Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH2:32][NH:31][CH2:30][CH2:29][C:5]=2[N:6]=[C:7]([C:9]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][N:13]3[S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[N:8]=1.FC(F)(F)S(O[C:39]1[CH:44]=[C:43]([CH:45]([CH3:47])[CH3:46])[CH:42]=[CH:41][C:40]=1[CH3:48])(=O)=O.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:45]([C:43]1[CH:42]=[CH:41][C:40]([CH3:48])=[C:39]([N:31]2[CH2:30][CH2:29][C:5]3[N:6]=[C:7]([C:9]4[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]5[C:10]=4[CH:11]=[N:12][N:13]5[S:19]([C:22]4[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[N:8]=[C:3]([O:2][CH3:1])[C:4]=3[CH2:32]2)[CH:44]=1)([CH3:47])[CH3:46]
Reactant: Cc1ccc(C(C)C)cc1OS(=O)(=O)C(F)(F)F
Reactant: COc1nc(-c2c(C)ccc3c2cnn3S(=O)(=O)c2ccc(C)cc2)nc2c1CNCC2
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: COc1nc(-c2c(C)ccc3c2cnn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(c1cc(C(C)C)ccc1C)CC2
Temperature: 140 °C

Procedure:
A mixture of 4-methoxy-2-(5-methyl-1-tosyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (250 mg, 0.556 mmol), 5-isopropyl-2-methylphenyl trifluoromethanesulfonate (235 mg, 0.834 mmol), X-Phos (53.0 mg, 0.111 mmol), Pd2(dba)3 (50.9 mg, 0.056 mmol), and Cs2CO3 (362 mg, 1.11 mmol) in THF (3 mL) was heated in a microwave reactor at 140° C. for 60 min. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc/heptane) to provide 6-(5-isopropyl-2-methylphenyl)-4-methoxy-2-(5-methyl-1-tosyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 582.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([Li])CCC.Cl[CH2:28]/[C:29](/[CH3:54])=[CH:30]/[CH2:31][CH2:32][C:33]1([CH3:53])[CH2:38][CH2:37][C:36]2[CH:39]=[C:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C:41]([CH3:44])=[C:42]([CH3:43])[C:35]=2[O:34]1.Cl>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:52][C:49]([Si:46]([CH3:47])([CH3:48])[O:45][C:40]1[C:41]([CH3:44])=[C:42]([CH3:43])[C:35]2[O:34][C:33]([CH2:32][CH2:31][CH:30]=[C:29]([CH3:28])[CH2:54][CH:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)(=[O:9])=[O:10])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=3)([CH3:53])[CH2:38][CH2:37][C:36]=2[CH:39]=1)([CH3:50])[CH3:51]
Reactant: Cc1ccc(S(=O)(=O)Cc2cccc(C(F)(F)F)c2)cc1
Reactant: C/C(=C\CCC1(C)CCc2cc(O[Si](C)(C)C(C)(C)C)c(C)c(C)c2O1)CCl
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(=CCCC1(C)CCc2cc(O[Si](C)(C)C(C)(C)C)c(C)c(C)c2O1)CC(c1cccc(C(F)(F)F)c1)S(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h

Procedure:
4-Methyl-1-[[[3-(trifluoromethyl)phenyl]methyl]sulfonyl]benzene (30 mmole) was dissolved in 100 mL of dry THF. The mixture was cooled to about -78° under nitrogen, and n-butyllithium (30 mmole) was added dropwise giving rise to a colored anion [yellowish-orange]. The solution was stirred for about 1 hour at about -78° before the addition of HMPA (5 mL) and [2-(5-chloro-4-methyl-3(E)-pentenyl)]-3,4-dihydro-6-[(1,1- dimethylethyl)dimethyl silyloxy]-2,7,8-trimethyl-2H-1-benzopyran (25 mmole). The mixture was stirred for about 1 hour at about -78°, then warmed to about -5° for about 12 hours, and poured into 1N HCl. The mixture was extracted with fresh ether. The combined organic fractions were washed With water and dried (brine, MgSO4). Concentration in vacuo gave a crude material that was purified by flash chromatography (gradient 10:1 to 2:1 hexanes:ether) to give the coupled product as colorless oil: IR (film) 2930, 1472, 1450, 1424, 1330, 1166, 1146, 1130, 1088 cm-1 ; 1H NMR (CDCl3) δ 0.16 (s, 6H), 1.00 (s, 9H), 1.09, 1.10 (s, 3H), 1.28 (m, 2H), 1.41, 1.39 (s, 3H), 1.60 (m, 2H), 1.91 (m, 2H), 2.02 (s, 3H), 2.07 (s, 3H), 2.39 (s, 3H), 2.56 (m, 2H), 2.74 (t, J=13.9 Hz, 1H), 3.09 (d, J=11.9 Hz, 1H), 4.22 (d of t, J=12.1, 4.0 Hz, 1H), 5.06 (m, 1H), 6.30 (s, 1H), 7.10 (s, 1H), 7.18 (d, J=8.5 Hz, 2H), 7.36 (m, 4H), 7.48 (d, J=6.5 Hz, 1H); MS m/e 701 (MH+).
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])([C:6]#[CH:7])[CH3:5].[CH3:11][C:12]1([CH3:19])[C:16]([CH3:18])([CH3:17])[O:15][BH:14][O:13]1.C12CCCC(CCC1)B12[H]B2(C3CCCC2CCC3)[H]1>O1CCCC1>[CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])(/[CH:6]=[CH:7]/[B:14]1[O:15][C:16]([CH3:18])([CH3:17])[C:12]([CH3:19])([CH3:11])[O:13]1)[CH3:5]
Reactant: CC1(C)OBOC1(C)C
Reactant: C#CC(C)(C)O[Si](C)(C)C
Solvent: C1CCOC1
Product: CC(C)(/C=C/B1OC(C)(C)C(C)(C)O1)O[Si](C)(C)C
Temperature: 60 °C
Yield: 22 %

Procedure:
To a solution of trimethyl(2-methylbut-3-yn-2-yloxy)silane (1.5 g, 9.6 mmol) in tetrahydrofuran (15 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.79 mL, 19.2 mmol), followed by 9-BBN dimer (0.117 g, 0.480 mmol). The mixture was heated at 60° C. for 24 hours, then cooled to ambient temperature and quenched by the careful addition of saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (2×15 mL). The organics were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, eluted with a gradient of 0-60% ethyl acetate in hexanes) to afford the title compound (600 mg, 22% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.06-0.08 (m, 9H) 1.19 (s, 12H) 1.25 (s, 6H) 5.41 (d, J=17.85 Hz, 1H) 6.53 (d, J=17.85 Hz, 1H); MS (DCI/NH3) m/z 285 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[N+:18]([C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].C(N(CC)CC)C>ClCCl>[N+:18]([C:21]1[CH:22]=[C:23]([S:27]([O:1][C@@H:2]2[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]2)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2cccc([N+](=O)[O-])c2)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Under an atmosphere of argon, (2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (10 g, 39.5 mmol, Eq: 1.00) was combined with dichloromethane (75 ml) to give a colorless solution. Then at 0° C., 3-nitrobenzene-1-sulfonyl chloride (9.58 g, 41.9 mmol, Eq: 1.06) was added. Also at 0° C., triethylamine (12.0 g, 16.5 ml, 119 mmol, Eq: 3.00) was added dropwise to the reaction mixture. The reaction was stirred for 1.5 h at 0° C. and then for 2 days at room temperature. The reaction mixture was diluted in dichloromethane (200 ml) and then extracted with 2×50 ml HC10.5N, 70 ml satd. NaHCO3 solution and 50 ml satd. NaCl solution. The organic layer was stirred over Na2SO4, filtered and concentrated under reduced pressure. The title compound was obtained as a brown gum (17.25 g, quant., MS (m/e)=431.3 [M+H+]. The product was used in the next step without further purification.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[CH:23][C:22]([C:25]2[S:29][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:26]=2)=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:34]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[I:34][C:23]1[C:22]([C:25]2[S:29][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:26]=2)=[N:21][N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:24]=1
Reactant: COC(=O)c1ccc(-c2ccn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)s1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2I)s1
Temperature: 80 °C
Reaction time: 24 h
Yield: 95.7 %

Procedure:
20 g methyl 5-(1-trityl-1H-3-pyrazolyl)-2-thiophene carboxylate and 10.6 g N-iodosuccinimide were stirred in 200 mL N,N-dimethylformamide at 80° C. for 24 hours. Additional N-iodosuccinimide, 10.6 g, was added thereto and stirred at 80° C. for 24 hours, and then an aqueous solution of sodium thiosulfate and an aqueous solution of sodium bicarbonate were added thereto and stirred for 1 hour, and the formed solid was collected by filtration. The solid was dissolved in dichloromethane and dried over magnesium sulfate, and the solvent was removed, whereby 24.5 g of the title compound was obtained as colorless crystals.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][N:12]([CH2:19][C:20]([OH:22])=[O:21])[CH2:11][CH2:10][CH2:9][N:8]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:7][CH2:6]1)([OH:3])=[O:2].[C:32](Cl)(Cl)=[S:33]>Cl.C(Cl)(Cl)Cl>[C:1]([CH2:4][N:5]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][N:12]([CH2:19][C:20]([OH:22])=[O:21])[CH2:11][CH2:10][CH2:9][N:8]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([N:31]=[C:32]=[S:33])=[CH:29][CH:30]=2)[CH2:7][CH2:6]1)([OH:3])=[O:2]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(CCN2CCCN(CC(=O)O)CCNCCCN(CC(=O)O)CC2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C(O)CN1CCCN(CCc2ccc(N=C=S)cc2)CCN(CC(=O)O)CCCNCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.3 %

Procedure:
To a solution of compound (12) (0.79 g, 1.81 mmol) in 0.5 M HCl (10 ml) was carefully added thiophosgene (CSCl2) (4.17 ml, 6.26 g, 54.4 mmol) in CHCl3 (10 ml). The reaction mixture was stirred at an ambient temperature for 5 hours to separate the layers. After removing the aqueous layer, the organic CHCl3 layer was washed with water (2×50 ml). The combined aqueous layer was washed with CHCl3 (3×50 ml) to remove the unreacted thiophosgene. Finally, the aqueous layer was lyophilized to obtain a white solid of compound (14) (0.85 g, 98% yield). 1H NMR (500 MHz, D2O): δ 7.67-7.65 (dd, 2H), 7.50-7.48 (dd, 2H), 3.923 (s, 4H), 3.48-2.52 (m, 20H), 1.98 (brs, 2H), 1.88 (brs, 2H); 13C NMR (125 MHz, D2O): δ 187.9, 174.4, 173.2, 145.7, 137.5, 136.8, 135.1, 129.1, 128.6, 125.5, 122.6, 121.6, 60.4, 59.7, 57.8, 57.2, 56.9, 56.1, 54.5, 48.5, 35.5, 29.7, 23.3, 20.7; HRMS (FAB) calculated for C23H36N5O4S: 478.2488 [(M+H)+], measured value: 478.2484 [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[C:13]([CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)#[CH:14]>C(N(CC)CC)C.[Cu](I)I.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>[CH:15]1([C:13]#[C:14][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C#CC1CCCC1
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CC2CCCC2)cc1C
Temperature: 80 °C

Procedure:
Methyl 4-bromo-2-methylbenzoate (1.0 g, 4.4 mmol) was dissolved in triethylamine (5 mL). To the mixture was added copper iodide (43 mg, 5 mol %), followed by PdCl2(PPh3)2 (157 mg, 5 mol %) and ethynylcyclopentane (0.75 mL, 5.3 mmol). The mixture was heated in a sealed pressure tube at 80° C. for 3 hours. After completion of the reaction, the triethylamine was evaporated and the residue was dissolved in EtOAc and filtered through Celite®. The organic layer was washed with water, brine, and dried (Na2SO4), then filtered and concentrated under vacuum. The residue was purified by column chromatography on sililca gel using EtOAc-hexane (0-100% gradient) as eluet to give the desired product.
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:11]([CH3:13])[CH3:12])[CH:3]=1.C([Mg]Cl)(C)C.[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:31]=1)[C:25](N(OC)C)=[O:26]>C1COCC1>[Br:19][C:20]1[CH:31]=[C:24]([C:25]([C:2]2[C:10]3[CH:9]=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH:11]([CH3:13])[CH3:12])[CH:3]=2)=[O:26])[CH:23]=[N:22][CH:21]=1
Reactant: CC(C)n1cc(I)c2cncnc21
Reactant: CON(C)C(=O)c1cncc(Br)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)n1cc(C(=O)c2cncc(Br)c2)c2cncnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a stirred solution of 5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (Preparation 93, 4.85 g, 16.9 mmol) in THF (90 mL) at 0° C., under nitrogen was added isopropyl magnesium chloride (9.28 mL, 18.6 mmol, 2.0 M in diethyl ether). The mixture was stirred at 0° C. for 1 hour then a solution of 5-bromo-N-methoxy-N-methylnicotinamide (Preparation 227, 4.55 g, 18.6 mmol) in THF (10 mL) was added dropwise at 0° C. The mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (200 mL) and extracted with ethyl acetate (3×200 mL). The combined organics were concentrated under reduced pressure and purified by silica gel column chromatography eluting with gradient of EtOAc:DCM 95:5 to 50:50 to afford a light brown oil. The crude material was recrystallised using EtOAc:heptane (15:200 mL) to afford the title compound as a white solid in 33% yield, 2.16 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:17]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:17]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:10](=[O:12])[C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 100.5 %

Procedure:
N-t-butyloxycarbonyl-L-proline (32.29 g, 150 mmole), L-proline benzylester hydrochloride (36.26 g, 150 mmole) and HOBT (20.27 g, 150 mmole) were dissolved in methylene chloride (500 ml), and triethylamine (15.18 g, 150 mmole) and WSC hydrochloride (28.76 g, 150 mmole) were added thereto at -30° C. The mixture was stirred for 2 hours at less than 0° C., and then overnight at room temperature. The solution was washed with 5% aqueous sodium bicarbonate (400 mg, twice), 5% aqueous citric acid (400 ml, twice) and water (400 ml) in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain N-t-butyloxycarbonyl-L-prolyl-L-proline benzylester (yield: 60.70 g, 100%).
Reaction SMILES: C[C:2]1[C:3](=[O:17])[CH2:4][CH2:5][N:6]2[C:11]=1[CH2:10][CH2:9][C:8]1[CH:12]=[C:13](C)[CH:14]=[CH:15][C:7]2=1.COC=CC(O[Si](C)(C)C)=C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH:5]1[N:6]2[CH:11]([CH2:2][C:3](=[O:17])[CH:4]=1)[CH2:10][CH2:9][C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]2=1
Reactant: CC1=C2CCc3cc(C)ccc3N2CCC1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C=C(C=COC)O[Si](C)(C)C
Solvent: ClCCl
Product: O=C1C=CN2c3ccccc3CCC2C1
Reaction time: 1 h
Yield: 25.1 %

Procedure:
To a stirred solution of compound 4 [(QW)n═H, R3═R4═H] (4 g, 14.42 mmol) of the example 3, in 75 ml of anhydrous CH2Cl2 under argon at −10° C. is added, dropwise in 7 min, 28.84 ml of a 1M solution of TiCl4 in CH2Cl2 maintaining the temperature below −5° C. Then 1 -methoxy-3-(trimethylsilyloxy)-1-3-butadiene (compound 6, R1═MeO, R2 ═H, R6═H) (3.29 ml, 17.3 mmol) is added by syringe at 0° C., and the reaction was left aside at room temperature for 1 h. The reaction mixture is added, cautiously, with 100 ml of NaHCO satured solution, and then stirred for 30 min. The organic layer is separated, washed with water, filtered on Celite and dried over Na2SO4. After removal of the solvent the crude product is purified by flash column chromatography (eluant light-petroleum ether/ethyl acetate 1:4) affording 0.72 g (25% yield) of the expected product (white crystals, m.p.: 135-137° C.).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[C:16]([C:33]([F:36])([F:35])[F:34])[CH:15]=1)=[CH:10][C:9]([C:37]1[CH:38]=[N:39][C:40]3[C:45]([CH:46]=1)=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:8][CH:7]=2.Cl[C:48](Cl)([O:50]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[O:50]=[C:48]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:22][CH2:21]3)=[C:16]([C:33]([F:36])([F:35])[F:34])[CH:15]=2)[C:12]2[C:11]3[CH:10]=[C:9]([C:37]4[CH:38]=[N:39][C:40]5[C:45]([CH:46]=4)=[CH:44][CH:43]=[CH:42][CH:41]=5)[CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[CH2:2][O:1]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3c(CO)cnc4ccc(-c5cnc6ccccc6c5)cc34)cc2C(F)(F)F)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C(=O)OCc4cnc5ccc(-c6cnc7ccccc7c6)cc5c43)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 4-(4-(3′-(hydroxymethyl)-3,6′-biquinolin-4′-ylamino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (35 mg, 0.05 mmol) in dichloromethane (5 mL) at 0° C. was added triphosgene (16 mg, 0.05 mmol), and the resultant solution was allowed to warm up to room temperature. The reaction was allowed to proceed for 4 h before quenching with a satd. aqueous sodium carbonate solution (3 mL). The reaction mixture was extracted with EtOAc (3×10 mL) and dried over Na2SO4. The crude product was taken onto the next step without further purification. LC-MS: (M+1)=656.30
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:20][N:21]1[C:27](=[O:28])[N:26]2[CH2:29][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:30]([OH:32])=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:33]([NH:35][NH2:36])=[O:34].CCOC(C)=O>C1COCC1.[Cl-].[Na+].O>[CH2:13]([O:20][N:21]1[C:27](=[O:28])[N:26]2[CH2:29][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:30]([NH:36][NH:35][CH:33]=[O:34])=[O:32])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NNC=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=CNNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 190.9 %

Procedure:
1,1′-Carbonyldiimidazole (5.8 g, 36.2 mmol) was added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (5.0 g, 18.1 mmol) in dry THF (200 mL) at 0° C. The reaction mixture was stirred at rt for 3 hrs. Formohydrazide (5.4 g, 90.5 mmol) was added in one portion, and the reaction mixture was stirred for additional 3 hrs. The mixture was then diluted with brine and exacted with EtOAc (3×). The combined organic layer was washed with Saturated sodium chloride (2×), dried over Na2SO4, and concentrated to afford crude (2S,5R)-6-(benzyloxy)-N′-formyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (˜11 g), which was directly used in the next step. ESI-MS (EI+, m/z): 319.1 [M+H]+.
Reaction SMILES: Cl.[CH:2]1([N:6]([C@@H:10]2[CH2:15][C:14]3[C:16]([O:21]C)=[CH:17][CH:18]=[C:19]([F:20])[C:13]=3[O:12][CH2:11]2)[CH2:7][CH2:8][CH3:9])[CH2:5][CH2:4][CH2:3]1.B(Br)(Br)Br>C(Cl)Cl>[CH:2]1([N:6]([C@@H:10]2[CH2:15][C:14]3[C:16]([OH:21])=[CH:17][CH:18]=[C:19]([F:20])[C:13]=3[O:12][CH2:11]2)[CH2:7][CH2:8][CH3:9])[CH2:3][CH2:4][CH2:5]1
Reactant: CCCN(C1CCC1)[C@H]1COc2c(F)ccc(OC)c2C1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: CCCN(C1CCC1)[C@H]1COc2c(F)ccc(O)c2C1
Temperature: -40 °C
Yield: 98.1 %

Procedure:
(R)-3-(N-Cyclobutyl-N-n-propylamino)-8-fluoro-5-methoxy-3,4-dihydro-2H-1 -benzopyran hydrochloride (1.0 g, 3.03 mmol) was dissolved in anhydrous CH2Cl2 (25 mL) and cooled to -40° C. To the solution was BBr3 (0.72 mL, 7.6 mmol), dissolved in anhydrous CH2Cl2 (4 mL), added dropwise. The cooling-bath was removed and after 2 h at room temperature the reaction was complete. The reaction was poured out onto an ice/2M NH3 solution and the CH2Cl2 portion was separated, the aqueous layer re-extracted, twice, with CH2Cl2. The combined CH2Cl2 portions were dried (MgSO4), filtered, and the solvent removed in vacuo to give the crude residue. Chromatography on silica (eluent: 25% ethyl acetate/hexane followed by 50% ethyl acetate/hexane) gave 0.83 g (98% yield) of the title compound as a gum. [α]21D =-80.5° (C=0.1; CHCl3) GC-MS (70 eV) M=279 (0.2%).
Reaction SMILES: [CH:1]1([C@@H:4]2[O:15][CH2:14][C:7]3=[N:8][O:9][C@@H:10]([CH2:11][O:12][CH3:13])[C@@H:6]3[CH2:5]2)[CH2:3][CH2:2]1.C1([C@@H]2OC[C@]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=4[F:35])NOC[C@@H]3C2)CC1>>[CH:1]1([C@@H:4]2[O:15][CH2:14][C@:7]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=4[F:35])[NH:8][O:9][C@@H:10]([CH2:11][O:12][CH3:13])[C@@H:6]3[CH2:5]2)[CH2:2][CH2:3]1
Reactant: COC[C@@H]1ON=C2CO[C@@H](C3CC3)C[C@H]21
Reactant: Fc1ccc([C@]23CO[C@@H](C4CC4)C[C@H]2CON3)c(F)c1
Product: COC[C@@H]1ON[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CC3)C[C@@H]12

Procedure:
rel-(3R,3aR,5R)-5-Cyclopropyl-3-(methoxymethyl)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C38) was converted to the product using the method described for synthesis of rel-(3aR,5R,7aS)-5-cyclopropyl-7a-(2,4-difluorophenyl)hexahydro-1H-pyrano[3,4-c][1,2]oxazole (C19) in Example 2. The product was obtained as an oil. Yield: 0.85 g, 2.6 mmol, 55%. LCMS m/z 326.2 [M+H+].
Reaction SMILES: [C:1]12([O:11][CH2:12][C:13]3[CH:14]=[C:15]([OH:25])[N:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])[N:17]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH2:28]([O:30][C:31]([C:33]1[CH:34]=[C:35]([N:39]=[C:40]=[O:41])[CH:36]=[CH:37][CH:38]=1)=[O:32])[CH3:29]>C1COCC1>[CH2:28]([O:30][C:31](=[O:32])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:40]([C:14]2[C:13]([CH2:12][O:11][C:1]34[CH2:8][CH:7]5[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]5)[CH2:2]3)[CH2:10]4)=[N:17][N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[C:15]=2[OH:25])=[O:41])[CH:34]=1)[CH3:29]
Reactant: CCOC(=O)c1cccc(N=C=O)c1
Reactant: Cc1ccccc1-n1nc(COC23CC4CC(CC(C4)C2)C3)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(NC(=O)c2c(COC34CC5CC(CC(C5)C3)C4)nn(-c3ccccc3C)c2O)c1
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
A solution of 5-(adamantan-1-yloxymethyl)-2-o-tolyl-2H-pyrazol-3-ol (160 mg, 0.47 mmol) in anhydrous THF (4 mL) was added to a suspension of sodium hydride (26 mg of 60% dispersion in oil, 0.65 mmol) in THF (2 mL) under a dry argon atmosphere at room temperature. The mixture was stirred for 30 min. and a solution of 3-ethoxycarbonylphenyl isocyanate (99 mg, 0.5 mmol) in THF (1 mL) added. Stirring was continued for 1 h and the mixture partitioned between 5% KHSO4 (40 mL) and EtOAc (40 mL). The organic phase was washed with brine (30 mL), and dried (MgSO4). Filtration and evaporation of the solvent afforded the product as a red solid, (250 mg, 100%).