Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH:4]([OH:6])[CH:3]([OH:7])[CH2:2]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:7][CH:3]1[CH:4]([O:6][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:5][O:1][CH2:2]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OC1COCC1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1COCC1OS(C)(=O)=O
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Into a round-bottom flask, was placed a solution of tetrahydrofuran-3,4-diol (500 mg, 4.80 mmol, 1.00 equiv) and triethylamine (1.45 g, 14.3 mmol, 3.00 equiv) in dichloromethane (8 mL). The mixture was cooled to 0-5° C. and a solution of methanesulfonyl chloride (1.40 g, 12.2 mmol, 2.50 equiv) in dichloromethane (2 mL) was added drop-wise. The solution was stirred at room temperature for 2 h, and then diluted with dichloromethane (100 mL). The solution was washed with aqueous NH4Cl (2×30 mL) then brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuum to obtain the title compound as a brown solid (1.00 g, 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[CH3:13][Mg]Br>C(OCC)C>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]([OH:6])[CH3:13]
Reactant: COc1cccc(C=O)c1OC
Reactant: C[Mg]Br
Solvent: CCOCC
Product: COc1cccc(C(C)O)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A solution of 2,3-dimethoxybenzaldehyde (10.0 g, 60.2 mmol) in dry ethyl ether (100 ml) was added at 0° C. with a 3M solution of methylmagnesium bromide in ethyl ether (35 ml) and left under stirring at 0° C. for 0.5 h. Afterwards the reaction mixture was added with a diphasic mixture of ethyl ether and an ammonium chloride saturated solution, extracting the aqueous phase with ethyl ether. The organic extracts were dried and the solvent was evaporated off under reduced pressure, thereby obtaining 10.06 g of the title compound (92% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:11]=O)[S:10][C:3]=12.[NH2:13][OH:14].Cl>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:11]=[N:13][OH:14])[S:10][C:3]=12
Reactant: NO
Reactant: O=Cc1cc2nccc(Cl)c2s1
Agent: Cl
Solvent: CO
Solvent: O
Product: ON=Cc1cc2nccc(Cl)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of aldehyde 14 (scheme 3) in MeOH was added NH2OH×HCl (227 mg, 3.26 mmol) in water (0.5 mL) and the mixture was stirred at room temperature for 0.5 h. The solvents were removed by under reduced pressure and the residue was partitioned between EtOAc and water. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness to afford the title compound 125 (458 mg, 85% yield) as a white solid. MS (m/z) 213.1/215.1 (M+H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][C:14]([CH3:38])([CH3:37])[CH2:15][O:16][C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([N+:34]([O-:36])=[O:35])[CH:28]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:18].O[CH:40]([CH2:62][CH2:63][CH3:64])[CH:41]([C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:53])[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43]>C1COCC1>[CH3:38][C:14]([CH3:37])([CH3:13])[CH2:15][O:16][C:17]([NH:19][C@H:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C@H:40]([CH2:62][CH2:63][CH3:64])[CH:41]([C:52]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[O:53])[C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])=[C:29]([N+:34]([O-:36])=[O:35])[CH:28]=1)=[O:18]
Reactant: CCCC(O)C(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)c([N+](=O)[O-])c1)NC(=O)OCC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: CCC[C@@H](Oc1ccc(C[C@H](NC(=O)OCC(C)(C)C)C(=O)OCC)cc1[N+](=O)[O-])C(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 16 h

Procedure:
5.43 g of polymer-bound DEAD (diethyl azodicarboxylate) in 30 ml of THF are added to a solution of 4 g of 12 and 5.35 g of dibenzyl 2-hydroxypentanedicarboxylate (X) in anhydrous THF. The mixture is shaken for 16 hours. The polymer is separated off, and the solvent is removed. The residue is taken up in ethyl acetate, and conventional work-up gives 13, which is not purified further for the further reaction.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].[I-:18].[Na+]>CC(C)=O>[I:18][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CI)CC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 81.4 %

Procedure:
A mixture of tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate (150 mg, 0.57 mmol) and sodium iodide (260 mg, 1.73 mmol) in acetone (6 mL) was stirred at room temperature for 21 h, and then the reaction mixture turned to a suspension containing white solid. The solids were eliminated by filtration, and the filtrate was dried to vacuo and washed with CH2Cl2 and H2O. The organic layer then dried over MgSO4, filtered and concentrated to give tert-butyl 4-(2-iodoacetyl)piperazine-1-carboxylate (164.4 mg, 84.4% yield). C11H191N2O3; brown solid; mp 69-71° C.; IR vmax (neat) 2976, 2926, 2861, 1696, 1650, 1459, 1419, 1366, 1258, 1168, 1028, 996, 750 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.76 (2H, s), 3.57 (2H, m), 3.51 (2H, m), 3.41 (4H, m) 1.47 (9H, s); 13C NMR (100 MHz, CDCl3) δ 166.5, 154.2, 80.4, 47.0, 43.0 (2×), 41.9 (2×), 28.4 (3×).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH2:6][CH2:5]2.CN(C)C=O.[Br:24]N1C(=O)CCC1=O>O>[Br:24][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C@H:7]([C@@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH2:8]2
Reactant: CC1(C2CCc3cc(O)ccc3C2)COC(=O)N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]1([C@H]2CCc3c(ccc(O)c3Br)C2)COC(=O)N1
Reaction time: 6 h
Yield: 95.8 %

Procedure:
To a mixture of 4-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-4-methyloxazolidin-2-one (100 mg, 0.0004 mol) (pure isomer 2) in N,N-Dimethylformamide (0.5 mL, 0.006 mol) was added N-Bromosuccinimide (72.0 mg, 0.000404 mol) in N,N-Dimethylformamide (0.5 mL, 0.006 mol) and was stirred at for 6 hrs. Water was added, and the mixture was extracted with dichloromethane. The solvent was removed and residue was purified with Isco (12 g silica gel, 0-40% MeOH:DCM) to give a white precipitate (125 mg, 95% yield). 1H NMR showed a single isomer. The solid (10.1 mg) was dissolved in MeOH (3 mL) and the solvent allowed to evaporate slowly to give white needles, which was washed with MeOH and collected (5.0 mg). LCMS 1.23 min 328.21 ([M+2], 100%). X-ray shows (S,S) configuration, see FIG. 2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[F:26])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29]>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[F:26])=[N:28][OH:29])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(c1ccc(C(F)(F)F)cc1F)C1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(c1ccc(C(F)(F)F)cc1F)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
A mixture of (1-benzyl-piperidin-4-yl)-(2-fluoro-4-trifluoromethyl-phenyl)-methanone (5.0 g, 13.66 mmol), hydroxylamine hydrochloride (1.1 g, 16.39 mmol) and pyridine (50 mL) was stirred at room temperature overnight when the mixture was distilled to remove pyridine (35 mL). The solid residue was washed with heptane then ether. The resulting solid was partitioned between a saturated solution of NaHCO3 and EtOAc. The organic layer was dried (MgSO4), filtered and evaporated. The solid residue was washed with 3:1 heptane/EtOAc and dried under vacuum to obtain 2.1 g (40%) of the desired product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[S-:14][C:15]#[N:16].[Na+]>C1(C)C=CC=CC=1.OS(O)(=O)=O>[C:15]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)(=[S:14])[NH2:16]
Reactant: COC(=O)[C@@H](C)c1ccc(N)cc1
Reactant: N#C[S-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](C)c1ccc(NC(N)=S)cc1
Temperature: 25 °C
Yield: 49.4 %

Procedure:
In a 500 ml round-bottomed flask equipped with condenser and magnetic stirrer, at room temperature methyl (2S)-2-(4-aminophenyl)propanoate (17.5 g, 98 mmol) was dissolved in toluene (300 ml) and conc. H2SO4 (2.6 mmol, 50 mmol) was slowly added to the solution Sodium thiocyanate (10.29 g, 128 mmol) was added and the reaction mixture refluxed 24 h. After cooling at room temperature, the solution was washed with a saturated solution of NH4Cl (2×100 ml), dried over anhydrous Na2SO4 and evaporated under vacuum to give a crude which, after purification by flash chromatography (n-hexane/EtOAc 1/1), afforded pure (S)-methyl 2-[4-(carbamothioylamino)phenyl]propanoate (10.7 g, 48.4 mmol) as white solid (49%). 1H-NMR (CDCl3): δ 8.25 (bs, 1H, CSNH), 7.40 (d, 2H, J=7 Hz), 7.20 (d, 2H, J=7 Hz), 6.20 (bs, 2H, CSNH2), 3.75 (m, 1H), 3.65 (s, 3H), 1.50 (d, 3H, J=7 Hz).
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)C=C)[CH2:2]CC.Br[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=1)[C:22]#[N:23].[Cl-].[NH4+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=1)[C:22]#[N:23])=[CH2:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1cncc(Br)c1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1cncc(C#N)c1
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 70.3 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (0.460 g, 0.66 mmol) and tributyl-vinyl-stannane (7.2 mL, 24.6 mmol) to a solution of 5-bromonicotinonitrile (3.0 g, 16.4 mmol) in toluene (50 mL) and stir at 110° C. for 150 min. Add an aqueous saturated solution of ammonium chloride and ethyl acetate and separate the layers. Wash the organic layer twice with an aqueous saturated solution of potassium fluoride and once with water. Dry (sodium sulfate), filter, and concentrate. Purify the residue by silica gel chromatography, eluting with 3:1 hexane:ethyl acetate, to give the title compound (1.5 g, 70%).
Reaction SMILES: C[Mg]Br.[Cl:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12].Br[CH2:14][C:15]#[C:16][CH2:17][CH:18]=[C:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[Cl-].[NH4+]>CCOCC.O1CCCC1>[Cl:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH2:14][C:15]#[C:16][CH2:17][CH:18]=[C:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCC(C)=CCC#CCBr
Reactant: C#CCCCCCCCl
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCC(C)=CCC#CCC#CCCCCCCCl
Temperature: 25 °C

Procedure:
To 21 ml. of 3M ethereal methyl magnesium bromide in 47.5 ml. of dry tetrahydrofuran under nitrogen was added 9.2 g. of 1-chloro-7-octyne in 15 ml. of tetrahydrofuran. The mixture was heated under reflux for 30 min., then was allowed to cool to room temperature during another 30 minutes after which 365 mg. of cuprous chloride was added. The mixture was heated under reflux for 20 min., then a solution of 14 g. of 1-bromo-6-methyl-undec-2-yn-5-ene in 12.9 ml. of tetrahydrofuran was added. The mixture was heated under reflux for 10 hrs. then cooled in an ice bath and 250 ml. saturated aqueous ammonium chloride was added. Ether was added and the mixture was filtered through Celite (diatomaceous earth filter ald) and separated. The thus obtained ether layer was washed with saturated aqueous sodium chloride, dried with magnesium sulfate, and evaporated. The thus obtained residue was distilled through a rocking short-path distillation apparatus, collecting 11.5 g. of a mixture comprising 1-chloro-14-methylnonadeca-7,10-dlyn-13-ene at a bath temperature of 180°-190°/0.005 mm.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5](F)=[O:6].[CH3:14][OH:15]>C(N(CC)CC)C>[Br:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([O:15][CH3:14])=[O:6]
Reactant: CO
Reactant: O=C(F)c1cc(F)c(F)c(Br)c1F
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(F)c(F)c(Br)c1F
Reaction time: 1 h

Procedure:
772 g of 3-bromo-2,4,5-trifluoro-benzoylfluoride are added dropwise with ice-cooling to a mixture of 1460 ml of methanol and 340 g of triethylamine. Stirring is carried out at room temperature for 1 hour. The reaction mixture is concentrated, the residue is taken up in water and methylene chloride, and the aqueous phase is again extracted by shaking with methylene chloride. After drying the organic phase over sodium sulphate, it is concentrated and the residue is distilled in vacuo. 752.4 g of methyl 3-bromo-2,4,5-trifluoro-benzoate of boiling point 122° C./20 mbar are obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Cl:11][C:12]1[CH:20]=[C:19]([CH:21]=O)[CH:18]=[C:17]2[C:13]=1[CH:14]=[N:15][NH:16]2>>[Cl:11][C:12]1[CH:20]=[C:19](/[CH:21]=[C:3]2/[C:2](=[O:10])[NH:1][C:9]3[C:4]/2=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:18]=[C:17]2[C:13]=1[CH:14]=[N:15][NH:16]2
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1cc(Cl)c2cn[nH]c2c1
Product: O=C1Nc2ccccc2/C1=C\c1cc(Cl)c2cn[nH]c2c1
Yield: 16.9 %

Procedure:
The compound was synthesized according to the method described for Example A1. Oxindole (8 mg, 0.06 mmol) was reacted with 4-chloro-1H-indazole-6-carbaldehyde (11 mg, 0.06 mmol) to give the title compound as an orange solid (3 mg, 13%). 1H NMR (400 MHz, CD3OD) δ 8.21 (s, 1H), 7.87 (s, 1H), 7.82 (s, 1H), 7.59 (d, 1H, J=7.8 Hz), 7.48 (s, 1H), 7.28 (t, 1H, J=7.9 Hz), 6.95 (d, 1H, J=7.7 Hz), 6.90 (t, 1H, J=8.2 Hz); MS ESI [M+H]+, calcd for [C16H10ClN3O+H]+ 296.1; found m/z 296.1.
Reaction SMILES: [C:1]1([C:6]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:7]=2[C:8]([NH:10][C:11]2([C:20]([OH:22])=[O:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH:2]=1>CCO.[Pd]>[CH:1]1([C:6]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:7]=2[C:8]([NH:10][C:11]2([C:20]([OH:22])=[O:21])[CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:19]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1C1=CCCC1
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1C1CCCC1
Yield: 50.1 %

Procedure:
To a solution of 2-(2-cyclopent-1-enyl-3-methyl-benzoylamino)-indan-2-carboxylic acid (132) (365 mg, 1.01 mmol) in absolute EtOH (15 mL) is added the catalyst, Pd—C (50% wetted powder, 10% Pd, 192 mg, 9% mmol) under argon. The resulting reaction mixture is moved to the Paar apparatus to run hydrogenation: 50 psi, 50° C., overnight. The catalyst is removed by the filtration through a pre-column (10 g silica gel) and washed by EtOH. The combined EtOH solution is concentrated in vacuo. The residue is purified by HPLC to give a pure product (133) as white solid (184 mg, 50%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:15][C:8]=2[C:7]=1[OH:20])=[O:5])[CH3:2].[CH:21](B(O)O)=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[N:13]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:15][C:8]=2[C:7]=1[OH:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2nc(C(C)(C)C)sc2c1O
Reactant: OB(O)C=Cc1ccccc1
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: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(C=Cc2ccccc2)c2nc(C(C)(C)C)sc2c1O
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere 4-bromo-2-tert-butyl-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (300 mg, 0.835 mmol), styreneboronic acid (185 mg, 1.25 mmol), cesium carbonate (675 mg, 2.08 mmol), and tetrakis(triphenylphosphine)palladium(0)(143 mg, 0.12 mmol) were suspended in 4 mL of anhydrous 1,4 dioxane. The reaction was heated at reflux temperature for 18 h, then cooled to room temperature and diluted with ethyl acetate. The organic mixture was successively washed with water, saturated sodium bicarbonate, and brine solutions. The organic fractions were dried over anhydrous sodium sulfate and concentrated to a crude solid residue, which was then purified by column chromatography, eluting the desired product from silica gel with a gradient of 10-90% ethyl acetate in hexanes: 180 mg of a yellow oil. MS: (+) m/z 382.9 (M+1).
Reaction SMILES: [NH2:1][N:2]1[C:6]([CH2:7][CH3:8])=[CH:5][CH:4]=[C:3]1[C:9]([C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)=O.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([CH3:30])=O)=[CH:23][CH:22]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:7]([C:6]1[N:2]2[N:1]=[C:28]([CH3:30])[C:27]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[C:3]2=[CH:4][CH:5]=1)[CH3:8]
Reactant: CCc1ccc(C(=O)c2ccc(C#N)cc2)n1N
Reactant: COc1ccc(CC(C)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ccc2c(-c3ccc(C#N)cc3)c(-c3ccc(OC)cc3)c(C)nn12
Temperature: 80 °C
Yield: 20.2 %

Procedure:
To a solution of 4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (100 mg) in toluene (1 mL) were added 1-(4-methoxyphenyl)acetone (103 mg) and p-toluene-sulfonic acid monohydrate (16 mg) at ambient temperature. The reaction mixture was heated at 80° C. for 3 hours. The mixture was evaporated in vacuo. The residue was purified by flash silica gel column chromatography eluting with hexane-ethyl acetate 20-1 and 15-1 to give 4-[7-ethyl-3-(4-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile (31 mg, 20.2%) as an yellow solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1([C:11]([F:14])([F:13])[F:12])[O:7][CH:6]([C:8](O)=[O:9])[CH2:5][O:4]1.N1C=CC=CC=1.S(Cl)([Cl:25])=O>>[F:1][C:2]([F:16])([F:15])[C:3]1([C:11]([F:14])([F:13])[F:12])[O:7][CH:6]([C:8]([Cl:25])=[O:9])[CH2:5][O:4]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1COC(C(F)(F)F)(C(F)(F)F)O1
Solvent: c1ccncc1
Product: O=C(Cl)C1COC(C(F)(F)F)(C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
2,2-Bis(trifluoromethyl)-1,3-dioxolan-4-oyl chloride was prepared from 2,2-bis(trifluoromethyl)-4-carboxy-1,3-dioxolane (see U.S. patent application 07/401,668, filed Aug. 30, 1989) (25.4 g, 0.1 mole). To this substrate was added pyridine (3.16 g, 0.04 mole) followed by thionyl chloride (14.3 g, 0.12 mole), with external cooling to maintain the pot at ambient temperature. When the addition was complete, the reaction mixture was heated slowly to 70° C. for 1.5 hour, then at 90° to 100° C. for 0.5 hour. The product was distilled from the reaction mixture, a clear colorless liquid, 22.0 g (81% yield) was obtained. Bp. 50° C./10 mm. 1H-NMR (Neat): δ 5.23 (t, J=7.0 Hz, 1H), 4.73 (m, 2H); 19F NMR (neat): -80.5 (q, J=8.5 Hz, 3F), -81.5 (q, J=8.5 Hz, 3F). Anal. Calc. for C6H3ClF6O3 : C: 26.44, H: 1.11, F: 41.83, Cl: 13.00; Found: C: 26.13, H: 1.11, F: 41.44, Cl: 13.38. ##STR6##
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:7][N:6]=1)([O-])=O.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[CH2:26][S:27][CH2:28][CH2:29]N>C(O)C>[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[CH2:26][S:27][CH2:28][CH2:29][NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:7][N:6]=1
Reactant: COc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: NCCSCc1nccs1
Solvent: CCO
Product: COc1ccc(Cc2cnc(NCCSCc3nccs3)[nH]c2=O)cn1
Yield: 60 %

Procedure:
An equimolar mixture of 2-nitroamino-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone and 2-(2-thiazolylmethylthio)ethylamine was heated under reflux in ethanol for 18 hours. The solid which crystallised out on cooling was recrystallised from ethanol to give 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone, m.p. 95°-7°, in 60% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15]2.[OH-].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[O:9])[CH:3]=1
Reactant: Fc1ccc2c(c1)CCN2
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(c1cc(Cl)ncn1)N1CCc2cc(F)ccc21
Reaction time: 1 h

Procedure:
0.92 g (4.9 mmol) 6-chloro-pyrimidine-4-carboxylic acid chloride in 40 mL DCM were cooled in an ice/acetone bath and mixed with 0.67 g (4.9 mmol) 5-fluoro-2,3-dihydro-1H-indole. Another 5 mL (5.0 mmol) of a 1N aqueous sodium hydroxide solution were added dropwise and the mixture was stirred for 1 h with cooling. Then 50 mL of a saturated sodium hydrogen carbonate solution were added and the mixture was stirred for a further 10 min. The organic phase was separated off, extracted with 1N aqueous hydrochloric acid solution and with water, dried and evaporated down.
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:36][CH3:37])=[C:25]([NH:27][C:28]2[C:33]([Cl:34])=[CH:32][N:31]=[C:30](Cl)[N:29]=2)[CH:26]=1>>[Cl:34][C:33]1[C:28]([NH:27][C:25]2[CH:26]=[C:21]([Cl:20])[CH:22]=[CH:23][C:24]=2[O:36][CH3:37])=[N:29][C:30]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:19])[CH3:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:31][CH:32]=1
Reactant: COc1cc2c(cc1N)CCN(CC(C)(F)F)CC2
Reactant: COc1ccc(Cl)cc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3cc(Cl)ccc3OC)n1)CCN(CC(C)(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-propyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (5-Chloro-2-methoxy-phenyl)-(2,5-dichloro-pyrimidin-4-yl)-amine in an analogous manner to Example 61e. Product isolated as an off-white solid (0.063 g, 71%). MP: 170-173° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.48 (s, 1H), 8.09 (s, 1H), 8.00 (s, 1H), 7.78 (s, 1H), 7.42 (s, 1H), 7.03-6.98 (m, 1H), 6.86-6.82 (m, 1H), 6.65 (s, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 2.89-2.78 (m, 10H), 1.68 (t, 3H, J=18.7 Hz). MS: 538 (MH)+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:27]=[CH:26][C:12]([O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=3[C:22]([F:25])([F:24])[F:23])=[C:11]([F:28])[CH:10]=2)[S:3]1.Cl[CH2:30][CH2:31][N:32]([CH3:34])[CH3:33]>>[CH3:33][N:32]([CH3:34])[CH2:31][CH2:30][N:6]1[C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:27]=[CH:26][C:12]([O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=3[C:22]([F:25])([F:23])[F:24])=[C:11]([F:28])[CH:10]=2)[S:3][C:2]1=[O:1]
Reactant: N#Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2F)c(C(F)(F)F)c1
Reactant: CN(C)CCCl
Product: CN(C)CCN1C(=O)SC(=Cc2ccc(Oc3ccc(C#N)cc3C(F)(F)F)c(F)c2)C1=O

Procedure:
The title compound was prepared using 4-[4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2-fluoro-phenoxy]-3-trifluoromethyl-benzonitrile and (2-Chloro-ethyl)-dimethyl-amine as described in Example 1. 1H NMR (400 Hz, CDCl3) δ 7.95 (s, 1H), 7.76 (s, 1H), 7.69 (dd, 1H), 7.27 (m, 3H), 6.84 (d, 1H), 3.91 (t, 2H), 2.76 (bt, 2H), 2.40 (s, 6H); LC/MS (m/z) [M+1]+ 480.1 (calculated for C22H18F4N3O3S, 480.45).