Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[Br:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(N(CC)CC)C>ClCCl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:29][C:30]1[CH:35]=[C:34]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])[CH:33]=[CH:32][CH:31]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reactant: OB(O)c1cccc(Br)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cccc(Br)c3)S(C)(=O)=O)c(C3CC3)cc12
Reaction time: 48 h
Yield: 38.7 %

Procedure:
A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide (500 mg, 1.24 mmol), 3-bromophenylboronic acid (1.5 g, 7.46 mmol), copper(II) acetate monohydrate (372 mg, 1.87 mmol), triethylamine (252 mg, 2.49 mmol), 4 Å molecular sieves (1 g) in dichloromethane (160 mL) was stirred for 2 days. The solid was filtered off, the filtrate was concentrated to dryness and purified by column chromatography to afford 6-(N-(3-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (270 mg, 0.48 mmol, 39% yield) as a brown solid. LCMS (m/z, ES+)=557, 559 (M+H+).
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6]Br.C(Br)=C.[C:11](=[O:13])=O.C(O)C.[Cl:17][C:18]1[CH:32]=[CH:31][C:21]2[S:22][CH2:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3C[C:20]=2[CH:19]=1>O1CCCC1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[S:22][CH2:23][C:24]3[CH:25]=[CH:27][CH:28]=[CH:29][C:30]=3[C:11]([CH:5]=[CH2:6])([OH:13])[C:31]=2[CH:32]=1
Reactant: O=C=O
Reactant: BrCCBr
Reactant: Clc1ccc2c(c1)Cc1ccccc1CS2
Agent: C=CBr
Agent: II
Agent: [Mg]
Solvent: CCO
Solvent: C1CCOC1
Product: C=CC1(O)c2ccccc2CSc2ccc(Cl)cc21
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 95 %

Procedure:
Magnesium (4.94 g, 0.203 mol) under tetrahydrofuran (15 ml) was activated with a grain of iodine and 1,2-dibromoethane (0.4 ml). After the reaction was finished, 10% of a solution of vinylbromide (21.4 g, 0.2 mol) in tetrahydrofuran (70 ml) was added (dry ice-ethanol condenser, nitrogen atmosphere). The reaction started immediately, and the remaining part of the vinylbromide solution was added dropwise under stirring at such a rate (over 45 minutes) as to maintain the temperature at 58-62° C. The mixture was heated at reflux temperature for 30 minutes and then cooled to 30° C. Over 1 h, a solution of 2-chloro-6,11-dihydrodibenzo[b,e]thiepine (28.9 g, 0.1 mol, prepared as described in Es. farmacie 11, 451, 1962) in tetrahydrofuran (70 ml) was added dropwise under stirring (30-35° C.). The mixture was allowed to stand overnight at room temperature and then quenched under cooling (ice and sodium chloride) with a solution of ammonium chloride (21 g) in water (100 ml). Toluene (100 ml) was added, the mixture was filtered and the aqueous layer was extracted with toluene (3×100 ml). The toluene solutions were combined, dried (MgSO4) and evaporated. The residue was crystallised from a mixture of benzene (50 ml) and hexane (100 ml) to give 27.4 g (95%) of 2-chloro-11-vinyl-6,11-dihydrodibenzo[b,e]thiepin-11-ol.
Reaction SMILES: [C:1]1([C:7]2[O:8][N:9]=[C:10]3[C:15]([CH2:16][C:17]([OH:19])=[O:18])=[CH:14][CH:13]=[CH:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20](I)[CH3:21].O>CN(C)C=O>[CH2:20]([O:18][C:17](=[O:19])[CH2:16][C:15]1[C:10]2[C:11](=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][N:9]=2)[CH:12]=[CH:13][CH:14]=1)[CH3:21]
Reactant: O=C(O)Cc1cccc2c(-c3ccccc3)onc12
Reactant: CCI
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cccc2c(-c3ccccc3)onc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5.9 %

Procedure:
To a stirred slurry of 0.7 g (0.014 mole) of washed (petroleum ether), 50% sodium hydride/oil in 5 ml of dry dimethylformamide was added a solution of 2.9 g (0.012 mole) of 3-phenyl-2,1-benzisoxazol-7-acetic acid in 15 ml of dimethylformamide. The mixture was stirred at ambient temperature for 10 minutes and then 2.0 g (0.013 mole) of ethyl iodide was added. The dark solution was stirred at ambient temperature for 1 hr and then poured into 500 ml of water and let stand overnight. The mixture was filtered and the collected solid was recrystallized from 2-propanol to give 0.2 g (6%) of solid, m.p. 97°-98° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.Cl[CH2:22][CH2:23][CH2:24][C:25]1[C:29]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:28]=2[O:27][N:26]=1.[C:35]([O-:38])([O-:37])=O.[K+].[K+]>CN(C=O)C>[C:9]([OH:8])(=[O:27])[C:35]([OH:38])=[O:37].[F:34][C:32]1[CH:31]=[CH:30][C:29]2[C:25]([CH2:24][CH2:23][CH2:22][N:1]3[CH2:2][CH2:3][CH:4]([CH:7]4[C:13]5=[CH:14][CH:15]=[CH:16][N:12]5[CH2:11][C:10]5[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=5[O:8]4)[CH2:5][CH2:6]3)=[N:26][O:27][C:28]=2[CH:33]=1
Reactant: O=C([O-])[O-]
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Reactant: Fc1ccc2c(CCCCl)noc2c1
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc2c(CCCN3CCC(C4Oc5ccccc5Cn5cccc54)CC3)noc2c1
Product: O=C(O)C(=O)O

Procedure:
To 50 ml dry DMF were added 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (3.0 g, 0.0112 mole), 3-(3-chloropropyl)-6-fluoro-1,2-benzisoxazole (4.2 g, 0.02 mole), milled K2CO3 (10 g, 0.07 mole) and KI (0.01 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:38]=[CH:37][C:20]([C:21]([N:23]([CH2:31][C:32](OCC)=[O:33])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>C(O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH2:31][CH2:32][OH:33])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])=[O:22])=[CH:37][CH:38]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1)c1ccccc1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(CCO)c3ccccc3C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-ethoxycarbonylmethyl-N-(2-methylphenyl)benzamide (100 mg) in ethanol (5 ml) was added sodium borohydride (37 mg) at 0° C. and the mixture was stirred for 2 hours at ambient temperature. Since the reaction was not completed and it was so slow, sodium borohydride (220 mg) was added to the mixture at 0° C. and stirred overnight. The reaction mixture was neutralized with 1N hydrochloric acid and diluted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. Filtering and the removal of solvents afforded 4-(4′-methylbiphenyl-2-carboxamido)-N-(2-hydroxyethyl)-N-(2-methylphenyl)benzamide (70 mg) as a colorless prisms.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.O[CH2:14][CH:15]([CH2:17]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.OS(O)(=O)=O.O>>[F:9][C:8]1[C:2]([F:1])=[CH:3][C:4]([N+:10]([O-:12])=[O:11])=[C:5]2[C:7]=1[CH:14]=[CH:15][CH:17]=[N:6]2
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(F)c(F)c2cccnc12
Yield: 82.8 %

Procedure:
In a similar fashion using route 10 general procedure 20, 4,5-difluoro-2-nitroaniline (200 mg, 1.15 mmol), glycerol (330 mg, 3.56 mmol), 3-nitrobenzenesulfonic acid sodium salt (336 mg, 1.49 mmol) and H2SO4/H2O (1.2 ml, 7:5) gave the title compound (200 mg, 83%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23])([O-:14])=[O:13]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([N+:12]([O-:14])=[O:13])=[C:16]([C:22]([F:23])([F:24])[F:25])[CH:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Product: O=C(Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1)c1cc(Br)ccc1O
Yield: 49.7 %

Procedure:
Using 5-bromosalicylic acid and 4-nitro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH3:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](O)=[O:19].F[C:22](F)(F)[C:23]([O:25][C:26](=O)[C:27](F)(F)F)=O.[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39]([CH3:46])=[CH:40][C:41]([O:43]CC)=[O:42].C(=O)([O-])[O-].[Na+].[Na+]>Cl(O)(=O)(=O)=O.CCOCC>[CH3:22][CH2:23][O:25][CH2:26][CH3:27].[O:19]=[C:18]([C:38]1[O:34][C:35]([C:39]([CH3:46])=[CH:40][C:41]([O-:43])=[O:42])=[CH:36][CH:37]=1)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH:7]=[CH:6][CH2:5][CH:4]=[CH:3][CH2:2][CH3:1]
Reactant: CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)C=C(C)c1ccco1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Product: CCC=CCC=CCC=CCCCCCCCC(=O)c1ccc(C(C)=CC(=O)[O-])o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 13.0 g (0.05 mole) of linolenic acid and 12.6 g (0.06 mole) of trifluoroacetic anhydride is stirred at room temperature for 1 hour. To the mixture 9.0 g (0.05 mole) of ethyl 3-(2-furanyl)-2-butenoate is added and the mixture is cooled and stirred at -10° C. To the mixture 5 drops of 70% perchloric acid is added and the mixture stirred at 0° C. for 3 hours. The mixture is diluted with 200 ml of ether and combined with 200 ml of saturated aqueous sodium carbonate. The layers are separated and the ether layer is washed with water, brine and evaporated to dryness. The residue is distilled under high vacuum to give ether 3-[5-(1-oxo-9,12,15-octadecatrienyl)-2-furanyl]-2-butenoate, which ester is dissolved in 300 ml of anhydrous ethanol and the solution is cooled on an ice-bath. To the mixture 14.6 g (0.2 mole) of diethylamine is added and the mixture allowed to warm up to room temperature and stand for 3 days. The reaction mixture is evaporated to dryness to give N,N-diethyl-3-[5-(1-oxo-9,12,14-octadecatrienyl)-2-furanyl]-2-butenamide.
Reaction SMILES: [S:1]([O:6]C)([O:4][CH3:5])(=[O:3])=[O:2].O.[N+:9]([C:12]1[CH:17]=[C:16]([NH2:18])[C:15]([S:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:14][C:13]=1[NH2:25])([O-:11])=[O:10]>C(OCC)(=O)C>[CH3:5][O:4][S:1]([O-:6])(=[O:3])=[O:2].[N+:9]([C:12]1[CH:17]=[C:16]([NH2:18])[C:15]([S:19][CH2:20][CH2:21][N+:22]([CH3:5])([CH3:23])[CH3:24])=[CH:14][C:13]=1[NH2:25])([O-:11])=[O:10]
Reactant: CN(C)CCSc1cc(N)c([N+](=O)[O-])cc1N
Reactant: COS(=O)(=O)OC
Solvent: O
Solvent: CCOC(C)=O
Product: COS(=O)(=O)[O-]
Product: C[N+](C)(C)CCSc1cc(N)c([N+](=O)[O-])cc1N

Procedure:
4.8 ml (0.05 mol) of dimethyl sulphate were added to a suspension, at room temperature, of 13.7 g (0.05 mol) of 2-nitro-5-(dimethylaminoethylthio)paraphenylenediamine monohydrate, prepared in Example 16, in 250 ml of ethyl acetate.
Reaction SMILES: N#N.Cl.[C:4]([O:9]CCN)(=O)[C:5]([CH3:7])=[CH2:6].C1(C=CC(O)=CC=1)O.C([N:23](CC)CC)C.[CH:28]([N:30]=[C:31]=[O:32])=[CH2:29]>C(Cl)(Cl)Cl>[C:4]([CH:29]=[CH:28][NH:30][C:31]([NH2:23])=[O:32])(=[O:9])[C:5]([CH3:7])=[CH2:6]
Reactant: C=CN=C=O
Reactant: CCN(CC)CC
Reactant: C=C(C)C(=O)OCCN
Agent: Cl
Agent: N#N
Agent: Oc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)C=CNC(N)=O

Procedure:
A 500 ml 3-necked round bottom flask equipped with a reflux condenser, a mechanical stirrer, a thermometer, a dropping funnel and an efficient N2 blanket, is charged with 2-aminoethyl methacrylate hydrochloride 41.4 g (0.25 mole), 50 mg of hydroquinone and 300 ml of chloroform. The contents are cooled to between 0 and 5 degrees C. and stirred. Through a dropping funnel 25.3 g (0.25 mole) of triethylamine and 13.3 g (0.25 mole) of vinyl isocyanate in 50 ml of chloroform are added into the reaction flask and maintained at between 0 and 5 degrees C. The temperature is allowed to rise to room temperature with the contents stirred constantly overnight, passed through a silica gel column and dried with magnesium sulfate. The contents are then evaporated under reduced pressure to give the named product.
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[N:27]=[C:26]([C:37]2[CH:42]=[CH:41][C:40]([NH:43][C:44]([NH:46][CH:47]3[CH2:49][CH2:48]3)=[O:45])=[CH:39][CH:38]=2)[CH:25]=1.[CH3:50][S:51][C:52]1[C:57](B2OC(C)(C)C(C)(C)O2)=[CH:56][CH:55]=[CH:54][N:53]=1>>[CH:47]1([NH:46][C:44]([NH:43][C:40]2[CH:41]=[CH:42][C:37]([C:26]3[CH:25]=[C:24]([C:57]4[C:52]([S:51][CH3:50])=[N:53][CH:54]=[CH:55][CH:56]=4)[N:29]=[C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]4[CH3:36])[N:27]=3)=[CH:38][CH:39]=2)=[O:45])[CH2:49][CH2:48]1
Reactant: CSc1ncccc1B1OC(C)(C)C(C)(C)O1
Reactant: C[C@H]1COCCN1c1nc(Cl)cc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: CSc1ncccc1-c1cc(-c2ccc(NC(=O)NC3CC3)cc2)nc(N2CCOC[C@@H]2C)n1
Yield: 65 %

Procedure:
Method as described for intermediate 5 using (S)-1-(4-(6-chloro-2-(3-methylmorpholino)pyrimidin-4-yl)phenyl)-3-cyclopropylurea (intermediate 22) and 2-(methylsulfanyl)pyridine-3-boronic acid pinacol ester to afford a yellow solid (160 mg, 65%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[CH2:19][C:18]1=[O:26]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:19]1[C:20]2[C:25](=[N:24][CH:23]=[CH:22][CH:21]=2)[NH:17][C:18]1=[O:26])([CH3:3])[CH3:2]
Reactant: O=C1Cc2cccnc2N1
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ncccc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was methylated and then formylated. The aldehyde was condensed with 7-aza-2-oxindole to give 0.2 g of 3-(3,5-diisopropyl-4-methoxy-benzylidene)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one as a yellow-orange solid.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([NH2:40])[CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][C:2]3[N:20]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)CC1

Procedure:
180 a) 4-(3-Nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was prepared from 1-bromo-3-nitro-benzene (3.0 g, 15 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.0 g, 16 mmol) in a manner analogous to Example 2c. Product isolated as a yellow oil (3.95 g, 88%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.23 (s, 1H), 8.11 (d, J=8.1 Hz, 1H), 7.69 (d, J=7.7 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 6.20 (br s, 1H), 4.12 (s, 2H), 3.70-3.65 (m, 2H), 2.56 (s, 2H), 1.50 (s, 9H). 180 b) 4-(3-Amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester was prepared from 4-(3-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.0 g, 3.3 mmol) in a manner analogous to Example 111a. Product isolated as a light purple solid (0.84 g, 92%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.09 (t, J=7.6 Hz, 1H), 6.61 (d, J=7.5 Hz, 1H), 6.56-6.52 (m, 2H), 4.22 (br s, 2H), 3.62 (br s, 2H), 2.82-2.72 (m, 2H), 2.59-2.49 (m, 1H), 1.80 (d, J=13.0 Hz, 2H), 1.68-1.53 (m, 2H), 1.48 (s, 9H). 180 c) 4-{3-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 1.625 mmol) and 4-(3-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (500.0 mg, 1.809 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (90.0 mg, 0.165 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.59 g, 66%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.52 (d, J=6.6 Hz, 1H), 8.23 (d, J=8.4 Hz, 2H), 8.09 (d, J=8.4 Hz, 2H), 7.66 (d, J=7.4 Hz, 1H), 7.47-7.41 (m, 2H), 7.30 (t, J=7.6 Hz, 1H), 7.03 (t, J=7.0 Hz, 1H), 6.92-6.85 (m, 2H), 4.27 (br m, 2H), 3.10 (s, 3H), 2.83 (t, J=11.9 Hz, 2H), 2.73-2.63 (m, 1H), 1.84 (d, J=13.1 Hz, 2H), 1.73-1.60 (m, 2H), 1.49 (s, 9H). MS=538 (MH)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[S:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[S:20].C(O)C.O>C(O)(=O)C>[CH3:4][C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:24]2[S:18][C:19](=[S:20])[NH:21][C:22]2=[O:23])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: O=C1CSC(=S)N1
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(C=C2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 117.2 g of 3,5- di-tert-butyl-4-hydroxybenzaldehyde, 66.6 g of rhodanine, and 143.5 g of fused sodium acetate were heated at reflux in 2500 ml of glacial acetic acid. After heating for 23 hours, the reaction mixture was cooled and poured into a mixture of 1 liter of ethanol and 1 liter of ice with stirring. 500 ml of water were added and, after stirring for 30 minutes, the resulting precipitate was recovered by filtration. The solid was slurried with 500 ml of ethyl acetate and filtered. The precipitate was then dissolved in 3 liters of ethanol, heated to boiling, and water was added until the solution remained cloudy, approximately 450 ml. Upon cooling to room temperature, 99.6 g of the desired title product were recovered by filtration, m.p. approximately 260° C.
Reaction SMILES: [NH3:1].[C:2]1([C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][O:4]1)=[O:3].C(OC(C)C)(C)C.C(OC)CCC>C(OCC)C.O1CCCC1>[CH2:8]1[CH:9]=[CH:10][C:11]2[C:2]([NH:1][C:5](=[O:4])[C:6]=2[CH2:7]1)=[O:3]
Reactant: O=C1OCc2ccccc21
Reactant: N
Agent: CCCCOC
Solvent: CCOCC
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: O=C1NC(=O)C2=C1C=CCC2

Procedure:
The 3-substituted phthalimidines of formula (I) wherein Z is OH can be prepared by reacting, under nondehydrating conditions, equivalent amounts of a 3-substituted phthalide of the formula ##STR3## wherein R, X, Y, a and b have the same meanings as above, and ammonia, or a primary aliphatic or aromatic amine. The reaction is preferably carried out in the presence of an inert organic solvent for the phthalide such as tetrahydrofuran, diethyl ether, diisopropyl ether, methyl n-butyl ether and the like. The solvent should have a boiling point below about 100° C. to permit ready separation from the reaction product by distillation at moderate temperatures. This serves to minimize dehydration of the 3-hydroxy group on the phthalimidine product. The primary amines employed in the reaction are those of the formula H2N--Q where Q has the same meaning as above. When the reaction is conducted at temperatures above about 100° C., dehydration takes place to produce a 3-substituted phthalimidine of formula (II).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[C:9]([CH:11](C)[CH2:12][CH:13]=O)[O:8][N:7]=1.[C:16]1([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)O[C:37](C)=O.[Na+].C(O)(=O)C>C(Cl)Cl>[C:29]1([CH:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:23]2[CH2:24][CH2:25][N:26]([CH2:37][CH2:13][CH2:12][CH2:11][C:9]3[O:8][N:7]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[CH2:27][CH2:28]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(CC=O)c1cc(-c2cccs2)no1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(C(c2ccccc2)N2CCN(CCCCc3cc(-c4cccs4)no3)CC2)cc1
Yield: 19.1 %

Procedure:
About 2 min after dissolving 3-(3-(2-thienyl)isoxazol-5-yl)butanal (14 mg, 0.063 mmol) and 1-(diphenylmethyl)piperazine (15.9 mg, 0.063 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (40.1 mg, 0.189 mmol), cold acetic acid (4.4, 0.077 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 17 hr and followed the same processes as in Example 1 to obtain 5.5 mg (19.1%) of the target compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:24])[CH2:7][CH2:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([NH:15][CH2:16][C@@H:17]([OH:22])[C:18]([O:20][CH3:21])=[O:19])=[CH:10][C:9]=2[F:23])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:32](Cl)(Cl)=[O:33]>C(Cl)Cl.C1(C)C=CC=CC=1>[O:24]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]2[C:9]([F:23])=[CH:10][C:11]([N:15]3[CH2:16][C@H:17]([C:18]([O:20][CH3:21])=[O:19])[O:22][C:32]3=[O:33])=[CH:12][C:13]=2[F:14])[CH2:4][CH2:3]1
Reactant: COC(=O)[C@H](O)CNc1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1CN(c2cc(F)c(N3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of methyl (2R)-3-{[4-(1,1-dioxidothiomorpholin-4-yl)-3,5-difluorophenyl]amino}-2-hydroxypropanoate (Step 1, 1.02 g, 2.90 mmol) in CH2Cl2 (25 mL) and triethylamine (1.0 g, 1.5 mL, 10.5 mmol) is cooled to 0° C. and treated with phosgene (1.94 mL of a 20% solution in toluene, 3.6 mmol). After stirring at room temperature for one hour, the reaction mixture is diluted with CH2Cl2 and washed with dilute NaHCO3, saline, and dried (MgSO4), filtered and concentrated. Chromatography on silica gel (10% acetonitrile-dichloromethane) provides the title compound (0.91 g, 83%), MS (m/z): [M+H]+=391; 1H NMR (300 MHz, CDCl3): δ 3.16-3.20 (m, 4H), 3.64 (m, 4H), 3.88 (s, 3H), 4.06-4.11 (m, 1H), 4.23 (t, 1H), 5.06-5.11 (m, 1H), 7.16 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:15][CH2:14]2)[CH3:11])=[O:25])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C[C@H]1CC[C@H](OCCCCO)CC1)C(=O)Oc1ccc(Cl)cc1
Product: CN(C[C@H]1CC[C@H](OCCCCOS(C)(=O)=O)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 3.4, trans-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester was treated with methanesulfonyl chloride to yield trans-methanesulfonic acid 4-(4-{[(4-chloro-phenoxy-carbonyl)-methyl-amino]-methyl}-cyclohexyloxy)-butyl ester as colorless viscous, MS: 448 (MH+, 1 Cl).