Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][CH:3]=[N:2]1.[N:10]1[C:18]2[C:13]3[C:14](=[CH:19][CH:20]=[CH:21][C:12]=3[C:11]=1S)[CH:15]=[CH:16][CH:17]=2.C(O)C.[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]>CC(C)=O>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:11]2[C:12]3[CH:21]=[CH:20][CH:19]=[C:14]4[C:13]=3[C:18](=[CH:17][CH:16]=[CH:15]4)[N:10]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: NCCCn1cccn1
Reactant: SC1=Nc2cccc3cccc1c23
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)=O
Solvent: CCO
Product: c1cc2c3c(cccc3c1)C(NCCCn1cccn1)=N2

Procedure:
A mixture consisting of 2.8 grams of 3-(1H-pyrazol-1-yl)propanamine, 3.7 grams of benz(cd)indol-2-thiol, 7.0 grams of mercuric acetate, and 400 ml of ethanol was stirred and heated under reflux, by the conditions of Example 55. The isolated crude free base, weight 4.0 grams, was dissolved in 150 ml of acetone and added to stirred boiling solution of 3.5 grams of fumaric acid in 800 ml of acetone. After cooling, the precipitate of the title compound was collected, washed with acetone, and dried. The yield was 4.1 grams; mp 178° C.-180° C. was decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:3]=N[C:5](Cl)=[N:6][CH:7]=1.[CH:9]([NH2:12])([CH3:11])[CH3:10].Cl.[CH2:14]1COCC1>>[Br:1][C:2]1[CH:3]=[CH:14][C:5]([NH:12][CH:9]([CH3:11])[CH3:10])=[N:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CC(C)N
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Product: CC(C)Nc1ccc(Br)cn1
Temperature: 65 °C

Procedure:
To a solution of 5-bromo-2-chloropyrimidine (600 mg) in THF (10 mL) was added isopropylamine (5.30 mL) and the reaction heated at 65° C. for 16 h. After cooling to room temperature the mixture was poured into 2 M aqueous HCl (30 mL) and washed with dichloromethane (30 mL). The aqueous layer was made basic with sodium carbonate and the product extracted into dichloromethane (3×20 mL). The organic layers were dried (MgSO4) and reduced in vacuo to give (5-bromo-pyridin-2-yl)-isopropylamine as an off-white solid.
Reaction SMILES: [C:1]1([OH:13])[CH:12]=[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[C:3]([OH:4])[CH:2]=1.C(N)CC.[CH3:18][C:19](=[CH:21][CH2:22][CH2:23][C:24](=[CH:26][CH:27]=O)[CH3:25])[CH3:20]>C1(C)C=CC=CC=1>[CH3:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1[CH:5]=[C:3]([OH:4])[C:2]2[CH:27]=[CH:26][C:24]([CH2:23][CH2:22][CH:21]=[C:19]([CH3:20])[CH3:18])([CH3:25])[O:13][C:1]=2[CH:12]=1
Reactant: CCCCCc1cc(O)cc(O)c1
Reactant: CC(C)=CCCC(C)=CC=O
Solvent: Cc1ccccc1
Solvent: CCCN
Product: CCCCCc1cc(O)c2c(c1)OC(C)(CCC=C(C)C)C=C2
Reaction time: 7 h

Procedure:
The reaction of 5 g. olivetol (27.8 mmole), 1.652 g. n-propylamine (2.3 ml., 27.8 mmole) and 4.6 ml. citral (27.8 mmole) in 55 ml. toluene was carried out in the same manner as described under Example 1. The refluxing time was 7 hours. Gas chromatographic analysis of the reaction mixture showed 61.62% CBC, 4.01% Cannabicitran and trace amount of iso-CBC.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][C@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C(N(CC)CC)C>O1CCCC1>[CH3:3][N:4]([C:16](=[O:18])[CH3:17])[C@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: CN[C@@H](Cc1ccncc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N(C)[C@@H](Cc1ccncc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
Methyl-3-(4-pyridinyl)alanine, dihydrochloride (1.4 g, 0.0053 mol) is stirred in dry tetrahydrofuran (20 mL) with acetic anhydride (0.9 mL, 0.0095 mol) and triethylamine (3.3 mL, 0.0233 mol) at room temperature. After stirring at room temperature overnight the mixture is diluted with 20 mL tetrahydrofuran and filtered and the solids washed with tetrahydrofuran. The filtrate is concentrated to a dark oil, dissolved in dichloromethane (50 mL) and washed with dilute sodium bicarbonate solution (50 mL). The organic layer is dried over magnesium sulfate and concentrated. The residue is triturated with diethyl ether, filtered, and dried to afford 0.83 g of the title compound as a tan solid; mp 86-88° C.
Reaction SMILES: [C:1]([S@@:5](/[N:7]=[CH:8]/[C:9]1[N:13]([CH3:14])[CH:12]=[C:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:10]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Mg]Br>C(Cl)Cl>[CH3:2][C:1]([CH3:4])([S@@:5]([NH:7][C@@H:8]([C:9]1[N:13]([CH3:14])[CH:12]=[C:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:10]=1)[CH3:22])=[O:6])[CH3:3]
Reactant: C[Mg]Br
Reactant: Cn1cc(C(=O)OC(C)(C)C)cc1/C=N/[S@@](=O)C(C)(C)C
Solvent: ClCCl
Product: C[C@@H](N[S@@](=O)C(C)(C)C)c1cc(C(=O)OC(C)(C)C)cn1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of (S,E)-tert-butyl 5-((tert-butylsulfinylimino)methyl)-1-methyl-1H-pyrrole-3-carboxylate (3.0 g, 10 mmol) in DCM (60 mL) was slowly added methylmagnesium bromide (13.3 mL, 3.0 M in ether) at −78° C. After stirring at −78° C. for 1 h, the solution was warmed to rt and stirred for 2 h. The reaction was quenched with sat. NH4Cl solution. After separation, the organic phase was washed with brine (5 mL), dried (Na2SO4) and concentrated. Flash column chromatography (petroleum ether: EtOAc, 10:1 to 1:1) afforded tert-butyl 5-((R)-1-((S)-1,1-dimethylethylsulfinamido)ethyl)-1-methyl-1H-pyrrole-3-carboxylate (2.2 g, 70%). 1H NMR (CDCl3, 400 MHz) δ 7.15 (s, 1H), 6.47 (s, 1H), 4.48 (m, 1H), 3.62 (s, 3H), 3.18 (m, 1H), 1.68 (d, J=6.6 Hz, 3H), 1.52 (s, 9H), 1.19 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8](Br)=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:12]([Cu])#[N:13].N>CN(C=O)C.CO>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:12]#[N:13])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Fc1ccc(Br)c2[nH]ccc12
Reactant: N#C[Cu]
Agent: N
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1ccc(F)c2cc[nH]c12
Temperature: 25 °C
Yield: 69.1 %

Procedure:
A mixture of 4-fluoro-7-bromoindole (600 mg, 2.8 mmol) and CuCN (1.004 g, 11.2 mmol) in DMF (4 ml) was refluxed for 16 hours. After cooling to room temperature, the reaction mixture was poured into a solution of ammonia in MeOH (30 ml, sat.) and the residue removed by filtration. The filtrate was added to a mixture of water (20 ml)/ammonia (20 ml, sat. aq.) and extracted with EtOAc/Ether (1/1) until TLC analysis showed no product in the aqueous phase. The combined organic extracts were washed with brine (2×200 ml) and water (200 ml), dried (MgSO4); evaporation in zacuo gave 4-fluoro-7-cyanoindole as a tan yellow solid (310 mg, 69%).
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:14])[O:11][CH3:12])=[O:9])[C:4](=[O:22])O1.C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:32][N:33](C)[C:34](C1CN(C)C(=O)C=1O)=O>CO>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:13]([N:10]([O:11][CH3:12])[C:8]([C:7]2[CH2:32][N:33]([CH3:34])[C:4](=[O:22])[C:5]=2[OH:6])=[O:9])[CH3:14])=[CH:20][CH:19]=1
Reactant: CON(C(=O)C=C1OC(C)(C)OC1=O)C(C)c1ccc(F)cc1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: CN
Solvent: CO
Product: CON(C(=O)C1=C(O)C(=O)N(C)C1)C(C)c1ccc(F)cc1
Yield: 47 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-[1-(4-fluorophenyl)-ethyl]-N-methoxy-acetamide, prepared using the methods described in the previous examples, was treated in methanol with paraformaldehyde and methylamine as described in the preparation Compound 12 to give the title compound as a white solid (47% yield); mp 136–138° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.68 (3H, d, J=7.1 Hz, CH3), 3.1 (3H, s, NCH3), 3.49 (3H, s, OCH3), 4.13 (2H, AB system, JAB=18.2 Hz, Δv=45.7 Hz, NCH2), 5.75 (1H, q, J=7.1 Hz, CH), 7.06 (2H, m, aromatics), 7.42 (2H, m, aromatics). Anal. calcd for C15H17FN2O4: C, 58.43; H, 5.55; N, 9.08. Found: C, 58.40; H, 5.38; N, 9.01.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)O)=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=2[O:19]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl.C1(C)C(C)=CC=CC=1>[C:2]1([C:8]2[NH:23][C:22]3[C:24]([C:10]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:25][C:26]2[O:27][CH2:18][O:19][C:20]=2[CH:21]=3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: Nc1ccc2c(c1)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1C
Product: c1ccc(-c2[nH]c3cc4c(cc3c2-c2ccccc2)OCO4)cc1

Procedure:
To a flask equipped with a stirrer and Dean-Stark water separator are charged 53g. of benzoin, 51g. of 3,4-methylenedioxyaniline, 2.5g. of p-toluenesulfonic acid and 300 ml. of xylene. The mixture is stirred and refluxed for 10 hours. After cooling to room temperature 1500 ml of chloroform are added and the organic layer is washed two times with 150 ml. of 10%, sulfuric acid. The organic layer is treated with charcoal, filtered and concentrated in vacuo to ca. 500 ml. On standing there is obtained 2,3-diphenyl- 5,6-methylenedioxyindole, m.p. 187°-188°C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[CH3:21])[C:11]2=[O:14])=[CH:6][CH:5]=1.Cl[C:23]1[N:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1.CO>CN(C=O)C.C(Cl)Cl>[F:29][C:26]1[CH:25]=[N:24][C:23]([O:3][C:4]2[CH:13]=[C:12]3[C:7]([CH2:8][CH2:9][N:10]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4[CH3:21])[C:11]3=[O:14])=[CH:6][CH:5]=2)=[N:28][CH:27]=1
Reactant: Cc1ccncc1N1CCc2ccc(O)cc2C1=O
Reactant: Fc1cnc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccncc1N1CCc2ccc(Oc3ncc(F)cn3)cc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.4 %

Procedure:
60% NaH (13 mg, 0.33 mmol) was added to a stirred solution of 7-hydroxy-2-(4-methyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (27A: 70 mg, 0.275 mmol) in DMF (2 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. This was followed by the addition of 2-chloro-5-fluoro-pyrimidine (44 mg, 0.33 mmol) at 0° C. and stirring was continued for a further 1 hour at room temperature. The reaction was monitored by TLC (5% methanol in DCM). The reaction mixture was quenched with chilled water and extracted with ethylacetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (2% methanol in DCM) afforded 10 mg of the product (10.4% yield).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[N:8]=1.[NH3:30]>CN(C)C=O>[F:1][C:2]([F:29])([F:28])[CH2:3][N:4]=[C:5]([NH2:30])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[N:8]=1
Reactant: O=C1c2ccccc2C(=O)N1CCSc1nccc(NC(=S)NCC(F)(F)F)n1
Reactant: N
Solvent: CN(C)C=O
Product: NC(=NCC(F)(F)F)Nc1ccnc(SCCN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-(2-phthalimidoethylthio)pyrimidine (0.65 g.), dimethylformamide (10 ml.), ethanolic ammonia solution (5 ml.) and yellow mercuric oxide was stirred at room temperature for 4 hours. The mixture was filtered and the filtrate evaporated to dryness to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(2-phthalimidoethylthio)pyrimidine (0.62 g.), m.p. 192°-195°.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[O:14])[CH:10]=2)[CH:5]=[CH:4]1)[CH3:2].[C:30]([S:34]([NH2:37])(=[O:36])=[O:35])([CH3:33])([CH3:32])[CH3:31].IC1C=CC(NC(C2C=CC(N3CCC(C(NS(C(C)(C)C)(=O)=O)=O)CC3)=NC=2)=O)=CC=1C>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:14])[C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][CH:24]([C:27]([NH:37][S:34]([C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:36])=[O:35])=[O:28])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[CH:10]=2)[CH:5]=[CH:4]1)[CH3:2]
Reactant: CCn1ccc2ccc(NC(=O)c3ccc(N4CCC(C(=O)O)CC4)cc3)cc21
Reactant: CC(C)(C)S(N)(=O)=O
Agent: Cc1cc(NC(=O)c2ccc(N3CCC(C(=O)NS(=O)(=O)C(C)(C)C)CC3)nc2)ccc1I
Product: CCn1ccc2ccc(NC(=O)c3ccc(N4CCC(C(=O)NS(=O)(=O)C(C)(C)C)CC4)cc3)cc21

Procedure:
N-(1-Ethyl-1H-indol-6-yl)-4-[4-(2-methyl-propane-2-sulfonylaminocarbonyl)-piperidin-1-yl]-benzamide was prepared form 1-[4-(1-ethyl-1H-indol-6-ylcarbamoyl)-phenyl]-piperidine-4-carboxylic acid and t-butyl sulfonamide in a manner similar to the one described in the synthesis of 4-(2-methyl-propane-2-sulfonylaminocarbonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (4-iodo-3-methyl-phenyl)-amide. The product was isolated after a silica gel column purification with 50-100% Et2O in hexanes to 50-100% EtOAc in hexane gradient. HRMS m/z calcd for C27H34N4O4S [M+H]+: 511.2374. Found: 511.2372.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Br[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH3:20])[CH:14]=1>>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:14][C:15]=1[CH3:20]
Reactant: Cc1cc(Br)ccc1O
Reactant: N#Cc1ccc(B(O)O)cc1
Product: Cc1cc(-c2ccc(C#N)cc2)ccc1O
Yield: 50 %

Procedure:
4-Cyanophenylboronic acid and 4-bromo-2-methylphenol were processed as described in Example 167A to provide the title compound (50% yield). 1HNMR (300 MHz, CDCl3) δ2.40 (s, 3H), 4.85 (bs, 1H), 6.83-7.65 (m, 7H); MS (CDI) m/z 210 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](C4C=CN=CC=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+].[CH2:39](O)[CH3:40].Cl>O>[N:19]1[CH:40]=[CH:39][CH:16]=[C:17]([C:27]2[CH:26]=[CH:25][C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:3])=[O:36])=[CH:10][CH:11]=4)[N:19]=3)=[CH:29][CH:28]=2)[CH:18]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccncc4)cc3)oc2C)cc1
Reactant: CCO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1oc(-c2ccc(-c3cccnc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1

Procedure:
To a 20 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-pyrid-4-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (0.268 mmoles), lithium hydroxide (0.535 mmoles, 0.268 mL of a 2N solution), and ethanol (5 mL). This solution was heated to reflux for 2 h. Distilled water was added to the mixture and the pH was adjusted to 3 using a 1N HCl solution. The organic layer was extracted with ethyl acetate, washed with brine, and concentrated in-vacuo. This crude oil was re-solvated in pure ethyl acetate and filtered over a pad of Celite. The filtrate was concentrated in-vacuo, and the crude oil was crystallized using acetonitrile. The crystals were collected and dried in-vacuo affording 2-(4-{2-[2-(4-pyrid-3-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) 7.99 (2H, d), 7.66 (2H, d), 7.45 (2H, m), 7.53 (1H, m), 7.42 (1H, m), 6.90 (2 h, m), 6.78 (2H, m), 4.17 (2H, t), 2.99 (2H, t) 2.39 (3H, s), 1.53 (6H, s).
Reaction SMILES: NC1N=[C:5]([C:7]2C=[C:11](C(C)(C)C)[C:10](OCOCCOC)=[C:9](C(C)(C)C)[CH:8]=2)[NH:4]N=1.C[O-].[Na+].CO.[C:33]([NH:36][NH2:37])([NH2:35])=[NH:34].[ClH:38]>CO>[NH2:34][C:33]1[N:35]=[C:11]([C:10]2[CH:9]=[CH:8][C:7]([Cl:38])=[CH:5][N:4]=2)[NH:37][N:36]=1
Reactant: COCCOCOc1c(C(C)(C)C)cc(-c2nc(N)n[nH]2)cc1C(C)(C)C
Reactant: Cl
Reactant: N=C(N)NN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1n[nH]c(-c2ccc(Cl)cn2)n1
Yield: 82 %

Procedure:
The synthesis method of Example 7-(2) was applied. The compound (3.94 g) obtained in (3) above, a 5M sodium methoxide-methanol solution (17 ml), methanol (20 ml) and aminoguanidine hydrochloride (9.39 g) were used as reagents. The mixture was stirred with refluxing for 18 hours and methanol was distilled away under reduced pressure. Water was added to the residue and the aqueous layer was adjusted to pH 3-4 with 3N hydrochloric acid to give 3.40 g of a pale-yellow solid that precipitated (yield 82%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH:37](=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C=O)C>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][N:11]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:34])[CH3:35])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCOP(=O)(CCNCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOP(=O)(CCN(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)Cc1ccccc1)OCC
Yield: 43.2 %

Procedure:
A solution of (2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonic acid diethyl ester (30 mg, 0.055 mmol), benzaldehyde (5.6 μL, 0.055 mmol), and sodium triacetoxyborohydride (23 mg, 0.11 mmol) was stirred with acetic acid (15.7 μL, 0.28 mmol) in DMF (0.5 mL) at room temperature over night. The reaction was quenched with a 10% aqueous Na2CO3 solution and the product was extracted with EtOAc. The organic layer was dried and concentrated under reduced pressure. The product was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 15 mg of the product (43%) as a clear gel. 1H NMR (300 MHz, CDCl3) δ 0.02 (s, 9H), 1.18-1.25 (m, 2H), 1.24 (t, 6H, J=7 Hz), 1.86 (s, 3H), 1.88-2.02 (m, 2H), 2.16 (s, 3H), 2.65-2.74 (m, 2H), 3.93 (s, 2H), 3.46 (br d, 4H, J=7 Hz), 3.76 (s, 3H), 4.00 (pent, 4H, J=7 Hz), 4.25-4.34 (m, 2H), 5.11 (s, 2H), 5.34-5.43 (m, 1H), 7.18-7.33 (m, 5H) ppm; 31P (121.4 MHz, CDCl3) δ 30.9 ppm; MS (m/z) 632.4 [M+H]+, 654.3 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[C:14]3[C:20]4([N:23]([CH3:31])[C:24](=[O:30])[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH2:21][CH2:22][C:17]([CH2:32]OS(C5C=CC(C)=CC=5)(=O)=O)([CH2:18][CH2:19]4)[CH2:16][N:15]3[C:44](=[O:47])[C:45]=2[OH:46])=[O:11])=[CH:4][C:3]=1[CH3:48].CCCC[N+](CCCC)(CCCC)CCCC.[F-:66].C1COCC1>>[F:66][CH2:32][C:17]12[CH2:22][CH2:21][C:20]([N:23]([CH3:31])[C:24](=[O:30])[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])([C:14]3[N:15]([C:44](=[O:47])[C:45]([OH:46])=[C:12]([C:10]([NH:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:48])[CH:4]=4)=[O:11])[N:13]=3)[CH2:16]1)[CH2:19][CH2:18]2
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(N(C)C(=O)C(=O)N(C)C)(CC2)c2nc(C(=O)NCc4ccc(F)c(C)c4)c(O)c(=O)n2C3)cc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: Cc1cc(CNC(=O)c2nc3n(c(=O)c2O)CC2(CF)CCC3(N(C)C(=O)C(=O)N(C)C)CC2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
A mixture of N-[2-[[[(4-fluoro-3-methylphenyl)methyl]amino]carbonyl]-6,7,8,9-tetrahydro-3-hydroxy-7-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-4-oxo-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl]-N,N′,N′-trimethyl-ethanediamide, Intermediate 28, (50 mg, 0.073 mmol) was treated with TBAF, 1M in THF (1.5 mL, 1.500 mmol) and 4 Å molecular sieves. The mixture was then stirred for 30 min at room temp and heated at 80° C. for 18 h. After cooling the reaction mixture was concentrated and purified by preparative HPLC to afford the title compound (14 mg, 0.025 mmol, 34.2% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ: 12.18 (1H, br. s.), 9.60 (1H, br. s.), 7.17-7.26 (2H, m), 6.94 (1H, t, J=8.85 Hz), 4.75 (1H, d, J=14.95 Hz), 4.56-4.65 (1H, m), 4.39-4.50 (1H, m), 4.28 (1H, d, J=2.75 Hz), 4.19 (1H, d, J=2.75 Hz), 3.42-3.57 (2H, m), 3.05 (3H, s), 3.03 (3H, s), 3.01 (3H, s), 2.27 (3H, s), 2.07-2.18 (3H, m), 1.80-1.88 (1H, m), 1.70-1.78 (2H, m), 1.42-1.52 (1H, m). LCMS (M+H)=532.4.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]#[N:9].[NH2:10][C:11](N)=[O:12].CC[OH:16]>Cl>[NH:10]1[C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:8](=[O:16])[NH:9][C:11]1=[O:12]
Reactant: CCO
Reactant: N#CC1CCCCC1=O
Reactant: NC(N)=O
Agent: Cl
Product: O=c1[nH]c2c(c(=O)[nH]1)CCCC2
Temperature: 0 °C

Procedure:
A solution of 2-oxocyclohexanecarbonitrile (615 mg, 5.0 mmol) and urea (600 mg, 10.0 mmol) in 1.25 N HCl in EtOH (20 mL) was refluxed over night. After it was cooled down to 0° C., the precipitation was collected by filtration, washed with EtOH/H2O, and dried under vacuum overnight to give the product as a white solid. 1H NMR (400 MHz, CD3OD) δ 1.67-1.80 (m, 4H), 2.25-2.29 (m, 2H), 2.38-2.42 (m, 2H). MS 167 (MH+).
Reaction SMILES: C[O:2][CH:3](O)[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][CH3:14].OCC1C=C([N+]([O-])=O)C=CC=1O>>[CH3:14][O:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[CH2:3][OH:2]
Reactant: COc1ccc([N+](=O)[O-])cc1C(O)OC
Agent: O=[N+]([O-])c1ccc(O)c(CO)c1
Product: COc1ccc([N+](=O)[O-])cc1CO
Yield: 76 %

Procedure:
This compound was prepared by reduction of 2-methoxy-5-nitrobenzaldehyde methyl hemiacetal using a method similar to that described for preparing 2-hydroxymethyl-4-nitrophenol in 76% yield: MP 121–122° C.; 1H NMR (DMSO-d6, 500 MHz) δ8.22 (d, 1H, J=1.22 Hz), 8.16 (dd, 1H, J=2.7 and 9.1), 7.16 (d, 1H, J=8.9 Hz), 4.50 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11](=[O:14])([O-])[O-].[Na+].[Na+].[CH2:17]1[CH2:21]O[CH2:19][CH2:18]1>C(Cl)(Cl)Cl.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.[Pd]>[CH3:2][N:6]1[C@H:5]2[C@@:17]([CH3:21])([C:17]3[CH:21]=[CH:9][C:8]([C:2]4[O:3][C:4]5[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=5[N:6]=4)=[CH:7][C:18]=3[CH2:19][CH2:4]2)[CH2:18][CH2:19][C:11]1=[O:14]
Reactant: O=C([O-])[O-]
Reactant: C1CCOC1
Reactant: Clc1nc2ccccc2o1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4nc5ccccc5o4)cc3CC[C@@H]12
Yield: 20 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium (0) (23 mg, 0.02 mmol), 2-chlorobenzoxazole (110 mg, 0.65 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 18 h. Additional palladium reagent (23 mg) was added, and the mixture was heated an additional 48 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (90-100% ethyl acetate/hexanes eluent) to give 45 mg (20%) of the title compound as an amorphous foam. FDMS: m/e=346.