Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]I.[CH:4]1[C:18]2=[C:19]3[C:10](=[CH:11][C:12]4[C:13](=[O:20])[CH2:14][CH2:15][CH2:16][C:17]=42)[CH2:9][CH2:8][C:7]3=[CH:6][CH:5]=1>CCOCC>[OH:20][C:13]1([CH3:1])[CH2:14][CH2:15][CH2:16][C:17]2[C:18]3=[C:19]4[C:10]([CH2:9][CH2:8][C:7]4=[CH:6][CH:5]=[CH:4]3)=[CH:11][C:12]1=2
Reactant: C[Mg]I
Reactant: O=C1CCCc2c1cc1c3c(cccc23)CC1
Solvent: CCOCC
Product: CC1(O)CCCc2c1cc1c3c(cccc23)CC1
Temperature: 25 °C
Yield: 62 %

Procedure:
Methylmagnesium iodide in ether (1.51 mL of 3.0M) was added slowly to an ice bath cooled suspension of 7,8,9,10-tetrahydroacephenanthren-7-one (Scott, L. T.; Reinhardt, G.; Roelofs, N. H. J. Org. Chem. 1985, 50, 5886) (0.25 g, 1.13 mmol) in ether (10 mL). The bath was removed and the reaction mixture was allowed to warm to room temperature over 1.5 h. The reaction mixture was again cooled to 0° C. and quenched with saturated aqueous ammonium chloride solution. The reaction mixture was concentrated under reduced pressure. The resulting solid was purified via flash chromotography to give 0.17 g (62%) of a crystalline solid: MS (CI) m/e (%) 239 (M+H+, 100); 1H NMR (CDCl3, 300 MHz) δ 7.64 (d, 1H, J=8.0 Hz), 7.57 (s, 1H), 7.46 (t, 1H, J=8.4 Hz), 7.28 (d, 1H, J=6.6 Hz), 3.37 (s, 4H), 3.08 (m, 2H), 2.02 (m, 4H), 1.80 (s, 1H), 1.63 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C@@H:25]3[O:42][C@H:41]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:26]3[O:27][C:28](=[O:30])[CH3:29])[CH:17]=2)=[C:12]([C:48]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[NH:50][CH:49]=2)[C:11]1=[O:57])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.II>C1C=CC=CC=1.C(OCC)(=O)C.[Hg]>[CH2:1]([O:8][CH2:9][N:10]1[C:11](=[O:57])[C:12]2[C:48]3[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[NH:50][C:49]=3[C:17]3[N:18]([C@@H:25]4[O:42][C@H:41]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:26]4[O:27][C:28](=[O:30])[CH3:29])[C:19]4[N:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:16]=3[C:13]=2[C:14]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C3=C(c4c[nH]c5ccccc45)C(=O)N(COCc4ccccc4)C3=O)c3cccnc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: II
Agent: [Hg]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(=O)OC[C@H]1O[C@@H](n2c3ncccc3c3c4c(c5c6ccccc6[nH]c5c32)C(=O)N(COCc2ccccc2)C4=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 0.5 h

Procedure:
To a solution of the compound of Example 1b (0.409 mmol), dissolved in 500 ml of benzene, there is added iodine (4.90 mmol). The mixture is irradiated in a quartz reactor equipped with an immersible medium-pressure mercury-vapour U.V. lamp of 400 W for 1 hour 30 minutes. The solvent is evaporated off; the crude reaction product is taken up in ethyl acetate and washed with aqueous sodium thiosulphite solution and then with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate and filtered, and the solvent is evaporated off. After purification by chromatography on silica gel (cyclohexane/ethyl acetate: 3/2), the expected product is isolated.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([CH3:29])([O:6][C:7]1[CH:8]=[C:9]([CH:13]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([O:27]C)=[O:26])[CH:19]=3)[NH:14]2)[CH:10]=[CH:11][CH:12]=1)[CH3:5].[OH-].[Na+]>CO.O1CCCC1>[C:3]([C:4]([O:6][C:7]1[CH:8]=[C:9]([CH:13]2[C:22]([CH3:23])([CH3:24])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]=3)[NH:14]2)[CH:10]=[CH:11][CH:12]=1)([CH3:29])[CH3:5])([OH:30])=[O:2]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(OC(C)(C)C(=O)OC)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(Oc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1)C(=O)O
Yield: 30.1 %

Procedure:
To a solution of methyl 2-(3-(1-methoxy-2-methyl-1-oxopropan-2-yloxy)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (216 mg, 0.52 mmol) in methanol (8 mL) and tetrahydrofuran (8 mL) was added a 1 M solution of sodium hydroxide (7.87 mL). The mixture was stirred and heated to reflux for 1.5 h. The mixture was concentrated, dissolved in water and acidified to pH=4 with 1M hydrochloric acid. The precipitated solid was filtered and redissolved in tetrahydrofuran, and the organic layers were dried over anhydrous magnesium sulfate. After evaporation of the organic solvent, the residue was treated with dichloromethane to afford 60 mg of 2-(3-(2-carboxypropan-2-yloxy)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid. Isolated yield: 30%; MS (ESI+APCI) M+1=384.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]3[C:9]2=[O:18])=[CH:4][CH:3]=1.O(C)[Na].[CH3:22][C:23]([CH3:34])([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]I)[C:24]([O:26][CH3:27])=[O:25]>CN(C=O)C>[O:18]=[C:9]1[C:10]2[C:11](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:13])[N:8]1[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:23]([CH3:22])([CH3:34])[C:24]([O:26][CH3:27])=[O:25])=[CH:7][CH:6]=1
Reactant: COC(=O)C(C)(C)CCCCCI
Reactant: O=C1c2ccccc2C(=O)N1c1ccc(O)cc1
Agent: CO[Na]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CCCCCOc1ccc(N2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C

Procedure:
N-[p-Hydroxyphenyl]phthalimide (5.0 g) described in Example 1 was dissolved in 100 ml of DMF and 1.13 g of NaOCH3 was added. The solution was stirred at room temperature for one-half hour, then 6.25 g of methyl 2,2-dimethyl-7-iodoheptanoate was added dropwise. The mixture was stirred at room temperature overnight and then heated at reflux for two hours and concentrated on rotary evaporator. H2O (100 ml) was added and a solid was obtained. The product was extracted with EtOAc leaving the insoluble starting material behind. Concentration of the ethyl acetate solution followed by recrystallization of the resulting solid from isopropyl ether gave the purified product; mp 82°-3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:25][O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14]([NH:31][C:30]3[CH:32]=[CH:33][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: COc1ccc(N)cc1
Product: COc1ccc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)cc1
Temperature: 180 °C

Procedure:
A mixture of 0.113 g (0.29 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 and 0.50 g (4.10 mmol) of 4-methoxyaniline was heated, with stirring, in a 180° C. oil bath. The resulting solution was heated for 10 minutes. Much of the excess aniline was evaporated at reduced pressure. The remainder was dissolved in 2 mL of ethyl acetate. The crystals that separated from the dark solution were filtered and washed with 2 mL of ethyl acetate, wt 0.102 g.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Brc1cccc(CN2CCCCC2)n1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 87.1 %

Procedure:
To a solution of 6-bromopyridine-2-carbaldehyde (25 g, 135 mmol) in dichloromethane (500 ml) was slowly added piperidine (12.6 g, 149 mmol) at 10° C. After stirring for 15 minutes at 10° C., acetic acid (8.9 g, 149 mmol) was added, followed by the portionwise addition of sodium triacetoxyborohydride, while the temperature was kept at 5-10° C. After stirring for 2 h at room temperature the reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate. The product was extracted into dichloromethane and the combined organic phases were washed with brine, dried over sodium sulphate and concentrated under reduced pressure. Column chromatography afforded 2-bromo-6-(piperidin-1-ylmethyl)pyridine (30 g) as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24]([O:26]C)=O.Cl.[OH-].[NH4+:30]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:30]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1c(F)cccc1F
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1c(F)cccc1F
Yield: 70 %

Procedure:
A solution of the 9-[(2,6-difluorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (514 mg, 1.4 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was stirred at room temperature for 64 hours. The pH was adjusted to 10.5 with 5 N HCl. The resultant precipitate was collected by filtration, resuspended in H2O, adjusted the pH to 11.7 with concentrated ammonium hydroxide. The resultant precipitate was collected by filtration. The precipitate was dissolved in ethyl acetate, washed three times with 5 N NaOH, H2O, and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated to afford 310 mg (70%) of the 9-[(2,6-difluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a yellow solid. 1H NMR (DMSO-d6) δ 10.4 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (d, 1H, J=8 Hz), 7.6-7.0 (m, 7H), 6.6 (d, 1H, J=8 Hz), and 5.7 (s, 2H). IR (KBr, cm−1) 3404, 3113, 1626, and 1587. MS (ES) m/e 351, 353.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10](=O)[CH2:11][C:12]1[C:13]([CH3:22])=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[O:16][CH2:15]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:24][C:25]1[C:29](=[O:30])[O:28][CH2:27][C:26]=1[N:31]1[CH2:35][CH2:34][C:33]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[C:32]1=[O:41].[Na]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Si:1]([O:8][CH2:9][CH:10]([N:38]1[CH2:39][CH2:40][C:33]2([C:32](=[O:41])[N:31]([C:26]3[CH2:27][O:28][C:29](=[O:30])[C:25]=3[CH3:24])[CH2:35][CH2:34]2)[CH2:36][CH2:37]1)[CH2:11][C:12]1[C:13]([CH3:22])=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[O:16][CH2:15]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1c(CC(=O)CO[Si](C)(C)C(C)(C)C)ccc2c1COC2=O
Reactant: CC1=C(N2CCC3(CCNCC3)C2=O)COC1=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Na]
Solvent: CO
Product: CC1=C(N2CCC3(CCN(C(CO[Si](C)(C)C(C)(C)C)Cc4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-(3-((tert-butyldimethylsilyl)oxy)-2-oxopropyl)-4-methylisobenzo furan-1(3H)-one (0.50 g, 1.5 mmol) in methanol (20 mL) was added 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-17) (0.45 g, 1.8 mmol) and titanium(IV) isopropoxide (2.10 g, 7.5 mmol). After stirring at for room temperature 48 h, sodium cyanoborohyride (190 mg, 3.0 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was quenched with water (10 mL), and the resulting inorganic precipitate was filtered off and washed with methanol (50 mL). The filtrate was then concentrated and the crude product was dissolved in ethyl acetate, filtered to remove the remaining inorganic solids, and concentrated. The residue was purified by flash column chromatography (0-10% methanol in dichloromethane) to give the title compound. LC-MS (ESI, m/z): 569 [M+1]+
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]#[C:6][CH:7]([OH:11])[CH:8]([CH3:10])[CH3:9])[CH3:2]>ClCCl.O=[Mn]=O>[CH2:13]([O:12][CH:4]([O:3][CH2:1][CH3:2])[C:5]#[C:6][C:7](=[O:11])[CH:8]([CH3:9])[CH3:10])[CH3:14]
Reactant: CCOC(C#CC(O)C(C)C)OCC
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOC(C#CC(=O)C(C)C)OCC
Yield: 36.1 %

Procedure:
6,6-Diethoxy-2-methyl-hex-4-yn-3-ol (3.18 g, 18.46 mmol) was dissolved in dichloromethane (100 ml) and treated with activated MnO2 (30 g) at rt for 15 h. The reaction mixture was filtered through a plug of celite and Na2SO4. The filtrated was concentrated under reduced pressure and purified by flash chromatography with 0-15% EtOAc in hexane to afford the desired product (1.32 g, 36% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH:5]([CH3:8])[CH2:6][OH:7].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(N(CC)CC)C>[CH3:14][S:15]([O:7][CH2:6][CH:5]([O:4][C:3]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=1[Cl:1])[CH3:8])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CO)Oc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Product: CC(COS(C)(=O)=O)Oc1ccc(Cl)cc1Cl
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 324 parts of 2-(2,4-dichlorophenoxy)-1-propanol and 700 parts of N,N-diethylethanamine were added dropwise at room temperature 335 parts of methanesulfonyl chloride (exothermic reaction: the temperature roses to reflux temperature). While cooling in a water-bath, stirring was continued for 30 minutes at room temperature. The reaction mixture was poured onto water and the product was extracted with 2,2'-oxybispropane. The extract was dried, filtered and evaporated. The residue was distilled by vacuum distillation, yielding 300 parts of 2-(2,4-dichlorophenoxy)-1-propanol methanesulfonate (ester); bp. 130° C. at 2×10-4 mm. pressure (intermediate 101).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:18])[CH2:16][Br:17])=[CH:11][C:10]=1[N+:19]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22](O)=[O:23].C(OC(=O)C)(=O)C>C1COCC1.C1(C)C=CC=CC=1.O=[Pt]=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:18])[CH2:16][Br:17])=[CH:11][C:10]=1[NH:19][CH:22]=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: O=[N+]([O-])c1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Agent: O=[Pt]=O
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=CNc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Reaction time: 16 h
Yield: 63 %

Procedure:
A Parr hydrogenator was charged with PtO2 and 1-(4-benzyloxy-3-nitro-phenyl)-2-bromo-1-(R)-ethanol (4) (0.72 g, 2.04 mmol) dissolved in a mixed solvent of THF (8 mL) and toluene (8 mL). The mixture was hydrogenated at 55 psi at rt for 16 h. Then a mixture of formic acid (0.13 mL, 3.45 mmol) and acetic anhydride (0.22 mL, 2.33 mmol) was added and stirring was continued at rt for 66 h. The catalyst was filtered through a Celite pad and the filtrate was concentrated by rotary evaporation. The resulting residue was purified by Biotage silica gel column chromatography eluting with ethyl acetate/dichloromethane (gradient 0% to 10%) to give the desired formamide 5 as a white solid (0.45 g, 63%): 1H NMR (300 MHz, CDCl3) δ 2.95 (s, 1H), 3.52 (m, 1H), 3.60 (m, 1H), 4.85 (m, 1H), 5.08 (s, 2H), 6.96 (d, 1H), 7.13 (dd, 1H), 7.39 (m, 5H), 7.88 (br, 1H), 8.37 (dd, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([NH:8][CH:9]=O)[CH:5]=[CH:6][CH:7]=1.CSC.B.Cl>C1COCC1>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH:8][CH3:9]
Reactant: O=CNc1cccc(Br)c1F
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: CNc1cccc(Br)c1F
Temperature: 25 °C
Yield: 29.7 %

Procedure:
Step 2 A suspension of N-(3-bromo-2-fluorophenyl)formamide (216 mg, 0.991 mmol) in THF (8 mL) was treated with borane dimethyl sulfide complex (2.0 M in THF, 1.486 mL, 2.97 mmol) and the resulting mixture was heated at reflux for 2 h. 1 M hydrochloric acid was added and the mixture was again heated at reflux for 1 h. The mixture was cooled to rt and concentrated and the residue was partitioned between NaHCO3 (aq) and EtOAc. The organic phase was washed with brine, dried and concentrated to provide 3-bromo-2-fluoro-N-methylaniline as a light yellow oil (60 mg, 30%). Mass spectrum m/z 204, 206 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:12]([N:14]([CH2:18][CH3:19])[CH2:15][CH2:16][NH2:17])[CH3:13].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:17][CH2:16][CH2:15][N:14]([CH2:18][CH3:19])[CH2:12][CH3:13])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: CCN(CC)CCN
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and N1,N1-diethylethane-1,2-diamine according to general procedure 1 providing the intermediate (160 mg, 80%) as a clear oil: Rf=0.22 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.55 (d, J=9.7 Hz, 1H), 7.40 (s, 1H), 6.68 (d, J=9.7 Hz, 1H), 3.52 (t, J=6.0 Hz, 2H), 2.79 (t, J=5.8 Hz, 2H), 2.68 (quart, J=7.2 Hz, 4H), 1.12 (t, J=7.2 Hz, 6H); ES-MS: (M+H)=312, 314 m/z.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].[C:11](OC(=O)C)(=[O:13])[CH3:12].Cl>O>[C:11]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])(=[O:13])[CH3:12]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
L-Valine (200 g, 1.7 mol eq) is dissolved in water (500 mL) followed by the addition of NaOH (30%, 170 mL).The mixture is cooled to 0°–5° C. followed by the addition of acetic anhydride (32 ml, 1.4 eq.). Sodium hydroxide (30%, 34 mL) is added while keeping the temperature at 0°–5° C. Acetic anhydride and 30% NaOH alternate additions are repeated six time while keeping the temperature (acetic anhydride, 6×32 mL; 30% NaOH 6×34 mL). After all the additions are completed, the mixture is stirred for an additional two hours at 0° C. Hydrochloric acid (32%, 380 mL) is added to lower the pH below 3 while keeping the temperature at 0° C. The resulting slurry is granulated for 12 hours, filter and the cake washed with HCl (0.1 N, 100 mL). The wet N-acetyl-L-valine was dried to produce 233 g (86% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.Cl.[N:35]1[CH:40]=[CH:39][N:38]=[CH:37][C:36]=1[C:41]1[CH:46]=[CH:45][C:44]([CH2:47][N:48]([NH2:72])[CH2:49][C@H:50]([OH:71])[C@@H:51]([NH:59][C:60](=[O:70])[C@H:61]([CH:67]([CH3:69])[CH3:68])[NH:62][C:63]([O:65][CH3:66])=[O:64])[CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:43][CH:42]=1.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C.O1CCOCC1.O>[N:35]1[CH:40]=[CH:39][N:38]=[CH:37][C:36]=1[C:41]1[CH:42]=[CH:43][C:44]([CH2:47][N:48]([NH:72][C:11](=[O:13])[C@H:6]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:49][C@H:50]([OH:71])[C@@H:51]([NH:59][C:60](=[O:70])[C@H:61]([CH:67]([CH3:69])[CH3:68])[NH:62][C:63]([O:65][CH3:66])=[O:64])[CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:45][CH:46]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cnccn2)cc1)C(C)C
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(-c2cnccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
142 mg (0.75 mmol) of N-methoxycarbonyl-(L)-iso-leucine and 223 mg (0.75 mmol) of TPTU in 3 ml of DMF are stirred at room temperature for 10 min and then a solution of 473 mg (0.75 mmol) of 1-[4-(pyrazin-2-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane hydrochloride (Example 40g) and 0.33 ml of NMM in 3 ml of DMF is added. The mixture is stirred at room temperature overnight. Working up is carried out by the slow, dropwise addition of the reaction mixture to 100 ml of water, stirring at room temperature for 20 min and isolation of the resulting precipitate by filtration. The precipitate is washed with water and taken up in methylene chloride; the organic phase is washed in succession with water, sat. sodium hydrogen carbonate solution/water 1:1, water and brine. After removal of the solvent, the residue is digested in ether, with the title compound being obtained in the form of a colourless powder. The compound can be lyophilised from dioxane. TLC: Rf =0.28 (ethyl acetate). HPLC20-100 : tRet =13.78. FAB MS(M+H)+ =692.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]1=[O:11].[CH3:12]I>C(Cl)(Cl)Cl>[CH3:12][O:11][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[N:1]=1
Reactant: O=c1ccc2c([nH]1)CCCC2
Reactant: CI
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(n1)CCCC2
Temperature: 25 °C

Procedure:
To a 0.33 M solution of 5,6,7,8-tetrahydroquinolin-2 (1H)-one in dry CHCl3 at room temperature was added 1.2 equiv of Ag2CO3 and 6 equiv of MeI. The final suspension was refluxed in the dark for 5 h. After allowing the reaction to cool to room temperature, the suspension was filtered through Celite and concentrated. The crude material was further purified by flash chromatography, eluting with a gradient from 100% hexanes to 10% EtOAc/hexanes to provide the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.[NH2:19][C:20]1[C:28]([NH2:29])=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[C:22]([OH:30])[CH:21]=1.O>CC(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[N:29][C:28]3[C:20](=[CH:21][C:22]([OH:30])=[C:23]([C:24]([OH:26])=[O:25])[CH:27]=3)[N:19]=2)=[CH:4][CH:3]=1
Reactant: Nc1cc(O)c(C(=O)O)cc1N
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc2nc(-c3ccc(F)cc3)c(-c3ccc(F)cc3)nc2cc1O
Temperature: 130 °C
Reaction time: 3 h
Yield: 18.6 %

Procedure:
A mixture of 1,2-bis(4-fluorophenyl)ethane-1,2-dione (175 mg, 0.71 mmol, 1.00 equiv) and 4,5-diamino-2-hydroxybenzoic acid (120 mg, 0.71 mmol, 1.00 equiv) in HOAc (3 mL) was allowed to react, with stifling, for 3 hrs while the temperature was maintained at 130° C. in an oil bath. The reaction solution was poured into 10 ml of H2O. The resulting solid was filtered and purified by prep-HPLC, yielding 50 mg (19%) of 2,3-bis(4-fluorophenyl)-7-hydroxyquinoxaline-6-carboxylic acid as a yellow solid.