1]([CH2:4][C:5]([CH3:8])=[CH:6][CH2:7][O:11][CH3:10])([O-:3])=[O:2]
Reactant: CO
Reactant: C=CC(C)=C[N+](=O)[O-]
Agent: [Na]
Product: COCC=C(C)C[N+](=O)[O-]
Reaction time: 8 h

Procedure:
0.1 Mol of 1-nitro-2-methyl-1,3-butadiene was added to a solution of 0.1 Mol of sodium in methanol and stirred overnight. The reaction mixture was quenched in ice and extracted with methylene chloride. The oily residue was purified via column chromatography. The product was obtained as a yellow liquid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1)=[O:4].[N-:21]=[N+:22]=[N-:23].[Na+]>>[N:21]([CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1)=[O:4])=[N+:22]=[N-:23]
Reactant: O=C(OCc1ccccc1)C1CN(C(=O)CCl)CCO1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCC(=O)N1CCOC(C(=O)OCc2ccccc2)C1
Yield: 86.4 %

Procedure:
In a 25-mL round-bottom flask, the benzyl 4-(2-chloroacetyl)morpholine-2-carboxylate (0.262 g, 0.88 mmol) was dissolved in dmf (4 mL). Sodium azide (0.066 g, 1.0 mmol) was added, and the flask was placed in a 60 deg oil bath overnight. The reaction was concentrated, and the residue was taken up in 80% ether-hexane (60 mL) and the organic layer was extracted with dilute sodium bicarbonate (2×7 mL) then with saturated brine (7 mL), then was dried over magnesium sulfate, filtered, and concentrated. The residue was purified through silica gel (50 mL) which had been deactivated with TEA (5 mL) using 60% EtOAc-hexane to afford the title compound (230 mg, 0.76 mmol). MS m/z 305 (M+1).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:6]1(=[O:25])=[O:24])([CH3:4])([CH3:3])[CH3:2].Br[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:14][CH2:13]2)=[C:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[S:6]1(=[O:25])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCc1ccccc1
Reactant: CC(C)(C)N1C(=O)C(NC2CCNCC2)=C(c2ccccc2)S1(=O)=O
Product: CC(C)(C)N1C(=O)C(NC2CCN(CCc3ccccc3)CC2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-tert-butyl-5-phenyl-4-(piperidin-4-ylamino)isothiazol-3(2H)-one 1,1-dioxide (Example 75) and (2-bromoethyl)benzene in a similar manner as described for Example 104. 1H NMR (500 MHz CDCl3): δ 7.64-7.50 (m, 2H), 7.48-7.45 (m, 3H), 7.30-7.25 (m, 2H), 7.22-7.17 (m, 1H), 7.16-7.12 (m, 2H), 5.22 (d, 1H), 3.00-2.90 (m, 1H), 2.81-2.74 (m, 2H), 2.73-2.67 (m, 2H), 2.50-2.43 (m, 2H), 1.82-1.60 (m, 13H), 1.46-1.36 (m, 2H); 13C NMR (125 MHz CDCl3): δ 159.9, 140.2, 134.3, 131.9, 130.0, 128.9, 128.6, 126.3, 125.4, 106.9, 61.8, 60.2, 51.8, 50.2, 33.8, 32.4, 27.9; Mass Spectrum: M+H+ 468
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:15]=[C:14]([NH2:16])[CH:13]=[CH:12][N:11]=3)[C:6]=2[CH:17]=1.N1CCCCC1.[S:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29]([OH:33])([C:31]#[CH:32])[CH3:30]>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.[Cu]I>[NH2:16][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:32]#[C:31][C:29]([C:25]4[S:24][CH:28]=[CH:27][N:26]=4)([OH:33])[CH3:30])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)[N:15]=1
Reactant: C#CC(C)(O)c1nccs1
Reactant: Nc1ccnc(-n2cnc3ccc(Br)cc32)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CC(O)(C#Cc1ccc2ncn(-c3nccc(N)n3)c2c1)c1nccs1
Temperature: 75 °C
Reaction time: 18 h
Yield: 11.5 %

Procedure:
To a pressure tube was added 2-(6-bromo-1,3-benzodiazol-1-yl)pyrimidin-4-amine (300 mg, 1.03 mmol), piperidine (2 mL), tetrakis(triphenylphosphine)palladium (119.5 mg, 0.10 mmol), copper(I) iodide (19.7 mg, 0.10 mmol) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (316.84 mg, 2.07 mmol). The reaction was stirred at 75° C. for 18 h. The reaction mixture was cooled before concentrating in vacuo. The crude product was purified by column chromatography (Biotage) eluted with DCM: methanol gradient (97:3 to 90:1). Material obtained was triturated with methanol to afford the title compound as a beige solid. (43 mg, 11.5% yield); 1H NMR (250 MHz, DMSO) delta 1.91 (3H, s), 6.41 (1H, d, J=5.79 Hz), 7.06 (1H, s), 7.37 (1H, d, J=1.52 Hz), 7.45 (2H, br. s.), 7.65-7.84 (3H, m), 8.19 (1H, d, J=5.79 Hz), 8.62 (1H, d, J=1.07 Hz), 9.00 (1H, s); LC-MS m/z+3.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.ClC1C=C2C(C3N=C(N[C@H]4CCCNC4)C(F)=CN=3)=CNC2=NC=1.C(N(C(C)C)CC)(C)C.[CH3:59][S:60](Cl)(=[O:62])=[O:61]>C(Cl)Cl.CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][N:21]([S:60]([CH3:59])(=[O:62])=[O:61])[CH2:20]4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1N[C@H]1CCCNC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of (S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-amine hydrochloride, 5b, (0.04 g, 0.11 mmol) in CH2Cl2 (1.4 mL) and DMF (0.30 mL) was added N,N-diisopropyl-N-ethylamine (0.30 mL, 1.70 mmol) followed by methanesulfonyl chloride (0.02 g. 0.20 mmol). The reaction mixture was allowed to stir at room temperature for 17 hours. The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formate-H2O/acetonitrile) to afford the desired product, 389.
Reaction SMILES: C[O:2][CH:3]=[CH:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.O>O1CCCC1>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([C@H:9]2[CH2:10][CH2:11][C@H:6]([CH2:5][CH2:4][CH:3]=[O:2])[CH2:7][CH2:8]2)=[CH:13][CH:14]=1)#[N:17]
Reactant: COC=CC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc([C@H]2CC[C@H](CCC=O)CC2)cc1

Procedure:
A solution of 2.04 g of p-[trans-4-(3-methoxy-2-propenyl)cyclohexyl]benzonitrile in 100 ml of tetrahydrofuran/2N hydrochloric acid (vol. 4:1) was heated to reflux for 1 hour. The reaction mixture was subsequently poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated, whereby 1.9 g (99%) of 3-[trans-4-(p-cyanophenyl)cyclohexyl]propionaldehyde were obtained as colourless crystals; Rf-value (ethyl acetate/petroleum ether vol. 10:90) 0.15.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:49]=[CH:48][C:27]([C:28]([N:30]2[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3/[C:34](=[CH:41]/[C:42]([O:44][CH3:45])=[O:43])/[C:33]([F:47])([F:46])[CH2:32][CH2:31]2)=[O:29])=[CH:26][CH:25]=1>>[F:47][C:33]1([F:46])[CH2:32][CH2:31][N:30]([C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([NH:23][C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[CH:49][CH:48]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2/[C:34]/1=[CH:41]/[C:42]([O:44][CH3:45])=[O:43]
Reactant: COC(=O)/C=C1/c2ccccc2N(C(=O)c2ccc(N)cc2)CCC1(F)F
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Product: COC(=O)/C=C1/c2ccccc2N(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccc(C)cc3)cc2)CCC1(F)F
Yield: 54.5 %

Procedure:
Using 630 mg of 2-(4-methylphenyl)benzoic acid, 0.389 ml of oxalyl chloride and 670 mg of methyl (Z)-[1-(4-aminobenzoyl)-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene]acetate, a similar procedure as in Reference Example 8 was repeated to obtain 556 mg of methyl (Z)-[4,4-difluoro-1-[4-[2-(4methylphenyl)benzoylamino]benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene]acetate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-trifluoromethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-trifluoromethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH2:26][NH2:27])[N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2].[S:29]1[CH:33]=[C:32]([CH:34]=O)[N:31]=[CH:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:28])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH2:26][NH:27][CH2:34][C:32]2[N:31]=[CH:30][S:29][CH:33]=2)[N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[O:17][CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1cscn1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(N)c(CN)n2)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(N)c(CNCc3cscn3)n2)c(OC)c1
Reaction time: 16 h
Yield: 29.4 %

Procedure:
To a solution of (5-amino-6-aminomethyl-pyridin-2-yl)-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (Example 20, product from Step 3) (422 mg, 1.1 mmol, 1 equiv), 1,3-thiazole-4-carbaldehyde (150 mg, 1.3 mmol, 1.2 equiv.) and acetic acid (32 μL, 2.2 mmol, 2 equiv) in DCE (5 mL) was added sodium triacetoxyborohydride (400 mg, 1.87 mmol, 1.7 equiv) and the reaction mixture was stirred for 16 h. Saturated NaHCO3 was added and the product was extracted with dichloromethane. The organic phase was dried (MgSO4), filtered and the solvent evaporated. The crude material was purified by column chromatography (SiO2, eluted with dichloromethane—MeOH/NH3 0-10%) to afford (5-amino-6-{[(thiazol-4-ylmethyl)-amino]-methyl}-pyridin-2-yl)-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (157 mg). MS: [M+H]+=486.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([CH:5]1[CH2:7][CH:6]1[O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)=O>CCOCC>[CH3:1][N:2]([CH3:15])[CH2:3][C@@H:5]1[CH2:7][C@H:6]1[O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: CN(C)C(=O)C1CC1OC1CCCCO1
Solvent: CCOCC
Product: CN(C)C[C@@H]1C[C@H]1OC1CCCCO1
Temperature: 0 °C

Procedure:
14 g of the compound obtained in Step 1 in 50 ml of ether are slowly added to a suspension of 3.1 g of AlLiH4 in 120 ml of ether. After 16 hours at reflux, the reaction mixture is cooled to 0° C., hydrolysed, filtered and then concentrated under reduced pressure. Chromatography of the residue over silica gel (dichloromethane/methanol: 90/10) allows the expected product to be isolated in a trans/cis diastereoisomeric ratio of 99/1.
Reaction SMILES: CC1C=CC(S([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13]2)(=O)=O)=CC=1.[Cl:20][C:21]1[N:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1.[OH-].[K+]>CN(C=O)C>[Cl:20][C:21]1[N:26]=[CH:25][C:24]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][C:14]([CH3:18])([CH3:19])[CH2:13]2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC(C)(C)C2)cc1
Reactant: Oc1ccc(Cl)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC1(C)CCCC(Oc2ccc(Cl)nc2)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
Under a nitrogen atmosphere, add 3,3-dimethylcyclohexyl 4-methylbenzenesulfonate (1.2 g, 4.25 mmol), 6-chloro-pyridin-3-ol (0.5 g, 3.86 mmol) and potassium hydroxide (238 mg, 4.25 mmol) to DMF (10 mL). Heat the mixture to 60° C. and stir overnight. Add water (20 mL) and diethyl ether (20 mL) and separate the layers. Extract the aqueous layer with diethyl ether (3×20 mL). Wash the combined organic extracts with brine (20 mL), dry over Na2SO4, filter, and concentrate in vacuo. Purify by chromatography on silica gel (80 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 1:1 over 60 min, 80 mL/min) to obtain the desired intermediate as a white solid (728 mg, 79%). MS (APCI+) m/z: 240 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([NH2:12])=[O:11])[CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([NH2:12])=[O:11])[CH:5]=1
Reactant: [H][H]
Reactant: NC(=O)c1cc([N+](=O)[O-])ccn1
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cc(N)ccn1
Yield: 87 %

Procedure:
99A was hydrogenated in MeOH with 10% Pd/C (40 mg) with a hydrogen balloon for 8 h. The Pd/C was removed by filtration. The filtrate was condensed to give 99B (80 mg, 87% yield). 1H NMR (400 MHz, Methanol-d4) δ ppm 6.65 (dd, J=5.71, 2.64 Hz, 1H) 7.27 (d, J=2.20 Hz, 1H) 8.03 (d, J=5.71 Hz, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[CH3:11][C:12]1[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1>>[CH3:11][C:12]1[CH:13]=[CH:14][C:15](=[O:18])[N:16]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH:17]=1
Reactant: Cc1ccc(=O)[nH]c1
Reactant: O=[N+]([O-])c1cccc(I)c1
Product: Cc1ccc(=O)n(-c2cccc([N+](=O)[O-])c2)c1
Yield: 75 %

Procedure:
The reaction of 24.9 g of 1-iodo-3-nitrobenzene (Aldrich Chemical Co.) with 10.9 of 5-methyl-2-(1H)-pyridone by the procedure described in Example 1 affords 16.2g (75%) of 5-methyl-1-(3-nitro-phenyl) pyridone.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[C:7]([NH2:13])[N:6]=1)=O.[BH4-].[Li+]>O1CCCC1>[NH2:13][C:7]1[N:6]=[C:5]([CH2:3][OH:2])[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=1
Reactant: COC(=O)c1cc(SC)cc(N)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1cc(N)nc(CO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
To a solution of 0.198 g 6-amino-4-methylsulfanyl-pyridine-2-carboxylic acid methyl ester in 4 ml tetrahydrofuran was added 0.044 g lithiumborohydride and the mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between ethyl acetate and brine. The phases were separated and the organic phase was purified by chromatography on silica gel with ethyl acetate to ethyl acetate:methanol=9:1. to yield 0.14 g of the title compound as beige crystals. MS (ISP): 171.1 [M+H]+.
Reaction SMILES: O[NH:2][C:3]([C:5]1[N:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[NH:12][C:13](=[O:14])[C:8]2=[CH:7][CH:6]=1)=[NH:4].C(O)(=O)C.C([O-])=O.[NH4+]>CO.[Pd].[Ni].O>[O:14]=[C:13]1[NH:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:10][N:9]2[C:5]([C:3]([NH2:4])=[NH:2])=[CH:6][CH:7]=[C:8]12
Reactant: N=C(NO)c1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)cn12
Agent: [Ni]
Agent: [Pd]
Agent: O=C[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: N=C(N)c1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)cn12
Temperature: 50 °C
Reaction time: 2 h
Yield: 45.5 %

Procedure:
A mixture of N-hydroxy-1-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-carboxamidine (Example 3) (0.03 g, 89.2 μmol) suspended in methanol (1.5 mL) and glacial acetic acid (0.15 mL) was treated with 10% palladium on carbon (5 mg). The reaction was stirred at room temperature under hydrogen (1 atm) at 50° C. for 2 h. The reaction was treated with ammonium formate (16.9 mg, 0.27 mmol) and then heated at reflux for 5 h. The reaction mixture was treated with slurry of Raney nickel in water (˜0.2 mL). The resulting mixture was stirred under hydrogen (1 atm) at room temperature overnight. At this time the reaction was filtered through Celite®. The filtrate was concentrated in vacuo to afford a light yellow semi-solid. The solid was triturated with diethyl ether, collected by filtration and then dried in vacuo to afford a light green solid. This solid was further triturated with a saturated aqueous sodium bicarbonate solution, collected by filtration and dried in vacuo to afford 1-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-pyrrolo[1,2-a]pyrazine-6-carboxamidine (13 mg, 44%) as light brown solid. 1H NMR (methanol-d4) δ ppm 8.11 (s, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.78-7.84 (m, 3H), 7.50-7.56 (m, 1H). LC-MS calcd. for C15H11F3N4O [(M+H)+] 321, obsd. 321.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1([Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:12][CH2:11][CH2:10][C:9](=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7.03 g, 38 mmol) in THF (130 mL) was added phenylmagnesium bromide (1.0 M solution, 50 mL) at −78° C. After stirring for 2 hour at −78° C., HCl (2 M, 35 mL) was added to quench the reaction, which was then warmed to room temperature and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organics were washed with brine (50 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to afford 9.56 g (96% yield) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH:6]=O.Cl.[CH2:24]1[C:26]2([CH2:31][CH2:30][NH:29][CH2:28][C@H:27]2[OH:32])[CH2:25]1>>[CH3:1][O:2][C:3](=[O:22])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH2:6][N:29]1[CH2:30][CH2:31][C:26]2([CH2:24][CH2:25]2)[C@H:27]([OH:32])[CH2:28]1
Reactant: COC(=O)[C@H](CC=O)N1CCN(c2ccccc2)CCC1=O
Reactant: O[C@@H]1CNCCC12CC2
Agent: Cl
Product: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(c2ccccc2)CCC1=O

Procedure:
In analogy to the procedure described in example 1K, (S)-4-oxo-2-(7-oxo-4-phenyl-[1,4]diazepan-1-yl)-butyric acid methyl ester and (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2) gave the title compound in 50% as light yellow foam. MS: 416.3 (MH+).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:30])[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[CH3:14].CI>C1COCC1.C(OCC)(=O)C>[CH2:13]([O:15][C:16](=[O:30])[C:17]1([CH3:1])[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]1)[CH3:14]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 105 %

Procedure:
To a stirring solution of diisopropylamine (20.0 mmol, 2.02 g) in THF (50 mL) cooled to -78° C. was added n-butyllithium (21.7 mmol, 8.68 mL of a 2.5M solution in hexanes). N-tert-butoxycarbonyl isonipecotic acid ethyl ester (16.7 mmol, 4.5 g) was then added dropwise followed by methyl iodide (16.7 mmol, 2.37g) and the reaction allowed to warm to room temperature. The mixture was then diluted with ethyl acetate (500 mL) and washed with water (1×200 mL), 10% KHSO4 (200 mL) and brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 4.76 g of the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([C@H:18]1[CH2:20][O:19]1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[O-]S(C(F)(F)F)(=O)=O.[Li+].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][NH2:37].[Cl-].[NH4+]>C(#N)C>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=1)[C@H:18]([OH:19])[CH2:20][NH:37][CH2:36][C:35]1[CH:38]=[CH:39][CH:40]=[C:33]([O:32][CH3:31])[CH:34]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(CN)c1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(F)c(F)c1)[C@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Product: COc1cccc(CNC[C@@H](O)[C@H](Cc2ccc(F)c(F)c2)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of (1R,2S)-[2-(3,4-difluoro-phenyl)-1-oxiranyl-ethyl]-carbamic acid tert-butyl ester (0.03 g, 0.1 mmol) in acetonitrile (1 mL) was treated with lithium triflate (0.032 g, 0.2 mmol) and stirred at ambient temperature for 20 minutes. Then 3-methoxybenzylamine (0.016 mL, 0.12 mmol) was added to the reaction neat in one portion. The reaction was stirred at ambient temperature for 14 hours. The reaction was poured into saturated ammonium chloride solution (5 mL), extracted with ethyl acetate, the organic phase separated, dried (MgSO4) and the solvent removed at reduced pressure. The product was obtained as an oil and used without further purification (0.041 g, 94%). MS: 437 (M+H, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13](O)[C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.ClCCl.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]2[O:9][CH2:8][C:7]([CH3:10])([CH3:11])[C:6]=2[CH:12]=1
Reactant: CC1(C)COc2c(C(O)C(C)(C)C)cc(Br)cc21
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)Cc1cc(Br)cc2c1OCC2(C)C

Procedure:
Following General Procedure J and using 1-(5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-2,2-dimethyl-propan-1-ol. (Intermediate 31, 0.951 g, 3.05 mmol), anhydrous dichloromethane (7 mL), triethyl silane (4 mL, 12.2 mmol) and trifluoroacetic acid (2 mL, 12.2 mmol) followed by flash column chromatography using 1% ethyl acetate in hexane as the eluent, the title compound was obtained (0.7 g, 78%).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][C@@H:10]1[OH:29])[CH3:8])[CH3:3]>C(OCC)(=O)C.[Pd]>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[CH:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][C@@H:10]1[OH:29])[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1[C@@H](O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)CCC[C@@H](C)[C@H]1[C@@H](O)C[C@H]2[C@@H]3CCC4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 33.5 %

Procedure:
Cholest-5-ene-3β,16β-diol (600 mg, 1.4 mmol) in ethyl acetate (15 mL) was hydrogenated at atmospheric pressure over 5% palladium on carbon for 3 days. Removal of catalyst by filtration through Celite and purification of the residue by flash chromatography gave the title compound (190 mg). The 1H-NMR spectrum (CDCl3, d) showed characteristic signals at: 0.81 (s, 3H), 0.86 (s, 3H), 0.89 (s, 3H), 3.55 (m, 1H, H-3), 4.31 (m, 1H, H-16). The 13C-NMR spectrum (CDCl3, d) showed characteristic signals at: 71.7 (C-3), 72.9 (C-8). The mass spectrum showed characteristic peaks at: 404.4 (M+).