Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([N:16]([CH2:24][C:25]([NH:27][CH2:28][CH2:29][N:30]=[N+:31]=[N-:32])=[O:26])C(OC(C)(C)C)=O)(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O>Cl.O1CCOCC1>[NH2:1][NH:16][CH2:24][C:25]([NH:27][CH2:28][CH2:29][N:30]=[N+:31]=[N-:32])=[O:26]
Reactant: CC(C)(C)OC(=O)N(CC(=O)NCCN=[N+]=[N-])N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: [N-]=[N+]=NCCNC(=O)CNN
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.5 %

Procedure:
Azide 5 (4.66 g, 10.17 mmol) was dissolved in 4 N HCl in dioxane (200 mL), and the solution was stirred at room temperature for 5 h. Solvent was removed under reduced pressure, and the residue was dissolved in water (15 mL) and purified by cation-exchange chromatography (Dowex 50WX8-200 ion-exchange resin, 1 M NH4OH) to give H2NNHCH2CONHCH2CH2N3 as a yellow oil (1.52 g, 95%). HRMS (ESI) [M+Na]+ calcd for C4H10N6ONa, 181.0814; found, 181.0805; 1H NMR (300 MHz, d6-DMSO) δ 8.03 (app bs, 1H), 3.80-3.40 (bs, 3H), 3.40-3.34 (m, 2H), 3.32-3.24 (m, 2H), 3.16 (s, 2H); 13C NMR (75 MHz, d6-DMSO) δ 171.2, 57.1, 50.0, 37.8.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]([C:18]([F:21])([F:20])[F:19])[CH2:14][CH2:15][CH2:16][CH3:17])(=O)=O)=CC=1.[OH:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.[Na].[H-]>CN(C)C=O>[F:19][C:18]([F:20])([F:21])[CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH2:11][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=1
Reactant: CCCCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCCC(CCOc1ccc(C(=O)OCC)cc1)C(F)(F)F
Temperature: 130 °C
Yield: 41.5 %

Procedure:
0.54 g of 3-trifluoromethylheptyl p-toluene-sulfonate obtained in Step (1), 0.27 g of ethyl p-hydroxybenzoate and 1 ml of dimethylformamide (DMF) were placed in a round-bottomed flask, and 0.07 g of sodium 60%-hydride was added thereto together with DMF, followed by 6 hours of stirring at 130° C. After the reaction, DMF was distilled off under a reduced pressure, and water was added, followed by extraction with diethyl ether. The ether solution was dried with sodium sulfate, followed by distilling-off of the solvent to obtain 0.62 g of a crude product. The crude product was then purified by thin layer chromatography with benzene as the developer to obtain 0.22 g of ethyl p-(3-trifluoromethylheptyloxy)benzoate (yield: 42%).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17](Br)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1.C1COCC1.CN(C=O)C.C(NC(C)C)(C)C.[CH3:39][C:40]([OH:44])([C:42]#[CH:43])[CH3:41]>O.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.[Cu]I>[NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:43]#[C:42][C:40]([OH:44])([CH3:41])[CH3:39])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1
Reactant: C#CC(C)(C)O
Reactant: NC1=N[C@]2(CO1)c1cc(O)ccc1Oc1ncc(Br)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(C)(O)C#Cc1cnc2c(c1)[C@@]1(COC(N)=N1)c1cc(O)ccc1O2
Temperature: 85 °C

Procedure:
Combined (R)-2′-amino-3-bromo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (2.259 g, 6.49 mmol), tetrakis(triphenylphosphine)palladium (0.750 g, 0.649 mmol), copper(i) iodide (0.124 g, 0.649 mmol) and THF (26.0 mL, 6.49 mmol) and DMF (26.0 mL, 6.49 mmol). Added diisopropylamine (18.19 mL, 130 mmol) then 2-methylbut-3-yn-2-ol (3.17 mL, 32.4 mmol) and flushed the reaction tube with argon. Sealed and heated at 85° C. for 3 hours. The mixture was diluted with water (100 mL) and extracted with DCM (1×100 mL, 2×50 mL). (DCM was used because this product is partially soluble in water and EtOAc is not as good a solvent for it). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The resuling liquid was poured onto a 25-g SCX-2 column and eluted with methanol. The product was then eluted with 2M ammonia in methanol. The filtrate was evaporated and purified by chromatography on a 120-g Redi-Sep column, eluting with 0-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM to give (R)-2′-amino-3-(3-hydroxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol as a tan solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([Cl:42])[CH:36]=1)=[O:34]>CN(C)C=O.O>[Cl:42][C:37]1[CH:36]=[C:35]([C:33](=[O:34])[CH3:32])[CH:40]=[CH:39][C:38]=1[O:41][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: CC(=O)c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(Oc3ccc(C(C)=O)cc3Cl)n2)cc1Cl
Temperature: 80 °C
Yield: 19.9 %

Procedure:
A mixture of compound 133 (0.30 g, 0.78 mmol), potassium carbonate (0.54 g, 3.92 mmol) in dimethylformamide (10 mL) was added 3-chloro-4-hydroxyacetophenone (0.133 g, 0.78 mmol). It was heated to 80° C. for 12 hours with stirring under nitrogen atmosphere. The mixture was then cooled, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue thus obtained was purified by column chromatography to afford the title compound as white solid (0.08 g, 67%). mp 186-196° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [mobile phase: 0.01 M KH2PO4: CH3CN (20:80)]; 212 nm, R, 12.33 min, 99.15% purity; MS (CI): m/z 516 (M+, 100).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([N:8]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([NH2:17])[C:9]1=[O:18])[CH3:7])=[O:5])[CH3:2].O=[C:20]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[CH2:1]([O:3][C:4]([CH:6]([N:8]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([NH:17][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:9]1=[O:18])[CH3:7])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: CCOC(=O)C(C)N1CCCCCCC(N)C1=O
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)NC1CCCCCCN(C(C)C(=O)OCC)C1=O

Procedure:
Hydrogenate 2.42 g 1-(1-ethoxycarbonylethyl)-3-aminoperhydroazonin-2-one and 3.09 g ethyl 2-oxo-4-phenylbutyrate in 100 ml ethanol containing 0.60 g acetic acid as described in Example 1.
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[N+:10]([C:13]1[C:26]2[C:25](=[O:27])[C:24]3[C:19](=[C:20]([N+:28]([O-])=O)[CH:21]=[CH:22][CH:23]=3)[C:18](=[O:31])[C:17]=2[CH:16]=[CH:15][CH:14]=1)([O-:12])=[O:11].S(=O)(=O)(O)[OH:33]>O>[OH:33][C:23]1[C:24]2[C:25](=[O:27])[C:26]3[C:17](=[CH:16][CH:15]=[CH:14][C:13]=3[N+:10]([O-:12])=[O:11])[C:18](=[O:31])[C:19]=2[C:20]([NH2:28])=[CH:21][CH:22]=1
Reactant: O=S(=O)(O)O
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2cccc([N+](=O)[O-])c21
Agent: O=S(=O)=O
Solvent: O
Product: Nc1ccc(O)c2c1C(=O)c1cccc([N+](=O)[O-])c1C2=O
Reaction time: 3 h

Procedure:
A mixture of 300 parts of 28% strength oleum and 30 parts of 1,5-dinitroanthraquinone are stirred for 3 hours at 50° to 60° C. After the addition of 85.5 parts of 78% strength sulphuric acid and 165 parts of water with cooling the reaction mixture is stirred for 6 hours at room temperature and then left to stand overnight. The mixture is added to 1,000 parts of water, and the product is filtered off with suction and washed with water until neutral. After drying, 23.3 parts of crude 1-hydroxy-4-amino-8-nitroanthraquinone are obtained, which can be purified by recrystallisation from dimethylformamide.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@@H:12]([N:25]2[C:29]([N:30]3[C:34](=[O:35])[C:33]4=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]4[C:31]3=[O:40])=[C:28]([C:41]([O:43]C(C)(C)C)=[O:42])[N:27]=[CH:26]2)[C@H:11]1[F:48])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.ClCCl>[C:1]([O:9][C@@H:10]1[C@@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:13][C@@H:12]([N:25]2[C:29]([N:30]3[C:31](=[O:40])[C:32]4=[CH:39][CH:38]=[CH:37][CH:36]=[C:33]4[C:34]3=[O:35])=[C:28]([C:41]([OH:43])=[O:42])[N:27]=[CH:26]2)[C@H:11]1[F:48])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@@H]2F)c1N1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OC[C@H]1O[C@@H](n2cnc(C(=O)O)c2N2C(=O)c3ccccc3C2=O)[C@@H](F)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 97 %

Procedure:
Compound (11) obtained in step (2) above (2.00 g) was dissolved in a mixture (30 ml) of trifluoroacetic acid-dichloromethane (1:4) and the resulting solution was kept overnight at room temperature, when the deesterification of compound (11) occurred. The reaction solution was concentrated and the solid obtained was washed with diethyl ether to yield the titled compound (12) (1.77 g) which was insoluble in diethyl ether. Yield: 97%.
Reaction SMILES: O=[CH:2][CH2:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][NH:6][S:5]1(=[O:15])=[O:14].[F:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH:27]=3)=[CH:22][NH:23]2)=[CH:19][CH:18]=1.N1C=CC=CC=1.B.[OH-].[Na+]>CO.O>[F:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]3[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][N:4]4[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[CH:7]=[N:6][S:5]4(=[O:15])=[O:14])[CH2:28][CH:27]=3)=[CH:22][NH:23]2)=[CH:19][CH:18]=1
Reactant: O=CCN1c2ccccc2CNS1(=O)=O
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CO
Solvent: O
Product: O=S1(=O)N=Cc2ccccc2N1CCN1CC=C(c2c[nH]c3cc(F)ccc23)CC1
Reaction time: 8 h

Procedure:
To a dry 100 ml round bottomed flask containing powdered molecular sieves 4A (1.5 g) was added 3,4-dihydro-1-(2-oxoethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide (0.8 g, 3.54 mmol) in methanol (30 ml)and 4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine (0.76 g) dissolved in methanol (10 ml). Borane-pyridine (1 ml) was added after 1 hour and the solution stirred overnight. 5 MHCl (10 ml) was added followed by 50% sodium hydroxide solution(5 ml) and water(5 ml). Solution was filtered through celite and ethyl acetate(3×50 ml) added. The organics were collected, washed with water, dried, filtered and the solvent removed in vacuo. Column chromatography through flash silica eluting with ethyl acetate/hexane gave product, 3,4-dihydro-(1-(2-[4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl]-1-ethyl}-1H-2,1,3-benzothiadiazine-2,2-dioxide, m.p. 183-185° C.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[N:8][N:7]=1)C.[OH-].[Na+]>C(O)C>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:9]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]([CH2:5][C:4]([OH:25])=[O:3])=[N:7][N:8]=2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)Cc1nnc(-c2ccc(OC)cc2)n1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2nnc(CC(=O)O)n2-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
A mixture of 4 g of the product of Example 16, 10 ml of 2N sodium hydroxide and 20 ml of ethanol was stirred at 60° C. under argon for 30 minutes and the ethanol was evaporated at 40° C. under reduced pressure. 9.9 ml of 2N hydrochloric acid were added to the aqueous solution and the mixture stood at 0° to 5° C. for 16 hours and was filtered. The recovered product was empasted several times with ice water to remove chlorides and was dried at room temperature under reduced pressure of 0.5 to 1 mmHg to obtain 3.6 g of 5-(4-methoxyphenyl)-4-phenyl-4H-1,2,4-triazole-3-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[N:7]([C:17](Cl)=[O:18])[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]=2[N:4]([CH3:20])[CH:3]=1.[CH2:21]([N:24]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[CH2:35][CH2:36][NH2:37])[CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23]>>[Cl:1][C:2]1[C:6]2[N:7]([C:17]([NH:37][CH2:36][CH2:35][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH:29]3[CH2:28][N:24]([CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27])=[O:18])[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]=2[N:4]([CH3:20])[CH:3]=1
Reactant: CCCN(CCC)CC1CCCCN1CCN
Reactant: Cn1cc(Cl)c2c1C(=O)Nc1ccccc1N2C(=O)Cl
Product: CCCN(CCC)CC1CCCCN1CCNC(=O)N1c2ccccc2NC(=O)c2c1c(Cl)cn2C
Yield: 57 %

Procedure:
Prepared analogously to Example 2 from 3-chloro-4-(chlorocarbonyl)-1-methyl-1,4,9,10-tetrahydro-pyrrolo[3,2-b][1,5]benzodiazepin-10-one and 2-[2-[(dipropylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 57% of theory.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[C:20]([O:22][CH3:23])=[O:21])[C@H:12]2[C@H:3]1[C@:4]1([CH3:24])[CH:9]([CH2:10][CH2:11]2)[CH2:8][CH:7]=[CH:6][CH2:5]1.[CH:25](=O)[CH2:26][CH:27]([CH3:29])[CH3:28].[BH4-].[Na+]>CO>[CH3:28][CH:27]([CH3:29])[CH2:26][CH2:25][NH:1][C@@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[C:20]([O:22][CH3:23])=[O:21])[C@H:12]2[C@H:3]1[C@:4]1([CH3:24])[C@@H:9]([CH2:10][CH2:11]2)[CH2:8][CH:7]=[CH:6][CH2:5]1
Reactant: CC(C)CC=O
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4CC=CC[C@]4(C)[C@H]3[C@H](N)C[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3[C@H](NCCC(C)C)C[C@]12C
Reaction time: 0.5 h

Procedure:
Methyl 11α-amino-androst-2-ene-17β-carboxylate (1.46 g) was dissolved in methanol (20 ml) and isovaleraldehyde (1.29 ml) was added in three portions. After stirring for 1 h at room temperature sodium borohydride (0.45 g) was added in several portions to avoid excessive gas evolution and the reaction mixture was stirred for 1/2 h. The methanol was removed at reduced pressure and the residual gum was partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed with M--H2SO4, water and saturated brine, dried and concentrated to about 15 ml. Petrol was added to incipient cloudiness and the solution was allowed to crystallise to give the title compound (1.15 g), m.p. 150°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[CH:9]=[C:8]([CH2:17][C:18]([OH:20])=[O:19])[CH:7]=1)=[O:5].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:22]=[CH:21][C:3]=1[CH:4]([OH:5])[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[CH:9]=[C:8]([CH2:17][C:18]([OH:20])=[O:19])[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)c2cc(CC(=O)O)cc3ccc(F)cc23)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(O)c2cc(CC(=O)O)cc3ccc(F)cc23)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a solution of [4-(2-chloro-4-methanesulfonyl-benzoyl)-6-fluoro-naphthalen-2-yl]-acetic acid (example 2-8) (920 mg, 2.19 mmol) in methanol (20 mL) was added sodium borohydride (248 mg, 6.56 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes before warming to room temperature. After 4 hours, the reaction was once again cooled to 0° C., and additional sodium borohydride (163 mg, 4.31 mmol) was added. The reaction mixture was then warmed to room temperature, and stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed once with a 0.5 N hydrochloric acid solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse phase preparative HPLC (using a Waters® Delta-Prep™ 3000 with a Varian Pursuit® C-18 column [10 μm, 20×150 mm]) gave {4-[(2-chloro-4-methanesulfonyl-phenyl)-hydroxy-methyl]-6-fluoro-naphthalen-2-yl}-acetic acid (500 mg, 54%) as an off-white powder. 1H NMR (300 MHz, 1.8:1 mixture of CD3OD and CDCl3) δ ppm 7.92 (s, 1 H), 7.75-7.85 (m, 3 H), 7.62-7.71 (m, 2 H), 7.16-7.29 (m, 2 H), 6.70 (s, 1 H), 3.64 (s, 2 H), 3.09 (s, 3 H); HRMS (ESI+) cald. for C20H16ClFO5S [(M+Na)+] 445.0283, obsd. 445.0281.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[C:6]([Br:11])[CH:7]=[CH:8][CH:9]=2)[C:4](=[O:12])[N:3]1C(C)(C1C=CC=CC=1)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[N+](C)([O-])=O>[Br:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[C:4](=[O:12])[NH:3][CH2:2]2
Reactant: CC(C)(c1ccccc1)N1C(=O)c2c(Br)cccc2C1O
Agent: CC[SiH](CC)CC
Solvent: C[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2cccc(Br)c21
Yield: 76.2 %

Procedure:
In a similar manner to Step 4 of Example 16, 3-hydroxy-7-bromo-2-(1-methyl-1-phenylethyl)isoindolinone (3.00 mg, 0.867 mmol) was dissolved in nitromethane (12 mL), and the solution was treated with trifluoroacetic acid (0.668 mL, 8.67 mmol) and triethylsilane (0.277 mL, 1.73 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=12/1) to obtain 7-bromoisoindolinone (140 mg, yield 76%).
Reaction SMILES: O[CH:2]([C:4]1[N:13]([CH3:14])[C:12]2[C:11](=[O:15])[N:9]([CH3:10])[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[N:5]=1)[CH3:3].S(Cl)([Cl:20])=O>>[Cl:20][CH:2]([C:4]1[N:13]([CH3:14])[C:12]2[C:11](=[O:15])[N:9]([CH3:10])[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[N:5]=1)[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1nc2c(c(=O)n(C)c(=O)n2C)n1C
Product: CC(Cl)c1nc2c(c(=O)n(C)c(=O)n2C)n1C

Procedure:
10 g of 8-α-hydroxyethylcaffeine (Arch. der Pharmazie, 289, 453, 1956) are added and under shaking with 100 ml of thionyl chloride. After 6 hours of reflux, the excess of reagent is evaporated to dryness under reduced pressure and the solid residue washed with petroleum ether. Nearly pure 8-α-chloroethylcaffeine is obtained with a quantitative yield, melting at 190° C from anhydrous benzene.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[CH2:9][CH2:8][C:7]1=[O:18].[C:19]([C:23]1[N:28]=[C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[C:25]([C:35]([F:38])([F:37])[F:36])[N:24]=1)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O>[C:19]([C:23]1[N:28]=[C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[C:10](=[O:17])[CH2:9][CH2:8][C:7]3=[O:18])[CH2:33][CH2:34]2)[CH:26]=[C:25]([C:35]([F:36])([F:37])[F:38])[N:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1nc(N2CCNCC2)cc(C(F)(F)F)n1
Reactant: O=C1CCC(=O)N(CCCCCl)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nc(N2CCN(CCCCN3C(=O)CCC(=O)c4ccccc43)CC2)cc(C(F)(F)F)n1

Procedure:
1-(4-Chlorobutyl)-3,4-dihydro-1H-1-benzazepine-2,5-dione (3.29 mmol, 1.75 g, 70%), 2-tert-butyl-4-piperazin-1-yl-6-(trifluoromethyl)pyrimidine (3.56 mmol, 1.03 g; preparation according to WO 99/02503) and triethylamine (13.17 mmol, 1.33 g) in dimethylformamide (100 ml) were stirred at 100° C. for 12 h. Afterward, ethyl acetate was added and the mixture was washed twice with water. The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The oily residue was purified by chromatography on silica gel (eluent: 95:5 v/v dichloromethane:methanol); yield 0.42 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([C:9]2[O:15][C:14](=[O:16])[C:11]3([CH2:13][CH2:12]3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[CH3:19][NH:20][O:21][CH3:22].N1C=CC=CC=1.C(Cl)Cl>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]([NH:10][C:11]1([C:14](=[O:16])[N:20]([O:21][CH3:22])[CH3:19])[CH2:13][CH2:12]1)=[O:15]
Reactant: CNOC
Reactant: COc1cccc(C2=NC3(CC3)C(=O)O2)c1C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cccc(C(=O)NC2(C(=O)N(C)OC)CC2)c1C
Temperature: 25 °C
Yield: 69.7 %

Procedure:
A mixture of 5-(3-methoxy-2-methyl-phenyl)-6-oxa-4-aza-spiro[2.4]hept-4-en-7-one (VII, R1=2-Me-3-MeO-Ph, R2═R3═—(CH2)2—, 1.90 g, 8.2 mmol), N,O-dimethylhydroxylamine hydrochloride (0.96 g, 9.9 mmol), pyridine (0.80 mL, 9.9 mmol) and methylene chloride (30 mL) was stirred at room temperature for 1 week. The mixture was diluted with ethyl acetate (150 mL), washed with 5% aqueous HCl (2×50 mL) and saturated aqueous NaHCO3 (2×50 mL), and dried. Removal of the solvent afforded a crude product (2.54 g) as a syrup. The crude product was purified by flash chromatography on a silica gel (75 g) column eluted sequentially with 0, 20, 40, 60, 80, 100% ether in hexanes (200 mL of each) and ethyl acetate (500 mL) to afford 3-methoxy-N-[1-(methoxy-methyl-carbamoyl)-cyclopropyl]-2-methyl-benzamide (1.67 g, 69%) as a white solid, mp 173-175° C. 1H NMR (CDCl3) δ (ppm): 1.15 (m, 2H), 1.53 (m, 2H), 2.23 (s, 3H), 3.22 (s, 3H), 3.69 (s, 3H), 3.82 (s, 3H), 6.67 (s, 1H), 6.86 (d, J=7.9 Hz, 1H), 6.90 (d, J=7.9 Hz, 1H), 7.13 (t, J=7.9 Hz, 1H); 13C NMR (CDCl3) δ 12.3, 15.1, 33.6, 35.1, 55.6, 61.0, 111.4, 118.6, 124.9, 126.5, 137.4, 157.9, 170.3, 170.9. Calculated for C15H20N2O4: C, 61.63; H, 6.90; N, 9.58. Found: C, 61.24; H, 6.75; N, 9.30.
Reaction SMILES: [BH4-].[Li+].CO.[Br:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:16])([CH3:15])[C:10](OCC)=[O:11].[NH4+].[Cl-]>ClCCl>[Br:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:16])([CH3:15])[CH2:10][OH:11]
Reactant: CCOC(=O)C(C)(C)CCCBr
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(CO)CCCBr
Temperature: 29 °C
Yield: 100.7 %

Procedure:
In a 1-L 3-neck round-bottomed flask fitted with condenser, dropping funnel pressure equalizer and magnetic stirrer were placed dichioromethane (300 mL) and lithium borohydride (12.97 g, 0.595 moles). The mixture was heated to 28-30° C., then the heating was discontinued and methanol (19.04 g, 0.595 moles) was added, at a rate that maintained the temperature below 30° C. To this solution, ethyl 5-bromo-2,2-dimethylpentanoate (94 g, 0.397 mol) in dichioromethane (100 mL) was added under argon atmosphere, allowing a gentle reflux during the addition. After the completion of the addition, the mixture was heated to 36-40° C. until no more starting material was detected by GC. The reaction mixture was cooled to 0° C. and was treated with crushed ice (130 g) under vigorous stirring until the effervescence ceased. The reaction mixture was treated with saturated aqueous NH4Cl (120 mL), stirred for 25 min, and warmed to above 15° C. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic phases were washed with saturated aqueous NH4Cl (2×100 mL). The organicphase was dried (MgSO4) and the solvent was evaporated under reduced pressure to give 5bromo-2,2-dimethyl-pentan-1-ol (78 g, 88.1% yield). 1H NMR (300 MHz, CDCl3/TMS): δ (ppm) 5.02 (s, 1H), 3.39-3.34 (t, J=14, 2H), 3.33 (s, 2H), 1.85-1.75 (m, 2H), 1.38-1.31 (m, 2H), 0.88 (s, 6H). 13C NMR (75 MHz, CDCl3=77.0 ppm/TMS): δ (ppm) 71.5, 37.1, 34.8, 34.6, 27.6, 23.8.