Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([I:31])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2Cl)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:36]C(F)(F)C1C=C(C(C)(C)C(N(C2C=NC(Cl)=CC=2C2C=CC(F)=CC=2)C)=O)C=C(C(F)(F)F)C=1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([I:31])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:36])=[CH:26][CH:25]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccc(F)cc1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(I)cc1-c1ccccc1Cl
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(I)cc1-c1ccc(F)cc1

Procedure:
The title compound is prepared according to the procedure described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-iodo-pyridin-3-yl]-N-methyl-isobutyramide (Example 25) using 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide (Example 30) instead of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[CH3:27]>>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:22][C:21]=1[CH3:27]
Reactant: Cc1cc(N)ccc1F
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: Cc1cc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)ccc1F
Yield: 61.5 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 240 mg of 4-fluoro-3-methylaniline in place of the 2,4-difluoroaniline. 204 mg of N-(4-fluoro-3-methylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12.[Cl:23][C:24]([Cl:29])([Cl:28])[CH:25](O)[OH:26].N1C=CC=CC=1.C(Cl)Cl>O>[OH:26][CH:25]([C:24]([Cl:29])([Cl:28])[Cl:23])[CH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: Cc1nnccc1-c1c(-c2ccccc2)nn2ccccc12
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: OC(Cc1nnccc1-c1c(-c2ccccc2)nn2ccccc12)C(Cl)(Cl)Cl
Reaction time: 20 h
Yield: 42.9 %

Procedure:
A mixture of 3-(3-methylpyridazin-4-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.40 g), chloral hydrate (0.70 g) and pyridine (4 ml) was stirred for 20 hours at 90°-100° C. After cooling, to the reaction mixture was added methylene chloride (4 ml) and water (4 ml) at room temperature, and stirred for 3 hours. The precipitates were collected by filtration to give 3-[3-(2-hydroxy-3,3,3-trichoropropyl)pyridazin-4-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.26 g).
Reaction SMILES: [C:1]([Si:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:44]1[C:48](=[O:49])[C:47]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:46]2[C:45]1=[O:54].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([Si:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][N:44]1[C:48](=[O:49])[C:47]2[C:46](=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:45]1=[O:54])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)[Si](OCCCCO)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCCCON1C(=O)c2ccccc2C1=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
4-(tert-Butyl-diphenyl-silanyloxy)-butan-1-ol (10.0 g, 30.5 mmol), triphenylphosphine (8.0 g, 30 mmol), and N-hydroxyphthalimide (4.97 g, 30.5 mmol) were combined in anhydrous tetrahydrofuran (200 ml) at 0° C. and the resultant solution was stirred at 0° C. for 1 hour. Diethyl azodicarboxylate (5.31 g, 30.5 mmol) was added at 0° C., and the reaction mixture was allowed to gradually warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform. Precipitation ensued, and the white solid was removed by filtration. The filtrate was concentrated and purified with column chromatography (hexane/ethyl acetate(3/1)) to afford 2-[4-(tert-butyl-diphenyl-silanyloxy)-butoxy]-isoindole-1,3-dione (11.06 g, 77% yield) as colorless crystals: 1H NMR (400 MHz, DMSO-d6) δ 7.84 (4H, s), 7.59 (4H, dd, J=7.6, 1.0 Hz), 7.39-7.43 (6H, m), 4.13 (2H, t, J=6.4 Hz), 3.68 (2H, t, J=5.8 Hz), 1.67-1.78 (4H, m), 0.95 (9H, s).
Reaction SMILES: C(N(CCCC)CCCC)CCC.C(O)=O.[Br:17][C:18]1[S:22][C:21]([C:23]([CH2:25][O:26][C:27]2[C:36](I)=[CH:35][C:34]3[C:33]([CH3:39])([CH3:38])[CH2:32][CH2:31][C:30]([CH3:41])([CH3:40])[C:29]=3[CH:28]=2)=[CH2:24])=[CH:20][CH:19]=1>C(#N)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[Br:17][C:18]1[S:22][C:21]([C:23]2([CH3:24])[CH2:25][O:26][C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][C:36]2=3)[C:33]([CH3:39])([CH3:38])[CH2:32][CH2:31][C:30]4([CH3:41])[CH3:40])=[CH:20][CH:19]=1
Reactant: C=C(COc1cc2c(cc1I)C(C)(C)CCC2(C)C)c1ccc(Br)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O=CO
Solvent: CCCCN(CCCC)CCCC
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)OCC3(C)c1ccc(Br)s1
Temperature: 60 °C

Procedure:
A mixture of tributylamine (2.66 ml, 18.39 mmol), palladium diacetate (53 mg, 0.24 mmol), formic acid (0.205 ml, 5.32 mmol) and 5-bromo-2-[1-(3-iodo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yloxymethyl)-vinyl]thiophene (2.57 mg, 4.84 mmol) in acetonitrile (75 ml) was heated at 60° C. for 4 h. The reaction medium was concentrated in a rotary evaporator under vacuum at 40° C. Water and ethyl ether were added. After decantation, the organic phase was washed twice with 20 ml of water, dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40° C.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[N:10][N:11]([CH3:12])[C:7]=2[CH:6]=[C:5]([C:13]2[CH:34]=[CH:33][C:16]([O:17][CH2:18][CH2:19][CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)=[C:15]([C:35]([F:38])([F:37])[F:36])[CH:14]=2)[N:4]=1)#[N:2].[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl.C(#N)C>[OH:45][C:39]([C:41]([F:44])([F:43])[F:42])=[O:40].[CH3:12][N:11]1[C:7]2[CH:6]=[C:5]([C:13]3[CH:34]=[CH:33][C:16]([O:17][CH2:18][CH2:19][CH:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]4)=[C:15]([C:35]([F:38])([F:37])[F:36])[CH:14]=3)[N:4]=[C:3]([C:1]#[N:2])[C:8]=2[N:9]=[N:10]1
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCN(C(=O)OC(C)(C)C)CC4)c(C(F)(F)F)c3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl 4-(2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)piperidine-1-carboxylate (6 g) in DCM (40 ml) and acetonitrile (20 ml) was added TFA (40 ml). The mixture was stirred at room temperature for 10 minutes, then solvent removed under vacuum. To the residue was then dissolved ethyl acetate (40 ml) and product was precipitated by adding ether (50 ml) and collected by filtration (6.05 g as TFA salt).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][OH:13].C(N(CC)C(C)C)(C)C.[CH3:23][O:24][CH2:25]Cl>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][O:13][CH2:23][O:24][CH3:25])[NH2:8]
Reactant: O=[N+]([O-])c1ccc(CCO)c(Cl)c1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOCCc1ccc(N)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-(2-chloro-4-nitrophenyl)ethanol (2.9 g) in dichloromethane (20 ml) were added N,N-diisopropyl-ethylamine (3.0 ml) and chloromethyl methyl ether (1.2 ml) under ice-cooling, and the mixture was stirred for 18 hours at room temperature. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in methanol (20 ml), 3% platinum sulfide on activated carbon (wet) (842 mg) was added, and the mixture was stirred for 10 hours under a hydrogen atmosphere. After the catalyst was removed by filtration, the solvent was removed under reduced pressure to give 3-chloro-4-[2-(methoxy-methoxy)ethyl]aniline (2.0 g).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[C:4](I)[C:3]=1[OH:19].C([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][CH3:30])#C.Cl.[CH2:32](N(CC)CC)[CH3:33]>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.[Cu]I>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:9]2)=[C:4]2[CH:32]=[C:33]([C:26]3[CH:27]=[CH:22][C:23]([CH2:28][CH2:29][CH3:30])=[CH:24][CH:25]=3)[O:19][C:3]=12
Reactant: CCCCCC1CCc2c(I)c(O)c(F)c(F)c2O1
Reactant: C#Cc1ccccc1CCC
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Product: CCCCCC1CCc2c(c(F)c(F)c3oc(-c4ccc(CCC)cc4)cc23)O1
Temperature: 0 °C

Procedure:
2.0 g (5.23 mmol) of 7,8-difluoro-5-iodo-2-pentylchroman-6-ol are firstly stirred for 6 h at 60° C. together with 1.13 g (7.85 mmol) of ethynyl-n-propylbenzene in the presence of 110 mg (0.16 mmol) of bis(triphenylphosphine)palladium(II) chloride and 30 mg (0.16 mmol) of copper(I) iodide in 22 ml of triethylamine. The mixture is subsequently refluxed for 18 h. After cooling, the batch is added to ice/water and acidified using hydrochloric acid. The mixture is extracted a number of times with MTBE, and the combined extracts are washed with water and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2,
Reaction SMILES: ClCl.[CH2:3]=[CH2:4].[CH2:5]=[CH:6][CH3:7]>O>[CH2:6]1[CH:7]2[CH:4]3[CH:3]=[CH:5][CH:6]([CH:4]2[CH:3]=[CH:5]1)[CH2:7]3
Reactant: C=CC
Reactant: C=C
Agent: ClCl
Solvent: O
Product: C1=CC2C3C=CC(C3)C2C1

Procedure:
4 liters of chlorine gas (20°C, 1 atmosphere) were passed during a period of 30 minutes at 25°C in diffuse daylight through a dispersion of 35 g of a terpolymer in 1 liter of water. The terpolymer was composed of 53.9% by weight of ethylene, 42% by weight of propylene, and 4.1% by weight of 5-ethylidenenorbornene-2. The dispersed terpolymer particles ranged in size from 3 -22 mm. The dispersion was intensively stirred during the passage of the chlorine gas. After the passage of the chlorine gas was complete, the dispersion was ventilated and pure nitrogen gas was passed through the dispersion to remove any excess chlorine. The chlorinated terpolymer was recovered by filtration, and the resulting rubbery crumb was washed with distilled water and dried. The resulting terpolymer contained 3.3% by weight of chlorine. According to the N.M.R. analysis the copolymer thus prepared contained no allylic bounded chlorine.
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([S:7]([CH:10]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=2)[NH:11][CH:12]=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.O=P(Cl)(Cl)Cl.CCN(CC)CC>COCCOC>[Br:24][C:16]1[CH:15]=[C:14]([CH:10]([N+:11]#[C-:12])[S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:25])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[CH:19]=[C:18]([O:20][CH3:21])[C:17]=1[O:22][CH3:23]
Reactant: COc1cc(C(NC=O)S(=O)(=O)c2ccc(C)cc2)cc(Br)c1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: [C-]#[N+]C(c1cc(Br)c(OC)c(OC)c1)S(=O)(=O)c1ccc(C)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Compound 3b (4.75 g, 10.75 mmol) was suspended in dry DME (100 mL) and cooled to −10° C. POCl3 (3.1 mL, 33.1 mol) was added and a mixture of Et3N (7.5 mL, 53.8 mmol) in DME (10 mL) was dropped slowly to the reaction mixture. After stirring for 2 h at −5° C., the reaction mixture was poured into ice water. The water phase was extracted with ethyl acetate, the organic phase was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuum. By refrigeration over night a brown solid crystallized from the residue, which was collected and dried in vacuum. Yield: 2.75 g (6.71 mmol, 62%); brown solid of mp 109-110° C.; νmax (ATR)/cm−1 2915, 2135, 1593, 1569, 1489, 1452, 1420, 1325, 1295, 1275, 1238, 1199, 1136, 1081, 1048, 1003, 862, 826, 759, 705, 670; 1H NMR (300 MHz, CDCl3) δ 2.47 (3H, s), 3.81 (3H, s), 3.86 (3H, s), 5.46 (1H, s), 6.81 (1H, d, J=2.2 Hz), 7.01 (1H, d, J=2.2 Hz), 7.35 (2H, d, J=8.3 Hz), 7.64 (2H, d, J=8.3 Hz); 13C NMR (75.5 MHz, CDCl3) δ 321.8, 56.2, 60.7, 75.5, 111.5, 117.8, 123.2, 125.0, 129.9, 130.0, 130.5, 146.9, 148.5, 153.6, 166.6; m/z (EI) 256 (52), 254 (45), 244 (78), 242 (100), 200 (30), 123 (48), 91 (31).
Reaction SMILES: [OH:1]CCC1C=CC(CCO)=CC=1.C1N2CCN(CC2)C1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C1COCC1>[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([OH:1])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1ccc(CCO)cc1
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a stirred solution of the intermediate from Step A in THF (50 mL) was added DABCO (1.51 g, 13.5 mmol) and then p-toluenesulfonyl chloride (50 mL). The resulting mixture was stirred overnight at room temperature and then filtered to remove precipitated hydrochloride salts. The filtrate was concentrated under reduced pressure and DCM (50 mL) was added to the residue. The organic layer was then washed with water (1×100 mL), saturated NaCl (1×100 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The resulting material was purified by silica gel chromatography (70% EtOAc/hexane) to afford 1.25 g of the title intermediate (43% yield).
Reaction SMILES: Cl.[O:2]([CH2:6][CH2:7][NH2:8])[N+:3]([O-:5])=[O:4].C[O-].[Na+].[C:12]([N:14]=[C:15]([C:20]1[CH:21]=[N:22][C:23]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:24][CH:25]=1)OCCC)#[N:13]>CO>[C:12]([NH:14][C:15]([C:20]1[CH:21]=[N:22][C:23]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:24][CH:25]=1)=[N:8][CH2:7][CH2:6][O:2][N+:3]([O-:5])=[O:4])#[N:13]
Reactant: CCCOC(=NC#N)c1ccc(N(CC)CC)nc1
Reactant: NCCO[N+](=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCN(CC)c1ccc(C(=NCCO[N+](=O)[O-])NC#N)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 42.1 %

Procedure:
To a solution of 2-nitroxyethylamine hydrochloride (314 mg, 2.20 mmol) in methanol (3 ml) was added sodium methoxide (115 mg, 2.13 mmol) followed by a solution of propyl N-cyano-6-diethylamino-3-pyridinecarboximidate (370 mg, 1.42 mmol) in methanol (2 ml), and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, the reaction mixture was concentrated to dryness under reduced pressure. The residue was suspended in water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography with a mixed solvent of ethyl acetate and hexane as an eluent to give the title compound (183 mg, yield 42%) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH2:19])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].CS(O[C@H:31]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32]1)(=O)=O>CN(C=O)C>[NH2:19][C:17]1[N:16]=[CH:15][N:14]=[C:13]2[N:12]([C@@H:35]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34]3)[N:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[C:18]=12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Reactant: Nc1ncnc2[nH]nc(-c3ccc([N+](=O)[O-])cc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2nc(-c3ccc([N+](=O)[O-])cc3)c3c(N)ncnc32)C1
Reaction time: 2 h
Yield: 45.8 %

Procedure:
A solution of 3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.5 g, 1.95 mmol), K2CO3 (1.08 g, 7.8 mmol), and (S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl methanesulfonate (0.62 g, 2.34 mmol) in DMF (20 mL) was brought to 80° C. under an argon atmosphere. The reaction mixture was left stirring for 2 hours, then cooled and filtered. The filtrate was concentrated in vacuo, but not to dryness. 20 mL of 0.1 sodium citrate was added causing a solid to form, which was collected by filtration to afford (R)-tert-butyl 3-(4-amino-3-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (0.38 g, 46% yield). ESI-MS m/z [M+H]+ found 426.5, calculated 426.2.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]([OH:14])[CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][C:19]1[S:20][CH:21]=[CH:22][C:23]=1[Cl:24]>O1CCCC1>[ClH:1].[Cl:1][C:2]1[S:6][C:5]([CH:7]([O:14][CH2:18][C:19]2[S:20][CH:21]=[CH:22][C:23]=2[Cl:24])[CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:4][CH:3]=1
Reactant: OC(Cn1ccnc1)c1ccc(Cl)s1
Reactant: Clc1ccsc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cl
Product: Clc1ccc(C(Cn2ccnc2)OCc2sccc2Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
A solution of 1-(5-chloro-2-thienyl)-2-(1-imidazolyl) ethanol (1.1 g, 4.8 mmole) dissolved in dry tetrahydrofuran (10 ml) was added to a stirred suspension of sodium hydride (0.4 g, as 80% dispersion in oil, 16 mmole) in dry tetrahydrofuran (40 ml). After stirring for 1 hour at room temperature the mixture was cooled in ice and a solution of 2-bromomethyl-3-chloro-thiophene (1.0 g, 4.7 mmole) in dry tetrahydrofuran (10 ml) was added dropwise. The mixture was allowed to stir for a further 1 hour at 15° C and the solvent then removed under vacuum. The residue was extracted several times with diethyl ether and the etheral extracts were combined and evaporated. The residue was taken up in a little diethyl ether and treated with a solution of hydrogen chloride in diethyl ether to precipitate a gum which solidified on trituration with acetone and ether. Recrystallization from a mixture of acetone, methanol and diisopropyl ether gave 1-[2-(5 -chloro-2-thienyl)-2-(3-chloro-2-thienyl methoxy)ethyl]imidazole hydrochloride as a white solid (0.5 g, 32%) m.p. 120°-121° C. (Found: C, 41.6; H, 3.35; N, 6.9. C14H12N2Cl2OS2. HCl requires C, 42.5; H, 3.3; N, 7.1%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1OC)([O-:3])=[O:2].[NH2:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20]>O>[N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20])([O-:3])=[O:2]
Reactant: COc1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-]
Reactant: NCC(O)CO
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(NCC(O)CO)c([N+](=O)[O-])c1

Procedure:
0.05 mol (10.6 g) of 2,6-dinitro-4-methylanisole is dissolved in 50 ml of absolute alcohol. 0.1 mol (9.1 g) of 1-aminopropane-2,3-diol is added gradually to this solution, whilst stirring. The solution is heated under reflux for 3 hours 30 minutes. The alcohol is driven off in vacuo and 40 ml of iced water are added to the residual red oil. The expected product crystallises. It is filtered off and washed with water. After recrystallisation from an aqueous-alcoholic mixture and drying in vacuo, it melts at 118° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[N:36][CH:35]=[CH:34][N:33]=2)[CH:27]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[N:36][CH:35]=[CH:34][N:33]=2)[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1Cl
Product: Cc1cc(NC(=O)CC(=O)c2cccc(-c3cnccn3)c2)c(NC(=O)OC(C)(C)C)cc1Cl

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-methyl-phenyl)-carbamic acid tert-butyl ester (Example J21) (257 mg, 1.0 mmol) and 3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K14) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as a white solid (390 mg, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[C:8]([O:10]C)=O.Cl[C:13]1[N:18]=[CH:17][C:16]([C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH3:7][C:5]1[S:4][C:3]2[C:8](=[O:10])[N:18]3[CH:17]=[C:16]([C:19]([NH2:21])=[O:20])[CH:15]=[CH:14][C:13]3=[N:1][C:2]=2[CH:6]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: COC(=O)c1sc(C)cc1N
Solvent: ClC(Cl)Cl
Product: Cc1cc2nc3ccc(C(N)=O)cn3c(=O)c2s1
Yield: 14.6 %

Procedure:
A mixture of 2.7 g (0.0158 mol) of 3-amino-5-methyl-2-thiophenecarboxylic acid, methyl ester (German Patent 1055007, April 16, 1959) and 2.5 g (0.0158 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) is heated in an oil bath at 180°-190° C. for one hour. The mixture is cooled and then suspended in hot chloroform and filtered to give 0.6 g of 2-methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxamide; mp 375°-377° C. after recrystallization from pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[NH:5][CH3:6].C(N(CC)CC)C.[Br:18][C:19]1[C:20]([Cl:29])=[CH:21][C:22]([F:28])=[C:23]([CH:27]=1)[C:24](Cl)=[O:25]>C(Cl)Cl>[Br:18][C:19]1[C:20]([Cl:29])=[CH:21][C:22]([F:28])=[C:23]([CH:27]=1)[C:24]([N:5]([C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[CH3:6])=[O:25]
Reactant: CNc1ccccc1OC
Reactant: O=C(Cl)c1cc(Br)c(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1F
Temperature: 25 °C
Yield: 77.8 %

Procedure:
2-Methoxy-N-methylaniline (7.4 g, 53.8 mmol) and triethylamine (10.9 g, 107.7 mmol) were added to 5-bromo-4-chloro-2-fluoro-benzoyl chloride (Step 21D, 11.7 g, 43.1 mmol) in DCM (200 mL) at 0° C. The mixture was then allowed to warm to rt and concentrated. The mixture was partitioned in water and ethyl acetate. The organic layer was separated, washed with NaHSO4 solution, water and brine, and was dried. After filtration and concentration, the residue was purified via silica gel flash column chromatography eluting with ethyl acetate in hexane (50%) to give 5-bromo-4-chloro-2-fluoro-N-(2-methoxy-phenyl)-N-methyl-benzamide (12.5 g). MS: [M+H]+374.0/372.0; tR=2.70 min (method 1)