Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[N:12]S(C(C)(C)C)=O.Cl>O1CCOCC1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[NH:12]
Reactant: CC(C)(C)S(=O)N=C1CCOc2ccc(Br)cc21
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N=C1CCOc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
N-(6-Bromochroman-4-ylidene)-2-methylpropane-2-sulfinamide (2.0 g, 6.0 mmol, Intermediate 1) was dissolved in dry dioxane (2 mL), and 4M HCl in dioxane (15 mL, 60.00 mmol) was added. A white precipitate started to form. The mixture was stirred at r.t. for 12 h. The mixture was diluted with dry Et2O (50 mL) and vacuum filtered. The filter cake was washed with dry Et2O (50 mL), then immediately dissolved by shaking in NaHCO3 (aq) and CH2Cl2. The organic phase was dried (K2CO3) and evaporated to give 6-bromochroman-4-imine (1.3 g, 5.7 mmol). The solid was dissolved together with 2-oxopropanethioamide (Intermediate 2, 1.7 g, 17 mmol, Intermediate 2) in dry methanol (5 mL) and the resulting solution was heated at 60° C. for 12 h. Evaporation onto silica and purification by flash chromatography (EtOAc in heptane) gave the title compound (0.39 g, 21% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 2.18 (m, 1 H), 2.35 (m, 1 H), 2.42 (s, 3 H), 4.35-4.40 (m, 1 H), 4.60 (m, 1 H), 6.81 (d, 1 H), 6.88 (d, 1 H), 7.33 (dd, 1 H); MS (ES+) m/z 311 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[Br:19][CH2:20][CH2:21][CH2:22]Br>CN(C)C=O.ClCCl>[Br:19][CH2:20][CH2:21][CH2:22][O:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: BrCCCBr
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1OCCCBr
Temperature: 90 °C

Procedure:
A stirred mixture of 2-methoxy-5-nitrophenol (5.0 g. 29.6 mmol) and powdered potassium carbonate (6.5 g, 47.4 mmol) in dimethylformamide (50 mL) was treated with 1,3-dibromopropane (80.8 g, 0.4 mol), heated to 90° C. for 2 h, cooled, diluted with dichloromethane (250 mL), and filtered. The filtrate was concentrated in vacuo and the residue was crystallized from methanol. The resulting solid was triturated with 30% ethyl acetate/hexane and then with boiling 30% ethyl acetate/hexane. The combined organic phases were concentrated in vacuo to give the title compound: 1H NMR (300 MHz, CDCl3) δ7.92 (dd, 1H), 7.75 (d, 1H), 6.92 (dd, 1H), 4.20 (t, 2H), 3.95 (s, 3H), 3.62 (t, 2H), 2.40 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([SH:10])=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:16][C:17]=1Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([S:10][C:17]2[CH:16]=[CH:15][C:14]([C:19]([F:22])([F:21])[F:20])=[CH:13][C:12]=2[Cl:11])=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7]
Reactant: Nc1cc(Cl)c(S)cc1F
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Cl)c(Sc2ccc(C(F)(F)F)cc2Cl)cc1F
Reaction time: 2 h
Yield: 66 %

Procedure:
5.00 Grams of 5-chloro-2-fluoro-4-mercaptoaniline, 12.2 g of 3,4-dichlorobenzotrifluoride and 4.31 g of potassium carbonate were dissolved in 30 ml of dimethylformamide, and the resulting solution was stirred for 2 hours at a temperature of from 100° to 110° C. in an oil bath. Thereafter, the reaction solution was poured into water and extracted with three 200-ml portions of diethyl ether. The extract obtained was washed with water, dried, filtered and concentrated. The residue obtained was subjected to chromatography on silica gel to obtain 6.57 g of 5-chloro-2-fluoro-4-[2-chloro-4-(trifluoromethyl)phenylthio]aniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=1.[C:29](Cl)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][O:18][C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 80 °C
Yield: 88 %

Procedure:
To a mixture of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (7.0 g, 17.1 mmole, prepared according to procedure described in J. Med. Chem. 2008; 51 (5); 1145-1149), trityl chloride (5.2 g, 18.8 mmole) in pyridine (50 mL) was added at room temperature and heated at 80° C. for 18 hrs. The excess pyridine was evaporated, reaction mixture was diluted with water (250 mL), washed with 1N dil. HCl (50 mL) extracted with dichloromethane (2×200 mL). The crude product obtained after the removal of solvent was purified using silica gel column chromatography (0.5% methanol in DCM) to furnish 9.8 g of (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-trityloxymethyl-tetrahydro-pyran-3,4,5-triol.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3([C:21]([NH:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[NH:29][CH:28]=[CH:27]5)=[O:22])[CH2:20][CH2:19]3)=[CH:17][C:12]=2[O:11][CH2:10]1.O>CN(C)C=O>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3([C:21]([NH:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[NH:29][CH:28]=[C:27]5[Br:1])=[O:22])[CH2:20][CH2:19]3)=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: O=C(Nc1ccc2[nH]ccc2c1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc2[nH]cc(Br)c2c1)C1(c2ccc3c(c2)OCO3)CC1
Reaction time: 0.08 h
Yield: 90.6 %

Procedure:
Freshly recrystallized N-bromosuccinimide (0.278 g, 1.56 mmol) was added portionwise to a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(1H-indol-5-yl)cyclopropanecarboxamide (0.500 g, 1.56 mmol) in N,N-dimethylformamide (2 mL) over 2 minutes. The reaction mixture was protected from light and was stirred bar for 5 minutes. The resulting green solution was poured into 40 mL of water. The grey precipitate which formed was filtered and washed with water to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-1H-indol-5-yl)cyclopropanecarboxamide (0.564 g, 91%). ESI-MS m/z calc. 398.0, found 399.3 (M+1)+. Retention time of 3.38 minutes. 1H NMR (400 MHz, DMSO-d6) 11.37 (s, 1H), 8.71 (s, 1H), 7.67 (d, J=1.8 Hz, 1H), 7.50 (d, J=2.6 Hz, 1H), 7.29 (d, J=8.8 Hz, 1H), 7.22 (dd, J=2.0, 8.8 Hz, 1H), 7.02 (d, J=1.6 Hz, 1H), 6.96-6.88 (m, 2H), 6.03 (s, 2H), 1.43-1.40 (m, 2H), 1.09-1.04 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].[Cl:11][C:12]1[CH:17]=[C:16]([N+]([O-])=O)[CH:15]=[CH:14][N:13]=1>>[Cl:11][C:12]1[CH:17]=[C:16]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:15]=[CH:14][N:13]=1
Reactant: Sc1ccccc1Cl
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(Sc2ccccc2Cl)ccn1
Yield: 94.7 %

Procedure:
Using the method of Example 3, Step A, 2-chlorobenzenethiol (912 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to afford 2-chloro-4-(2-chlorophenylthio)pyridine (1.53 g, 95% yield) as an oil. 1H NMR (CDCl3) δ 8.15 (d, 1H), 7.65 (d, 1H), 7.46 (t, 1H), 7.36 (t, 1H), 6.89 (s, 1H), 6.84 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:25]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:17]C(=O)OC(C)(C)C)[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:4]2[N:3]=1.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>CN(C)C(=O)C.O>[NH2:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:8]1[CH:7]=[CH:6][C:5]2[N:4]([N:3]=[C:2]([NH:1][C:29]([CH:26]3[CH2:28][CH2:27]3)=[O:30])[N:25]=2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(N)nn3c2)c1
Reactant: O=C(Cl)C1CC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Yield: 78.1 %

Procedure:
To a solution of tert-butyl {3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]phenyl}carbamate (10.5 g, 30.8 mmol) in N,N-dimethylacetamide (40 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (8.39 mL, 92.4 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, trifluoroacetic acid (50 mL) was added to the residue, and the mixture was stirred at 0° C. for 30 min. The solvent was evaporated under reduced pressure, and the residue was dissolved in water. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (7.44 g, 78%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:4].[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1F.O>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1[N:6]([O:5][CH2:3][CH3:4])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: CCONS(=O)(=O)c1ccc(C)cc1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCON(c1ccc([N+](=O)[O-])cc1Cl)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 71.6 %

Procedure:
To a suspension of sodium hydride (60%, 0.18 g (4.50 mmol)) in 6.0 ml of DMF, N-ethoxy-p-toluenesulfonamide (0.90 g (4.18 mmol)) was added under cooling with ice and with stirring. To the resulting mixture, after 15 minutes' stirring under cooling with ice, 3-chloro-4-fluoronitrobenzene (0.70 g (3.99 mmol)) was added and the mixture was stirred under cooling with ice for one hour and at room temperature for 18 hours. The reaction mixture was then poured into water and extracted with diethyl ether. The extract was washed twice with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give crude crystals. These crystals were filtered while washing with diisopropyl ether to give 1.06 g (72%) of the title compound as pale yellow crystals.
Reaction SMILES: O.[OH:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]([OH:11])[C:8]([O-:10])=[O:9])=[CH:5][CH:4]=1.[Na+].[OH-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O>[CH2:17]([O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]([OH:11])[C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: O=C([O-])C(O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(O)c1ccc(OCc2ccccc2)cc1
Yield: 68.9 %

Procedure:
A solution of 41.6 g (0.20 mol) of sodium 4-hydroxymandelate monohydrate, 9.6 g (0.24 mol) of sodium hydroxide and 27.9 g (0.22 mol) of benzyl chloride in 50 ml of water is stirred for 17 hours at 70° C. It is then diluted using 50 ml of water, and a further 4.0 g (0.10 mol) of sodium hydroxide are added. The reaction mixture is refluxed for one hour, then cooled and acidified using concentrated hydrochloric acid, and the product which has precipitated is filtered. The residue is washed with cold water and subsequently dried under a high vacuum. 35.6 g (69%) of 4-benzyloxymandelic acid, m.p. 148°-155° C., result.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH:20]=[CH:21][N:22]3[Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH:5]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.[NH2:37][C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=1>>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][O:8][C:6]2[CH:7]=[C:2]([NH:37][C:38]3[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=3)[CH:3]=[C:4]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[Si:27]([CH:31]([CH3:33])[CH3:32])([CH:34]([CH3:35])[CH3:36])[CH:28]([CH3:29])[CH3:30])[CH:5]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(COc2cc(Br)cc(-c3cccc4c3ccn4[Si](C(C)C)(C(C)C)C(C)C)c2)cc1
Reactant: N#Cc1ccc(N)cc1
Product: COc1ccc(COc2cc(Nc3ccc(C#N)cc3)cc(-c3cccc4c3ccn4[Si](C(C)C)(C(C)C)C(C)C)c2)cc1

Procedure:
4-[3-Bromo-5-(4-methoxy-benzyloxy)-phenyl]-1-triisopropylsilanyl-1H-indole was coupled with 4-amino-benzonitrile to give 4-[3-(4-methoxy-benzyloxy)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenylamino]-benzonitrile using the conditions of Example 80. This compound was deprotected to give 4-[3-hydroxy-5-(1H-indol-4-yl)-phenylamino]-benzonitrile as described in Example 35. 1H NMR (400 MHz, CD3OD): δ 7.46 (d, J=2.0 Hz, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.25 (d, J=3.1 Hz, 1H), 7.15-7.11 (m, 3H), 7.06 (dd, J=7.2, 1.0 Hz, 1H), 6.96 (t, J=1.7 Hz, 1H), 6.84 (dd, J=2.1, 1.4 Hz, 1H), 6.66 (t, J=2.1 Hz, 1H), 6.62 (q, J=1.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH:18][CH2:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)=[CH:16][CH:15]=[N:14]1.[F:26][C:27]([F:31])([F:30])[S:28]Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:17]([NH:18][CH2:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)=[C:16]([S:28][C:27]([F:31])([F:30])[F:26])[CH:15]=[N:14]1
Reactant: FC(F)(F)SCl
Reactant: FC(F)(F)c1cc(Cl)c(-n2nccc2NCc2cnccn2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)Sc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1NCc1cnccn1
Reaction time: 8 h

Procedure:
To a solution of 3.0 g of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(pyrazin-2-ylmethylamino)pyrazole dissolved in 30 ml of dried methylene chloride under a nitrogen atmosphere was added 14 ml of dried methylene chloride solution of trifluoromethylsulfenyl chloride at room temperature over about 1 hour, followed by stirring overnight. Saturated aqueous sodium hydrogen carbonate solution was added thereto, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and water several times. Thereafter, the layer was purified by a silica gel column chromatography. After removal of solvent, drying in vacuo afforded 3.59 g of 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfenyl-5-(pyrazin-2-ylmethylamino)pyrazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].C(N(CC)CC)C.[CH3:20][N:21]=[C:22]=[O:23]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:22](=[O:23])[NH:21][CH3:20])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: CN=C=O
Reactant: O=C1Nc2ccc(F)cc2C1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)N1C(=O)C(=O)c2cc(F)ccc21
Yield: 74.5 %

Procedure:
A mixture of 5-fluoroisatin (9.9 g), triethylamine (1 ml) and dimethylformamide (30 ml) is stirred under ice-cooling, and thereto is added dropwise methyl isocyanate (3 g) at the same temperature. The mixture is stirred at room temperature for 30 minutes, and the precipitates are taken by filtration to give 5-fluoro-1-methylcarbamoylisatin (8.7 g). M.p. 230°-232° C.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16].[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl>[CH:26]1([NH:32][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: NC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(CNC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
NaB(OAc)3H (11.0 mmol, 2.33 g) was added to a mixture of 4-nitro-benzaldehyde Compound 4a (10.0 mmol, 1.51 g), cyclohexylamine Compound 10a (10.5 mmol, 1.2 mL) and glacial acetic acid (5 drops) in CH2Cl2 (40 mL) and the resulting suspension was allowed to stir at room temperature for 12 hrs. An aliquot of the reaction mixture showed the formation of product (MS m/e 235, 100%). The reaction mixture was basified with 2N NaOH solution and was extracted with CH2Cl2. The organic layer was washed with brine, separated and dried over Na2SO4. The drying agent was filtered and the solvent was removed in vacuo to yield cyclohexyl-(4-nitro-benzyl)-amine Compound 10b as yellow oil (1.56 g, 67% yield), which was used in the next step without purification.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][N:25]4C3CCCCO3)=[CH:16][CH:15]=2)=[S:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CCOCC>O1CCOCC1>[C:1]1([CH2:7][C:8]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)=[CH:18][CH:19]=2)=[S:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3c2ncn3C2CCCCO2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3[nH]cnc23)cc1
Reaction time: 1 h
Yield: 66.4 %

Procedure:
To 2-phenyl-N-{[(4-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]oxy}phenyl)-amino]carbonothioyl}acetamide (190 mg, 0.38 mmol) in 30 mL of dioxane was added 3 mL of 4N HCl in dioxane and let to stir for 1 h. On concentration of the reaction mixture and trituration with ether yielded 2-phenyl-N-({[4-(9H-purin-6-yloxy)phenyl]amino}carbonothioyl)acetamide (102 mg, 65% yield) as a colorless solid. 1H NMR (400 MHz, DMSO d6): δ 12.40 (s, 1H), 11.80 (s, 1H), 8.6 (s, 1H), 8.4 (s, 1H), 7.70 (m, 2H), 7.35 (m, 7H), 3.8 (s, 2H). MS (ESI) for C20H16N6O2S: 433 (MH+).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][CH2:7]1.[Br:18]Br>C(Cl)Cl>[CH3:5][C:6]1([CH3:17])[C:15]2[C:10](=[CH:11][C:12]([Br:18])=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][CH2:7]1
Reactant: CC1(C)CCC(=O)c2ccccc21
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(=O)c2cc(Br)ccc21
Temperature: 25 °C
Yield: 80 %

Procedure:
A 100 ml three-necked flask, fitted with an efficient reflux condenser and drying tube, and addition funnel, was charged with a mixture of AlCl3 9.5g (71.4 mmol) and 3 ml of CH2Cl2. The 3,4-dihydro-4,4-dimethyl-1(2H)naphthalenone (5.0 g, 28.7 mmol), was added dropwise with stirring (Caution:Exothermic Reaction|) to the mixture at room temperature. Bromine, 5.5 g (34.5 mmol), was then added very slowly, and the resulting mixture stirred for 2 hours at room temperature. (Note: if stirring stops, the mixture can be warmed to 70° C. until stirring resumes.) The reaction was then quenched by the slow addition of ice-cold 6M HCl. The mixture was extracted with Et2O and the combined organic layers washed with water, saturated aqueous NaHCO3, and saturated NaCl, before being dried over MgSO4. Removal of the solvent under reduced pressure, and distillation of the residue afforded 5.8 g (80%) of the product as a pale-yellow oil which solidified on standing, bp: 140° C./0.4 mm Hg. 1H NMR (CDCl3): δ 8.11 (1H, d, J=3.0 Hz), 7.61 (1H, dd, J=3.0, 9.0 Hz), 7.31 (1H, d, J=9.0 Hz), 2.72 (2H, t, J=6.0 Hz), 2.01 (2H, t, J=6.0 Hz), 1.28 (6H, s).
Reaction SMILES: CC([O:4]C(/N=N/C(OC(C)C)=O)=O)C.OCCC1N=CSC=1C.[C:24]1([P:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[C:37]1([P:30](=[O:4])([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cc1scnc1CCO
Solvent: C1CCOC1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
DIAD (3.16 ml, 16.1 mM) was added to a stirred solution of methyl 3-nitro-5-hydroxy benzoate (2.11 g, 10.7 mM), 4-(2-hydroxy ethyl)-5-methylthiazole (1.55 ml, 12.8 mM), and triphenylphosphine (4.21 g, 16.1 mM) in THF (50 ml) under an argon atmosphere at room temperature. After 1 hr reaction mixture concentrated in vacuo, residue triturated with diethyl ether to give a colourless solid (triphenylphosphine oxide). Diethyl ether conc. to give a dark brown gum, purification on silica gel (50% to 75% EtOAc/iso-hexane) gave the product contaminated with reduced DIAD and triphenylphosphine oxide (6.8 g). The crude product was dissolved/suspended in MeOH (80 ml), 2M NaOH (20 ml, 40 mM) added, heated at 65° C. for 4 hrs then cooled and concentrated. The residue was diluted with water (140 ml)/2M NaOH (40 ml), the precipitated triphenylphosphine oxide filtered, then acidified with c. HCl to pH1-2. The precipitate was filtered, washed with water, dried under high-vacuum to give 3-{2-(4-methyl thiazol-5-yl)ethoxy}-5-nitro benzoic acid as a colourless solid (3.12 g, 79% over 2 steps); 1H NMR δ (d6-DMSO): 2.39 (s, 3H), 3.23 (t, 2H), 4.35 (t, 2H), 7.78 (s, 1H), 7.90 (m, 1H), 8.22 (s, 1H), 8.93 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH2:31][CH2:32][CH2:33][OH:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH2:31][CH2:32][CH2:33][OH:34])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: NCCCO
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCCCO)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 3-amino-1-propanol (0.015 mL, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(3-hydroxypropylaminomethyl)indol-2-yl]isoindolinone.