Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[N+:11]([C:14]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:15]=1[NH2:16])([O-:13])=[O:12]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=2[N+:11]([O-:13])=[O:12])=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Product: O=C(Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])c1ccc(Cl)nc1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 2,4-dinitroaniline and was obtained as a yellow solid as described in Example 1. 1H NMR (CDCl3): 11.69 (bs, 1H), 9.28-9.23 (m, 2H), 9.06-9.05 (m, 1H), 8.61-8.57 (m, 1H), 8.28-8.24 (m, 1H), 7.59-7.56 (m, 1H).
Reaction SMILES: [CH3:1][C@:2]1([NH:8][C:9]2[CH:14]=[N:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:7].[N:19]1[N:20]([C:24]2[C:25]([C:30](O)=[O:31])=[N:26][CH:27]=[CH:28][CH:29]=2)[N:21]=[CH:22][CH:23]=1.C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C@:2]1([NH:8][C:9]2[CH:14]=[N:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][N:10]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:30]([C:25]1[C:24]([N:20]2[N:21]=[CH:22][CH:23]=[N:19]2)=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:31]
Reactant: O=C(O)c1ncccc1-n1nccn1
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1

Procedure:
A solution of (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 80 mg, 0.31 mmol), 3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid (CAS number 1252907-86-0; 70 mg, 0.37 mmol), EDC (177 mg, 0.92 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (126 mg, 0.922 mmol) and DIPEA (161 μl, 0.92 mmol) in dry DCM (1 ml) was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate (20 ml) and water (10 ml). The organics were washed with water (2×10 ml), brine (10 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica, 0 to 100% ethyl acetate/petrol) followed by a trituration in pentane/diethyl ether to afford the title compound. 1H NMR (400 MHz, DCM-d2) δ ppm 1.43 (s, 3H), 1.66-1.99 (m, 4H), 2.14-2.30 (m, 1H), 2.49-2.68 (m, 1H), 4.40-4.55 (m, 1H), 7.38-7.48 (m, 1H), 7.56 (br. s., 1H), 7.62-7.67 (m, 1H), 7.69 (br. s., 1H), 7.84 (s, 2H), 8.08-8.14 (m, 1H), 8.23 (br. s., 1H), 8.65-8.70 (m, 1H)
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12][NH2:13])(=[O:11])=[O:10].[NH2:15][C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=1>C(Cl)Cl>[NH2:13][N:17]1[CH:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:16]1=[NH2+:15].[CH3:8][C:3]1[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:14])[C:2]=1[S:9]([O-:12])(=[O:11])=[O:10]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Cc1cccnc1N
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Cc1cccn(N)c1=[NH2+]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of O-(mesitylsulfonyl)hydroxylamine (6.45 g, 30.0 mmol) in DCM (30 mL) was stirred at room temperature, then 2-amino-3-methylpyridine (1.08 g, 10.0 mmol) was added slowly. The reaction mixture was stirred at room temperature for 12 h, the solvent was removed under vacuum, and the crude product was used for the next step without further purification. ESI MS: m/z 124 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C([O-])(=O)C.[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][CH:28]=1)[NH:14][C:15]1[C:16]2[CH:23]=[C:22]([CH:24]=O)[NH:21][C:17]=2[N:18]=[CH:19][N:20]=1>O.CO>[CH3:2][O:3][N:4]=[CH:24][C:22]1[NH:21][C:17]2[N:18]=[CH:19][N:20]=[C:15]([NH:14][C:13]3[CH:26]=[CH:27][CH:28]=[C:11]([Cl:10])[CH:12]=3)[C:16]=2[CH:23]=1
Reactant: CON
Reactant: O=Cc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CON=Cc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reaction time: 4 h

Procedure:
69.3 mg (0.83 mmol) of O-methylhydroxylamine hydrochloride and 69.3 mg (0.845 mmol) of sodium acetate in 1 ml of water are added to 163.3 mg (0.5 mmol) of 4-(3-chloroanilino)-6-formyl-7H-pyrrolo[2,3-d]pyrimidine (stage1.6) in 1 ml of methanol. The suspension is heated to boiling for 4 h, cooled and filtered, and the residue is washed with water/isopropanol and finally diethyl ether. 4-(3-Chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde O-methyl oxime is obtained; HPLC: tRet(Grad20)=11.3; TLC-Rf=0.31 (CH2Cl2/methanol 10:1) FAB-MS: (M+H)+=302.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:15])[CH:7](CCC)[CH2:8][CH2:9][CH2:10]N)([CH3:4])[CH3:3].C1C([N+]([O-])=O)=CC=C([Cl-]C([O-])=O)C=1.C(=O)(O)[O-].[Na+].CCCCCC>O.ClCCl>[CH3:4][C:2]([O:5][C:6](=[O:15])[CH2:7][CH2:8][CH2:9][CH3:10])([CH3:1])[CH3:3]
Reactant: CCCC(CCCN)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O
Product: CCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 160 mg (0.74 mmol) of rac-5-amino-2-propylpentanoic acid 1,1-dimethylethyl ester (8) in 1 mL of water and 1 mL of dichloromethane, 153 mg (0.76 mmol) of 4-nitrophenylchloroformate and 267 mg of sodium bicarbonate were added at 0° C. The mixture was stirred at room temperature overnight and then diluted with 50 mL of dichloromethane and 30 mL of water. The organic part was separated. The aqueous part was extracted with 2×50 mL of dichloromethane. The organic parts were combined and washed with 2×50 mL of 5% sodium bicarbonate followed by 50 mL of water, dried over MgSO4 and concentrated. The residue was purified by preparative thin layer chromatography using 1:1 ethyl acetate:hexane as the eluent to yield 185 mg (0.48 mmol, 66%) of rac-5-[[(4-nitrophenoxy)carbonyl]amino]-2-propyl]pentanoic acid 1,1-dimethylethyl ester (9) asan offwhite solid. NMR, IR and MS data confirmed compound identity.
Reaction SMILES: O1[C:3]23[C@:16]([CH3:21])([CH2:17][CH2:18][C:19](=[O:20])[CH:2]12)[C@@H:15]1[C@H:6]([C@H:7]2[C@@:11]([CH2:13][CH2:14]1)([CH3:12])[C@@H:10]([C:22]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:9][CH2:8]2)[CH2:5][CH2:4]3.[N-:29]=[N+]=[N-].[Na+].[N-]=[N+]=[N-].S(=O)(=O)(O)O>CS(C)=O>[NH2:29][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22]([NH:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CCC45OC4C(=O)CC[C@]5(C)[C@H]3CC[C@]12C
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3C=CC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A solution of 4,5-epoxy-N-(1,1-dimethylethyl)-3-oxoandrostane-17β-carboxamide (3.0 g, 7.7 mmole) in dimethyl sulfoxide (40 mL), under a nitrogen atmosphere, was placed in an oil bath heated at 60° C. The solution was stirred vigorously as sodium azide (8.11 g, 0.338 mole) was slowly added. After the addition of the azide was complete, concentrated sulfuric acid (0.54 mL) was added. The bath temperature was raised to 100° C. and the reaction was stirred at this temperature for 90 minutes. The reaction was removed from the oil bath and cooled to room temperature and the resulting solid mass was broken up and poured into cold water (550 mL). The mixture was stirred for 30 min and the solids were collected by filtration, washed with water and dried to a yellow solid. The crude product was purified by flash chromatography (hexane-30% ethyl acetate) to give 4-amino-N-(1,1-dimethylethyl)-3-oxoandrosta-4,6-diene-17β-carboxamide as a crystalline, yellow solid (0.90 g, 30%) (aq methanol). IR 3442, 3372, 1662, 1616, 1592, 1570, 1512 cm-1 ; MS (CI) m/z 385 (100%, M+ +1); (EI) m/z 384 (35%, M+), 150 (100%); 1H NMR (CDCl3) δ 0.77 (3H, s, C18 -Me), 1.06 (3H, s, C18 -Me), 1.37 (s, tBu-Me's), 2.44-2.54 (1H, pr dd), 2.58-2.72 (1H, pr dd), 3.70 (1.6H, br, NH2), 5.13 (1H, s, NH), 5.97 (1H, dd), 6.30 (1H, dd); 13C NMR (CDCl3) δ 132.27, 132.44, 135.90, 171.51, 194.27. This compound has the following structure: ##STR3##
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1Br)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Cl-:20].[NH4+].[C:22]([O:25]CC)(=O)[CH3:23]>>[C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:22](=[O:25])[CH2:23][Cl:20])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: [Cl-]
Reactant: CC(C)(C)NS(=O)(=O)c1sccc1Br
Agent: [Li]CCCC
Agent: [NH4+]
Product: CC(C)(C)NS(=O)(=O)c1sccc1C(=O)CCl
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
2.98 g (0.0| mole) of N-t-butyl-3-bromo-2-thiophenesulfonamide was dissolved in 50 ml of dry tetrahydrofura mixture was cooled to -78° C. under nitrogen gas. To the reaction solution was slowly added dropwise 8.4 ml of n-butyl lithium(2.5N) and then the temperature of the mixture was raised slowly to -20° C. and again cooled to -78° C. 1.4 g (0.012 mole) of ethyl chloroacetates was added slowly to the mixture. The temperature of the reaction mixture was raised slowly to -20° C. again and then the mixture was stirred for 10 minutes. To the mixture was added 100 ml of aqueous ammonium chloride solution and then added 100 ml of ethyl acetate to separate the organic layer. The extracted organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography on silica gel to obtain 1.9 g (Yield: 69%) of the pure title compound as a liquid.
Reaction SMILES: CN1C=CN=C1.[CH:7]1([CH2:12][C@H:13]([CH2:34][N:35]([CH:44]=[O:45])[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:14]([N:16]2[C@H:20]([C:21]([OH:23])=O)[CH2:19][CH2:18][N:17]2[C:24](OCC2C=CC=CC=2)=O)=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1.S(Cl)(C)(=O)=O.[NH2:51][C:52]1[CH:57]=[CH:56][N:55]=[CH:54][N:53]=1>CN(C=O)C>[CH:7]1([CH2:12][C@H:13]([CH2:34][N:35]([CH:44]=[O:45])[O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:14]([N:16]2[C@H:20]([C:21]([NH:51][C:52]3[CH:57]=[CH:56][N:55]=[CH:54][N:53]=3)=[O:23])[CH2:19][CH2:18][N:17]2[CH3:24])=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Nc1ccncn1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Product: CN1CC[C@@H](C(=O)Nc2ccncn2)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 80 %

Procedure:
1-Methylimidazole (38.2 μl, 0.479 mmol) was added into a solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidine carboxylic acid (100 mg, 0.240 mmol) in 1.0 ml of DMF. The solution was cooled to 0° C., and then mesyl chloride (24.26 μl, 0.311 mmol) was added dropwise at 0° C. 4-Aminopyrimidine (34.2 mg, 0.359 mmol) dissolved in another 1.0 ml of DMF was then added. The reaction mixture was stirred for 3.5 h at rt. The reaction mixture was concentrated and purified by RP-HPLC to afford (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-methyl-N-4-pyrimidinyl-3-pyrazolidinecarboxamide (95 mg, 0.192 mmol, 80%) as a white foam solid. LC-MS (ES) m/e 495.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][CH2:5]Br.C(N(CC)CC)C.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:31]3[C:30]([NH:32][CH:33]4[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]4)=[N:29][CH:28]=[N:27][C:26]=3[O:25][C:24]=2[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:19][CH:18]=1>C1COCC1.ClCCl>[CH3:1][O:2][C:3](=[O:7])[CH:4]([N:35]1[CH2:36][CH2:37][CH2:38][CH:33]([NH:32][C:30]2[C:31]3[C:23]([C:20]4[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=4)=[C:24]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:25][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:34]1)[CH3:5]
Reactant: COC(=O)CCBr
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NC4CCCNC4)c23)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(C)N1CCCC(Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)C1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Add 82 μl (0.749 mmol) of 3-bromopropanoic acid methyl ester and 104 μl (0.749 mmol) of triethylamine to a solution of 150 mg (0.375 mmol) of (+/−)-5-(4-methoxyphenyl)-6-phenyl-N-piperidin-3-ylfuro[2,3-d]pyrimidin-4-amine (Example 39A) in 0.75 ml of THF, and stir at 20-40° C. overnight. Dilute the mixture with dichloromethane and wash with saturated sodium hydrogencarbonate solution. After concentration under reduced pressure, stir the residue with methanol, filter off the precipitated product with suction and dry under high vacuum. Isolate a second product batch from the filtrate after concentration by preparative RP-HPLC (eluent: acetonitrile/water gradient). A total of 124 mg (67.1% of theory) of the target product are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](B(O)O)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][CH:9]=[C:8]3[CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:22][CH:23]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Nc1ccc(Br)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(B(O)O)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1ccc(-c2ccc3[nH]cc(C4CCN(C)CC4)c3c2)cc1
Yield: 39.3 %

Procedure:
The title compound was prepared by the procedure of Example 10, beginning with 3-(1-methylpiperidin-4-yl)-1H-indole-5-boronic acid (0.200 g, 0.77 mmol), 1-bromo-4-acetamidobenzene (0.158 g, 0.74 mmol), tetrakis(triphenylphosphine)palladium(0) (0.045 g, 0.039 mmol), and 2M aqueous sodium carbonate solution (2 mL) in 15 mL of tetrahydrofuran:methanol (1:1) to give the title compound (0.101 g, 40%) as an amorphous solid. FDMS m/e=348 (M+). EA calculated for C22H25N3O.¼ H2O: C, 75.07; H, 7.16; N, 11.94. Found: C, 74.94; H, 7.00; N, 11.61.
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:18]3[C:13](=[C:14]([OH:32])[C:15]4[C:24](=[O:25])[C:23]5[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:22]=5[C:20](=[O:21])[C:16]=4[C:17]=3[OH:19])[CH2:12][C@@:11]([OH:37])([C:33]([CH2:35][OH:36])=[O:34])[CH2:10]2)[CH2:5][C@H:4]([NH:38][C:39]([C:41]([F:44])([F:43])[F:42])=[O:40])[C@@H:3]1[OH:45].N1C=CC=CC=1.[C:52](Cl)(=[O:57])[CH2:53][CH2:54][CH2:55][CH3:56]>C(Cl)(Cl)Cl>[CH3:56][CH2:55][CH2:54][CH2:53][C:52]([O:36][CH2:35][C:33]([C@:11]1([OH:37])[CH2:12][C:13]2[C:18](=[C:17]([OH:19])[C:16]3[C:20](=[O:21])[C:22]4[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:23]=4[C:24](=[O:25])[C:15]=3[C:14]=2[OH:32])[C@@H:9]([O:8][CH:6]2[O:7][CH:2]([CH3:1])[CH:3]([OH:45])[CH:4]([NH:38][C:39]([C:41]([F:44])([F:42])[F:43])=[O:40])[CH2:5]2)[CH2:10]1)=[O:34])=[O:57]
Reactant: CCCCC(=O)Cl
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCC(=O)OCC(=O)[C@]1(O)Cc2c(O)c3c(c(O)c2[C@@H](OC2CC(NC(=O)C(F)(F)F)C(O)C(C)O2)C1)C(=O)c1c(OC)cccc1C3=O

Procedure:
A solution containing 5.0 mg. of N-trifluoroacetyladriamycin dissolved in 0.5 ml. of anhydrous pyridine was treated with 18 microliters of valeroyl chloride, which was added in small portions over a two-day period. The reaction was monitored by thin layer chromatography and when the presence of N-trifluoroacetyladriamycin could no longer be observed, the reaction mixture was diluted with 10 ml. of chloroform. The chloroform solution was extracted three times with pH 4 gaseous buffer and once with pH 7 buffer. The dried chloroform solution was then evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography on silica gel G with chloroform:methanol:water (120:20:1 by volume) as the solvent system. The major orange-colored band was removed and washed free of silica gel with a mixture of methanol and ethyl acetate. Upon evaporation of the methanol and ethyl acetate, 2.19 mg. of N-trifluoroacetyladriamycin-14-valerate was obtained. This material was idential by spectral and chromatographic comparison with samples of N-trifluoroacetyladriamycin-14-valerate prepared by the earlier described methods.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH:15]=[CH:16][S:17][C:3]1=2.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:31][C:32]1[NH:36][N:35]=[N:34][N:33]=1>CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH:31][C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[O:14])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH:15]=[CH:16][S:17][C:3]1=2
Reactant: O=C(O)c1ccc2nc3ccsc3c(=O)n2c1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1ccc2nc3ccsc3c(=O)n2c1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid (1.0 g, 0.0041 mol) and 1,1'-carbonyldiimidazole (1.35 g, 0.0082 mol) in dimethylformamide (10 ml) is heated at 95°-100° C. with stirring under nitrogen for 1.5 hours. 5-Aminotetrazole monohydrate (0.42 g, 0.0041 mol) is added and the resulting mixture is heated at 100° C. for 1-5 hours. The precipitate is filtered off, washed with tetrahydrofuran and recrystallized from dimethylformamide to give the product (0.6 g.), mp 295°-296° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[N:3][CH:2]=1.NC1N=C(N)[C:19]2[C:14](=NC=C(C=C)N=2)N=1.ClCC(=O)C=NO.NC1C=CC=CN=1>>[CH:14]([C:2]1[N:3]=[CH:4][C:5]2[C:10](=[N:9][CH:8]=[CH:7][N:6]=2)[N:1]=1)=[CH2:19]
Reactant: c1cnc2ncncc2n1
Reactant: C=Cc1cnc2nc(N)nc(N)c2n1
Agent: Nc1ccccn1
Agent: O=C(C=NO)CCl
Product: C=Cc1ncc2nccnc2n1
Yield: 15 %

Procedure:
An interesting extension of the above systems is the preparation and use of a pteridine-based monomer. Such an example is 2,4-diamino-6-vinylpteridine (XIII). This molecule is synthesised in five synthetic steps, from -chloropyruvaldoxime, in 15% yield following the method of Taylor & Kobayashi (J. Org. Chem., 38, 2187-2821 (1973)). 6. Aminopyridine Based Monomers
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.O1CCCC1.[CH3:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:23][C:24]3[CH:30]=[C:29]([O:31][CH2:32][CH2:33][F:34])[CH:28]=[CH:27][C:25]=3[CH:26]=2)=[CH:18][CH:17]=1>O>[CH3:14][N:15]([C:16]1[CH:17]=[CH:18][C:19]([C:22]2[S:23][C:24]3[CH:30]=[C:29]([O:31][CH2:32][CH2:33][F:34])[CH:28]=[CH:27][C:25]=3[CH:26]=2)=[CH:20][CH:21]=1)[CH3:1]
Reactant: CNc1ccc(-c2cc3ccc(OCCF)cc3s2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1ccc(-c2cc3ccc(OCCF)cc3s2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 46.1 %

Procedure:
Potassium carbonate (35 mg, 0.245 mmol) and iodomethane (CH3I, 21 μL, 0.330 mmol) were added to an anhydrous tetrahydrofuran (5 mL) solution having the 2-[4-(N-monomethylamino)phenyl]-6-(2-fluoroethoxy)benzothiophene (1-12, 50 mg, 0.165 mmol) prepared in Example 12 dissolved therein, and stirred at 80° C. for 12 hours. The reaction mixture was cooled to room temperature and water was added. Organic compounds were extracted with ethyl acetate and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 2-[4-(N,N-dimethylamino)phenyl]-6-(2-fluoroethoxy)benzothiophene (1-16, 24 mg, 46%). The obtained target compound 1-16 had a melting point of 183.9-195.9° C., and the following physical data;
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:3]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([B:30]2[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]2)=[CH:26][CH:25]=1.C(O)(=O)C>O1CCCC1.C1(C)C=CC=CC=1>[O:1]=[C:2]1[NH:6][C:5]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([B:30]3[O:31][C:32]([CH3:38])([CH3:37])[C:33]([CH3:36])([CH3:35])[O:34]3)=[CH:28][CH:29]=2)([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:3]1
Reactant: CCOC(=O)[C@@H]1CCC(=O)N1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC(=O)N1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
Ethyl (2S)-5-oxopyrrolidine-2-carboxylate (0.200 g, 1.27 mmol) was azeotroped three times from toluene (25 mL each), dissolved in tetrahydrofuran (4.4 mL) and cooled to −78° C. 1 M lithium hexamethyldisilazide in tetrahydrofuran (1 M, 3.75 mL) was added via syringe and the colorless solution was stirred 30 min before addition of 2-[4-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.4 g, 1.0 mmol) in tetrahydrofuran (2.0 mL). The slightly yellow solution was stirred at −78° C. for 30 min and then at −10° C. for 1 h and warmed to rt for an additional 1 h before it was cooled back to −78° C. and quenched with acetic acid (1.00 mL, 17.6 mmol). Evaporation and purification by preparative LCMS gave the desired product as a colorless glass, (296 mg, 62%). 1H NMR (400 MHz, CD3OD): δ 7.67 (d, J=7.4 Hz, 2H), 7.22 (d, J=7.4 Hz, 2H), 4.20 (q, J=7.2 Hz, 2H), 3.08 (d, J=13.0 Hz, 1H), 3.05 (d, J=13.0 Hz, 1H), 2.35 (m, 1H), 2.23 (m, 1H), 2.15 (m, 1H), 1.79 (m, 1H), 1.35 (s, 12H), 1.25 (t, J=7.0 Hz, 3H); LCMS found for C20H29BNO5 (M+H)+: m/z=374.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([O:23][Si](C)(C)C)C#N)=[C:16]([F:28])[CH:15]=1.[C:29]([N:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1)(=[O:31])[CH3:30]>C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:35]2([OH:38])[CH2:36][CH2:37][N:32]([C:29](=[O:31])[CH3:30])[CH2:33][CH2:34]2)=[O:23])=[C:16]([F:28])[CH:15]=1
Reactant: C[Si](C)(C)OC(C#N)c1ccc(Cl)cc1F
Reactant: CC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(=O)N1CCC(O)(C(=O)c2ccc(Cl)cc2F)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
To a solution of diisopropylamine (4.42 mL, 31.59 mmol) in THF (20 mL) at 0° C. under Ar, was added n-BuLi (12.63 mL, 31.59 mmol, 2.5 M solution in hexane). The mixture was stirred at 0° C. for 30 min. After cooling to −78° C., (4-chloro-2-fluoro-phenyl)-trimethylsilanyloxyacetonitrile (8.12 g, 31.59 mmol) was added. After stirring at −78° C. for 1.5 h, 1-acetyl-piperidin-4-one (4.45 g, 31.59 mmol) was added. The final mixture was stirred at −20° C. for overnight. After concentration, EtOAc (100 mL) was added. The organic phase was washed with Sat. NH4OAc solution, Sat. NaHCO3 solution and concentrated. The residue was dissolved in MeOH (30 mL). 1N HCl solution (20 mL) was added. The mixture was stirred at RT for 2 h. After concentrating the mixture, EtOAc (50 mL) was added. The organic layer was basified with Sat. NaHCO3, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (Ethyl acetate) to give the desired product (4 g, 42% yield) as a white solid. MS: (ESI), M/Z, 300 (M+1). Retention time: 0.87 min (FA-standard).