Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][C:10]([CH3:38])=[CH:11][C:12]=3[CH:14]([O:16][CH2:17][C:18]3([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=O)[CH2:20][CH2:19]3)[CH3:15])[CH:7]=[N:6]2)[CH2:3][CH2:2]1.C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][C:10]([CH3:38])=[CH:11][C:12]=3[CH:14]([O:16][CH2:17][C:18]3([C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)[CH3:15])[CH:7]=[N:6]2)[CH2:2][CH2:3]1
Reactant: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C(=O)OC(C)(C)C)CC2)c2c(cnn2CC2CC2)c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C)CC2)c2c(cnn2CC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-tert-Butyl 4-((1-(1-(cyclopropylmethyl)-5-methyl-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (7 mg, 0.01 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 1 mL) and stirred at room temperature for 1 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2 M ammonia in methanol and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., and treated with sodium cyanoborohydride (4.2 mg, 0.07 mmol) and formalin (37 μL). After 5 min, the reaction was treated with a few drops of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and purified by flash chromatography on silica gel (10% methanolic ammonia/methylene chloride) to afford 4 mg (68%). LC/MS (HPLC method 1): tR=2.49 min, 436.59(MH)+.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:17]=[CH:16][C:7]2[C@H:8]([CH2:11][C:12]([O:14]C)=[O:13])[CH2:9][O:10][C:6]=2[CH:5]=1.Cl>CO>[OH:3][C:4]1[CH:17]=[CH:16][C:7]2[C@H:8]([CH2:11][C:12]([OH:14])=[O:13])[CH2:9][O:10][C:6]=2[CH:5]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C[C@@H]1COc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1081 mL) was added (internal temperature: 10 C or lower) to a solution of (S)-methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate (180 g) in methanol (360 mL) at 5 C over 30 minutes, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, 1 M hydrochloric acid (2354 mL) was added at 5 C, followed by extraction with ethyl acetate (900 mL×2). The extracts were washed with brine (140 mL) and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (166 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH:13]3[O:15][CH2:14]3)[C:10](=[O:16])[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1.S(=O)(=O)(O)[OH:26].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH:13]([OH:26])[CH2:14][OH:15])[C:10](=[O:16])[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1
Reactant: O=S(=O)(O)O
Reactant: O=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1CC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1CC(O)CO

Procedure:
1 g of crude 7-chloro-1-(2,3-epoxypropyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one is dissolved in 15 ml of methanol and 15 ml of 2 N sulfuric acid and stirred for 1 hour at 25°C. Then the solution is made alkaline with 3 N sodium hydroxide and the methanol is carefully distilled on a rotary evaporator. The aqueous phase is extracted with ethyl acetate and the ethyl acetate solution is washed with water, dried over magnesium sulfate, filtered and concentrated. By chromatography of the residue on silica gel with ethyl acetate/methanol (9:1) there is isolated 7-chloro-1-(2,3-dihydroxypropyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one of melting point 116°-117°C.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.O.[CH2:22](O)[CH3:23]>>[CH2:1]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([C:17]([O:19][CH2:22][CH3:23])=[O:18])=[CH:12][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCO
Reactant: CCCCCCCc1cc2cc(C(=O)O)ccc2[nH]1
Agent: Cl
Solvent: O
Product: CCCCCCCc1cc2cc(C(=O)OCC)ccc2[nH]1

Procedure:
A solution of 2-(n-heptyl)indole-5-carboxylic acid (18.4 g) in ethanol (80 ml) containing a solution of hydrogen chloride gas in ethanol (110 ml, of strength 34% w/v) was refluxed for 6 hours. The solution was poured into water and the solid was collected and was recrystallised from methanol to give ethyl 2-(n-heptyl)indole-5-carboxylate (10.7 g), in the form of buff crystals, m.p. 66°-69° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=O)[O:18]C2C=CC([N+]([O-])=O)=CC=2)=[CH:12][CH:11]=1)([O-:9])=[O:8]>C(Cl)Cl.O>[O:4]1[CH2:5][CH2:6][CH:2]([O:1][C:17](=[O:18])[O:16][C:13]2[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:15][CH:14]=2)[CH2:3]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: O[C@H]1CCOC1
Solvent: ClCCl
Solvent: O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCOC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.9 %

Procedure:
(S)-(+)-3-Hydroxy-tetrahydrofuran (0.88 mL, 13 mmol) was dissolved in DCM (5 mL) and H2O (40 mL), carbonic acid bis-(4-nitro-phenyl) ester (5.8 g 19 mmol) and TEA (2.8 mL, 20 mmol) were added slowly. The reaction was allowed to stir at room temperature for 24 h. After concentrated, diluted with EtOAc, washed with brine and H2O, dried over Na2SO4, the crude product was purified on silica (12 g, 25-75% EtOAc/hexanes) to give carbonic acid 4-nitro-phenyl ester tetrahydro-furan-3-yl ester as light yellow solid (2.3 g, 71%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:20][O:21][C:22]1[C:23](=[O:50])[C:24]([CH3:49])=[C:25]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:41][CH2:42][C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)=[C:36]([CH:40]=2)[C:37](O)=[O:38])[C:26](=[O:30])[C:27]=1[O:28][CH3:29]>C(Cl)Cl>[CH3:20][O:21][C:22]1[C:23](=[O:50])[C:24]([CH3:49])=[C:25]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:41][CH2:42][C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)=[C:36]([CH:40]=2)[C:37]([N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)=[O:38])[C:26](=[O:30])[C:27]=1[O:28][CH3:29]
Reactant: CC1CCNCC1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)N3CCC(C)CC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.9 %

Procedure:
4-Methylpiperidine (0.094 g, 0.946 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.272 g, 1.42 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.200 g, 0.473 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=9:1) to obtain the titled compound (0.100 g, 0.198 mmol, 42%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[CH3:26].S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[Cl:12][C:7]1[CH:8]=[C:9]([Cl:11])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:21]([C:20]1[CH:23]=[C:24]([CH3:25])[C:17]([O:16][CH2:15][CH2:14][OH:13])=[C:18]([CH3:26])[CH:19]=1)=[N:1]2
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: NC(=O)c1c(N)cc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3cc(Cl)cc(Cl)c3c(=O)[nH]2)cc(C)c1OCCO
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a solution of 2-amino-4,6-dichloro-benzamide (1.54 g, 7.50 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (1.46 g, 7.50 mmol) in N,N-dimethylacetamide (15 mL) were added sodium hydrogen sulfite (58.5 wt %, 1.51 g, 8.25 mmol) and p-toluenesulfonic acid monohydrate (0.28 g, 1.50 mmol). The reaction mixture was stirred at 120° C. for 16 hours under nitrogen, and then cooled to room temperature. Solvent was evaporated under reduced pressure. Water (100 mL) was added. The separated solid was filtered, washed with water (50 mL), and dried under vacuum. Crude compound was further washed with ether and dried under vacuum to give 5,7-dichloro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethylphenyl]-3H-quinazolin-4-one as a white solid. Yield: 2.42 g (85%).
Reaction SMILES: CS(C)=O.[F:5][C:6]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:11]=[CH:10][C:7]=1[C:8]#[N:9].Cl[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([F:37])[CH:30]=1.C(N(C(C)C)C(C)C)C>O>[C:33]([C:32]1[CH:35]=[CH:36][C:29]([O:28][CH2:27][CH2:26][CH2:25][N:21]2[CH2:22][CH2:23][CH:18]([CH2:17][CH2:16][CH2:15][O:14][C:12]3[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([F:5])[CH:13]=3)[CH2:19][CH2:20]2)=[CH:30][C:31]=1[F:37])#[N:34]
Reactant: N#Cc1ccc(OCCCC2CCNCC2)cc1F
Reactant: N#Cc1ccc(OCCCCl)cc1F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1ccc(OCCCC2CCN(CCCOc3ccc(C#N)c(F)c3)CC2)cc1F
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 57.9 %

Procedure:
To a dimethylsulfoxide (4.0 mL) solution of 0.26 g of 2-fluoro-4-[3-(4-piperidinyl)propoxy]benzonitrile and 0.21 g of 4-(3-chloropropoxy)-2-fluorobenzonitrile was added 0.88 mL of N-ethyldiisopropylamine, which was then stirred at 80 to 90° C. for 8 hours and 15 minutes. The reaction mixture was cooled down to room temperature, to which water was then added, followed by extraction with ethyl acetate. The extract was washed twice with water and dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; chloroform:methanol=10:1) to provide 0.25 g of 4-(3-{1-[3-(4-cyano-3-fluorophenoxy) propyl]-4-piperidinyl}propoxy)-2-fluorobenzonitrile as brown solid form.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19]Cl)=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:21]([OH:25])[CH2:22][CH2:23][OH:24]>>[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][O:24][CH2:23][CH2:22][CH2:21][OH:25])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCCCO
Reactant: ClCc1nn(Cc2ccccc2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: OCCCOCc1nn(Cc2ccccc2)c2ccccc12
Temperature: 130 °C

Procedure:
To a solution of NaOH (2.8 g; 0.07 mol) in 1,3-propanediol (150 ml) stirred at room temperature was added 1-benzyl-3-chloromethylindazole, prepared as described in Example 2a of EP 382 276 (17.6 g; 0.07 mol). The solution was heated at 130° C. for 4 hours and then cooled to room temperature, and the solvent was evaporated off under reduced pressure. The residue was taken up in water (100 ml) and the product was extracted with ethyl acetate (3×100 ml). The combined organic phases were concentrated under reduced pressure and the crude residue obtained was purified by flash chromatography on silica gel, using as eluent a 1/1 hexane/ethyl acetate mixture. The product was purified by crystallization from an approximately 1/1 hexane/ethyl acetate mixture.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[S:6][C:7]([CH3:10])=[CH:8][CH:9]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F-].[K+].[F:33][C:34]([F:48])([F:47])[C:35]1[CH:40]=[CH:39][C:38]([C:41]2[S:42][C:43](I)=[CH:44][N:45]=2)=[CH:37][CH:36]=1>C(#N)C.C(N(CC)CC)C.C(OCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:48][C:34]([F:33])([F:47])[C:35]1[CH:36]=[CH:37][C:38]([C:41]2[S:42][C:43]([C:3]#[C:4][C:5]3[S:6][C:7]([CH3:10])=[CH:8][CH:9]=3)=[CH:44][N:45]=2)=[CH:39][CH:40]=1
Reactant: Cc1ccc(C#C[Si](C)(C)C)s1
Reactant: FC(F)(F)c1ccc(-c2ncc(I)s2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CC#N
Product: Cc1ccc(C#Cc2cnc(-c3ccc(C(F)(F)F)cc3)s2)s1
Yield: 27.8 %

Procedure:
Under a dry nitrogen atmosphere, a stirred mixture of 0.70 gram (0.0036 mole) of 1-trimethylsilyl-2-(5-methylthien-2-yl)ethyne, 0.11 gram (0.0040 mole) of tetrabutylammonium fluoride, and 0.24 gram (0.0041 mole) of potassium fluoride in 7 ml of acetonitrile and 20 ml of triethylamine was heated at reflux for one hour. To this mixture was added 1.0 gram (0.0033 mole) of 2-(4-trifluoromethylphenyl)-5-iodothiazole, 0.03 gram (4.0×10-4 mole) of dichlorobis(triphenylphosphine)palladium (II), and 0.02 gram (8.0×10-4 mole) of copper (I) iodide. This mixture was stirred at reflux for approximately 18 hours. The mixture was cooled and was diluted with diethyl ether. This mixture was washed in succession with an aqueous, saturated ammonium chloride solution, water, dilute hydrochloric acid, and an aqueous, saturated sodium chloride solution. The washed organic solution was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure leaving a solid residue. This residue was purified by column chromatography on silica gel, eluting first with methylene chloride:hexane (50:50), then methylene chloride: hexane (50:40), and finally acetone:hexane (10:90), to yield 0.32 gram of 1-[2-(4-trifluoromethylphenyl)thiazol-5-yl]-2-(5-methylthien-2-yl)ethyne as a solid, m.p. 107°-108.5° C., Compound 33 of Table 1.
Reaction SMILES: C1N(COCCO)[C:4]2N=C(N)N=C(O)[C:3]=2N=1.[C:17]([NH:27][C@H:28]([C:33]([OH:35])=[O:34])[C@H:29]([CH2:31][CH3:32])[CH3:30])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:3]([O:34][C:33](=[O:35])[C@H:28]([C@H:29]([CH2:31][CH3:32])[CH3:30])[NH:27][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1nc(O)c2ncn(COCCO)c2n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)CC
Temperature: 25 °C
Reaction time: 96 h
Yield: 61.4 %

Procedure:
A mixture of acyclovir (1.0 g, 4.4. mmol; Burroughs Wellcome Co.), 4-dimethylaminopyridine (74 mg, 0.6 mmol; Aldrich Chemical Co. and Chem. Ber. 89 2921-33 [1956]), 1,3-dicyclohexylcarbodiimidide (1.6 g, 8.0 mmol; Aldrich Chemical Co. and U.S. Pat. No. 2,656,383), N-carbobenzoxy-L-isoleucine (1.8 g, 6.6 mmol; Sigma Chemical Co. and Bull. Chem. Soc. Jap (1966) 39 947 or Tetrahedron 40 (24) 5207-11 [1984]), and molecular sieves (0.3 g, Davison type 3A; Fisher Scientific, Co.) in dry N,N-dimethylformamide (80 ml) was stirred at room temperature under nitrogen. After 4 days, additional 1,3-dicyclohexylcarbodiimide (1.6 g, 8.0 mmol) and N-carbobenzoxy-L-isoleucine (1.8 g, 6.6 mmol) were added. Stirring at room temperature was continued for 7 days. The resulting mixture was filtered and the clear filtrate was concentrated in vacuo to a semi-solid residue. Elution of the residue from silica gel 60 (EM, 230-400 mesh; 8.5×14 cm) with 2.5-5% methanol/methylene chloride gave 2-[2-Amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl-N-[(benzyloxy)carbonyl]-L-isoleucinate 0.8 g, 45%) as a white solid; mp 155°-157° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].S(=O)(=O)(O)O.[Br:9][C:10]1[CH:26]=[C:25]([CH2:27]Cl)[CH:24]=[C:23]([Br:29])[C:11]=1[CH2:12][C:13]1[CH:14]=[C:15]([CH:20]([CH3:22])[CH3:21])[C:16](=[O:19])[NH:17][N:18]=1>CS(C)=O>[Br:9][C:10]1[CH:26]=[C:25]([CH2:27][C:1]#[N:2])[CH:24]=[C:23]([Br:29])[C:11]=1[CH2:12][C:13]1[CH:14]=[C:15]([CH:20]([CH3:22])[CH3:21])[C:16](=[O:19])[NH:17][N:18]=1
Reactant: CC(C)c1cc(Cc2c(Br)cc(CCl)cc2Br)n[nH]c1=O
Reactant: [C-]#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)c1cc(Cc2c(Br)cc(CC#N)cc2Br)n[nH]c1=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A suspension of sodium cyanide (279 mg, 5.69 mmol) in dimethyl sulfoxide (2.0 mL) was treated with concentrated sulfuric acid (0.10 mL), 6-(2,6-dibromo-4-chloromethyl-benzyl)-4-isopropyl-pyridazin-3-one (62) (346 mg, 0.79 mmol) and an addition rinse of dimethyl sulfoxide (3.0 mL). The reaction was stirred at 25° C. for 5 min and at 40° C. for 1 h. At this time, the reaction was heated to 60° C. for 1 h and then was cooled to 25° C. The mixture was poured onto a mixture of ice and a saturated aqueous sodium bicarbonate solution (50 mL). This mixture was extracted into ethyl acetate (3×50 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1:2 hexanes/ethyl acetate) afforded [3,5-dibromo-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-acetonitrile (63) (227 mg, 67%) as a light orange solid; LRMS for C16H15Br2N3O (M+H) at m/z=424. Molecular Weight=425.1255; Exact Mass=422.9582
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([OH:20])[N:17]=[C:16]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>C(OCC)C>[ClH:27].[N:21]1([C:16]2[N:17]=[C:18]([OH:20])[CH:19]=[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:15]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(O)nc(N3CCOCC3)n2)CC1
Agent: Cl
Solvent: CCOCC
Product: Oc1cc(C2CCNCC2)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(6-Hydroxy-2-morpholin-4-ylpyrimidin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.19 g, 0.52 mmol) was added to 2 N hydrogen chloride in diethyl ether and stirred for 18 hours at room temperature. The resultant product was isolated by filtration and washed with ether to provide 2-morpholin-4-yl-6-piperidin-4-yl-pyrimidin-4-01, hydrochloride salt (0.16 g, 91% yield) as a white solid. 1H NMR (300 MHz, CD3OD/TMS): δ=6.17 (s, 1H), 3.90-3.78 (m, 8H), 3.60-3.50 (m, 2H), 3.26-3.1 (m, 3H), 2.32-2.20 (m, 2H), 2.00-1.80 (m, 2H). 13C NMR (75 MHz, CD3OD/TMS): δ=171.60, 164.86, 155.10, 97.63, 66.93, 45.13, 46.92, 44.81, 38.29, 28.41.
Reaction SMILES: [CH3:1][CH:2]([C:4](=[O:16])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[CH3:6])[CH3:3].[BH4-].[Na+].Cl>CO>[CH3:3][CH:2]([CH:4]([OH:16])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[CH3:6])[CH3:1]
Reactant: CC(C)C(=O)C(C)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C(O)C(C)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
In a 25 ml flask was prepared a solution of 2-methyl-4-(2-nitro-phenyl)-pentan-3-one (390 mg, 1.8 mmol) in dry methanol (9 ml). It is cooled with an ice-water bath. The temperature in the reaction mixture was 4° C. Sodium borohydride (73 mg, 1.9 mmol) was added, spoon by spoon. It was stirred one hour at 0° C. The cooled mixture was added to HCl 1N (7 ml). This addition was exothermic. Methanol was evaporated. The aqueous phase was extracted with ethyl acetate (50 ml). The organic phase was washed with water (1×25 ml), brine (1×25 ml) and dried with magnesium sulfate. 2-methyl-4-(2-nitro-phenyl)-pentan-3-ol (380 mg—yield 97%) was then obtained as a pale yellow oil.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:15])[N:6]1[CH3:16])=[O:4].[OH-].[Na+].Cl>CO>[CH3:16][N:6]1[C@H:5]([C:3]([OH:4])=[O:2])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:15]
Reactant: COC(=O)[C@@H]1Cc2ccccc2C(=O)N1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C(=O)c2ccccc2C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
(3S)-3-Methoxycabonyl-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline (1.1 g) is dissolved in methanol (10 ml), and an aqueous 1N-sodium hydroxide solution (6 ml) is added thereto. The solution is stirred at 0° C. for one hour. The mixture is acidified with 10% HCl, and extracted with ethyl acetate. The extract is distilled to remove ethyl acetate, whereby (3S)-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (350 mg) is obtained as crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.[NH2:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:21]([O:20][C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:10]([C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)=[O:12])=[CH:26][CH:25]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)c2ccc3cc[nH]c3c2)cc1
Temperature: 60 °C
Reaction time: 72 h
Yield: 30.2 %

Procedure:
A solution of 1H-indole-6-carboxylic acid (1.00 g, 6.20 mmol), tert-butyl 4-aminobenzoate (1.20 g, 6.20 mmol), 4-methylmorpholine (3.14 g, 31.0 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (3.53 g, 9.31 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 min, then 4-(dimethylamino)pyridine (758 mg, 6.20 mmol) was added, and the solution was stirred at 60° C. for 3 days. After cooling, the reaction mixture was partitioned between water, heptane, and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) followed by trituration in dichloromethane yielded 4-[(1H-indole-6-carbonyl)-amino]-benzoic acid tert-butyl ester (629 mg, 30%). White solid, MS (ISP): m/e 337.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[CH3:13][C:14](=[CH2:16])[CH3:15]>ClCCl.OS(C(F)(F)F)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][C:14]([CH3:16])([CH3:15])[CH3:13])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: C=C(C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)Oc1ccc2cc(Br)ccc2c1
Temperature: -39 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of 6-bromo-2-hydroxynaphthalene (1.5 g, 6.72 mmol) and liquefied iso-butylene (6 mL) in dry dichloromethane (6 mL) at −78° C. was added triflic acid (6 drops). The resulting solution was stirred for 4 hours as it warmed from −78 to 0° C. The reaction was quenched by adding excess saturated aqueous sodium bicarbonate and partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated under vacuum. Purification on silica gel with 25% ether/hexanes gave the title compound (1.64 g, 80%) as a colorless oil.