Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:8][C:9]1[N:18]=[C:17]([C:19]([N:21]2[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)=[O:20])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:30]3[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=3[CH2:38][OH:39])[CH:15]=2)[N:10]=1.C(OCC)(=O)C.O>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1]([O:39][CH2:38][C:31]1[CH:32]=[C:33]([F:37])[C:34]([F:36])=[CH:35][C:30]=1[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([NH2:8])[N:18]=[C:17]2[C:19]([N:21]1[CH2:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29]1)=[O:20])=[O:6]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CO)ccc2n1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
47 μl of pivaloyl chloride are added to a solution of 200 mg of [2-amino-6-(4,5-difluoro-2-hydroxymethylphenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone and 2 mg of 4-(dimethylamino)pyridine (DMAP) in 4 ml of dimethylformamide, and the mixture is stirred at 80° C. for 16 h. 8 ml of ethyl acetate and 8 ml of water are added, the organic phase is separated off and evaporated to dryness in vacuo. The residue is dissolved in 1 ml of dimethyl sulfoxide and purified by chromatography (reversed phase HPLC).
Reaction SMILES: S=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]#[N:12])[CH:9]=[CH:10][C:4]=2[O:3]1.S(Cl)([Cl:15])=O>CN(C=O)C.C(Cl)Cl>[Cl:15][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc2oc(=S)[nH]c2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc2oc(Cl)nc2c1
Temperature: 67.5 °C
Yield: 65 %

Procedure:
To a mixture of 2-thioxo-2,3-dihydrobenzooxazole-5-carbonitrile (2.56 g, 14.5 mmol) and thionylchloride (14.1 mL) was added two drops of DMF. The mixture was heated at 65-70° C. for 1 h. Then the mixture was cooled to rt and diluted with CH2Cl2. The solvent and excess thionylchloride were removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: 20% EtOAc in Petroleum ether) to give 2-chlorobenzo-oxazole-5-carbonitrile 1.69 g (65%).
Reaction SMILES: O[CH:2]1[C:6]2([CH2:9][N:8](C(OCC3C=CC=CC=3)=O)[CH2:7]2)[CH2:5][O:4][CH2:3]1.[H][H].C[OH:23]>[Pd]>[CH2:9]1[C:6]2([CH2:2][CH2:3][O:4][CH2:5]2)[CH:7]([OH:23])[NH:8]1
Reactant: O=C(OCc1ccccc1)N1CC2(COCC2O)C1
Reactant: [H][H]
Reactant: CO
Agent: [Pd]
Product: OC1NCC12CCOC2
Yield: 98 %

Procedure:
Benzyl 8-hydroxy-6-oxa-2-azaspiro[3.4]octane-2-carboxylate (from step (iv); 456 mg, 1.7 mmol) was dissolved in methanol (20 mL) and 10% palladium on carbon (50 mg) added. This suspension was hydrogenated at 20 psi hydrogen for 2 hrs then filtered. The filtrate was concentrated to give the title compound as a gum (214 mg, 1.66 mmol, 98% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10]C(=O)C(F)(F)F)[CH3:9])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](NC(=O)C(F)(F)F)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](N)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
(R)-N-(1-(4-bromophenyl)ethyl)-2,2,2-trifluoroacetamide (20 g, 68 mmol) was dissolved in methanol (200 mL) and cooled in an ice-water bath. Then aqueous NaOH (2 M, 100 mL) was added to the above mixture. The reaction mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated and then partitioned between CH2Cl2 and water. The aqueous layer was extracted with addition CH2Cl2 and the combined organic phases were dried over Na2SO4, filtered and concentrated to give (R)-1-(4-bromophenyl)ethan amine (9.8 g, 73%). 1H NMR (DMSO): 1.19 (m, 3H), 3.92 (m, 1H), 7.28 (m, 2H), 7.42 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:12][C@H:11]([CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])[C@@H:10]1[O:41][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.O>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:12][C@H:11]([CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])[C@@H:10]1[OH:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O[Si](C)(C)C(C)(C)C)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.1 %

Procedure:
A solution of diethyl (((2S,3R,4S,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)methyl)phosphonate (3.3 g, 4.72 mmol, 1.0 equiv) in DCM (50 mL) was cooled to 0° C., and a mixture of trifluoroacetic acid and water (3.3 mL/0.33 mL) was added. The reaction mixture was then stirred at room temperature for 16 hours. The mixture was then sequentially washed with saturated aqueous sodium bicarbonate solution (120 mL) and water (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The product thus obtained was purified by silica gel chromatography, eluting with 70% EtOAc in petroleum ether to give diethyl (((2S,3R,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-hydroxytetrahydro-2H-pyran-2-yl)methyl)phosphonate as a white solid (2.1 g, 76%). 1H NMR (300 MHz, CDCl3) δ 7.36-7.22 (m, 15H), 4.66-4.56 (m, 3H), 4.52 (s, 2H), 4.41-4.31 (m, 2H), 4.18-4.00 (m, 4H), 3.87-3.70 (m, 4H), 3.67 (td, J=4.1, 1.5 Hz, 1H), 2.24-2.17 (m, 1H), 2.14 (d, J=6.9 Hz, 1H), 1.82-1.67 (m, 2H), 1.34-1.28 (m, 6H). MS (ESI positive ion) m/z: 585.0 (M+1); calc for C32H41O8P 584.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1([C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:16][CH:15]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1.FC(F)(F)C(O)=O>O>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)CC1(c2ccc(NC(c3ccccc3)c3ccccc3)cc2)CCc2ccccc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CC1(c2ccc(N)cc2)CCc2ccccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
[1-(4-(Benzhydryl-amino)-phenyl)-indan-1-yl]-acetic acid methyl ester [(0.15 g, Reference Example 19(b)] was treated with a mixture of trifluoroacetic acid (9 mL) and water (1 mL). The resulting deep red solution was stirred at 50° C., under argon, for 2 hours and then evaporated. The residue was chased with toluene (25 mL) and then placed under vacuum to give the title compound (0.19 g) as a red gum. LC-MS: RT=2.54 minutes, MS(ES+): 282(M+H)+. This material was used immediately for the preparation of Reference Example 9(b).
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([C:7]1[CH:16]=[CH:15][C:10]2[S:11][CH:12]=[C:13]([CH3:14])[C:9]=2[CH:8]=1)=[S:6])[CH3:3].[CH2:17]=O>C(Cl)(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH2:2]([O:4][C:5]([C:7]1[CH:16]=[CH:15][C:10]2[S:11][C:12]([CH2:17][Cl:1])=[C:13]([CH3:14])[C:9]=2[CH:8]=1)=[S:6])[CH3:3]
Reactant: CCOC(=S)c1ccc2scc(C)c2c1
Reactant: C=O
Reactant: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: CCOC(=S)c1ccc2sc(CCl)c(C)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Hydrogen chloride was passed for 2 hours through a stirred mixture of 3-methylthiobenzo[b]thiophene-5-carboxylic acid ethyl ester (1.0 g), paraformaldehyde (0.24 g) and anhydrous zinc chloride (0.2 g) in chloroform (30 ml) at 0° C. The resulting mixture was stirred at room temperature for 18 hours and then washed with water. The organic layer was separated, dried (Na2SO4) and evaporated to give an oil which was chromatographed on silica gel. Elution with toluene gave a solid which was crystallised from petrol (b.p. 60°-80°) to give 2-chloromethyl-3-methylthiobenzo[b]thiophene-5-carboxylic acid ethyl ester (0.42 g), m.p. 95°-96°.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.N1CCCCC1.[CH:15](=O)/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[C:18]1([CH:17]=[CH:16][CH:15]=[C:2]2[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]2=[O:8])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CCCC(=O)C1
Reactant: O=C/C=C/c1ccccc1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1CCCC(=O)C1=CC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 11.2 g (0.1 mol) of 1,3-cyclohexanedione in 110 mL of ethanol was stirred at room temperature while 1 mL of piperidine was added followed by the dropwise addition of 13 mL (0.103 mol) of trans-cinnamaldehyde over a 2 min period. The resulting mixture was stirred at room temperature for 2 hr and then in an ice-bath for 1 hr. The resulting yellow slurry was filtered with suction and the solid dried under high vacuum giving 13.9 g (61.5%) of the title dione. Recrystallization of a sample of this material from ethyl acetate gave yellow solid, mp 115.5°-118° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH3:17])[CH2:10][C:11](N(OC)C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][Mg]Br.C(OCC)C.Cl>C1COCC1>[CH2:1]([O:8][C@@H:9]([CH3:17])[CH2:10][C:11](=[O:12])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)C[C@H](C)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)C[C@H](C)OCc1ccccc1
Reaction time: 3 h
Yield: 27.7 %

Procedure:
Under a nitrogen atmosphere, to a solution of the above (3S)-3-(benzyloxy)-N-methoxy-N-methylbutanamide (196 g) in THF (1.5 L), a 3M methyl magnesium bromide/diethyl ether solution (0.38 mL, 1.1 mol) was gradually added under ice-cooling, and the mixture was stirred at the same temperature for 3 hours. After the reaction, the reaction mixture was poured to 2N hydrochloric acid, and after THF was distilled off under reduced pressure, it was extracted with diethyl ether. After it was successively washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, it was dried with sodium sulfate and the solvent was distilled off under reduced pressure to give a crude product. This was purified by reduced pressure distillation to give a title compound (44 g) as an oil.
Reaction SMILES: [CH2:1]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][C:15]=1[C:16]([OH:18])=O.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH2:7]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:16](=[O:18])[C:15]1[CH:19]=[C:20]([CH:23]=[O:24])[CH:21]=[CH:22][C:14]=1[O:13][CH3:12])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCNCCCCC
Reactant: COc1ccc(C=O)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CCCCCN(CCCCC)C(=O)c1cc(C=O)ccc1OC
Reaction time: 8 h
Yield: 99.8 %

Procedure:
Di-n-pentylamine (873 mg, 5.55 mmol, 2 eq) was added to a solution of 2-methoxy-5-formylbenzoic acid (500 mg, 2.78 mmol, 1 eq), 1-hydroxy-7-azabenzotriazole (755 mg, 5.55 mmol, 2 eq), and N-methylmorpholine (0.83 mL, 7.58 mmol, 2.73 eq) in N,N-dimethylformamide (10 mL). To this was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.06 g, 5.55 mmol, 2 eq) and the reaction mixture stirred overnight. The reaction mixture was diluted with ethyl acetate (20 mL) and washed sequentially with 10% HCl (3×20 mL), brine (20 mL), saturated aqueous sodium bicarbonate (2×20 mL) and brine (20 mL). The organic solution was dried over sodium sulfate and evaporated in vacuo to give the product as a pale brown oil (886 mg, 99%). 1H NMR (CDCl3) δ9.83 (s, 1H, O═C—H), 3.85 (s, 3H, OCH3), 3.52 (m, 1H, NCH2), 3.38 (m, 1H, NCH2), 2.98 (m, 2H, NCH2).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:22]([OH:24])=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.[N+:33](=[CH2:35])=[N-:34]>>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:22](=[O:24])[CH:35]=[N+:33]=[N-:34])=[CH:19][CH:18]=1
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Reactant: C=[N+]=[N-]
Agent: CC(C)COC(=O)Cl
Product: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)C=[N+]=[N-])cc1

Procedure:
In a manner analogous to that described in Example 19(i), 3.10 g of N-(benzyloxycarbonyl)-3-(4-methoxyphenyl)-L-alanine were treated with isobutyl chloroformate followed by diazomethane to give 2.83 g of benzyl [2-(4-methoxyphenyl)-1(S)-(2-diazoacetyl)ethyl]carbamate as a pale yellow solid of melting point 88°-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=O)[CH2:7][CH2:8][C:9]=2[CH:10]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:27])=[C:17]([C@@:19]2([CH3:26])[NH:24][C:23](=[O:25])[CH2:22][O:21][CH2:20]2)[CH:18]=1.[B][B][B][B][B][B][B][B][B][B].C(=O)([O-])O.[Na+]>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([F:27])=[C:17]([C@@:19]4([CH3:26])[NH:24][C:23](=[O:25])[CH2:22][O:21][CH2:20]4)[CH:18]=3)[CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: O=C1CCc2cc(Cl)cnc21
Reactant: C[C@@]1(c2cc(N)ccc2F)COCC(=O)N1
Agent: O=C([O-])O
Agent: [B][B][B][B][B][B][B][B][B][B]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: C[C@@]1(c2cc(NC3CCc4cc(Cl)cnc43)ccc2F)COCC(=O)N1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 3-chloro-5,6-dihydro-[1]pyrindin-7-one (34.5 mg, 0.21 mmol) and (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholin-3-one (50.1 mg, 0.22 mmol) in a mixture of methanol (7.3 ml) and dichloromethane (0.9 ml) was treated with decaborane (6.9 mg, 0.21 mmol). The reaction mixture was stirred at room temperature for 22 hours. For the workup, the mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate, thereafter extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate, then evaporated at reduced pressure. The crude material was purified by flash chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 20:80 as the eluent. The (R)-5-[5-((RS)-3-chloro-6,7-dihydro-5H-[1]pyrindin-7-ylamino)-2-fluoro-phenyl]-5-methyl-morpholin-3-one was obtained as an orange solid (50 mg, 71%); (calculated) C19H19ClFN3O2 [375.83]; (found) [M]+=376, [M+2]+=378.
Reaction SMILES: C[N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.P(Cl)(Cl)(Cl)=O.[N+:13]([C:16]1[O:20][C:19]([C:21]2[N:26]=[C:25]([NH:27][NH2:28])[CH:24]=[CH:23][N:22]=2)=[CH:18][CH:17]=1)([O-:15])=[O:14].O1CCOC[CH2:30]1>>[CH3:30][N:28]([N:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1)[NH:27][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([C:19]2[O:20][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)[N:26]=1
Reactant: C1COCCO1
Reactant: CN1CCCC1=O
Reactant: NNc1ccnc(-c2ccc([N+](=O)[O-])o2)n1
Solvent: O=P(Cl)(Cl)Cl
Product: CN(Nc1ccnc(-c2ccc([N+](=O)[O-])o2)n1)N1CCCC1
Reaction time: 1 h

Procedure:
2.08 ml. 1-methyl-2-pyrrolidone were dissolved in 8.6 ml. anhydrous dioxan, 1.92 ml. phosphorus oxychloride were added dropwise and the mixture was stirred for 1 hour at 25° - 30°C. 2.2 g. 2-(5-nitro-2-furyl)-4-hydrazino-pyrimidine were then added, a further 6.2 ml. anhydrous dioxan were added and the reaction mixture stirred for 1.5 hours at 30° - 35°C. The reaction mixture was then poured on to ice, filtered with activated charcoal and neutralized with a dilute aqueous solution of ammonia. There were thus obtained 2.6 g. (87% of theory) of a red-brown product, which was recrystallized from dioxan. There was thus obtained 1-methyl-2-[2-(5-nitro-2-furyl)-4-pyrimidinyl]-hydrazino-pyrrolidine, which melted at 175° - 177°C. The spectral and elementary analysis confirmed the structure.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C=O.[C:21](O)(=O)C>CO>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH2:21][NH:1][C:2]2[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=2)=[CH:14][CH:13]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: COc1cc(C)nc(N)n1
Reactant: CC(=O)O
Agent: C=O
Solvent: CO
Product: COc1cc(C)nc(NCSc2ccc(Cl)cc2)n1

Procedure:
A mixture of 13.99 g of 2-amino-4-methoxy-6-methylpyrimidine (0.1 mole), 14.8 g of 4-chlorothiophenol (0.1 mole), 9.4 g of aqueous 35% formaldehyde (0.11 mole) and 1 g of acetic acid are heated under reflux for 1 hour in 100 ml of methanol. The resultant solution is clarified by filtration, diluted with 150 ml of toluene and then the solvent is removed in a rotary evaporator. The residue crystallises after standing for some time. The melting point is 78°-82° after recrystallisation from hexane. The yield is 24 g (81% of theory).
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH3:11])[CH2:4][CH2:5][S:6][CH2:7][CH2:8][OH:9])[CH3:2].C[Si]([N-:16][Si](C)(C)C)(C)C.[Li+].[Cl:22][CH2:23][CH2:24][N:25]([CH2:30][CH2:31][Cl:32])[P:26](Cl)(Cl)=[O:27]>O1CCCC1>[Cl:22][CH2:23][CH2:24][N:25]([CH2:30][CH2:31][Cl:32])[P:26]([NH2:16])(=[O:27])[O:9][CH2:8][CH2:7][S:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:10][CH3:11]
Reactant: CCN(CC)CCSCCO
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=P(Cl)(Cl)N(CCCl)CCCl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)CCSCCOP(N)(=O)N(CCCl)CCCl
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-[2-(diethylamino)ethylthio]ethanol (420 mg, 2.4 mmol) in tetrahydrofuran, cooled to −78° C., was added with stirring lithium bis(trimethylsilyl)amide (1.0M in tert-butyl methyl ether, 2.62 mL, 2.62 mmol), followed by a solution of N,N-bis(2-chloroethyl)phosphoramidic dichloride (680 mg, 2.62 mmol) in tetrahydrofuran (10 mL). The orange reaction mixture was stirred at −78° C. for 90 minutes, then allowed to warm to −20° C. and ammonia gas bubbled through it for 10 minutes. The reaction mixture was stirred for an additional 10 minutes, then poured into a separatory funnel containing water (200 mL) and dichloromethane (200 mL). The organic and aqueous layers were separated, and the aqueous layer washed with dichloromethane (3×200 mL). The organic layer and washings were combined, dried over magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a yellow oil. The oil was purified by chromatography on a 25 g silica column, eluting with 90% chloroform/10% (5% ammonium hydroxide in methanol), to give 2-{[2-(diethylamino)ethyl]thio}ethyl N,N-bis(2-chloroethyl)phosphorodiamidate as a clear oil, 97% pure by HPLC. MS (ES): m/z=380 [C12H28Cl2N3O2PS+H+].
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[H][H].[F:16][C:17]1[CH:35]=[CH:34][C:20]([CH2:21][N:22]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:25](=O)[O:24]C2=O)=[CH:19][CH:18]=1.Cl>CC(N(C)C)=O>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[N:22]([CH2:21][C:20]2[CH:19]=[CH:18][C:17]([F:16])=[CH:35][CH:34]=2)[C:27]2[C:26]([C:25]=1[OH:24])=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:4])[CH3:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=c1oc(=O)n(Cc2ccc(F)cc2)c2ccccc12
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(O)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Temperature: 90 °C
Yield: 76.8 %

Procedure:
A solution of diethyl malonate (8.0 g, 51 mmol) was added slowly to a suspension of sodium hydride (60% in mineral oil, 2.21 g, 55 mmol) in dimethylacetamide under N2 atmosphere. The mixture was stirred at room temperature until the evolution of hydrogen gas ceased, then heated to 90° C. for 30 min. and cooled to room temperature. A solution of Compound 5 (15 g, 53 mmol) in dimethylacetamide was added slowly to the mixture, which was heated overnight at 120° C. The mixture was cooled to room temperature, poured into ice water, and acidified by cold 10% HCl. The solids formed were filtered and washed several times by water to yield 13.37 g (78%) of white solids. M.P. 116-120° C. 1H NMR (DMSO-d6): δ 1.31 (t, J=7.0 Hz, 3H), 4.36 (q, J=7.0 Hz, 2H), 5.43 (s, 2H), 7.13 (m, 2H), 7.23-7.30 (m, 3H), 7.37 (d, J=8.5 Hz, 1H), 7.63 (t, J=7.0 Hz, 1H), 8.08 (d, J=7.6 Hz, 1H), 13.20 (s, 1H). EIMS m/z 342 (M+1), 364 (M+23). Anal. (C19H16FNO4) C, H, N.
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])([O-:5])=[O:4]>C(O)C>[N+:3]([C:6]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:7]=1[CH2:8][OH:9])([O-:5])=[O:4]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(CO)c([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 57.9 %

Procedure:
Sodium borohydride (0.2 g, 10 mmol) in ethanol (40 ml) was added dropwise to 2,4-dinitrobenzaldehyde (1.96 g, 10 mmol) in ethanol (40 ml) and stirred for 1 h. The reaction mixture was then evaporated in vacuo, partitioned between ether and aqueous sodium bicarbonate, the ether layer dried (magnesium sulphate) and evaporated in vacuo to yield 2,4-dinitrobenzyl alcohol as a brown solid (1.147 g, 58%), m.p. 105°-110° C.;
Reaction SMILES: [CH2:1]([N:3]([CH:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[C:29]3[C:28]4[C@@H:27]([CH2:30][CH2:31][OH:32])[CH2:26][CH2:25][C:24]=4[S:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH2:13][CH2:12]1)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:45][Cr](O[Cr]([O-])(=O)=O)(=O)=O>CN(C=O)C.O>[C:6]([O:5][C:4]([N:3]([CH2:1][CH3:2])[CH:11]1[CH2:12][CH2:13][CH:14]([O:17][C:18]2[C:29]3[C:28]4[C@@H:27]([CH2:30][C:31]([OH:45])=[O:32])[CH2:26][CH2:25][C:24]=4[S:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH2:15][CH2:16]1)=[O:10])([CH3:8])([CH3:7])[CH3:9]
Reactant: CCN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO)CC4)CC1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(=O)O)CC4)CC1
Yield: 67.2 %

Procedure:
A solution of tert-butyl N-ethyl-N-(4-[[(3R)-3-(2-hydroxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)carbamate (450 mg, 0.97 mmol, 1.00 equiv) and PDC (1791 mg, 4.76 mmol, 4.88 equiv) in 5 mL of DMF was stirred for 14 hrs at 25° C. After completion, the resulting solution was diluted with water and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with 3×20 mL of brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1) to give 310 mg (67%) of 2-[(3R)-12-[(4-[[(tert-butoxy)carbonyl](ethyl)amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetic acid as a colorless oil. MS (ES): m/z 476 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](OCC)[CH2:9][N:8]=[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:6]=2[CH:23]=1.CO.O.[NH2:27][NH2:28]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:27][NH2:28])[CH2:9][N:8]=[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:6]=2[CH:23]=1
Reactant: CCOC1=Nc2ccc(Cl)cc2C(c2ccc(OC)cc2)=NC1
Reactant: NN
Solvent: O
Solvent: CO
Product: COc1ccc(C2=NCC(NN)=Nc3ccc(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 0.11 part of 7-chloro-2-ethoxy-5-(4-methoxyphenyl)-3H-1,4-benzodiazepine in 5 parts by volume of methanol is added 0.2 part by volume of hydrazine hydrate (100%). The mixture is stirred at room temperature for 1.5 hours, and poured into 20 parts by volume of water. The mixture is extracted with chloroform. Chloroform layer is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off. Treatment of the residue with benzene gives 7-chloro-2-hydrazino-5-(4-methoxyphenyl)-3H-1,4-benzodiazepine as crystals melting at 213°-215° C.