Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH3:4])=[C:2]=[O:3].[NH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:19]([CH2:20][C:21]3[O:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:10][CH2:9]1>O1CCCC1>[CH3:4][NH:1][C:2]([NH:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:19]([CH2:20][C:21]3[O:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:3]
Reactant: Cc1ccc(Cn2c(NC3CCN(CCN)CC3)nc3ccccc32)o1
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(C)o2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.1 %

Procedure:
A mixture of 0.7 parts of isocyanatomethane, 2.5 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(5-methyl-2-furanyl)methyl]-1H-benzimidazol-2-amine and 135 parts of tetrahydrofuran was stirred for 3 hours at room temperature. The precipitated product was filtered off and dried, yielding 1.2 parts (41.1%) of N-methyl-N'-[2-[4-[[1-[(5-methyl-2-furanyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]urea; mp. 200.1° C. (compound 40).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[Cl:32][C:33]1[C:34]([S:39]([NH2:42])(=[O:41])=[O:40])=[N:35][CH:36]=[CH:37][CH:38]=1>>[Cl:32][C:33]1[C:34]([S:39]([NH:42][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([N:4]3[C:5]([CH3:13])=[C:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:2]([CH3:1])=[N:3]3)=[CH:15][CH:16]=2)=[O:31])(=[O:40])=[O:41])=[N:35][CH:36]=[CH:37][CH:38]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: NS(=O)(=O)c1ncccc1Cl
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ncccc3Cl)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 3-chloro-2-pyridinesulfonamide (U.S. Pat. No. 4,490,380): 1H-NMR (DMSO-d6) δ 8.62 (1H, d, J=4.3 Hz), 8.20 (1H, d, J=7.9 Hz), 7.71-7.67 (1H, m), 7.49-7.31 (9H, m), 6.57 (1H, br.s), 3.37-3.28 (2H, m), 2.79-2.74 (2H, m), 2.27 (3H, s), 2.23 (3H, s).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:31][S:32]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[CH3:25])[C@@H:13]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:12]1)=O)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[Cl:66]CCl>>[ClH:66].[ClH:66].[NH2:8][C@@H:9]([CH2:31][SH:32])[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[CH3:25])[C@@H:13]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:12]1
Reactant: ClCCl
Reactant: CCCC[C@H]1CN(C[C@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)OC(C)(C)C)CCN1C(=O)c1cccc(C)c1C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCC[C@H]1CN(C[C@@H](N)CS)CCN1C(=O)c1cccc(C)c1C
Product: Cl

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step E except using 4-[2(R)-tert-butoxycarbonylamino-3-triphenylmethylthiopropyl]-2-(S)n-butyl-1-(2,3-dimethylbenzoyl)piperazine (1.28 g, 1.81 mmol), triethylsilane (1.16 mL, 7.24 mmol), and trifluoroacetic acid (8 mL) in dichloromethane (16 mL). The crude product was purified by preparative HPLC (gradient: 100% Solvent A to 50% Solvent A/50% Solvent B). After ion exchange and lyophilization, the title compound was obtained as a white powder (0.127 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([NH:20][C@H:21]([C:26](O)=O)[C:22]([OH:25])([CH3:24])[CH3:23])(OC(C)(C)C)=O.C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>O1CCOCC1.CCOC(C)=O>[NH2:20][C@H:21]([C:26]1[NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]=2[N:12]=1)[C:22]([CH3:24])([OH:25])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)O
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc2[nH]c([C@@H](N)C(C)(C)O)nc2c1
Reaction time: 0.5 h
Yield: 1.6 %

Procedure:
A solution of 4-tert-butyl-1,2-diaminobenzene (1 g, 6 mmol), N-boc-3-hydroxy-L-valine (1.4 g, 6 mmol) and triethylamine (1.5 mL, 15.1 mmol) in dioxane (50 mL) was stirred at 0° C. for 15 minutes. T3P (50% w/w in EtOAc, 4.6 mL, 7.3 mmol) was added dropwise and the reaction continued stirring at this temperature for 30 minutes. The reaction was then heated to reflux for 5 hours before cooling and diluting with EtOAc. The solution was washed with saturated aqueous sodium carbonate solution twice, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-50% EtOAc in heptanes. The residue was dissolved in dioxane (10 mL) at 0° C. and treated with 4M HCl in dioxane (10 mL). The reaction was stirred at room temperature for 2 hours before concentrating in vacuo. The residue was washed with EtOAc and pentane before basifying with saturated aqueous NaOH solution and extracting into EtOAc. The organic layer was collected, dried over Na2SO4, concentrated in vacuo and triturated with 10% EtOH in pentane (5 mL) to afford the title compound (25 mg, 2%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10](=[O:18])[C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=[N:6][CH:7]=1.[CH3:19]I.[H-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH3:19])[C:10](=[O:18])[C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CI
Reactant: O=C(NCc1cncc(Br)c1)c1ncccc1Cl
Agent: [H-]
Agent: [Na+]
Product: CN(Cc1cncc(Br)c1)C(=O)c1ncccc1Cl

Procedure:
In analogy to the procedure described for the preparation of intermediate A-41, N-((5-bromopyridin-3-yl)methyl)-3-chloropicolinamide (intermediate A-56) was reacted with MeI in presence of NaH (60% in mineral oil) to give the title compound as a dark brown oil. MS: 340.2 and 342.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:23]([O-:25])=[O:24])=[C:9]([CH:22]=1)[O:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[O:13][CH2:14][C:15](Cl)=[O:16].N.C(O)C.C[N:36](C)C=O>O>[Cl:1][C:2]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:23]([O-:25])=[O:24])=[C:9]([CH:22]=1)[O:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[O:13][CH2:14][C:15]([NH2:36])=[O:16]
Reactant: O=C(Cl)COc1ccccc1Oc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: N
Solvent: CCO
Solvent: O
Product: NC(=O)COc1ccccc1Oc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A mixture of {o-[5-(2,4-dichlorophenoxy)-2nitrophenoxy]phenoxy}acetyl chloride (1.11 g, 2.38 mmol), ammonia solution (5 mL of a 35% solution), ethanol (5 mL) and N,N-dimethylformamide (10 mL) is stirred for one hour, poured into water and extracted with an ether/ethyl acetate (1:1) solution. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as a yellow oil (1.0 g) which is identified by NMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:19])[CH:3]=1.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2[CH2:26][CH2:27][CH2:28][CH2:29][C:21]1=2.C(O)(=O)C>O>[Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([N:6]2[C:23](=[O:24])[C:22]3[CH2:26][CH2:27][CH2:28][CH2:29][C:21]=3[C:20]2=[O:25])=[C:4]([F:19])[CH:3]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: CCCCCOC(=O)COc1cc(N)c(F)cc1Cl
Solvent: O
Solvent: CC(=O)O
Product: CCCCCOC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 89.4 %

Procedure:
A mixture of the compound (II) (12.0 g), 3,4,5,6-tetrahydrophthalic anhydride (7.56 g) and acetic acid (50 g) was heated at 90° to 95° C. for 7 hours. The reaction mixture was cooled to room temperature, and water (75 g) was added thereto. The precipitated crystals were collected by filtration to give the compound (I) (15.7 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18]([OH:20])=[O:19])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: Nc1ccccc1C(=O)O
Product: O=C(O)c1ccccc1N1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 14.8 %

Procedure:
4-nitrophthalic anhydride (0.5 g, 0.0026 mol) and o-aminobenzoic acid (0.36 g, 0.0026 mol) were refluxed as above for four days. The clear solution was purified as per 120 with an additional final crystallisation from acetone/H2O to yield 0.12 g (15%) 147 as a very pale dull yellow powder: mp=242–243° C.; Rf 0.80 (A): Rf 0.88 (C): Rf 0.49 (D): IR (cm−1): 2725–3100 (OH), 3071 (C═CH), 2646 (C—H), 1786 (C═O), 1730 (C═O), 1693 (C═O), 1620 (C═C), 1601 (C═C), 1538 (N═O), 1491 (C═C), 1452 (C═C), 1383 (C—O), 1345 (N═O), 1123 (C—O), 723 (C═CH); MS m/z (rel intensity) 311 (33), 267 (76), 241 (54), 136 (100).
Reaction SMILES: Br[C:2]1[C:3]2[C:4](Cl)=[C:5]3[N:14]([CH3:15])[N:13]=[CH:12][C:6]3=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1.C[O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)(O)[O-:29].[Na+].COCCOC>C(OCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:3]3[C:4](=[O:29])[C:5]4[N:14]([CH3:15])[N:13]=[CH:12][C:6]=4[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C([O-])O
Reactant: Cn1ncc2nc3cccc(Br)c3c(Cl)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: Cn1ncc2[nH]c3cccc(-c4ccc(O)cc4)c3c(=O)c21
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixture of 8-bromo-9-chloro-1-methyl-1H-pyrazolo[4,3-b]quinoline (EXAMPLE 38, step 1, 100 mg, 0.337 mmol), 4-methoxyphenylboronic acid (56 mg, 0.371 mmol) and dichlorobis(triphenylphosphine)palladium (II) (24 mg, 0.034 mmol) in a mixture of saturated aqueous sodium bicarbonate (0.5 ml) and 1,2-dimethoxyethane (2.5 ml) was refluxed for 5 h. After cooling to room temperature, the mixture was diluted with diethyl ether (100 ml), washed with saturated aqueous sodium bicarbonate (30 ml) and dried over magnesium sulfate. Removal of solvent gave a solid, which was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (1:5) to afford 65 mg (60%) of the title compound as a yellow solid.
Reaction SMILES: [CH:1]1([NH:6][CH:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[NH2:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:13]1([C:16]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:17]=2[C:18](O)=[O:19])[CH2:15][CH2:14]1>>[CH:1]1([NH:6][CH:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[NH:12][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:23]([C:25]([F:26])([F:27])[F:28])=[CH:24][C:16]=2[CH:13]2[CH2:14][CH2:15]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C1CC1
Reactant: NC1CCCC1NC1CCCC1
Product: O=C(NC1CCCC1NC1CCCC1)c1ccc(C(F)(F)F)cc1C1CC1

Procedure:
The title compound, brown oil, MS: m/e=381.4 [(M+H)+], was prepared in accordance with the general method of example 5 from (1RS,2SR)—N-cyclopentyl-cyclopentane-1,2-diamine (intermediate AE) and 2-cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate K).
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C@@H:9]([CH3:10])[CH2:8][CH2:7][C@H:6]1[C:11]([NH2:13])=O)=[O:4].N1C=CN=C1.O=P(Cl)(Cl)Cl.[NH4+].[Cl-]>N1C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:5]1[C@@H:9]([CH3:10])[CH2:8][CH2:7][C@H:6]1[C:11]#[N:13])=[O:4]
Reactant: C[C@H]1CC[C@@H](C(N)=O)N1C(=O)CCl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Temperature: -35 °C
Reaction time: 1 h

Procedure:
(2S,5S)-1-(2-Chloro-acetyl)-5-methyl-pyrrolidine-2-carboxylic acid amide (0.25 g, 1.2 mmol) and imidazole (85 mg, 1.25 mmol) ware mixed in pyridine (5 mL). The mixture was cooled to −35° C. and POCl3 (0.18 mL, 1.8 mmol) was added slowly. The mixture was stirred at −35° C. for 1 h. Saturated NH4Cl (20 mL) was added, and the mixture was extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The oil was purified by flash chromatography (hexane:EtOAc, 2:1) to yield the title compound. MS (DCI) m/z 187 (M+H)+.
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].C1(C)C=CC(S(O[CH2:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:28][CH2:27]2)(=O)=O)=CC=1>C(O)C.O>[CH2:35]([O:34][C:32]([N:29]1[CH2:30][CH2:31][CH:26]([CH2:25][CH2:24][CH2:23][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:27][CH2:28]1)=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)OCC

Procedure:
To a solution of sodium (5.8 g) in ethanol (300 ml) are added diethyl malonate (40 g) and 3-(1-benzyloxycarbonyl-4-piperidyl)propyl p-toluenesulfonate (90.5 g). The resulting mixture is refluxed for 2 hours with stirring, cooled, diluted with water (1 l) and extracted with ethyl acetate (500 ml). The extract is dried over magnesium sulfate and evaporated in vacuo to give ethyl 5-(1-benzyloxycarbonyl-4-piperidyl)-2-ethoxycarbonylvalerate as an oil. To the stirred solution of this oil in ethanol (200 ml) is added dropwise a solution of sodium hydroxide (34 g) in water (200 ml). After the addition is complete, the mixture is diluted with water (300 ml) and extracted with a mixture of ether and petroleum ether (1:1, 300 ml). The aqueous layer is acidified with concentrated hydrochloric acid and extracted with ethyl acetate (500 ml). The extract is washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo to yield 5-(1-benzyloxycarbonyl-4-piperidyl)-2-carboxyvaleric acid as an oil. This oil is heated at 160°-170° C. for 45 minutes with stirring to give 5-(1-benzyloxycarbonyl-4-piperidyl)valeric acid (50 g) as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[C:13]2[C:4]=1[N:5]=[C:6]1[C:11](=[N:12]2)[C:10]([O:21][CH2:22][O:23][CH3:24])=[CH:9][CH:8]=[CH:7]1.C(N(CC)CC)C.[Cr](Cl)([O-])(=O)=[O:33].[NH+]1C=CC=CC=1>CS(C)=O.ClCCl.F[B-](F)(F)F.[Ag+]>[CH:2]([C:3]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[C:13]2[C:4]=1[N:5]=[C:6]1[C:11](=[N:12]2)[C:10]([O:21][CH2:22][O:23][CH3:24])=[CH:9][CH:8]=[CH:7]1)=[O:33]
Reactant: COCOc1cc(CBr)c2nc3cccc(OCOC)c3nc2c1
Reactant: O=[Cr](=O)([O-])Cl
Agent: [Ag+]
Agent: F[B-](F)(F)F
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COCOc1cc(C=O)c2nc3cccc(OCOC)c3nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 205 %

Procedure:
To a solution of silver fluoroborate (359 mg, 1.86 mM) in anhydrous dimethylsulfoxide (15 ml) was added 6-bromomethyl-1,8-di(methoxymethoxy)phenazine (600 mg, 1.53 mM) and the resulting suspension was stirred overnight at room temperature under an argon atmosphere. It was then treated with triethylamine (0.5 ml) and the stirring continued for 30 more minutes. The reaction was diluted with dichloromethane and filtered through Celite. The filtrate was thoroughly washed with water, brine and dried over anhydrous magnesium sulfate. Evaporation under reduced pressure provided yellow solid which was taken up in dry dichloromethane (5 ml) and added to a solution of pyridinium chlorochromate (130 mg, 0.6 mM) in the same solvent (2 ml). After stirring for 3 hours, the reaction was worked up in a standard fashion (ether quench) to give orange solid. Purification by flash chromatography on silica gel (Whatman LPS-1) using chloroform as eluent gave the title compound (406 mg) as yellow needles, melting point 148°-150° C. from chloroform-ether.
Reaction SMILES: C1(C2ON=C([C:9]3[N:13]4[C:14]5[C:19]([C:20](=[O:25])[N:21]([CH:22]6[CH2:24]C6)[C:12]4=[CH:11][N:10]=3)=[C:18](Cl)[CH:17]=[CH:16][CH:15]=5)N=2)CC1.C1([N:30]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34]C=CC=3Cl)[NH:32][C:31]2=O)CC1.C1(C2ON=C(C[N+]#[C-])N=2)CC1>>[CH:38]1([C:39]2[O:40][N:32]=[C:31]([C:11]3[N:10]=[CH:9][N:13]4[C:14]5[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=5)[C:20](=[O:25])[N:21]([CH2:22][CH3:24])[C:12]=34)[N:30]=2)[CH2:33][CH2:34]1
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)n1C1CC1
Reactant: O=c1c2c(Cl)cccc2n2c(-c3noc(C4CC4)n3)ncc2n1C1CC1
Agent: [C-]#[N+]Cc1noc(C2CC2)n1
Product: CCn1c(=O)c2ccccc2n2cnc(-c3noc(C4CC4)n3)c12

Procedure:
3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl-4,5-dihydro-4-cyclopropyl-5-oxo-6-chloro-imidazo(1,5-a)quinazoline. M.p. 232°-235° C. by reaction between 3-cyclopropyl-5-chloro-1,2,3,4-tetrahydro-2,4-dioxo-quinazoline and 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[C:4]([C:6]1[S:10][C:9]2[C:11]([N+:23]([O-:25])=[O:24])=[C:12]([O:19]C(=O)C)[C:13]([O:15]C(=O)C)=[CH:14][C:8]=2[C:7]=1[Cl:26])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH2:27]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[S:10][C:9]2[C:11]([N+:23]([O-:25])=[O:24])=[C:12]([OH:19])[C:13]([OH:15])=[CH:14][C:8]=2[C:7]=1[Cl:26])=[O:5])[CH3:28]
Reactant: CCN(CC)C(=O)c1sc2c([N+](=O)[O-])c(OC(C)=O)c(OC(C)=O)cc2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCN(CC)C(=O)c1sc2c([N+](=O)[O-])c(O)c(O)cc2c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5,6-Diacetoxy-3-chloro-7-nitro-benzo[b]thiophene-2-carboxylic acid diethylamide (0.32 g) was dissolved in methanol (16 ml) and a solution of potassium carbonate (0.61 g) in water (3 ml) was added to the reaction solution. It was stirred at room temperature for one hour. Methanol was evaporated and the residue was kept in cool and filtered. The solid was washed with water and recrystallized from methanol.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.N1CCCCC1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:21]=[C:22]([C:29]3[CH:30]=[C:31]4[C:36](=[CH:37][CH:38]=3)[CH:35]=[C:34](C=O)[CH:33]=[CH:32]4)[CH:23]=[C:24]3[O:28][CH2:27][O:26][C:25]=23)[CH:15]=1.[S:41]1[CH2:45][C:44](=[O:46])[NH:43][C:42]1=[O:47]>C(O)(=O)C>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:21]=[C:22]([C:29]3[CH:30]=[C:31]4[C:32](=[CH:37][CH:38]=3)[CH:33]=[C:34]([N:43]3[C:44](=[O:46])[C:45](=[CH2:1])[S:41][C:42]3=[O:47])[CH:35]=[CH:36]4)[CH:23]=[C:24]3[O:28][CH2:27][O:26][C:25]=23)[CH:15]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc2cc(-c3cc4c(c(-c5cccnc5)c3)OCO4)ccc2c1
Reactant: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: C=C1SC(=O)N(c2ccc3cc(-c4cc5c(c(-c6cccnc6)c4)OCO5)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of toluene (8 mL), piperidine (0.008 mL), acetic acid (0.009 mL) and 6-[3-(3-pyridyl)-4,5-methylenedioxyphenyl]-2-naphthaldehyde (0.304 g, 0.86 mmol) and 2,4-thiazolidinedione (101 mg, 0.86 mmol) was heated at reflux for 16 hours under an argon atmosphere. The resulting suspension was filtered and the solid was stirred at room temperature in EtOH. After 1 hours, the solid was filtered and dried under high vacuum to afford 78.0 mg of 6-[3-(3-pyridyl)-4,5-methylenedioxyphenyl]-naphthalen-2-yl-methylene-2,4-thiazolidinedione, mp 298–300° C. 1H NMR (300 MHz, DMSO-d6): δ 6.16 (s, 2H), 7.10–7.28 (m, 4H), 7.51 (dt, J1=8.0 Hz, J2=1.5 Hz, 1H), 7.66 (dd, J1=8.4 Hz, J2=1.8 Hz, 1H), 7.75–7.85 (m, 2H), 7.90 (s, 1H), 7.93 (d, J=8.7 Hz, 1H), 8.11 (s, 1H), 8.25 (d, J=1.5 Hz, 1H), 8.34 (dd, J1=4.8 Hz, J2=1.4 Hz, 1H), 12.69 (brs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([NH2:16])[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.CCN(CC)CC.[O:25](C(OC(C)(C)C)=O)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C@@:4]([NH2:16])([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:25])[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COC(=O)[C@@H](N)CSCc1ccc(OC)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@](N)(CSCc1ccc(OC)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-2-amino-3-(4-methoxy-benzylsulfanyl)-propionic acid methyl ester (30.7 g, 127.3 mmol) prepared in Step A was dissolved in DCM. Et3N (26.4 g, 190 mmol) and (BOC)2O (27.7 g, 127.3 mmol) were added thereto, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction mixture was distilled under reduced pressure to remove DCM, and was used in the next reaction without further purification.
Reaction SMILES: CN(CCO)C.[CH2:7]([Li:11])[CH2:8][CH2:9][CH3:10].[C:12]1([C:18]2C=CC=C[N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCCCCC>[Li:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:19]=1
Reactant: c1ccc(-c2ccccn2)cc1
Reactant: [Li]CCCC
Agent: CN(C)CCO
Solvent: CCCCCC
Product: [Li]c1cccc(-c2ccccc2)n1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A hexane (150 ml) solution of N,N-dimethylaminoethanol (21.0 ml, 210.0 mmol) was dropwise added to a hexane solution of n-butyllithium (266 ml, 1.58 M, 420.0 mmol) at 5° C. while 1 hour. Next, a hexane (15 ml) solution of 2-phenylpyridine (15.0 ml, 105.0 mmol) was dropwise added to the mixture at 5° C. while 20 minutes. A hexane solution of 2-lithio-6-phenylpyridine was prepared by the mixture stirred at 5° C. for 1 hour additionally.
Reaction SMILES: [CH2:1]([O:3][PH:4]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].C(N(CC)CC)C.C[Si](C)(C)Cl.[C:25](O)(=[O:27])[CH3:26].Cl[CH2:30][Cl:31]>O1CCCC1>[CH2:1]([O:3][P:4]([CH2:26][C@@H:25]([OH:27])[CH2:30][Cl:31])([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCO[PH](=O)CC1CCCCC1
Reactant: ClCCl
Reactant: CC(=O)O
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(=O)(CC1CCCCC1)C[C@@H](O)CCl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
20.0 g of cyclohexylmethylphosphinic acid ethyl ester are dissolved in 150 ml of tetrahydrofuran, and at 0° 11.0 g of triethylamine and then, dropwise, 12.0 g of trimethylchlorosilane are added, a white precipitate being formed. The resulting suspension is stirred at room temperature for 24 hours and then filtered under argon. The filtrate is concentrated by evaporation under reduced pressure. 10.9 g of (R)-epichlorohydrin and 2.0 g of anhydrous zinc chloride are added to the residue. When the exothermic reaction has died away, the mixture is heated under reflux at 60° for a further 24 hours. The reaction mixture is allowed to cool to room temperature, diluted with dichloromethane and washed with water. The organic phase is separated off, dried over sodium sulfate and concentrated by evaporation. The residue is dissolved in dichloromethane and washed with water. Drying over sodium sulfate and concentration by evaporation yield an oil. The oil is taken up in % methanolic acetic acid, left to stand at room temperature for 24 hours and then concentrated by evaporation. The residue is purified by chromatography on silica gel, yielding 3-chloro-2(R)-hydroxy-propyl(cyclohexylmethyl)phosphinic acid ethyl ester; 1H-NMR spectrum (in CDCl3): δ=4.47 (1H,d), 4.21-4.02 (3H,m), 3.6 (2H,m), 2.11-1.54 (9H,m), 1.38-0.97 (9H,m).