Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].O.CS([C:7]1[N:12]=[CH:11][C:10]2=[CH:13][CH:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]2[N:8]=1)=O>C(O)(=O)C>[OH:1][C:7]1[N:12]=[CH:11][C:10]2=[CH:13][CH:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]2[N:8]=1
Reactant: [OH-]
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN(c1ccccc1-c1ccc2cnc(O)nn12)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Into a 8-dram vial, 19.10 M of Sodium hydroxide in Water (7.88 mL, 1.50E2 mmol) and Water (7.88 mL, 438 mmol) water were added. The mixture was heated at 100° C. N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (2.00 g, 5.49 mmol) was added portion wise over 10 minutes. The reaction mixture was heated at 120° C. for 60 minutes. HPLC suggested no SM. The reaction was cooled to room temperature. Glacial acetic acid was added to adjust pH to 4. The mixture was stirred at room temperature for 30 minutes. The solid was filtered, washed with water and subsequently with Et2O. The resulting solid was dried under vacuum overnight to give N-[2-(2-Hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide as a yellow solid (1.60 g, 92%).
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20]>CCO>[CH2:11]([O:10][C:2](=[O:9])[CH:3]([CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:12]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COCCOCCBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCOCCOC)C(=O)OCC
Yield: 48.3 %

Procedure:
Sodium (0.72 g, 31.31 mmol) was added in portions to EtOH (99.5%, 35 mL) under stirring. When all sodium had dissolved, diethyl malonate (4.80 g, 29.97 mmol) was added slowly during 5 minutes and the reaction mixture was stirred for another 15 minutes. 1-Bromo-2-(2-methoxyethoxy)-ethane (5.50 g, 30.05 mmol) was added and the reaction mixture was refluxed for 2 hrs. Any solids were filtered off and the clear solution was concentrated in vacuo. The residue was taken up in water and diethyl ether and the two phases were separated. The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with EtOAc/MeOH:20/1) to give the title compound as a colourless oil (3.80 g), 1H NMR (300 MHz, CDCl3) δ 4.19 (q, 4H), 3.54 (m, 7H), 3.38 (s, 3H), 2.19 (m, 2H), 1.27 (t, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([CH2:36][CH2:37][CH2:38][OH:39])[CH2:15][CH2:14][CH2:13][CH:12]([O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][C:26]=2[Cl:27])[C:23]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:22][CH:21]=[CH:20]3)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:44].CO>C1COCC1>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([CH2:36][CH2:37][CH2:38][O:39][CH3:44])[CH2:9][CH2:10][CH2:11][CH:12]([O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][C:26]=2[Cl:27])[C:23]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:22][CH:21]=[CH:20]3)[CH2:13][CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(CCCO)CCCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COCCCC1(NC(=O)OC(C)(C)C)CCCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
A solution of 405 mg (0.71 mmol) of [5-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-1-(3-hydroxy-propyl)-cyclooctyl]-carbamic acid tert-butyl ester (59) in 5 mL of THF was dropped into a suspension of 31.3 mg (0.78 mmol) of sodium hydride (60%) in 5 mL THF at 0° C. 88.6 μL (1.42 mmol) of iodomethane were added, and after stirring for 1 h at room temperature another 88.6 μL (1.42 mmol). The reaction mixture was stirred at room temperature until LCMS indicated complete conversion, then 5 mL of methanol were added and the volatiles removed in vacuo. The crude material was purified by silica gel chromatography. 196 mg of [5-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-1-(3-methoxy-propyl)-cyclooctyl]-carbamic acid tert-butyl ester (61) as diastereomeric mixture could be isolated. Rt=1.89 min, 2.02 min (Method I). Detected mass: 583.3 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].C1(=O)N[C:16](=[O:18])[C:15]2=CC=CC=C12.[K].O.[NH2:26]N>C(O)CO>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2([CH2:3][CH2:2][NH2:26])[O:18][CH2:16][CH2:15][O:5]2)=[CH:7][CH:8]=1
Reactant: NN
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(CCCl)c1ccc(Cl)cc1
Agent: [K]
Solvent: OCCO
Solvent: O
Product: NCCC1(c2ccc(Cl)cc2)OCCO1

Procedure:
3,4′-Dichloropropiophenone was treated with potassium phthalimide, the product treated with ethylene glycol and then this product cleaved with hydrazine hydrate following the methods described in J. Org. Chem. 1972, 221-225, to give 2-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]ethylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][S:8][C:9](=[NH:25])[C:10]([C:23]#[N:24])=[C:11]([SH:22])[NH:12][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])=[CH:5][CH:4]=1.N1C=CC=CC=1.II.Cl>C(OCC)(=O)C>[C:16]1([O:15][C:13](=[O:14])[NH:12][C:11]2[S:22][N:25]=[C:9]([S:8][CH2:7][C:6]3[CH:26]=[CH:27][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:10]=2[C:23]#[N:24])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(CSC(=N)C(C#N)=C(S)NC(=O)Oc2ccccc2)cc1
Agent: Cl
Agent: II
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(CSc2nsc(NC(=O)Oc3ccccc3)c2C#N)cc1
Reaction time: 1 h
Yield: 62.9 %

Procedure:
To a mixture of 2-Cyano-3-mercapto-3-phenoxycarbonylamino-thioacrylimidic acid 4-methoxy-benzyl ester (11 g, 28 mmol) and ethyl acetate (250 mL) was added, at 0° C., pyridine (4.4 g, 55 mmol). A solution of iodine (7.0 g, 28 mmol) in 350 mL of ethyl acetate was added dropwise over 1 hour. The resulting suspension was stirred for 1 hour, treated with 200 mL of 1 M HCl and filtered, affording 7.0 g (64%) of [4-cyano-3-(4-methoxy-benzylsulfanyl)-isothiazol-5-yl]-carbamic acid phenyl ester as a colorless solid. The filtrate was extracted with 1 l of ethyl acetate, and the organic phase was washed with aqueous NaHCO3, dried over Na2SO4, filtered and concentrated, yielding an additional 2.8 g (26%) of [4-cyano-3-(4-methoxy-benzylsulfanyl)-isothiazol-5-yl]-carbamic acid phenyl ester. 1H NMR (400 MHz, CDCl3) δ11.95 (s, 1H), 7.35 (t, 2H, J=8.4 Hz), 7.20 (m, 3H), 7.13 (d, 2H, J=8.0 Hz), 6.78 (t, 2H, J=8.6 Hz), 4.34 (s, 2H), 3.73 (s, 3H) ppm; MS (APCI, m/z): 398 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][CH:17]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]#[N:26])[CH2:21][CH2:20]4)[CH2:16][C:15]=3[CH:27]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH:28][NH:29][C:30]([CH:32]1[CH2:34][CH2:33]1)=N>>[CH:32]1([C:30]2[N:26]=[C:25]([N:22]3[CH2:21][CH2:20][CH:19]([CH:17]4[CH2:16][C:15]5[CH:27]=[C:11]([C:8]6[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=6)[CH:12]=[CH:13][C:14]=5[O:18]4)[CH2:24][CH2:23]3)[O:28][N:29]=2)[CH2:34][CH2:33]1
Reactant: N=C(NO)C1CC1
Reactant: CS(=O)(=O)c1ccc(-c2ccc3c(c2)CC(C2CCN(C#N)CC2)O3)cc1
Product: CS(=O)(=O)c1ccc(-c2ccc3c(c2)CC(C2CCN(c4nc(C5CC5)no4)CC2)O3)cc1

Procedure:
The title compound is prepared from 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carbonitrile and N-hydroxy-cyclopropanecarboxamidine following a procedure analogous to that described in Example 2. LC (method 2): tR=1.08 min; Mass spectrum (ESI+): m/z=466 [M+H]+.
Reaction SMILES: Cl.[CH2:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.CCN(C(C)C)C(C)C.Br[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(#N)C>[CH2:31]([N:3]1[CH2:4][CH2:5][C:6]2[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:2]1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Reactant: BrCCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)Cn1c2c(c3ccccc31)CN(CCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
Step a): To a stirred solution of Intermediate 1 (50 mg, 0.17 mmol) and DIEA (73 μl, 0.42 mmol) in acetonitrile (1 ml) is added (2-bromo-ethyl)-benzene (26 μl, 0.19 mmol). The reaction mixture is stirred at rt overnight. The solvent is removed under reduced pressure and the crude product is purified by silica gel column chromatography (hexane/EtOAc 3:1, 1% NEt3), affording pure ethyl (2-phenethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-acetate (37 mg) in 60% yield: tR (LC-2) 1.69 min; ESI-MS (pos. ion): m/z 363.26 [M+H]+ (calcd 362.46 for C23H26N2O2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[CH:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:13]#[N:14].S1C=CC=C1.[H][H]>CO.[Pt]>[NH2:8][C:6]1[CH:5]=[C:4]([Cl:11])[C:3]([CH:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:13]#[N:14])=[C:2]([Cl:1])[CH:7]=1
Reactant: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Reactant: [H][H]
Agent: [Pt]
Solvent: c1ccsc1
Solvent: CO
Product: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc(N)cc1Cl

Procedure:
A mixture of 31.1 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-nitrobenzeneacetonitrile (intermediate 1), 2 parts of a solution of 4% thiophene in methanol and 480 parts of methanol is hydrogenated in the Parr apparatus at 50 degrees C with 3 parts of 5% platinum-on-charcoal catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off, washed with tetrahydrofuran and the filtrate is evaporated in vacuo. The residue is crystallized from 160 parts of 2-propanol. The product is filtered off, washed with 2,2'-oxybispropane and dried, yielding 4-amino-2,6-dichloro-α-(4-chlorophenyl)benzeneacetonitrile. (intermediate 2).
Reaction SMILES: O[C:2]1([OH:16])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[C:3]1=[O:15].[CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1OC)([CH3:19])[CH3:18].[C:28](O)(C(F)(F)F)=[O:29]>>[OH:16][C:2]1([C:23]2[CH:22]=[CH:21][C:20]([CH:17]([CH3:18])[CH3:19])=[CH:25][C:24]=2[O:29][CH3:28])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[C:3]1=[O:15]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)C1(O)O
Reactant: COc1ccccc1C(C)C
Product: COc1cc(C(C)C)ccc1C1(O)C(=O)c2cccc([N+](=O)[O-])c2C1=O
Temperature: 60 °C
Reaction time: 6 h
Yield: 16 %

Procedure:
A solution of 4-nitro-2,3-dihydro-1H-inden-1-one (4.00 g, 20.9 mmol) in 1,4-dioxane (40 ml) and glacial acetic acid (4 ml) was added with selenium dioxide (5.10 g, 46.03 mmol), and refluxed for 3 hrs. After filtration at high temperature, the filtrate was concentrated to afford 2,2-dihydroxy-4-nitro-2H-inden-1,3-dione (4.67 g, 100%). To a solution of 2,2-dihydoxy-4-nitro-2H-inden-1,3-dione (4.67 g, 20.9 mmol) in TFA (10 ml) was added isopropyl anisole (3.14 g, 20.9 mmol), followed by stirring at 60° C. for 6 hrs. The reaction mixture was concentrated in a vacuum, and extracted with aq. sodium bicarbonate and ethylacetate. The concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (1.19 mg, 16%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:9][NH:10][CH:11]([CH3:13])[CH3:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=1>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1([CH2:9][N:10]([C:23]2[C:24]([N+:28]([O-:30])=[O:29])=[CH:25][N:26]=[C:21]([Cl:20])[N:22]=2)[CH:11]([CH3:12])[CH3:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CNC(C)C)CC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(CN(c2nc(Cl)ncc2[N+](=O)[O-])C(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl1-[(propan-2-ylamino)methyl]cyclopropane-1-carboxylate (Intermediate 211; 9.55 g, 50 mmol) in acetone (300 mL) was added potassium carbonate (7.05 g, 51 mmol) followed by 2,4-dichloro-5-nitropyrimidine (Aldrich; 10.675 g, 55 mmol). The mixture was stirred overnight at room temperature, concentrated in vacuo and partitioned between EtOAc and water. The EtOAc layer was separated, dried over sodium sulfate, then purified by column chromatography (EtOAc/isohexane 10:90), to yield the title compound as a yellow oil. (11 g, 64%)
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:35]=[CH:34][C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][Si](C)(C)C)=[CH2:20])=[C:15]([O:26][Si](C)(C)C)[C:14]=2[CH2:31][CH2:32][CH3:33])=[CH:9][CH:8]=1.[H-].[Na+].[O:38]=[C:39]1[O:43][N:42]=[C:41]([C:44]2[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=2)[CH:47]=[O:48])[NH:40]1>O1CCCC1>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:10]2[CH:34]=[CH:35][C:7]([CH:47]([OH:48])[C:46]3[CH:45]=[C:44]([C:41]4[NH:40][C:39](=[O:38])[O:43][N:42]=4)[CH:51]=[CH:50][CH:49]=3)=[CH:8][CH:9]=2)=[C:14]([CH2:31][CH2:32][CH3:33])[C:15]=1[OH:26])(=[O:21])[CH3:20]
Reactant: C=C(O[Si](C)(C)C)c1ccc(OCc2ccc(I)cc2)c(CCC)c1O[Si](C)(C)C
Reactant: O=Cc1cccc(-c2noc(=O)[nH]2)c1
Agent: CC(C)[Mg]Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1c(OCc2ccc(C(O)c3cccc(-c4noc(=O)[nH]4)c3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Add isopropyl magnesium chloride (2M solution in tetrahydrofuran, 0.496 ml, 0.992 mmol) to a solution of 1-(4-iodo-benzyloxy)-2-propyl-3-trimethylsilanyloxy-4-(1-trimethylsilanyloxy-vinyl)-benzene (500 mg, 0.901 mmol) in tetrahydrofuran (0.1M) at 0° C. After 15 minutes, warm to room temperature. After 1 hour, cool to −78° C. Add sodium hydride (60% dispersion, 24 mg, 0.992 mmol) to a solution of 3-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzaldehyde (189 mg, 0.992 mmol) in tetrahydrofuran (0.1M). Sonicate the solution for 5 minutes, then add it via syringe to the gringard reagent. After 30 minutes warm the reaction to room temperature. Quench with 10% aq hydrochloric acid (3 mL). Pour the reaction into brine and extract with 25% isopropyl alcohol:75% dichloromethane. Combine organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes:acetic acid 50%:50%:0.1% to yield the title product as a off white solid (110 mg, 26%): 1H NMR (DMSO-d6) δ 0.86 (t, 3H), 1.47 (sextet, 2H), 2.56 (m, 5H), 5.21 (s, 2H), 5.79 (d, 1H), 6.11 (d, 1H), 6.70 (d, 1H), 7.41 (q, 4H), 7.51 (t, 1H), 7.63 (t, 2H), 7.78 (d, 1H), 7.90 (s, 1H), 12.83 (s, 1H), 12.97 (bs, 1H); MS (esi negative) m/z (rel intensity) 473 (100).
Reaction SMILES: C[O:2][C:3](=[O:10])[CH2:4][C:5](=[CH2:9])[C:6]([OH:8])=[O:7].[H][H].[CH3:13]OC(=O)C[C@@H](C)C(O)=O>CO>[CH3:13][O:8][C:6](=[O:7])[CH:5]([CH3:9])[CH2:4][C:3]([OH:2])=[O:10]
Reactant: C=C(CC(=O)OC)C(=O)O
Reactant: COC(=O)C[C@@H](C)C(=O)O
Reactant: [H][H]
Solvent: CO
Product: COC(=O)C(C)CC(=O)O
Temperature: 135 °C
Reaction time: 4 h

Procedure:
133 mg (0.182 mmol) of (RophosARhCOD)CF3SO3 (=precatalyst) were introduced under protective gas into 21 ml of methanol in a 4 l (enamel) Pfaudler autoclave and 526 g (3-65 mol) of 2-methylenesuccinic acid 4-monomethyl ester (=substrate) dissolved in 704 ml of methanol were added. Hydrogenation was then carried out at 40° C. under 5 bar of hydrogen. Conversion of the substrate was complete after 4 h (1H-NMR, 500 MHz). The enantiomeric excess of the product (2R)-methylsuccinic acid 4-monomethyl ester was determined by gas chromatography to be >98% (from: BGB-Analytik, column type: BGB-174, length: 30 m, internal diameter: 0.25 ml, film thickness: 0.25 μm, carrier gas: helium, inlet pressure: 2.35 bar, temperature: 135° C., heating rate: 1.2° C./min, retention time of R enantiomer: 23.3 min, retention time of S enantiomer: 22.6 min). The s/c ratio was 20 000:1.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1.[CH3:15][CH:16]([NH2:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([NH2:24])[CH3:23].[C:26](=[O:29])([O-])[O-].[K+].[K+]>C(Cl)CCl>[CH3:23][CH:22]([NH:24][C:26](=[O:29])[C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:13])[F:14])=[CH:12][CH:11]=1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]([NH:25][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=1)[CH3:15]
Reactant: O=C([O-])[O-]
Reactant: CC(N)CCCCCC(C)N
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Agent: [K+]
Solvent: ClCCCl
Product: CC(CCCCCC(C)NC(=O)c1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OC(F)(F)F)cc1
Reaction time: 8 h

Procedure:
A solution containing 12.8 g. of 4-trifluoromethoxybenzoyl chloride in 50 ml. of ethylene dichloride was added dropwise with stirring to a mixture of 4.50 g. of 2,8-nonanediamine, 8.42 g. of potassium carbonate and 100 ml. of ethylene dichloride, the latter mixture being at 10° C. The reaction mixture was stirred while allowing its temperature to rise to room temperature (about 25°-30° C.) and was then stored at 5° C. overnight (about sixteen hours). The precipitated white solid was collected, washed well with water and dried to yield 12.2 g. of white needles. The filtrate was separated and the aqueous portion was extracted with one 100 ml. portion of ethylene dichloride. The extract was combined with the ethylene dichloride portion of the filtrate and the combined solution was dried successively over anhydrous sodium sulfate and anhydrous potassium carbonate. Removal of the solvent under reduced pressure left 2.6 g. of a pale yellow oil which completely crystallized on standing at room temperature. The 12.2 and 2.6 g. portions of crystalline product were combined and recrystallized from 95% ethanolbenzene and dried in vacuo at 50° C. for eighteen hours to yield 11.5 g of N,N'-(1,7-dimethylheptamethylene)bis(4-trifluoromethoxybenzamide), m.p. 156°-160° C.
Reaction SMILES: O=S(Cl)Cl.[Br:5][C:6]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[CH3:17]O>O>[Br:5][C:6]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:7]=1[C:8]([O:10][CH3:17])=[O:9]
Reactant: COc1ccc(C(=O)O)c(Br)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(OC)cc1Br
Temperature: 79 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
SOCl2 (7.5 mL, 103.0 mmol) is added dropwise to a stirred 0° C. suspension of 2-bromo-4-methoxybenzoic acid (3) (6.5 g, 28.1 mmol) in methanol (12 mL). The mixture is next stirred at 79° C. for 18 h and then cooled to room temperature before removal of methanol and excess SOCl2 at reduced pressure. The residue is diluted with H2O (50 mL) and extracted with ethyl acetate (100 mL and 70 mL). The extract is washed (2 N NaOH and brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (14.3% to 16.7% ethyl acetate/hexane) to give 5.9 g (85%) of 4 as a colorless liquid. IR 2952, 1728, 1597, 1261 cm−1; 1H NMR (CDCl3) δ 3.83 (s, 3H, CH3O), 3.89 (s, 3H, CO2CH3), 6.86 (dd, J=7.2, 2.0 Hz, 1H, 5-PhH), 7.18 (d, J=2.0 Hz, 1H, 3-PhH), 7.85 ppm (d, J=7.2 Hz, 1H, 6-PhH).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][Br:4].[CH2:5]([P:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])[CH2:6][CH3:7]>C(#N)C>[Br-:4].[CH2:3]([P+:8]([CH2:12][CH2:13][CH3:14])([CH2:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:1]
Reactant: CCCP(CCC)CCC
Reactant: CCCBr
Solvent: CC#N
Product: CCC[P+](CCC)(CCC)CCC
Product: [Br-]
Temperature: 25 °C

Procedure:
In a 250 mL round bottom flask, n-propyl bromide (21.1 g, 171.5 mmol) (available from Sigma-Aldrich Canada) was dissolved in anhydrous acetonitrile (100 mL) under Ar-atmosphere, and tripropylphosphine (25 g, 156.0 mmol) (available from Sigma-Aldrich Canada) was added. The reaction mixture was heated at gentle reflux for 35 hrs. After cooling to room temperature, the solvent was removed under reduced pressure. The solid residue was suspended in toluene (50 mL) and the solvent was removed under reduced pressure. This process was repeated once. The solid residue was suspended in hexane (100 mL), filtered, washed with hexane (3×50 mL), and air-dried. The desired tetra (n-propyl)phosphonium bromide was obtained as colourless crystals (42.5 g, 96%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9](OCC)OCC)=[CH:4][C:3]=1[F:17].C(=O)(O)O.[NH2:22][NH:23][C:24]([NH2:26])=[NH:25].[OH-].[K+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:22]=[N:23][C:24]([NH2:26])=[N:25][CH:9]=2)=[CH:4][C:3]=1[F:17]
Reactant: N=C(N)NN
Reactant: CCOC(OCC)C(=O)c1ccc(Br)c(F)c1
Agent: O=C(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Temperature: 110 °C

Procedure:
A mixture of 1-(4-bromo-3-fluorophenyl)-2,2-diethoxyethanone (Step 4, 15.2 g, 50 mmol), aminoguanidine bicarbonate (10.2 g, 75 mmol) and potassium hydroxide (6.6 g, 100 mmol) in ethanol (200 mL) and water (4 mL) was refluxed overnight. The solvent was evaporated under reduced pressure and the residue was washed with acetonitrile and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), washed with water, brine, and concentrated under reduced pressure. The residue was dissolved in ethanol (50 mL). To the solution was added 0.2N hydrochloric acid (50 mL). The resultant mixture was heated to 110° C. for 8 h, and cooled with an ice-water bath. The precipitate that formed was collected by filtration and washed with isopropanol to give the desired product. (5.5 g, 41%) LCMS: (M+H) 286.8/288.8. 1H-NMR (400 MHz, CDCl3): 8.60 (s, 1H), 7.79 (dd, J=8.6, 2.0 Hz, 1H), 7.68 (dd, J=8.3, 7.0 Hz, 1H), 7.61 (dd, J=8.3, 2.0 Hz, 1H), 5.43 (s, 2H).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[C:17]([CH2:26][CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][C:34]3[S:38][C:37]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=4)=[N:36][CH:35]=3)[CH2:29][CH2:28]2)=[C:16]1[C:45]([O:47][CH3:48])=[O:46])=O)C1C=CC=CC=1.I[Si](C)(C)C>C(#N)C.C(OCC)(=O)C>[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[C:17]([CH2:26][CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][C:34]3[S:38][C:37]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=4)=[N:36][CH:35]=3)[CH2:29][CH2:28]2)=[C:16]1[C:45]([O:47][CH3:48])=[O:46]
Reactant: COC(=O)c1c(CC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)c(=O)c2ccccc2n1CCCNC(=O)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1c(CC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)c(=O)c2ccccc2n1CCCN
Yield: 16.9 %

Procedure:
A solution of the compound prepared in Example 330 (37 mg) in acetonitrile (1 mL) was treated with iodotrimethylsilane (0.015 mL) for 30 minutes at room temperature. The solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the crude material, which was purified by preparative thin layer chromatography (eluant: 20% (9:1 methanol/concentrated ammonium hydroxide)/ethyl acetate) to furnish the title compound (5 mg) with the following physical properties.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][NH2:12])[N:4]=1.[ClH:13].[N:14]#[C:15][NH2:16]>C(O)C>[ClH:13].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][NH:12][C:15]([NH2:16])=[NH:14])[N:4]=1
Reactant: COc1cc(OC)nc(NN)n1
Reactant: N#CN
Agent: Cl
Solvent: CCO
Product: COc1cc(OC)nc(NNC(=N)N)n1
Yield: 92 %

Procedure:
A mixture of 17.0 g (0.1 mol) of 4,6-dimethoxy-2-hydrazino-pyrimidine, 8.3 ml of concentrated hydrochloric acid, 4.2 g (0.1 mol) of cyanamide and 100 ml of ethanol is boiled to reflux for 18 hours. The mixture is then evaporated, the residue is crystallized using diethyl ether, and the crystalline product is isolated by filtering off with suction. 22.9 g (92% of theory) of (4,6-dimethoxy-pyrimidin-2-yl-amino)-guanidine hydrochloride of melting point 214° C. are obtained.