Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]2)(=O)C.Cl.[OH-].[Na+]>>[NH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]2
Reactant: CC(=O)Nc1ccc2c(c1)CCC(CN(C)C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(C)CC1CCc2cc(N)ccc2C1
Yield: 36.4 %

Procedure:
6-Acetylamino-2-(N,N-dimethylamino)methyltetralin hydrochloride (0.879 g; obtained in Reference Example 31) was added to 2 N hydrochloric acid. The reaction mixture was heated under reflux for 90 minutes, and then an aqueous solution of 1 N sodium hydroxide was added thereto to thereby make the resulting mixture have pH of 9. Then, this was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate/hexane=1/1) to obtain the entitled compound (0.231 g).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH2:4]O.B.C1C[O:15][CH2:14]C1>>[CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH2:4][CH2:14][OH:15]
Reactant: C1CCOC1
Reactant: Cc1ccc(CO)c(C)c1
Agent: B
Product: Cc1ccc(CCO)c(C)c1
Reaction time: 8 h

Procedure:
A solution of carboxylic acid 9 (3.40 g; 17.87 mmol) in THF (100 ml) was cooled to 0° C. and treated with 35 ml of a 1.0M solution of borane in THF. After stirring this mixture overnight it was quenched with 1N HCl and the product was extracted into ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and freed of solvent. The crude product was filtered through a plug of silica gel eluting with 20% ethyl acetate in hexane to obtain 2.75 g (quantitative yield) of the product as a clear light oil. 1H NMR (CDCl3): δ2.25, 2.28 (s, 3H each); 2.88 (t, 2H); 3.78 (t, 2H); 6.97-7.07 (m, 3H). IR (neat): 3340, 2947, 1504, 1448, 1265, 1044 cm-1.
Reaction SMILES: [OH:1][C:2]([P:8](=[O:11])([OH:10])[OH:9])([P:4](=[O:7])([OH:6])[OH:5])[CH3:3].[CH:12](Cl)(Cl)Cl.[N+](=C)=[N-]>CCOCC>[CH3:12][O:11][P:8]([C:2]([P:4](=[O:6])([OH:5])[OH:7])([OH:1])[CH3:3])(=[O:9])[OH:10]
Reactant: CC(O)(P(=O)(O)O)P(=O)(O)O
Reactant: ClC(Cl)Cl
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: COP(=O)(O)C(C)(O)P(=O)(O)O
Reaction time: 1 h
Yield: 42 %

Procedure:
Finely ground (1-hydroxyethylidene)bisphosphonic acid (0.005 moles) was mixed with 100 ml of chloroform and to the mixture 25 ml of an appr. 2% ether solution of diazomethane were slowly added at room temperature. After the addition, the mixing was continued for 1 hour, whereafter the solution was evaporated at reduced pressure (yield 42%, 31-P NMR 17.25/24.84 ppm, J=27.3; D2O).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.S(O)(O)(=O)=O.[NH2:60][C:61]1[NH:62][CH:63]=[CH:64][N:65]=1>CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:60][C:61]2[NH:62][CH:63]=[CH:64][N:65]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ncc[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ncc[nH]1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Yield: 33 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared in Example 38, 200 mg, 0.70 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (310 mg, 0.70 mmol), N,N-diisopropylethylamine (244 μL, 1.40 mmol), and 2-aminoimidazole sulfate (140 mg, 1.05 mmol) in dry N,N-dimethylformamide (5 mL) was stirred at 25° C. under nitrogen for 15 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with a 1N aqueous hydrochloric acid solution, washed with water, and washed with a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, ⅓ hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(1H-imidazol-2-yl)-propionamide (81.4 mg, 33%) as a white solid: mp 58-60° C.; EI-HRMS m/e calcd for C17H19Cl2N3O (M+) 351.0905, found 351.0901.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:12][CH2:13][CH2:14]C)[CH:6]2[OH:11].C(N(CC)CC)C.[CH3:23][Si:24](Cl)([CH3:26])[CH3:25].[C:28](=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:12][CH:13]([CH3:14])[CH3:28])[CH:6]2[O:11][Si:24]([CH3:26])([CH3:25])[CH3:23]
Reactant: C[Si](C)(C)Cl
Reactant: O=C([O-])O
Reactant: CCCCC1Cc2c(Br)cccc2C1O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC1Cc2c(Br)cccc2C1O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
A 300-ml three-necked round flask equipped with a stirring bar, a Dimroth condenser, a dropping funnel and a thermometer was charged with 34.4 g (127.8 mmol) of 4-bromo-2-1-butyl-1-hydoxyindane, 23.1 ml (166.2 mmol) of triethylamine and 118 ml of methylene chloride. To the mixture was added dropwise 20 ml of a methylene chloride solution containing 19.45 ml (153.4 mmol) of trimethylsilyl chloride under a nitrogen atmosphere while cooling with ice bath. After the addition was completed, the temperature was elevated to room temperature, and the mixture was further stirred for 1.5 hours. The reaction mixture was poured onto a mixture of 200 ml of ice water and 20 ml of a saturated aqueous solution of sodium bicarbonate. Then, the organic phase was separated, and the aqueous phase was further extracted with 50 ml of methylene chloride two times. The combined organic phase was washed with 100 ml of a saturated NaCl aq., followed by dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure. The residue was distilled under reduced pressure to obtain 41.8 g of the desired product (mixture of two isomers) as a pale yellow liquid (yield: 96%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([O:14][CH3:15])[C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([O:14][CH3:15])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccc(O)cc1)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
Methyl 3-(4-hydroxyphenyl)-2-methoxypropanoate (132 g, 0.631 mol) was dissolved in methanol (700 mL) and 5N sodium hydroxide (631 mL, 3.16 mol) was added dropwise at ambient temperature. The solution was stirred for 16 h at ambient temperature. The methanol was removed under vacuum, and water (500 mL) was added. The mixture was extracted with MTBE (2×500 mL). The aqueous solution was brought to pH=1 with concentrated HCl and then extracted with MTBE (2×500 nL). The organic extracts were dried (MgSO4), filtered, and concentrated under vacuum to give racemic 3-(4-hydroxyphenyl)-2-methoxypropanoic acid as an oil (110 g), which crystallized upon standing. 1H-NMR (DMSO): 7.0 (d, 2H); 6.6 (d, 2H); 4.0 (m, 1H); 2.8 (m, 2H); MS (ES−) m/z 195.1 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([OH:20])([CH3:19])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:21]1[C:26]([C:27]([NH2:29])=O)=[CH:25][N:24]=[CH:23][N:22]=1.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([OH:20])([CH3:19])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[C:21]1[C:26]([C:27]#[N:29])=[CH:25][N:24]=[CH:23][N:22]=1
Reactant: CC(C)(O)c1cnn2c(-c3ccc(F)c(-c4ncncc4C(N)=O)c3)cnc2n1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(O)c1cnn2c(-c3ccc(F)c(-c4ncncc4C#N)c3)cnc2n1

Procedure:
A suspension of 4-{2-fluoro-5-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7-yl]phenyl}pyrimidine-5-carboxylic acid amide (50 mg, 0.13 mmol) was formed in dry toluene (50 ml). Dibutyltin oxide (6 mg, 0.03 mmol) was added and the mixture heated at reflux for 18 h. The solvent was removed under reduced pressure then purification by chromatography (silica gel, 3% MeOH/CH2Cl2) gave the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 1.72 (6H, s), 3.23 (1H, s), 7.45 (1H, dd, J 9, 1 Hz), 8.24-8.29 (1H, m), 8.30 (1H, s), 8.42 (1H, dd, J 7, 2 Hz), 8.81 (1H, s), 9.14 (1H, s), 9.51 (1H, s); MS (ES+) m/z 376 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]=[CH:8][C:7]=2[CH:14]=1)#[N:2]>C(O)C.[Pd]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[CH2:9][CH2:8][C:7]=2[CH:14]=1)#[N:2]
Reactant: CC1(C)C=Cc2cc(C#N)ccc2O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CCc2cc(C#N)ccc2O1
Reaction time: 2 h
Yield: 102.7 %

Procedure:
A solution of 6-cyano-2,2-dimethyl-2H-1-benzopyran (5.5 g, 29.7 mmoles, prepared according to Evans et al., J. Med. Chem., 1983, 26, 1582 and J. Med. Chem. 1986, 29, 2194) in anhydrous ethanol (40 ml) was treated with palladium on carbon (0.35 g) and stirred under hydrogen gas for 2 hours. The catalyst was filtered through celite and the filter cake washed with ethyl acetate. The filtrate was concentrated under vacuum to obtain 5.71 g of a yellow oil. The crude product was dissolved in ethyl acetate (60 ml) and washed successively with 5% hydrogen chloride solution (60 ml), saturated sodium hydrogen carbonate solution (60 ml), saturated sodium chloride solution (60 ml) and dried over anhydrous magnesium sulfate. The solvent was recovered under vacuum to yield 5.14 g of the title A compound as a yellow solid (m.p. 30°-31° C.) which was used in the next step without further purification. 1H NMR (CDCl3) δ 7.37 (s, 1H), 7.34 (s, 1H), 6.80 (d, J=8.8 Hz, 1H), 2.78 (dd, 2H), 1.80 (dd, 2H), 1.35 (s, 6H). 13C NMR (CDCl3) δ 157.95, 133.82, 131.34, 122.07, 119.53, 118.24, 102.66, 75.76, 32.13. 26.81. 22.06.
Reaction SMILES: FC1C=C(C2C3CN(C(OC(C)(C)C)=O)CCC=3[NH:11][N:10]=2)C=CC=1F.[O:25]1[CH2:30][CH2:29][CH2:28][C:27](=O)[CH2:26]1.[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([F:42])=[C:37]([CH:41]=1)[C:38](Cl)=O>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([F:42])=[C:37]([C:38]2[C:28]3[CH2:29][CH2:30][O:25][CH2:26][C:27]=3[NH:10][N:11]=2)[CH:41]=1
Reactant: O=C(Cl)c1cc(Cl)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(F)c(F)c3)c2C1
Reactant: O=C1CCCOC1
Product: Fc1ccc(Cl)cc1-c1n[nH]c2c1CCOC2

Procedure:
Intermediate 16C was prepared according to the procedure for the synthesis of intermediate 15 by replacing 1-Boc-4-piperidone with dihydro-2H-pyran-3(4H)-one, and replacing 3,4-difluorobenzoyl chloride with 5-chloro-2-fluorobenzoyl chloride. LCMS (+ESI) m/z=253 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:10])=[CH:3][CH2:4]/[CH:5]=[C:6](/[CH:8]=[CH2:9])\[CH3:7].C([O-])(=[O:13])C.[Na+].C(OO)(=O)C>C(Cl)Cl>[CH3:1][C:2]([CH3:10])=[CH:3][CH2:4][C@@H:5]1[O:13][C@@:6]1([CH:8]=[CH2:9])[CH3:7]
Reactant: CC(=O)[O-]
Reactant: C=C/C(C)=C/CC=C(C)C
Agent: CC(=O)OO
Agent: [Na+]
Solvent: ClCCl
Product: C=C[C@@]1(C)O[C@H]1CC=C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of 204 g. of trans-ocimene and 150 g. of sodium acetate in 750 ml. of methylene chloride was stirred for one hour at room temperature, then it was cooled to 0° C. within about 15 min. Then, the addition of a solution of 3 g. of sodium acetate in 315 g. of 42% peracetic acid was started dropwise at a rate adjusted so that the temperature rose to 20°-25°. Without removing the cooling device but by maintaining a suitable rate of addition, the temperature was kept constant until the addition of the peracetic acid was completed. Under these conditions, the addition took one hour. The mixture was stirred for an additional four hours period at room temperature then the solid was removed by filtration and rinsed with methylene chloride. The combined methylene chloride solutions were poured into ice-water, the resulting mixture was shaken vigorously and the organic layer was separated and washed with 125 ml. portions of the following solvents: water (1 fold), saturated Na2CO3 (2 fold), water (1 fold). After the usual drying and concentrating procedure, distillation of the residue gave 205 g. of trans-epoxyocimene (90% yield), b.p. 45°-47°/0.1 Torr. d420 = 0.9082; nD20 = 1.4802.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)=[CH:9][CH:10]=3)[C:5]3([CH2:25][S:24][C:23]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:22]3)[C:4]=2[CH:3]=1.[CH3:31][C:32]([CH3:36])([CH3:35])[C:33]#[CH:34].C(NC(C)C)(C)C>[Cu]I.CN(C=O)C>[C:27]([NH:26][C:23]1[S:24][CH2:25][C:5]2([N:22]=1)[C:4]1[CH:3]=[C:2]([C:34]#[C:33][C:32]([CH3:36])([CH3:35])[CH3:31])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:16]2[CH:21]=[N:20][CH:19]=[N:18][CH:17]=2)=[CH:9][CH:10]=1)([CH3:29])([CH3:28])[CH3:30]
Reactant: C#CC(C)(C)C
Reactant: CC(C)(C)NC1=NC2(CS1)c1cc(Br)ccc1Oc1ccc(-c3cncnc3)cc12
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C#Cc1ccc2c(c1)C1(CSC(NC(C)(C)C)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A resealable tube was charged with (t-4)-tetrakis(triphenylphosphine)palladium (27.1 mg, 0.023 mmol), copper(i) iodide (8.94 mg, 0.047 mmol),2′-bromo-N-tert-butyl-7′-(pyrimidin-5-yl)-5H-spiro[thiazole-4,9′-xanthen]-2-amine (113 mg, 0.235 mmol), 3,3-dimethylbut-1-yne (144 μL, 1.174 mmol), diisopropylamine (669 μL, 4.69 mmol) and DMF (1.9 mL). The mixture was heated at 80° C. After 18 hrs, the mixture was cooled to RT, filtered through celite with EtOAc, and concentrated in vacuo. The residue was adsorbed onto silica gel and purified by silica gel chromatography using 30-75% Hexanes:EtOAc to afford N-tert-butyl-2′-(3,3-dimethylbut-1-ynyl)-7′-(pyrimidin-5-yl)-5H-spiro[thiazole-4,9′-xanthen]-2-amine as an off-white foam. MH+=483.2.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]4[N:20]=[CH:21][CH:22]=[CH:23][C:11]=4[N:10]3[C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([C:31]3([NH:35]C(=O)OC(C)(C)C)[CH2:34][O:33][CH2:32]3)=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([C:7]2[N:8]=[C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]4[N:20]=[CH:21][CH:22]=[CH:23][C:11]=4[N:10]3[C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([C:31]3([NH2:35])[CH2:32][O:33][CH2:34]3)=[CH:29][CH:30]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)COC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(c2ccc(-c3c(-c4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a suspension of tert-butyl {3-[4-(2-phenyl-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]oxetan-3-yl}carbamate (29 mg) in dichloromethane (4 mL) was added trifluoroacetic acid (2 mL) at 0° C. dropwise. After being stirred at room temperature for 1 h, the reaction mixture was concentrated under reduced pressure. Purification by column chromatography (NH-silica gel: 0-3% methanol in chloroform) gave the product (16 mg, 68%). 1HNMR (DMSO-d6) 400 MHz δ: 8.57 (s, 1H), 8.08 (dd, J=4.8, 1.6 Hz, 1H), 7.96 (dd, J=7.8, 1.4 Hz, 1H), 7.61 (d, J=8.3 Hz, 2H), 7.53-7.49 (m, 2H), 7.38-7.21 (m, 7H), 7.12 (t, J=7.6 Hz, 1H), 6.90 (dd, J=8.0, 1.6 Hz), 6.74 (dd, J=8.0, 4.8 Hz, 1H), 4.71-4.65 (m, 4H). LCMS: 458 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C@@H:7]([CH3:19])[CH2:8][N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1.Cl>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]([C:29]([CH:26]3[CH2:28][CH2:27]3)=[O:30])[C@@H:7]([CH3:19])[CH2:8][N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)c2cc(Br)ccc2N1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)OC(C)(C)C)c2cc(Br)ccc2N1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A 100-mL round bottomed flask fitted with a nitrogen inlet and magnetic stir bar was charged with (S)-tert-butyl 7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (4.75 g, 14.52 mmol), dichloromethane (50 mL), pyridine (1.996 mL, 24.68 mmol), and cyclopropanecarbonyl chloride (1.976 mL, 21.77 mmol). The reaction mixture was stirred at rt for 2 h and then 1 M aqueous HCl solution (25 mL) was added. The organic layer was separated and concentrated under reduced pressure to afford (S)-tert-butyl 7-bromo-4-(cyclopropanecarbonyl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (5.72 g, 99%) as a solid, which was used directly in next step. MS (ESI, pos. ion) m/z 395, 397 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([F:32])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.[C:33](Cl)(=[O:35])[CH3:34]>N1C=CC=CC=1>[F:32][C:5]1[CH:4]=[N:3][C:2]([NH:1][C:33](=[O:35])[CH3:34])=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:31])[C:12](=[O:13])[N:14]3[CH2:15][CH2:16][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:18][CH2:19]3)[C:6]=12
Reactant: Nc1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Temperature: 50 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
1-(7-amino-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (100 mg, 0.23 mmol) was dissolved in pyridine (2 mL) and the mixture was heated at 50° C. Acetyl chloride (65 uL, 0.92 mmol) was added and the mixture was stirred at this temperature for 1 h. Solvent was removed in vacuum and the residue was purified using reverse phase prep HPLC to afford the title compound as a white solid (55 mg). 1HNMR (500 MHz, DMSO-D6) δ 8.34 (s, 1H), 8.04 (d, J=1.0 Hz, 1H), 7.70-7.58 (m, 5H), 3.69 (m, 2H), 3.45 (m, 2H), 3.34 (m, 2H), 3.16 (m, 2H), 2.17 (s, 3H). LCMS: m/e 478 (M+H)+, ret time 1.07 min (method 3).
Reaction SMILES: C(OC(N[CH2:9][P:10]([CH2:15][NH:16][C:17](OC(C)(C)C)=O)(=[O:14])[O:11][CH2:12][CH3:13])=O)(C)(C)C.Cl.[C:25]1([C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[NH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[C:33]1([C:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:32][CH2:9][P:10]([CH2:15][N:16]=[C:17]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:14])[O:11][CH2:12][CH3:13])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCOP(=O)(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CCOP(=O)(CN=C(c1ccccc1)c1ccccc1)CN=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.8 %

Procedure:
The tert-butoxycarbonyl protective group is removed from the ethyl phosphinate 2 (100 mg; 0.28 mmol) using 3N methanolic hydrochloric acid (30 ml) (check via DC). The reaction solution is evaporated under reduced pressure. Diphenylmethanimine (0.100 ml; 0.60 mmol) is added dropwise to the suspension of the crude product in methylene chloride (20 ml) under an atmosphere of nitrogen. The reaction solution is filtered after being stirred for 16 hours at room temperature. The filtrate is evaporated under reduced pressure. The crude product is taken up in ether, filtered and extracted with water (2×20 ml). The organic phase is dried over Na2SO4 and evaporated under reduced pressure. The diphenylmethylene phosphinate 3 (71 mg, 53% of theory) is obtained after purification on silica gel using column chromatography (ethyl acetate/heptane=1/1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2[OH:17].[CH3:18][C:19]1([CH3:27])[CH2:24][C:23](=[O:25])[CH2:22][C:21](=O)[CH2:20]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:18][C:19]1([CH3:27])[CH2:20][C:21]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[N:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]3[OH:17])=[CH:22][C:23](=[O:25])[CH2:24]1
Reactant: CCOC(=O)c1nnc2ccc(N)cc2c1O
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1nnc2ccc(NC3=CC(=O)CC(C)(C)C3)cc2c1O

Procedure:
A mixture of ethyl 6-amino-4-hydroxycinnolin-3-yl carboxylate (0.932 g.), 5,5-dimethylcyclohexan-1,3-dione (2.24 g.) and p-toluenesulphonic acid (0.4 g.) in ethanol (100 ml.) was heated under reflux on a steam bath for 16 hours. The solution was evaporated in vacuo and the residue was applied to a silica column (100 g. Kieselgel 60). Elution with a mixture of 15% v/v ethanol and 85% v/v chloroform, and evaporation of the appropriate fractions gave crystalline ethyl 6-[(5,5-dimethylcyclohexen-3-one-yl)amino]-4-hydroxycinnolin-3-yl carboxylate, m.p. 274° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCC
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccccc1)(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
A solution of 628 mg (1.76 mmol) of 1-(t-butoxycarbonyl)-4-(2,2-bis(carbethoxy)ethyl)piperidine (from EXAMPLE 32, Step B) in 8 mL of THF at 0° C. was treated with 2.0 mL of 1.0 M sodium bis(trimethylsilyl) amide solution in THF and stirred cold for 10 min. The resulting mixture was treated with 0.35 mL (2.9 mmol) of benzyl bromide then warmed to rt and stirred for 1 h. The reaction was quenched with 10 mL of sat'd NH4Cl and the quenched mixture was partitioned between 50 mL of ether and 25 mL of H2O. The layers were separated and the organic layer was washed with 25 mL of sat'd NaCl, dried over MgSO4 and concentrated. Flash chromatography on 30 g of silica gel using 4:1 v/v hexanes/ether afforded 760 mg (96%) of the title compound: 1H NMR (500 MHz) δ 1.08-1.16 (m, 2H), 1.23 (t, J=7.0,66H), 1.45 (s, 9H), 1.54-1.58 (m, 2H), 1.60-1.66 (m, 1H), 1.78 (d, J=6.0, 2H), 2.68 (app t, J=11.5, 21), 3.28 (s, 2H), 4.01 (br s, 2H), 4.15 (q, J=7.0, 4H), 7.06-7.25 (5H).