Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].C(Br)C.[Mg].[C:9]([O:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17](Cl)[CH:16]=1)([CH3:12])([CH3:11])[CH3:10]>CCOCC.C1COCC1.CN1C(=O)CCC1>[C:9]([O:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([CH2:1][CH3:2])[CH:16]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC[Mg]Br
Reactant: Cc1cc(C(=O)OC(C)(C)C)cc(Cl)n1
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1cc(C(=O)OC(C)(C)C)cc(C)n1
Temperature: 25 °C

Procedure:
A solution of ethylmagnesiumbromide (freshly prepared from ethylbromide (392 mg, 3.6 mmol) and magnesium (83 mg, 3.4 mmol)) in Et2O (10 mL) is added to a cooled (−40° C.) and mechanically stirred solution of 2-chloro-6-methyl-isonicotinic acid tert-butyl ester (0.76 g, 3.34 mmol), Fe(acac)3 (21.2 mg, 0.06 mmol) and NMP (0.6 mL) in THF (60 mL). The mixture is warmed to rt during 0.5 h, diluted with Et2O (150 mL) and quenched with aq. KHSO4 (1 M, 40 mL). The phases are separated and the aq. phase is extracted with Et2O (2×50 mL). The combined organic extracts are dried (MgSO4), filtered and evaporated. The residue is purified by reversed phase MPLC to give 2-ethyl-6-methyl-isonicotinic acid tert-butyl ester; LC-MS: tR=0.67 min, [M+1]+=222.19; 1H NMR (CDCl3): δ 7.44 (s, 2H), 2.83 (q, J=7.6 Hz, 2H), 2.58 (s, 3H), 1.59 (s, 9H), 1.30 (t, J=7.6 Hz, 3H).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:23])[N:3]=1.[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1.[F-].[Cs+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:24][C:25]([F:39])([F:40])[C:26]1[CH:27]=[C:28]([C:2]2[S:6][N:5]=[C:4]([CH2:7][N:8]3[C:16]4[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=4)[CH:10]=[C:9]3[CH3:23])[N:3]=2)[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nsc(Cl)n1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nsc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
To a solution of 1-[(5-chloro-1,2,4-thiadiazol-3-yl)methyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 326) (0.1 g, 0.28 mmol) in dry DME (3 mL) were added [3,5-bis(trifluoromethyl)phenyl]boronic acid (0.145 g, 0.56 mmol), cesium fluoride (0.13 g, 0.84 mmol) and [1,4-bis(diphenylphosphino)butane]palladium(II) dichloride (0.1 g, 0.17 mmol). The mixture was stirred at 90° C. in a sealed tube overnight. Solid was filtered and the filtrate was then concentrated in vacuo. The residue was purified by radial chromatography (0-50% EtOAc-hexanes gradient) to afford the title compound (0.06 g, 40% yield): 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 2H), 8.04 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 6.66 (s, 1H), 5.65 (s, 2H), 2.67 (s, 3H); MS (ES) m/z 533 (M−1).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1C=CC=CC=1>[CH2:1]([NH:8][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Solvent: c1ccccc1
Product: CCOC(=O)C(NCc1ccccc1)C(=O)OCC
Yield: 20.9 %

Procedure:
Benzylamine (18.3 g) and diethyl bromomalonate (20.3 g) were dissolved in dry benzene (100 ml), and the mixture was heated under reflux for 14 hours with stirring. The precipitated salt was removed by filtration from the reaction mixture. The filtrate was washed with dilute hydrochloric acid to remove the unreacted benzylamine. The benzene layer was washed with water three times, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using hexane/ethyl acetate (4:1) as an eluent to give 4.7 g (yield 21%) of diethyl benzylaminomalonate having the following NMR data.
Reaction SMILES: [CH:1]1([NH:7][C:8]([CH2:10][C:11]2[CH:12]=[C:13]([CH2:17][C:18](O)=[O:19])[CH:14]=[CH:15][CH:16]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>ClCCl>[CH:1]1([NH:7][CH2:8][CH2:10][C:11]2[CH:12]=[C:13]([CH2:17][CH2:18][OH:19])[CH:14]=[CH:15][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)Cc1cccc(CC(=O)NC2CCCCC2)c1
Solvent: ClCCl
Product: OCCc1cccc(CCNC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
(3-Cyclohexylcarbamoylmethyl-phenyl)-acetic acid (620 mg) was dissolved in dry dichloromethane (25 mL) and treated with borane-methyl sulphide complex (2M, 12 mL) at room temperature. The reaction was stirred at room temperature for 1 hour and at reflux for a further 1 hour. The mixture was cooled, quenched with methanol and treated with 2M hydrochloric acid (25 mL). The acidified mixture was heated at reflux for 10 minutes, cooled and basified with 2M sodium hydroxide. The basic mixture was extracted with dichloromethane (2×50 mL). The organic extracts were combined, dried over anhydrous sodium sulphate, filtered and concentrated to yield 500 mg of the sub-titled compound as an oil.
Reaction SMILES: [O:1]1[C:5]([CH:6]=O)=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:19][C:20](=[O:22])[CH3:21])C=CC=CC=1.O>CS(C)=O>[O:1]1[C:5]([CH:6]=[CH:19][C:20](=[O:22])[CH3:21])=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc2ccccc2o1
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)C=Cc1cc2ccccc2o1

Procedure:
A solution of benzo[b]furan-2-carboxaldehyde (3.3 g) and 1-triphenylphosphoranylidene-2-propanone (1.2 equivalents) in dimethyl sulfoxide (180 ml) was stirred at a temperature of 35° C. for a period of 30 minutes. The cooled mixture was poured into water and the aqueous mixture was extracted with diethyl ether. The solvent was evaporated from the dried (MgSO4) fraction and the residue was purified by column chromatography over silica gel (dichloromethane elution) to give 1-(benzo[b]furan-2-yl)but-1-en-3-one (3.0 g) as an orange solid, mp 100°-101° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].II>C(#N)C>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:3]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1cc(C)[nH]n1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)n1nc(C)cc1C
Reaction time: 24 h
Yield: 71.2 %

Procedure:
A suspension of 3,5-dimethyl-1H-pyrazole (ALDRICH, 8 g, 0.083 mol), anhydrous K2CO3 (ALDRICH, 11.50 g, 0.083 mol) and ethyl 2-bromopropanoate (ALDRICH, 15 g, 0.083 mol) in 50 mL of dry ACN was refluxed with mechanical stirring for 24 h. Reaction was checked by TLC (iodine), and starting material was detected. 0.2 equivalents of K2CO3 were added to the mixture which was refluxed over the weekend. Reaction was checked, starting material was still detected. 0.2 eq. of K2CO3 were added to the mixture, which was refluxed during 24 additional hours. Reaction mixture was filtered. Solvent was evaporated under reduced pressure. Residue was diluted with 50 ml of DCM, and washed with water. Organic layer was separated and aqueous fraction was extracted three times with 70 mL of DCM. Combined organic extracts were washed with brine, dried over Na2SO4 (anh), filtered and concentrated under reduce pressure. Residue was purified using a 70 g silica gel cartridge with a linear gradient of hexane/EtOAc 100/0 to 20/80 to yield the title compound (11.6 g 71%) as colourless oil. 1H NMR (300 MHz, CDCl3) δ ppm: 5.83 (s, 1H), 4.85 (q, 1H), 4.08-4.25 (m, 2H), 2.22-2.23 (m, 6H), 1.79 (d, 3H), 1.23 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:33]([F:35])[F:34])[N:3]=1.[CH3:36][S:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])=[O:38].CCN(C(C)C)C(C)C>C1COCC1>[F:35][CH:33]([F:34])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([N:43]3[CH2:44][CH2:45][N:40]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:41][CH2:42]3)[N:7]=[C:6]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:5]=2)[C:18]2[CH:19]=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COc1cc(NC(=O)OC(C)(C)C)cc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC(=O)OC(C)(C)C)cc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(C)(=O)=O)CC2)n1
Yield: 79.4 %

Procedure:
A mixture of tert-butyl 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazol-6-yl-carbamate (0.333 g, 0.65 mmol), 1-(methylsulfonyl)piperazine (0.32 g, 2 mmol), and DIPEA (0.17 g, 1.3 mmol) in THF (50 mL) was heated under reflux for 3 hrs. The solution was concentrated and then diluted with 100 mL of water containing 1% HOAc to give a solid, which was collected and dried. Chromatography on silica eluting with CH2Cl2/EtOAc (4:1), followed by recrystallization from MeOH, gave 0.33 g (79% yield) of tert-butyl 2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylcarbamate: mp 223° C. (decomp.); 1H NMR (CDCl3) δ 8.63 (br s, 1H), 7.44 (t, JHF=53.6 Hz, 1H), 6.62 (br s, exchangeable with D2O, 1H), 6.35 (d, J=1.7 Hz, 1H), 4.09-3.80 (m, 15H), 3.35 (m, 4H), 2.80 (s, 3H), 1.52 (s, 9H); Anal. Calcd. for C26H35F2N9O6S: C, 48.8; H, 5.5; N, 19.7. Found: C, 48.9; H, 5.6; N, 19.9%.
Reaction SMILES: [BrH:1].[CH3:2][O:3][CH2:4][C@H:5]([NH:30][C:31]([C:33]1[S:37][C:36]([CH3:38])=[N:35][CH:34]=1)=[O:32])[C:6]([NH:8][C@@H:9]([CH2:27][O:28][CH3:29])[C:10]([NH:12][C@@H:13]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14]([C@@:16]1([CH3:19])[CH2:18][O:17]1)=[O:15])=[O:11])=[O:7]>O1CCOCC1.C(Cl)Cl>[Br:1][CH2:18][C@:16]([OH:17])([CH3:19])[C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[C@@H:5]([NH:30][C:31]([C:33]1[S:37][C:36]([CH3:38])=[N:35][CH:34]=1)=[O:32])[CH2:4][O:3][CH3:2])[CH2:27][O:28][CH3:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Br
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@]1(C)CO1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
Hydrobromic acid (2 eq., 0.314 mL) was added to N—((S)-3-methoxy-1-(((S)-3-methoxy-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide (1.0 g, 1.88 mmol) in dioxane (20 mL) at 0° C., the reaction allowed to warm to room temperature and stirred overnight. The mixture was diluted with DCM, washed with aqueous saturated sodium bicarbonate, brine, dried (Na2SO4) and evaporated. The residue was purified by Biotage flash column chromatography to give product as a white solid (0.722 g, 48%); 1H NMR (CDCl3): δ 8.06(s, 1H), 7.28-7.18 (m, 6H), 7.02 (d, J=7.6 Hz, 1H), 6.85 (d, J=6.4 Hz, 1H), 5.45-5.40 (m, 1H), 4.71-4.66(m, 1H), 4.53-4.48 (m, 1H), 4.20 (s, 1H), 3.85-3.75 (m, 3H), 3.57-3.52 (m, 2H), 3.44-3.39 (m, 4H), 3.31 (s, 3H), 3.23-3.18 (m, 1H), 2.94-2.89 (m, 1H), 2.75 (s, 3H), 1.18 (s, 3H); MS for C25H33BrN4O7S m/z 614 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:15]#[N:16])=[C:4]([NH:8]C(=O)C(F)(F)F)[CH:5]=[CH:6][CH:7]=1.Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[NH2:16][C:15]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[NH:8][C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: N#Cc1c(F)cccc1NC(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)c1[nH]c2cccc(F)c2c1N

Procedure:
Follow the procedure of Example 5, but start with 3-fluoro-N-(2-cyano-phenyl)-2,2,2-trifluoroacetamide (synthesis described in J. Fluorine Chem. 1981, 18, (2), 185–95) and tert-butyl bromoacetate to obtain the title compound: MS 251(M+H), TLC (silica gel, dichloromethane/methanol, 7:1) Rf=0.38.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])[CH3:2].[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([N+]([O-])=O)[C:14]=1[C:15]#[N:16])([O-:12])=[O:11]>>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][C:17]1[CH:18]=[CH:19][CH:20]=[C:13]([N+:10]([O-:12])=[O:11])[C:14]=1[C:15]#[N:16])[CH3:2]
Reactant: CCOCCOCCO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CCOCCOCCOc1cccc([N+](=O)[O-])c1C#N
Yield: 66 %

Procedure:
Prepared as in Example 215c from 2-(2-ethoxyethoxy)ethanol and 2,6-dinitrobenzonitrile in 66% yield. MS 281 (MH+).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[N:12]=[C:13](Br)[CH:14]=[C:15]([O:16][CH3:17])[C:10]3=[N:9][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]3([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])=O.[Na+]>[Pd].CN(C=O)C.O.CO>[CH3:17][O:16][C:15]1[C:10]2[N:11]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:19]3[CH:20]=[CH:21][C:22]([C:25]4([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:33])[CH3:34])[CH2:28][CH2:27][CH2:26]4)=[CH:23][CH:24]=3)[N:9]=2)[N:12]=[CH:13][CH:14]=1
Reactant: COc1cc(Br)nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COc1ccnn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a mixture of tert-butyl (1-{4-[3-phenyl-6-bromo-8-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-7 (0.075 g, 0.14 mmol) and 5% palladium on carbon (0.007 g) in DMF (1 mL) was added a solution of sodium formate (0.074 g, 1.09 mmol, 8.0 eq) in water (0.2 mL). The resulting mixture was stirred at 80° C. for 3 h, diluted with MeOH (10 mL) and stirred at room temperature for 1 h. The resulting solution was filtered through a membrane filter, and the solids were washed with MeOH (1 mL). The resulting solution was diluted with EtOAc (25 mL), washed with water (2×25 mL), dried (Na2SO4 anh.) and concentrated under reduced pressure to give tert-butyl {1-[4-(8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate approximately 75% purity (0.058 g, 90%):
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]1[C:21]([C:27](O)=[O:28])=[N:22][CH:23]=[C:24]([F:26])[CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:21]3[C:20]([F:19])=[CH:25][C:24]([F:26])=[CH:23][N:22]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ncc(F)cc1F
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ncc(F)cc3F)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 3,5-difluoro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=401.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:13]2[C@H:22]3[C:23]([O:25][CH2:26][C@@H:21]3[C@@H:20]([OH:27])[C:19]3[CH:18]=[C:17]4[O:28][CH2:29][O:30][C:16]4=[CH:15][C:14]2=3)=[O:24])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9]C.CSC.CS(O)(=O)=O>FC(F)(F)C(O)=O>[OH:9][C:8]1[C:7]([O:11][CH3:12])=[CH:6][C:5]([CH:13]2[CH:22]3[C:23](=[O:24])[O:25][CH2:26][CH:21]3[CH:20]([OH:27])[C:19]3[C:14]2=[CH:15][C:16]2[O:30][CH2:29][O:28][C:17]=2[CH:18]=3)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@H](O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1OC
Agent: CS(=O)(=O)O
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C2c3cc4c(cc3C(O)C3COC(=O)C23)OCO4)cc(OC)c1O
Yield: 5.7 %

Procedure:
10 g (24 mmol) of podophyllotoxin are dissolved in 60 ml of trifluoroacetic acid. 5.4 ml (72 mmol) of dimethyl sulphide and 47 ml (72 mmol) of methanesulphonic acid are successively added. Stirring is maintained for 9 hours, 5.4 ml (72 mmol) of dimethyl sulphide are again added and stirring is maintained for 9 hours. The medium is run quickly onto ice (600 ml) and extracted with ethyl acetate (3×300 ml). The organic phases are washed with water and then with a NaHCO3 solution to neutrality. After drying over sodium sulphate, filtering and evaporating, 6.3 g of crude demethylation product are obtained. Flash chromatography on silica (elution: CH2Cl2/acetone 9/1) makes it possible to isolate 550 mg of 5-(4-hydroxy-3,5-dimethoxyphenyl)-9-hydroxy-5,8,8a,9-tetrahydro-5aH-furo[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-6-one, that is to say 4′-demethylepipodophyllotoxin of formula (Va). 1.10·g of 5-(3,4-dihydroxy-5-methoxyphenyl)-9-hydroxy-5,8,8a,9-tetrahydro-5aH-furo[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-6-one (Analysed: C20H18O8.0.15H2O; calculated: C %, 61.74; H %, 4.74. found: C %, 61.67; H %, 4.68), and then 1.9 g of 9-hydroxy-5-(3,4,5-trihydroxyphenyl)-5,8,8a,9-tetrahydro-5aH-furo[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-6-one are also isolated. The latter compound has a proton NMR spectrum with the following characteristics: 1H NMR (d6-DMSO) δ 8.65 (m, 2H), 7.95 (m, 1H), 6.71 (s, 1H, H5), 6.47 (s, 1H, H8), 5.98 (d, 2H, J=2 Hz, OCH2O), 5.93 (s, 2H, H2′, H6′), 4.68 (d, 1H, J=3.2 Hz, H4), 4.34 (t, 1H, J=8 Hz, H11a), 4.29 (d, 1H, J=5.2 Hz, H1), 4.16 (dd, 1H, J=8 Hz, J′=10 Hz, H11b), 3.17 (dd, 1H, J=5.2 Hz and J′=14 Hz, H2), 2.76 (m, 1H, H3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16](=O)[NH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C(COC)OC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16](=[S:28])[NH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(N)=O)CC1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(OCC(N)=S)CC1

Procedure:
A solution of 4-carbamoylmethoxypiperidine-1-carboxylic acid tert-butyl ester (Preparation 13, 67.5 mg, 260 μmol) and Lawesson's reagent (116 mg, 287 μmol) in dimethoxyethane (1.5 ml) was stirred at rt for 24 h. The solvent was evaporated and the residue purified by flash chromatography (5% MeOH in CH2Cl2) to afford the title compound: δH (CDCl3) 1.50 (9H, s), 1.55-1.63 (2H, m), 1.88-1.95 (2H, m), 3.12 (2H, ddd), 3.59-3.66 (1H, m), 3.79-3.87 (2H, m), 4.40, (2H, s), 7.65 (1H, bs), 8.04 (1H, bs).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]2[N:16]([CH:17]=1)[C:15]([CH2:18]O)=[CH:14][S:13]2)([O-:3])=[O:2].S(Cl)([Cl:22])=O>ClCCl.CN(C=O)C>[Cl:22][CH2:18][C:15]1[N:16]2[CH:17]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[N:11]=[C:12]2[S:13][CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccccc1-c1cn2c(CO)csc2n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1-c1cn2c(CCl)csc2n1
Reaction time: 0.08 h

Procedure:
To a stirred solution of [6-(2-Nitro-phenyl)-imidazo[2,1-b]thiazol-3-yl]-methanol (1.0 g, 3.63 mmol) in anhydrous dichloromethane (15 ml) was slowly added thionyl chloride (2 ml, 7.5 eq). The solution turned homogenous, followed by development of a yellow precipitate. After 5 minutes, a catalytic amount of DMF (1 drop) was added and the mixture was stirred for 1 hour, concentrated to dryness, chased with CH2Cl2 (2×) then Ether (1×), and dried under reduced pressure. 1.53 g of yellow solid was obtained, and assumed to be quantitative yield. (MS, M++H=294.0)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1O)([CH3:4])([CH3:3])[CH3:2].C1([OH:22])C=CC=CC=1>>[C:1]([C:5]1[CH:6]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:9][C:10]=1[OH:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Product: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1

Procedure:
106 grams of crude 2,6-di-tert-butylphenol containing 75.4% 2,6-di-tert-butylphenol and 0.43% 2-sec-6-tert-di-butylphenol was transalkylated with phenol using 5 grams of Dowex® 2030 ion exchange resin (DR-2030; a styrenic plastic bead functionalized with sulfonic acid groups) at 75° C. for 5 hours to produce 75.4% 2,4-di-tert-butylphenol containing 0.3% 2-sec-4-tert-di-butylphenol and no measurable amounts of 2-sec-6-tert-di-butylphenol.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[CH:3]=[C:4]([NH:8][CH3:9])[N:5]=[CH:6][N:7]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CNc1cc(Cl)ncn1
Reactant: Nc1cccc(Cl)c1
Product: CNc1cc(Nc2cccc(Cl)c2)ncn1

Procedure:
The title compound is prepared analogously as described in Example 105A from (6-chloro-pyrimidin-4-yl)-methyl-amine and 3-chloroaniline. The ethyl acetate layer is dried over Na2SO4 and evaporated. The solid residue is suspended in CH2Cl2, filtered off and dried in vacuo to afford the title compound.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[S:26][N:25]=[CH:24][CH:23]=2)[C:19]2[C:27](=[O:37])[N:28](C(OC(C)(C)C)=O)[CH2:29][C:18]=2[C:17]=1[F:38])=O)(C)(C)C.Cl.O1CCOCC1.CCO>CO>[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[S:26][N:25]=[CH:24][CH:23]=2)[C:19]2[C:27](=[O:37])[NH:28][CH2:29][C:18]=2[C:17]=1[F:38]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(-c2ccns2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Solvent: CO
Product: N[C@H]1CCCC[C@H]1Nc1nc(-c2ccns2)c2c(c1F)CNC2=O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
To a stirred solution of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-7-fluoro-4-(isothiazol-5-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (65.9 mg, 0.120 mmol) in MeOH (1.0 mL) was added 4N HCl/dioxane (1.0 mL, 4.00 mmol). The reaction mixture was heated to 60° C. for 1 hour and was subsequently concentrated in vacuo. The residue was triturated with EtOAc and filtered. The filter cake was washed with EtOAc to give a yellow solid, which was suspended into EtOH. The mixture was stirred at 80° C. for 30 minutes and allowed to cool to room temperature. The resulting precipitate was collected by filtration and washed with EtOH to yield a hydrochloride salt of the title compound as an off-white solid (18.6 mg, 40%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.36-1.55 (m, 2H), 1.58-2.06 (m, 6H), 3.77 (br s, 1H), 4.17-4.33 (m, 1H), 4.39-4.54 (m, 2H), 7.19 (d, J=5.86 Hz, 1H), 7.88 (br s, 3H), 8.62 (d, J=1.95 Hz, 1H), 8.69 (s, 1H), 8.97 (d, J=1.95 Hz, 1H). ESI-MS m/z [M+H]+ calc'd for C16H18FN5OS, 348. found, 348.