Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[CH3:6][CH:7]([CH2:9][CH2:10][CH2:11][C@H:12]([C@@H:14]1[C@:31]2([CH3:32])[C:17](=[C:18]3[C@H:28]([CH2:29][CH2:30]2)[C@:26]2([CH3:27])[C@H:21]([CH2:22][C@@H:23]([N+]4C=CC=CC=4)[CH2:24][CH2:25]2)[CH2:20][CH2:19]3)[C:16](=[O:39])[CH2:15]1)[CH3:13])[CH3:8].CC(CCC[C@H]([C@@H]1[C@]2(C)C(=C3[C@H](CC2)[C@]2(C)[C@H](C[C@@H]([N+]4C=CC=CC=4)CC2)CC3)C(=O)C1)C)C.[Cl-].[K+:75]>O>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH3:6][CH:7]([CH2:9][CH2:10][CH2:11][C@H:12]([C@@H:14]1[C@:31]2([CH3:32])[C:17](=[C:18]3[C@H:28]([CH2:29][CH2:30]2)[C@:26]2([CH3:27])[C@H:21]([CH2:22][C@@H:23]([K:75])[CH2:24][CH2:25]2)[CH2:20][CH2:19]3)[C:16](=[O:39])[CH2:15]1)[CH3:13])[CH3:8]
Reactant: O=S(=O)([O-])[O-]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC(=O)C2=C3CC[C@H]4C[C@@H]([n+]5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: [K+]
Agent: [Cl-]
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC(=O)C2=C3CC[C@H]4C[C@@H]([K])CC[C@]4(C)[C@H]3CC[C@@]21C
Product: O=S(=O)(O)O

Procedure:
5α-Cholest-8(14)-en-15-on-3β-yl pyridinium sulfate (1.0 g; 1.79 mmol) was dissolved in distilled water (50 ml) at room temperature and an aqueous saturated solution of potassium chloride was slowly added to the stirred mixture. After 15 min the resulting suspension was filtered, washed with water, and dried in a vacuum desiccator for several hours. The resulting white residue (0.85 g; 89%), was shown by i.r., n.m.r., and m.s. analyses to be 5α-cholest-8(14)-en-15-on-3β-yl potassium sulfate (monohydrate) having the structure: ##STR56##
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([CH3:27])[CH:26]=1)[NH:23][C:22](=[O:28])[C:21]2=[O:29].N1C=CC=C(C)C=1.CS(Cl)(=O)=O>C(#N)C>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([Cl:17])=[CH:26][C:25]=3[CH3:27])[C:21](=[O:29])[C:22]2=[O:28])=[O:9])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: Cc1cc(Cl)cc2c1NC(=O)C2=O
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: Cc1cccnc1
Product: Cc1cc(Cl)cc2c1N(C(=O)c1cc(Br)nn1-c1ncccc1Cl)C(=O)C2=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 77.6 %

Procedure:
To a suspension of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (see PCT Patent Publication WO 03/015519 for preparation) (97.6% purity, 13.02 g, 42 mmol) and 5-chloro-7-methylindoline-2,3-dione (K. Tsuji et al., Bioorg. Med. Chem. Letters, 2002, 12(17), pp 2427-2430) (7.82 g, 40 mmol) in dry acetonitrile (50 mL) was added 3-picoline (11.9 g, 127 mmol). The mixture was cooled to 0° C., and then methanesulfonyl chloride (6.87 g, 60 mmol) was added dropwise at 0-10° C. After stirring 5 minutes at this temperature, the mixture was warmed to room temperature for 20 hours. The precipitated solids were filtered, washed with acetonitrile (3×5 mL), and dried under nitrogen to afford the title product, a compound of the present invention, as a yellow powder, 14.90 g (77.6% yield), m.p. 173-177° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[O:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH2:9][N:10]([C:11]3[C:12](=[O:19])[C:13](=[O:18])[C:14]=3OCC)[C:4]=2[CH:3]=1.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[ClH:1].[Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[O:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH2:9][N:10]([C:11]3[C:12](=[O:19])[C:13](=[O:18])[C:14]=3[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[C:4]=2[CH:3]=1
Reactant: NCc1ccncc1
Reactant: CCOc1c(N2Cc3ccccc3Oc3ccc(Cl)cc32)c(=O)c1=O
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cl
Product: O=c1c(NCc2ccncc2)c(N2Cc3ccccc3Oc3ccc(Cl)cc32)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of the product of Example 5 (0.75 g), 4-(aminomethyl)pyridine (0.14 mL) and diphenylether (2 mL) was heated to reflux for 3 hours. The mixture was cooled and added to hexane (200 mL) and the separated thick oil was recovered by decantation. The oil was triturated with methanol. The precipitated solid was filtered and stirred with methanol at ambient temperature for 16 hours. The solid was then filtered and dissolved in CHCl3 (4 mL). To the solution was added 7 N HCl (1 mL) and the mixture was concentrated in vacuo. The residue was triturated with ether and filtered to obtain the title compound as a yellow solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>>[C:32]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:35])[CH2:33][CH3:34]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc12
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A158) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:15][C:16]([C:17]([NH:19][C@@H:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([OH:23])=[O:22])=[O:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O/[N:56]=[C:57](\[NH2:59])/[CH3:58]>CN(C=O)C.O>[NH2:59]/[C:57](=[N:56]\[O:22][C:21](=[O:23])[C@@H:20]([NH:19][C:17]([C:16]1[N:15]=[C:14]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C:10]=12)=[O:18])[C:24]([CH3:26])([CH3:27])[CH3:25])/[CH3:58]
Reactant: CC(C)(C)OC(=O)N1CCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)O)C(C)(C)C)c2C1
Reactant: C/C(N)=N/O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C/C(N)=N/OC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2)C(C)(C)C
Reaction time: 0.5 h

Procedure:
Intermediate 22B (0.25 g, 0.55 mmol) was dissolved in DMF and EDCI (0.17 g, 0.87 mmol) was added, followed by HOBt (0.12 g, 0.87 mmol). The resulting mixture was stirred for 30 min and (Z)-N′-hydroxy-acetimidamide (0.06 g, 0.82 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed successively with water, 2N Na2CO3 solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was used in the next step without purification. LCMS (+ESI) m/z 1025.2 [2M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[S:10]([OH:13])(=[O:12])=[O:11].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]=[C:22]=[O:23])[CH:16]=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[Br:14][C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:23])[NH:1][C:2]2[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=2[S:10]([OH:13])(=[O:12])=[O:11])[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cc(S(=O)(=O)O)c(N)cc1Cl
Reactant: O=C=Nc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)O)c(NC(=O)Nc2cccc(Br)c2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
2-Amino-4-chloro-5-methyl-benzenesulfonic acid (665 mg, 3.0 mmol) was suspended in 30 ml dry THF and 1-bromo-3-isocyanato-benzene (624 mg, 3.15 mmol) was added. Upon addition of triethylamine (354 mg, 3.15 mmol) the suspension cleared and became a solution. The solution was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with diluted aqueous hydrochloric acid. The organic phase was dried over sodium sulphate and reduced to dryness under vacuum. The title compound was recrystallised from ethyl acetate/heptane to give 820 mg (65%) of white crystals (m.p. 275° C.; decomposition).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=O)[C:6]2[S:7][CH2:8][C:9](=[O:14])[N:10]([CH3:13])[C:11]=2[N:12]=1)[CH3:2].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:5]1[C:6]2[S:7][CH2:8][C:9](=[O:14])[N:10]([CH3:13])[C:11]=2[N:12]=[C:3]([CH2:1][CH3:2])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1nc2c(c(=O)[nH]1)SCC(=O)N2C
Product: CCc1nc(Cl)c2c(n1)N(C)C(=O)CS2
Yield: 83 %

Procedure:
The 6,7-dihydro-2-ethyl-8-methyl-3H-pyrimido-[5,4-b][1,4]thiazine-4,7-dione of Example 115 (2.7g, 12.04 mmole) was suspended in approximately 150ml of phosphorus oxychloride and refluxed for about 20 hours. The solution was concentrated in vacuo and the excess phosphorus oxychloride was decomposed with the careful addition of ice and water. The aqueous solution was neutralized with the cautious addition of concentrated ammonium hydroxide, followed by the addition of sodium bicarbonate. The aqueous solution was extracted numerous times with chloroform; the extracts were combined, washed well with water, then brine, dried over magnesium sulfate, filtered and evaporated in vacuo to provide 2.4g (83%) of an off-white solid. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: Cl[CH2:2][C:3]([O:8][C:9](=[O:14])[NH:10][CH:11]1[CH2:13][CH2:12]1)=[N:4][O:5][CH2:6][CH3:7].[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=1)=[P:23](=[O:25])[O-:24].[K+].[I-].[K+]>C(C(C)=O)C>[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=1)=[P:23](=[O:24])[O:25][CH2:2][C:3]([O:8][C:9](=[O:14])[NH:10][CH:11]1[CH2:13][CH2:12]1)=[N:4][O:5][CH2:6][CH3:7]
Reactant: CCON=C(CCl)OC(=O)NC1CC1
Reactant: Cc1ccccc1S(c1ccc(Br)cc1)=P(=O)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCON=C(COP(=O)=S(c1ccc(Br)cc1)c1ccccc1C)OC(=O)NC1CC1
Temperature: 25 °C

Procedure:
1-Chloro-2-(N-cyclopropylcarbamoyloxy)-2-ethoxyiminoethane (11 grams; 0.05 mole), methyl ethyl ketone (80 ml), potassium 2-methylphenyl(4-bromophenyl)thionophosphinate (17 grams; 0.05 mole) and a few crystals of potassium iodide are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 8 hours. After this time the reaction mixture is cooled to room temperature and is filtered to remove inorganic salts. The salts are washed with acetone and the washings combined with the filtrate. The resulting solution is stripped of solvents in a rotary evaporator. The remaining residue is dissolved in ether and the ether solution is washed with water and dried over anhydrous magnesium sulfate. The dried solution is filtered and stripped of ether to yield the desired product O-[2-(N-cyclopropylcarbamoyloxy)-2-ethoxyiminoethyl] 2-methylphenyl(4-bromophenyl)thionophosphinate.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].[NH:33]1[CH2:38][CH2:37][CH:36]([CH2:39][OH:40])[CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:40][CH2:39][CH:36]1[CH2:37][CH2:38][N:33]([CH2:2][CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([O:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=4[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:24])=[CH:10][CH:11]=[N:12]3)=[CH:7][C:6]=2[O:31][CH3:32])[CH2:34][CH2:35]1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCl
Reactant: OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCN1CCC(CO)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (50 mg), 4-piperidine methanol (38 mg), and potassium carbonate (76 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (31 mg, yield 54%).
Reaction SMILES: [CH2:1]1[C@H:5]2[C:6](=[O:16])[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[N:4]2[CH2:3][CH2:2]1.[H-].[Na+].[CH3:19]I.O>CN(C=O)C>[CH3:19][N:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10](=[O:11])[N:4]2[CH2:3][CH2:2][CH2:1][CH:5]2[C:6]1=[O:16]
Reactant: O=C1Nc2ccccc2C(=O)N2CCC[C@@H]12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (S)-(+)-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazapine-5,11(10H,11aH)-dione (9.9 g, 45.8 mmol) in DMF (150 ml) at 0° C. was added NaH (2.0 g, 50.4 mmol). The mixture was warmed to room temperature and stirred for 1 h before methyl iodide (8.56 ml, 137 mmol) was added dropwise, After stirring for an additional 1 h, the mixture was dumped into water (1 l) and extracted with ethyl acetate (3×100 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered, and concentrated to a solid which was recrystallized from ethyl acetate-hexane (5.7 g, 54%), m.p. 118-120° C.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC([N:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[CH2:32]OS(C1C=CC(C)=CC=1)(=O)=O)=O)(C)(C)C>>[C:1]1([C:7]2[O:11][C:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:32][C@H:28]4[CH2:29][CH2:30][CH2:31][NH:27]4)=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(Cc2ccc(-c3ccccc3)o2)cc1
Product: c1ccc(-c2ccc(Cc3ccc(OC[C@H]4CCCN4)cc3)o2)cc1
Yield: 60 %

Procedure:
The title compound (80 mg, 50%) was prepared from the product of step 4 (0.1 g, 0.4 mmol) and (R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.17 g, 0.48 mmol) using the procedure of Example 154, step 3; 1HNMR (400 MHz, CD3OD) δ 7.58 (d, J=8 Hz, 2H), 7.32 (t, J=6 Hz, 2H), 7.26 (d, J=8 Hz, 2H), 7.19 (t, J=8 Hz, 1H), 7.17 (d, J=3.6 Hz, 1H), 6.98 (d, J=8.4 Hz, 2H), 6.63 (d, J=3.2 Hz, 1H), 6.09 (d, J=3.2 Hz, 1H), 4.32 (dd, J=7.2, 3.6 Hz, 1H), 4.08 (t, J=9.4 Hz, 1H), 4.01 (m, 1H), 3.98 (s, 2H), 3.35 (m, 2H), 2.25 (m, 1H), 2.11 (m, 2H), 1.98 (m, 1H); LC/MS (ESI+) m/z: 91%; 334 (M+1, 100).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:34][C:35]1[N:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1>>[O:31]1[CH2:32][CH2:33][N:28]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([S:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=5[F:27])(=[O:19])=[O:20])[CH2:16][CH2:17]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:38]3[CH:37]=[N:36][C:35]([NH2:34])=[N:40][CH:39]=3)[N:3]=2)[CH2:29][CH2:30]1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: O=S(=O)(c1ccccc1F)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(=O)(=O)c5ccccc5F)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-[4-(2-fluoro-benzenesulfonyl)-piperazin-1-ylmethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica and recrystallization from hot DCM/hexane gave 282. NMR (CDCl3/MeOD): 2.53-2.56 (4H, m), 3.15-3.20 (4H, m), 3.75 (2H, s), 3.75-3.81 (4H, m), 3.89-3.93 (4H, m), 7.15 (1H, s), 7.14-7.25 (2H, m), 7.51-7.58 (1H, m), 7.71-7.77 (1H, m), 9.08 (2H, s). MS (ESI+): MH+571.22 (80%)
Reaction SMILES: [CH:1]([N:3]([CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][C:14]([CH3:21])([CH3:20])[CH2:13]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:2].[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[C:23]#[CH:24]>C1(C)C=CC=CC=1>[CH3:18][C:16]1([CH3:19])[CH2:17][CH:12]([N:3]([CH:1]=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][C:14]([CH3:20])([CH3:21])[N:15]1[CH:24]=[CH:23][C:22]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: C#CC(=O)OCC
Reactant: CCCCCCCCN(C=O)C1CC(C)(C)NC(C)(C)C1
Solvent: Cc1ccccc1
Product: CCCCCCCCN(C=O)C1CC(C)(C)N(C=CC(=O)OCC)C(C)(C)C1
Yield: 101.5 %

Procedure:
59.2 g of 4-(N-formyl-N-octylamino)-2,2,6,6-tetramethylpiperidine and 20 g of ethyl propiolate were refluxed in 500 ml of toluene for 20 hours. Removal of the solvent by distillation under reduced pressure resulted in 80 g of the compound of the formula shown below in the form of a dark oil which crystallized after a few days to give a solid at melting point 58°-60° C. ##STR20##
Reaction SMILES: [CH2:1]([O:4][CH:5]([O:8][CH2:9][CH2:10][CH3:11])[CH2:6][NH2:7])[CH2:2][CH3:3].Br[CH2:13][CH:14]1[O:18][CH:17]([CH3:19])[CH2:16][O:15]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:9]([O:8][CH:5]([O:4][CH2:1][CH2:2][CH3:3])[CH2:6][NH:7][CH2:13][CH:14]1[O:18][CH:17]([CH3:19])[CH2:16][O:15]1)[CH2:10][CH3:11]
Reactant: CCCOC(CN)OCCC
Reactant: CC1COC(CBr)O1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCOC(CNCC1OCC(C)O1)OCCC
Temperature: 25 °C

Procedure:
2,2-Dipropoxyethylamine (0.11 mole), 2-bromomethyl-4-methyl-1,3-dioxolane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(2,2-dipropoxyethyl)-N-(4-methyl-1,3-dioxolan-2-ylmethyl)amine.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[O:11])=[C:8]([CH3:21])[CH:7]=[C:6]([Cl:22])[N:5]=1.[OH2:23].[CH3:24]O>>[Cl:22][C:6]1[N:5]=[C:4]([O:23][CH3:24])[C:9]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[O:11])=[C:8]([CH3:21])[CH:7]=1
Reactant: CO
Reactant: O
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Product: COc1nc(Cl)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 54 %

Procedure:
330 mg (8.3 mmol, 60% w/w in mineral oil) NaH were slowly added to Methanol (30 ml) at RT and stirring was continued at RT for 45 min. Then 2.35 g (7.5 mmol) 2,6-dichloro-N-(3-fluorobenzyl)-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section a) of example 2) were added and the RM was heated to 70° C. for 24 h. After cooling to RT water (10 ml) was added and most of the MeOH was removed in vacuo. The mixture was then extracted with EtOAc and the organic layer was washed twice with brine, dried over MgSO4 and concentrated in vacuo. Crystallisation (hexane/EtOAc 3:1) of the residue yielded 1.24 g (0.4 mmol, 54%) 6-Chloro-N-[(3-Fluorophenyl)-methyl]-2-methoxy-4-methyl-pyridine-3-carboxylic acid amide.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[CH:22]([C@H:25]1[CH2:30][CH2:29][C@H:28]([C:31](O)=[O:32])[CH2:27][CH2:26]1)([CH3:24])[CH3:23]>ClCCl.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:31]([C@H:28]1[CH2:29][CH2:30][C@H:25]([CH:22]([CH3:24])[CH3:23])[CH2:26][CH2:27]1)=[O:32]
Reactant: CC(C)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: COC(=O)[C@H](N)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H]1CC[C@H](C(C)C)CC1
Temperature: 2.5 °C
Reaction time: 14 h

Procedure:
D-Phenylalanine methyl ester hydrochloride (10 g, 0.046 mol) was suspended in a solution of triethylamine (33 mL) in dichloromethane (50 mL). The mixture was cooled to 0-5° C. and trans-4-isopropylcyclohexane carboxylic acid (7.9 g, 0.046 mol) was added. A solution of propane phosphonic acid anhydride (46.4 mL, 0.046 mol) in ethyl acetate was added dropwise over a period of 30 minutes, maintaining the temperature at 0-5°. The resulting mixture was stirred for 14 hours at ambient temperature. The reaction mixture was washed with 1.5 N HCl, 5% sodium bicarbonate solution and brine. The organic layer was concentrated to yield 12.5 g of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine methyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:40][NH:41][OH:42]>O1CCCC1>[OH:42][NH:41][C:14](=[O:15])[CH2:13][CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[N:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:26].[OH:42][N:41]([CH3:40])[C:14](=[O:15])[CH2:13][CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[N:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:26]
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)ccc1OC
Reactant: CNO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)N(C)O)N2Cc3ccccc3C2=O)ccc1OC
Product: CCOc1cc(C(CC(=O)NO)N2Cc3ccccc3C2=O)ccc1OC
Yield: 120.8 %

Procedure:
N-Hydroxy-3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propanoic acid (1.0 g, 2.8 mmol), carbonyldiimidazole (500 mg, 3.1 mmol) and N-methyl-hydroxylamine hydrochloride (300 mg, 3.5 mmol) in tetrahydrofuran (10 mL) to afford N-hydroxy-N-methyl-3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propionamide as a white solid (650 mg, 61% yield): mp, 122.0-124.5° C.; 1H NMR (CDCl3) δ1.43 (t, J=7.0 Hz, 3H, CH3), 3.14 (s, 3H, NCH3), 3.37-3.48 (m, 2H, CH2), 3.86 (s, 3H, CH3), 4.02 (q, J=7.0 Hz, 2H, CH2), 4.11 (d, J=17.2 Hz, NCHH), 4.51 (d, J=17.2 Hz, 1H, NCHH), 5.95 (dd, J=6.5, 10.9 Hz, 1H, NCH), 6.83-6.97 (m, 3H, Ar), 7.34-7.55 (m, 3H, Ar), 7.81 (d, J=7.1 Hz, 1H, Ar), 9.44 (br s, 1H, OH); 13C NMR (DMSO-d6) δ14.71, 36.04, 38.11, 48.14, 52.36, 55.95, 64.52, 111.42, 112.42, 119.45, 122.95, 123.63, 128.06, 130.57, 131.88, 141.72, 148.65, 149.18, 170.00, 170.17; Anal Calcd for C21H24N2O5: C, 65.61; H, 6.29; N, 7.29. Found: C, 65.56; H, 6.26; N, 7.09.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[Cl:18][C:19]1[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:18][C:19]1[C:24]([N:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH:2]3[O:1][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3]3)[CH2:17][CH2:16]2)=[N:23][CH:22]=[CH:21][N:20]=1
Reactant: Clc1nccnc1Cl
Reactant: c1ccc2c(c1)OCC(CN1CCNCC1)O2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Clc1nccnc1N1CCN(CC2COc3ccccc3O2)CC1
Temperature: 75 °C
Yield: 60.6 %

Procedure:
1-(2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)piperazine (2.35 g, 10 mmole), 2,3-dichloropyrazine (1.5 g, 10 mmole) and diisopropylethylamine (1.3 g, 10 mmole) were combined in 100 ml of dimethylformamide and heated at 75° C. under N2 for 24 hours. The solvent was removed in vacuum and the residue was filtered through 75 g of silica gel using choroform as the eluent. The relevant fractions were combined, the solvent evaporated and the residue crystallized from isopropanol with addition of 4N isopropanolic HCl to give 2.1 g of title compound as the hydrochloride, m.p. 217°-218° C.