Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[CH:4][CH:3]=1.[NH3:16].CO>C(O)CO.O>[CH3:9][O:8][C:6]1[N:7]=[C:2]([NH2:16])[CH:3]=[CH:4][C:5]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1
Reactant: N
Reactant: COc1nc(Br)ccc1-n1cnc(C)c1
Solvent: CO
Solvent: O
Solvent: OCCO
Product: COc1nc(N)ccc1-n1cnc(C)c1
Temperature: 100 °C
Yield: 100 %

Procedure:
To a mixture of 6-bromo-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine (1.000 g, 3.73 mmol) and cuprous oxide (0.053 g, 0.373 mmol) in 8.3 mL of ethylene glycol was added a 7 N solution of ammonia in methanol (7.99 mL, 55.9 mmol). The reaction mixture was heated in a high-pressure vessel at 100° C. overnight. Upon cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum to give 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine (762.0 mg, 3.73 mmol, 100% yield) as brown semisold. LC-MS (M+H)+=205.10. 1H NMR (500 MHz, CDCl3) δ ppm 7.53 (1H, s), 7.26 (1H, d, J=8.2 Hz), 6.78 (1H, s), 6.07 (1H, d, J=8.2 Hz), 3.86 (3H, s.), 2.25 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:10][C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[C:5]([F:16])=[C:4]([NH:17][NH2:18])[N:3]=1.[CH:19]1([CH2:24][C@H:25]([CH2:29][N:30]([CH:38]=[O:39])[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][NH:18][C:26](=[O:27])[C@H:25]([CH2:24][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:29][N:30]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH:38]=[O:39])[C:5]([F:16])=[C:6]([N:8]([CH2:10][C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[N:7]=1
Reactant: CN(Cc1ccco1)c1nc(Cl)nc(NN)c1F
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN(Cc1ccco1)c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c1F
Reaction time: 8 h
Yield: 77.6 %

Procedure:
2-Chloro-5-fluoro-N-(2-furanylmethyl)-6-hydrazino-N-methyl-4-pyrimidinamine (0.400 g) and (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (0.764 g, 1.770 mmol) were dissolved in DMF. NMM (0.65 mL, 5.912 mmol) was added, followed by HOAt (0.241 g, 1.772 mmol) and EDC (0.3396 g, 1.771 mmol). After stirring overnight, the reaction mixture was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(2-furanylmethyl)(methyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide as an orange solid (0.6318 g). LCMS: (M+H)+=553.2.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:24])[N:6]2[CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][OH:23].[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([OH:36])=[O:35])=[CH:29][CH:28]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.O>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:24])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:25][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][C:34]([OH:36])=[O:35])=[CH:31][CH:32]=1)[CH2:20][CH2:21][CH2:22][OH:23]
Reactant: O=Cc1ccc(CC(=O)O)cc1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCCCO)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(CCCO)Cc3ccc(CC(=O)O)cc3)c2n1
Reaction time: 0.17 h

Procedure:
To 6-amino-2-butoxy-9-{3-[(3-hydroxypropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one (described in WO2007/031726 Example 1 step (viii)) (0.5 g) in NMP, the product from step (i) (0.35 g) was added and the mixture stirred for 10 mins. Sodium triacetoxyborohydride (1.25 g) was then added and stirred at rt for 16 hrs. The reaction mixture was diluted with water and passed through a SCX column, eluted with MeCN/2% NH3 (aq), and solvent removed to give the crude product. The product was purified via RPHPLC to afford the subtitle compound as a solid; 1H NMR DMSO 67.14-7.20 (m, 4H), 6.40 (s, 2H), 4.12 (t, 2H), 3.67 (t, 2H), 3.51 (s, 2H), 3.47 (s, 2H), 3.39 (t, 2H), 2.36-2.44 (m, 4H), 1.78-1.86 (m, 2H), 1.52-1.65 (m, 4H), 1.32-1.41 (m, 2H), 0.90 (t, 3H) MS multimode (+) 487
Reaction SMILES: [Cl:1][CH:2]([CH3:13])[CH2:3][NH:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12].[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.[I-].[K+]>C(OCC)(=O)C>[ClH:1].[CH3:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=1[NH:4][CH2:3][CH:2]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([Cl:14])=[CH:16][CH:17]=1)[CH3:13]
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1cccc(C)c1NCC(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1NCC(C)Nc1ccc(Cl)cc1
Product: Cl
Temperature: 60 °C
Reaction time: 3 h
Yield: 30.1 %

Procedure:
A mixture of 28.2 g (0.143 moles) of N-(β-chloropropyl)-2,6-dimethylaniline, prepared as described in Example 3, Method (b), point (a), 36.4 g (0.285 moles) of 4-chloroaniline and 1.6 g (10 mmoles) of potassium iodide is stirred at 140° to 145° C. for 3 hours under nitrogen atmosphere. The mixture is allowed to cool to about 60° C., and 30 ml of ethyl acetate are added. The mixture is cooled to room temperature, and the separated precipitate is filtered off, washed with ethyl acetate and dried. 14.0 g of 1-(2',6'-dimethyl-phenylamino)-2-(4'-chlorophenyl-amino)-propane hydrochloride (fraction A) are obtained. The filtrate is acidified with isopropanolic hydrochloric acid (acid content: about 15 g/100 ml), the separated precipitate is filtered off, washed with isopropanol and dried. 28.8 g of the same compound (fraction B) are obtained. Fractions A and B are combined, triturated with 100 ml of water, filtered, washed with water, dried, and the resulting solid, weighing 25.7 g, is recrystallized from methanol. 21.4 g (46.0%) of pure 1-(2',6'-dimethylphenylamino)-2-(4'-chlorophenyl-amino)-propane hydrochloride are obtained; m.p.: 170°-176° C. This salt is converted to the free base as described in Example 3, Method (b), point (b), and the base is separated by extracting the reaction mixture with chloroform.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1CCCCC1.[Br:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]([CH2:30]Br)[N:24]=1.Cl.[Cl-].[NH4+]>O1CCCC1>[Br:22][C:23]1[N:24]=[C:25]([CH2:30][C:11]2([C:14]#[N:15])[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: Fc1ccc(CBr)nc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(Cc2ccc(F)c(Br)n2)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
N-Boc-4-cyanopiperidine (5.35 g, 25.4 mmol) was dissolved in 100 mL of tetrahydrofuran. After cooling the resulting mixture to −78° C., a solution of lithium diisopropylamide/tetrahydrofuran complex in cyclohexane (1.5 M, 16.5 mL, 24.8 mmol) was added while keeping the internal temperature at or below −70° C. The resulting reaction mixture was stirred at −78° C. for 20 minutes. To the reaction mixture thus obtained, 10 mL of a solution of 2-bromo-6-(bromomethyl)-3-fluoropyridine in THF (6.28 g, 23.4 mmol) was added while keeping the internal temperature at or below −70° C., followed by stirring at −78° C. for 20 minutes. To this reaction solution, a mixture of hydrochloric acid (5M, 4.95 mL, 24.8 mmol) and 95 mL of a saturated aqueous solution of ammonium chloride was added, followed by stirring at room temperature and then extraction with ethyl acetate. The extract thus obtained was washed with saturated brine and dried over anhydrous sodium sulfate, and then filtered and concentrated. The tarry residue was dissolved in 6 mL of ethyl acetate, and 50 mL of heptane was added dropwise while stirring. Seed crystals were then added, followed by stirring at room temperature for one hour. To the resulting light yellow suspension, 50 mL of heptane was further added dropwise, followed by stirring overnight. The solid thus obtained was collected by filtration and washed with a solution of ethyl acetate in heptane, and then dried under reduced pressure, whereby the titled product was obtained as an off-white solid (7.10 g, 17.8 mmol) (yield 76%). The physical property values are shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:32])([CH3:31])[CH2:9][C:10]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH:11]=[N:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([C:23]([NH2:25])=[O:24])=[N:18]3)=[C:4]([O:33][CH3:34])[CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:31])([CH3:32])[CH2:9][C:10]([OH:30])([C:26]([F:29])([F:27])[F:28])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([C:23]([NH2:25])=[O:24])=[N:18]3)=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(C)(C)CC(O)(C=Nc1cccc2nc(C(N)=O)ccc12)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)ccc1C(C)(C)CC(O)(CNc1cccc2nc(C(N)=O)ccc12)C(F)(F)F

Procedure:
Analogously to Example 40, 340 mg (0.69 mmol) of 5-[4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidenamino]quinoline-2-carboxylic acid amide is dissolved in 10 ml of methanol and mixed several times with 110 mg (2.89 mmol) of sodium borohydride. After working-up and purification on silica gel with hexane-ethyl acetate (0-100%), 280 mg (82% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][N:2]([C:4]1[S:8][N:7]=[C:6]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:5]=1)[NH2:3].[CH:13](=O)[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16]>C(O)C>[CH3:1][N:2]([C:4]1[S:8][N:7]=[C:6]([C:9]([Cl:10])([Cl:12])[Cl:11])[N:5]=1)[N:3]=[CH:13][C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16]
Reactant: CN(N)c1nc(C(Cl)(Cl)Cl)ns1
Reactant: O=Cc1ccccc1O
Solvent: CCO
Product: CN(N=Cc1ccccc1O)c1nc(C(Cl)(Cl)Cl)ns1
Temperature: 37 °C
Yield: 61 %

Procedure:
A mixture of 2.50 g (0.01 mole) 5-(1-methylhydrazino)-3-trichloromethyl-1,2,4-thiadiazole and 1.30 g (0.01 mole) salicylaldehyde was stirred. An exothermic reaction ensued and the reaction mixture warmed to 37° C. After 15 minutes ethanol was added and the solid product extracted. The product crystallized and was filtered to yield 2.15 g (61% yield) [mp. 207°-209° C. (dec)].
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=[O:3])[CH3:2].[C:16]([NH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)(=[O:18])[CH3:17]>N1CCCCC1.C(Cl)(Cl)Cl>[C:16]([NH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH:2][C:1]([CH:4]2[C:9]([OH:10])=[C:8]([C:11](=[O:13])[CH3:12])[C:7](=[O:14])[O:6][C:5]2=[O:15])=[O:3])=[CH:22][CH:21]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(C=CC(=O)C2C(=O)OC(=O)C(C(C)=O)=C2O)cc1

Procedure:
To a mixture of 2.11 g. (0.01 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one and 1.63 g. (0.01 m.) of p-acetamidobenzaldehyde in 200 ml. of chloroform is added with stirring 25 drops of piperidine. The resulting solution is refluxed and azeotroped for 12 hours, filtered hot and the solid is washed with dilute hydrochloric acid, water and ether to give 3-(p-acetamidocinnamoyl)-5-acetyl-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 230°-231° C.
Reaction SMILES: N(C(=O)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5])N.ClC([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=O>N1C=CC=CC=1>[CH2:29]([O:28][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:14][CH2:15][C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:18]2)=[CH:11][CH:12]=1)=[O:5])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Solvent: c1ccncc1
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Intermediate 43 (3.31 g, 13.40 mmol) in dry pyridine (18 mL) under an inert atmosphere at 0° C. was added benzyl chloroformate (2.30 mL, 16.08 mmol) then allowed to warm to ambient temperature and stirred for 18 hours. After concentrating in vacuo the residue was partitioned between Et2O (150 mL) and 1M aqueous HCl (20 mL). The organic phase was dried (MgSO4), filtered and evaporated to a yellow solid. Purification by chromatography through silica gave the title compound (3.50 g, 68%) as an off white solid; 1H NMR (CDCl3) δ1.03-1.12 (2H, m), 1.35-1.46 (2H, m), 1.74-1.82 (5H, m), 2.17-2.18 (2H, m), 2.33-2.39 (1H, m), 3.61 (3H, s), 5.12 (2H, s), 6.50 (1H, s), 7.06 (2H, d), 7.19-7.34 (7H, m)
Reaction SMILES: [NH:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[SH:4](=[O:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:3]1.[C:18](Cl)(=[O:20])[CH3:19].C(N(CC)CC)C.O>O1CCOCC1>[C:18]([N:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[SH:4](=[O:17])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:3]1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: N=C1N[SH](=O)(c2ccccc2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N=C1N[SH](=O)(c2ccccc2)c2ccccc21

Procedure:
1.2 g. 3-imino-1-phenyl-3H-1,2-benzisothiazole-1-oxide are heated under reflux for 15 minutes with 0.4 g. acetyl chloride and 0.7 g. triethylamine in dioxan. Thereafter, the reaction mixture is poured into water and the precipitate obtained is filtered off with suction and recrystallised from ethyl acetate. There is thus obtained 3-(acetylimino)-1-phenyl-3H-1,2-benzisothiazole-1-oxide; m.p . 119°C.
Reaction SMILES: CS[C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH3:18])=[CH:12][N:11]=1>C(#N)C>[Cl:9][C:10]1[N:11]=[CH:12][C:13]([CH2:16][N:17]([CH3:18])[C:3]([NH2:8])=[N:4][N+:5]([O-:7])=[O:6])=[CH:14][CH:15]=1
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: CNCc1ccc(Cl)nc1
Solvent: CC#N
Product: CN(Cc1ccc(Cl)nc1)C(N)=N[N+](=O)[O-]
Yield: 31.2 %

Procedure:
A mixture of 0.676 g of S-methyl-N-nitroisothiourea, 0.783 g of 2-chloro-5-(methylaminomethyl)pyridine and 6 ml of acetonitrile was refluxed for 17 hours, and concentrated. The residue was recrystallized from ethanol to obtain 0.38 g of 1-(6-chloro-3-pyridylmethyl)-1-methyl-2-nitroguanidine (Compound No. 7).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][CH:8]=[C:7]([C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=1)[C:6]2=[O:24])[CH3:2].IC.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:27])[O:9][CH:8]=[C:7]([C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=1)[C:6]2=[O:24])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCc1cc2c(=O)c(-c3ccc4ccccc4c3)coc2cc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCc1cc2c(=O)c(-c3ccc4ccccc4c3)coc2cc1OC
Yield: 95.8 %

Procedure:
6-Ethyl-7-hydroxy-3-naphthalen-2-yl-chromen-4-one (d, 0.36 g) was dissolved in dry dimethyl formamide (DMF) (5 mL) and treated with iodomethane (MeI) (0.5 mL) and potassium carbonate (1 g) at room temperature for 2 h. The mixture was diluted with water (50 mL) and the precipitate was collected by filtration, washed with water and dried under vacuum to give 6-ethyl-7-methoxy-3-naphthalen-2-yl-chromen-4-one (e, 0.36 g).
Reaction SMILES: [NH3:1].[CH2:2]([C:4]1([CH2:14][CH3:15])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]1=[O:13])[CH3:3]>CO.O>[CH2:2]([C:4]([CH2:14][CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[OH:6])[C:5]([NH2:1])=[O:13])[CH3:3]
Reactant: N
Reactant: CCC1(CC)C(=O)Oc2ccccc21
Solvent: CO
Solvent: O
Product: CCC(CC)(C(N)=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7N Ammonia in methanol (10 mL) was added to 3,3-diethyl-2(3H)-benzofuranone (Example 266a, 1.14 g) and the reaction stirred at room temperature for 16 h. 880 Ammonia (20 mL) was added and the mixture stirred for 5 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated to afford crude product (1.21 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[N:11]=[C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[NH:15][C:14]([O:20][C@@H:21]([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])=[N:13]2.Br[CH2:28][CH2:29][CH2:30][CH2:31][Cl:32]>>[Cl:32][CH2:31][CH2:30][CH2:29][CH2:28][N:11]1[C:10]([O:9][CH3:8])=[N:18][C:17]2[C:12]1=[N:13][C:14]([O:20][C@@H:21]([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])=[N:15][C:16]=2[NH2:19]
Reactant: CCCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: ClCCCCBr
Solvent: O=C(O)C(F)(F)F
Product: CCCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1

Procedure:
Prepared similarly to Intermediate 44 from 8-(methyloxy)-2-{[(1S)-1-methylpentyl]oxy}-1H-purin-6-amine trifluoroacetate and 1-bromo-4-chlorobutane.
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:16])(=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1>C1C=CC=CC=1.CCCCC>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:15][C:7](=[NH:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[S:26])=[CH:20][CH:19]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: CCCCCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCCCC
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CCCCCCCC(=N)NC(=S)Nc1ccc(Cl)cc1

Procedure:
Following a procedure similar to that described in Example 1 but using 2 g. sodium in 250 ml. dry acetone, 15.7 g. octanamidine hydrochloride, and 15 g. 4-chlorophenyl isothiocyanate in 70 ml. dry acetone there was obtained 1-(4-chlorophenyl)-3-(octanimidoyl)-2-thiourea, m.p. 98°-99° C. (from benzene-n-pentane); hydrochloride (18.7 g.), m.p. 155°-157° C. (from acetonitrile).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(COc3ccccc3)n[nH]c(=O)c2c1
Product: COc1ccc2c(COc3ccccc3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 7-methoxy-4-phenoxymethyl-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][C:12]([CH3:21])([CH3:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:9][CH:8]=1.Br[CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:31][C:30]=1[CH3:41])=[O:27].C(=O)(O)[O-].[Na+].O>CN(C)C=O>[CH:35]1([C:32]2[CH:33]=[CH:34][C:29]([NH:28][C:26](=[O:27])[CH2:25][N:5]([CH2:6][C:7]3[CH:23]=[CH:22][C:10]([O:11][C:12]([CH3:21])([CH3:20])[C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])=[CH:9][CH:8]=3)[CH2:4][CH2:3][O:2][CH3:1])=[C:30]([CH3:41])[CH:31]=2)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: COCCNCc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1
Reactant: Cc1cc(C2CCCCC2)ccc1NC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCN(CC(=O)Nc1ccc(C2CCCCC2)cc1C)Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
0.303 g (0.94 mmol) of tert-butyl 2-(4-{[(2-methoxyethyl)amino]methyl}phenoxy)-2-methylpropanoate (Example III-33) is initially charged in 5 ml of dimethylformamide. At room temperature, 0.319 g (1.03 mmol) of 2-bromo-N-(4-cyclohexyl-2-methylphenyl)acetamide (Example III-19) and 0.086 g (1.03 mmol) of sodium bicarbonate are added. The mixture is stirred at 90° C. for 2 hours. The reaction mixture is then allowed to cool, and water is added. The mixture is extracted with ethyl acetate and the organic phase is washed with water and saturated sodium chloride solution. The organic phase is dried over sodium sulphate and freed from the solvent under reduced pressure. The residue is purified chromatographically on silica gel (cyclohexane/ethyl acetate 3:1) and the product is dried under reduced pressure. This gives 0.464 g (90% of theory) of the title compound.
Reaction SMILES: C(C1N=C(N2CC[C@H](O)C2)C2C(=NN(CC3C(C)=NON=3)N=2)N=1)(C)(C)C.[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([O:45]C(=O)C(F)(F)F)[CH2:41]2)[C:34]2[N:39]=[N:38][NH:37][C:35]=2[N:36]=1)([CH3:30])([CH3:29])[CH3:28].Cl.Cl[CH2:54][C:55]1[N:59]([CH3:60])[N:58]=[N:57][CH:56]=1>>[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41]2)[C:34]2[C:35](=[N:37][N:38]([CH2:54][C:55]3[N:59]([CH3:60])[N:58]=[N:57][CH:56]=3)[N:39]=2)[N:36]=1)([CH3:28])([CH3:30])[CH3:29]
Reactant: Cn1nncc1CCl
Reactant: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Agent: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Agent: Cl
Product: Cn1nncc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 5-(chloromethyl)-1-methyl-1H-1,2,3-triazole hydrochloride and isolated as light yellow gum. MS (m/e): 358.3 (MH+).
Reaction SMILES: [CH:1]12[C:9](=[C:10]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21]C(C)(C)C)=[O:20])=[CH:13][CH:12]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.C(O)(C(F)(F)F)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[CH:5]12[C:9](=[C:10]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=3)[CH:1]([CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH2:4]2
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2C3CCCC2CCC3)c2ccc(O)cc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccc(C(=C2C3CCCC2CCC3)c2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 74.3 %

Procedure:
To an ice-cooled solution of 44 (0.32 g, 0.755 mmol) in CH2Cl2 (4 mL) was added TFA (4 mL) slowly. The stirred reaction mixture was allowed to warm to RT over a period of 3 h. The reaction mixture was concentrated to give a yellow solid. The solid was dissolved in toluene, and the solution was concentrated to give a powder. The powder was triturated with CH2Cl2 and dried to give compound 45 as a tan powder (0.21 g, 74%). 1H NMR (400 MHz, DMSO-d6): δ 1.50-1.53 (m, 2H), 1.72 (s, 8H), 1.93-2.01 (m, 2H), 2.53-2.60 (m, 2), 6.43 (d, J=16.1 Hz, 1H), 6.66 (d, J=8.4 Hz, 2H), 6.88 (d, J=8.3 Hz, 2H), 7.09 (d, J=7.8 Hz, 2H), 7.52 (d, J=16.0 Hz, 1H), 7.57 (d, J=8.1 Hz, 2H), 9.30 (s, 1H), 12.33 (s, 1H). The compound was silated prior to EI analysis. HRMS (EI) Calcd for C31H42O3Si2: 518.2673 (M+). Found: 518.2685.