Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:21]=[C:22]([NH:26][C:27]([NH:29][C:30]4[CH:34]=[C:33]([C:35]([CH3:38])([CH3:37])[CH3:36])[O:32][N:31]=4)=[O:28])[CH:23]=[CH:24][CH:25]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>>[C:35]([C:33]1[O:32][N:31]=[C:30]([NH:29][C:27]([NH:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][C:13]3[C:12]4[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=4)[N:16]=[CH:15][N:14]=3)[CH:21]=2)=[O:28])[CH:34]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OCc5ccccc5)ccc34)c2)no1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(O)ccc34)c2)no1
Temperature: 85 °C
Yield: 60.1 %

Procedure:
1-(3-(7-(Benzyloxy)quinazolin-4-yloxy)phenyl)-3-(5-tert-butylisoxazol-3-yl)urea (725 mg, 1.42 mmol) was treated with trifluoroacetic acid (7 mL) and heated at 85° C. for 3 h. The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate/water. The solution was neutralized with saturated sodium bicarbonate (pH=8) and the organic layer separated. After extraction of the aqueous phase with ethyl acetate, the organic fractions were combined, dried (MgSO4) and concentrated under reduced pressure. The solid was triturated with ethyl acetate to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-hydroxyquinazolin-4-yloxy)phenyl)urea (358 mg, 60%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.92 (s, 1H), 9.64 (s, 1H), 9.07 (s, 1H), 8.58 (s, 1H), 8.24 (d, 1H), 7.57 (s, 1H), 7.41 (t, 1H), 7.30 (d, 2H), 7.20 (s, 1H), 6.97 (d, 1H) 6.49 (s, 1H), 1.27 (s, 9H); LC-MS (ESI) m/z 420 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[NH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][O:19][C:20]2=[O:25].[O-]S([O-])(=O)=O.[Mg+2]>CC#N>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:14]=[CH:13][C:10](/[CH:11]=[N:15]/[C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH2:18][O:19][C:20]3=[O:25])=[CH:9][CH:8]=1
Reactant: CN1CCCC1c1ccc(C=O)cc1
Reactant: Nc1cccc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: CN1CCCC1c1ccc(/C=N/c2cccc3c2COC3=O)cc1
Temperature: 120 °C
Yield: 41 %

Procedure:
A mixture of 4-(1-methylpyrrolidin-2-yl)benzaldehyde (1.89 g, 10 mmol), 4-aminoisobenzofuran-1(3H)-one (1.49 g, 10 mmol) and MgSO4 (12 g, 100 mmol) in CH3CN (60 mL) was refluxed at 120° C. for 4 days. After a hot filtration, CH3CN was partially removed under reduced pressure and a white precipitate was appeared, the title compound was obtained by a direct filtration (1.3 g, yield 41%) as a white solid. LC-MS (ESI) m/z: 440 (M+1)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.[NH4+].[Cl-].Cl>C(OCC)C>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:15]([CH:16]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:14]=1
Reactant: CCCCCCCCCBr
Reactant: COc1cccc(C=O)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCCCC=Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 63.7 %

Procedure:
To dry diethyl ether (50 mL) containing Mg turnings (1.22 g; 50 mmol) under N2 was added 1-bromononane (8.6 mL; 50 mmol) at a rate sufficient to maintain slow reflux. The reaction mixture was stirred for 45 minutes after the end of addition, cooled on an ice/water bath and 3-methoxy benzaldehyde (6.1 mL; 50 mmol) was then added drop wise. The reaction mixture was allowed to warm to room temperature overnight, added saturated aqueous NH4Cl (50 mL) and then 4 M HCl (aq.; 10 mL). The organic phase was isolated, dried (MgSO4), filtered and purified by column chromatography (SiO2; EtOAc/PE80-100° C.=1:10) to yield 7.4 g (64%) pure product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][CH:28]([OH:30])[CH3:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][CH2:27][CH:28]([OH:30])[CH3:29])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: CC(O)CN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(C)O)c2c1

Procedure:
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 1-1) and 1-aminopropan-2-ol. MS obsd. (ESI+) [(M+H)+] 412, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (dd, J=7.71, 1.14 Hz, 1 H), 7.84 (d, J=7.07 Hz, 1 H), 7.71 (s, 1 H), 7.64 (td, J=7.58, 1.26 Hz, 1 H), 7.55 (d, J=8.59 Hz, 1 H), 7.50-7.41 (m, 1 H), 7.37 (dd, J=8.59, 1.52 Hz, 1 H), 6.03 (s, 1 H), 5.16 (s, 2 H), 4.08 (dd, J=11.49, 6.44 Hz, 1 H), 3.62 (t, J=4.80 Hz, 2 H), 3.44-3.35 (m, 4 H), 2.42 (s, 3 H), 1.33 (d, J=6.06 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[N:20][N:19]=[N:18]2)=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])[CH2:10][NH:11][CH:12]1[CH2:14][CH2:13]1.[C:22]([O:26][C:27]([NH:29][C@@H:30]([C:36](O)=[O:37])[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[C:22]([O:26][C:27]([NH:29][C@@H:30]([C:36]([N:11]([CH:12]1[CH2:13][CH2:14]1)[CH2:10][C:9]([NH:8][CH2:7][C:6]1[CH:16]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N:17]1[CH:21]=[N:20][N:19]=[N:18]1)=[O:15])=[O:37])[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C(CNC1CC1)NCc1cc(Cl)ccc1-n1cnnn1
Reactant: CC(C)(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CC(=O)NCc1cc(Cl)ccc1-n1cnnn1)C1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of N1-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-N2-cyclopropylglycinamide (50 mg, 0.16 mmol), N-(tert-butoxycarbonyl)-4-methyl-D-leucine (42 mg, 0.17 mmol), EDC (49 mg, 0.26 mmol) and HOAt (16 mg, 0.12 mmol) in DMF (1.4 mL) was stirred for 16 h at room temperature. The title compound was isolated by reverse phase HPLC as a white foam and was carried on directly to deprotection. LCMS (M+H): 534.1.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:26]=[C:25]2[C:9]([CH2:10][C:11]3([C:18]42[NH:22][C:21](=[S:23])[C:20]([CH3:24])=[N:19]4)[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]3)=[CH:8][CH:7]=1.FS([C:31]([F:36])([F:35])C(O)=O)(=O)=O.O.CCOC(C)=O>C(#N)C>[F:35][CH:31]([F:36])[O:17][CH:14]1[CH2:15][CH2:16][C:11]2([C:18]3([NH:22][C:21](=[S:23])[C:20]([CH3:24])=[N:19]3)[C:25]3[C:9](=[CH:8][CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][F:1])[CH:26]=3)[CH2:10]2)[CH2:12][CH2:13]1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: CC1=NC2(NC1=S)c1cc(OCCCF)ccc1CC21CCC(O)CC1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC1=NC2(NC1=S)c1cc(OCCCF)ccc1CC21CCC(OC(F)F)CC1
Temperature: 60 °C
Yield: 103.5 %

Procedure:
6′-(3-Fluoropropoxy)-4-hydroxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Intermediate 33, 290 mg, 0.77 mmol) was suspended in dry acetonitrile (10 mL). Cuprous iodide (14.67 mg, 0.08 mmol) was added and the resulting mixture was heated at 60° C. for 5 min under an atmosphere of argon. 2-(Fluorosulphonyl)difluoroacetic acid (0.127 mL, 1.16 mmol) was added in a stream and the reaction mixture was heated for 20 min. Additional 2-(Fluorosulphonyl)difluoroacetic acid (0.042 mL, 0.39 mmol) was added, and the mixture was heated for an additional 45 min. The mixture was cooled to r.t. Water and EtOAc were added, and the phases were separated and the aqueous phase was re-extracted with EtOAc twice. The combined organic phases were dried using a phase separator and concentrated to give 340 mg of 4-(difluoromethoxy)-6′-(3-fluoropropoxy)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione, which was suspended in ammonia (7 M in methanol, 4 mL, 28 mmol), and heated in the MW at 100° C. for 60 min. The mixture was concentrated, re-dissolved in ammonia (7 M in methanol, 4 mL, 28 mmol) and heated at 100° C. for 60 min. This procedure was repeated eight times in total. The mixture was cooled to r.t., concentrated, and purified by flash column chromatography using a gradient of 0-50% EtOAc in heptane, followed by 0-20% MeOH (containing 1% NH3) in EtOAc, to give 82 mg (25% yield) of the title compound. MS (MM-ES+APCI)+m/z 410.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:3]=12.[CH3:19][C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:30]=[CH:29][C:28]([Sn](CCCC)(CCCC)CCCC)=[CH:27][CH:26]=2)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([C:28]4[CH:29]=[CH:30][C:25]([N:23]5[CH:24]=[C:20]([CH3:19])[N:21]=[CH:22]5)=[CH:26][CH:27]=4)=[C:3]3[CH:10]=[CH:9]2)=[CH:13][CH:14]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(-n2cnc(C)c2)cc1
Reactant: Fc1ccc(Cn2ccc3c(Cl)ccnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: Cc1cn(-c2ccc(-c3ccnc4c3ccn4Cc3ccc(F)cc3)cc2)cn1
Temperature: 25 °C
Yield: 10.8 %

Procedure:
To 4-chloro-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine (36 mg, 0.14 mmol), 4-methyl-1-(4-(tributylstannyl)phenyl)-1H-imidazole (100 mg, 0.21 mmol) and Potassium carbonate (100 mg, 0.7 mmol) was added 3 ml Toluene followed by Pd(PPh3)4 (20 mg, 0.014 mmol) then heat to 120 C for 2 hrs. The reaction was worked up by cooling to RT then adding water and DCM. Extract aqueous layer 3×DCM, then dry over sodium sulfate and filter and concentrate to dryess. The residue was purified by chromatography over silica gel (eluted with DCM/MeOH 99:1 to 90:10) to provide 5.8 mg (10%) of product. 1H NMR (CDCl3 400 MHz): 8.4 (d, 1H), 8.01 (s, 2H), 7.78-7.8 (m, 1H), 7.4 (s, 2H), 7.26-7.27 (m, 3H), 6.95-7.02 (m, 3H), 6.65-6.72 (m, 1H), 5.53 (s, 1H), 3.93 (s, 3H), 2.33 (s, 3H). LCMS (MH+)=413; retention time=3.19 min.
Reaction SMILES: [OH:1][CH:2]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][C:24]=1[F:35])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH:6]1[C:19]([O:21]C)=[O:20].O1CCOCC1.[OH-].[Na+]>O.C(OCC)C>[OH:1][CH:2]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][C:24]=1[F:35])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH:6]1[C:19]([OH:21])=[O:20]
Reactant: COC(=O)C1CN(CCSc2cccs2)CCC1CCC(O)c1c(F)cnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: COc1ccc2ncc(F)c(C(O)CCC3CCN(CCSc4cccs4)CC3C(=O)O)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
A solution of 630 mg of methyl (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-carboxylate, 6-cm3 of dioxane and 3-cm3 of a 1 N aqueous sodium hydroxide solution was heated with stirring at a temperature in the region of 60° C. for 2 hours. 3-cm3 of a 1 N aqueous sodium hydroxide solution were added and the solution was heated for 1 hour at 60° C. After concentrating the reaction mixture under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained was taken up in 20-cm3 of water and 20-cm3 of diethyl ether. The aqueous phase was separated after settling out and was then acidified by pouring in 6-cm3 of 1 N hydrochloric acid. The white precipitate formed was extracted with 150-cm3 of ethyl acetate. The organic phase was washed twice with 10-cm3 of a saturated aqueous sodium chloride solution and dried over magnesium sulfate, filtered, and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 499 mg of (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-carboxylic acid were obtained in the form of a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:13]=[CH:14][C:3]=12.C([OH:23])C>Cl>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:12]1[C:4]2[NH:5][C:6]3[C:11]([C:2](=[O:23])[C:3]=2[CH:14]=[N:13]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: Clc1c2ccccc2nc2c1cnn2-c1ccccn1
Reactant: CCO
Agent: Cl
Product: O=c1c2ccccc2[nH]c2c1cnn2-c1ccccn1
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of 4-chloro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (14 g, 0.050 mol) in ethanol (600 mL), 6N hydrochloric acid (30 mL) was added and the mixture was heated under reflux for 12 hours. The reaction solution was allowed to cool to room temperature, and concentrated and evaporated under reduced pressure. The residue was made basic by addition of an aqueous sodium hydroxide solution, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform:methanol=96:4) to give the title compound (10.8 g, 82% yield).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11](Br)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[N:32][CH:33]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11]([C:30]2[CH:31]=[N:32][CH:33]=[C:28]([Cl:27])[CH:29]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Reactant: OB(O)c1cncc(Cl)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2cncc(Cl)c2)nc1

Procedure:
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 5-chloro-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=40%).
Reaction SMILES: C(C1C=CC(CCC2C=CC([C:18]3[CH:23]=[C:22]([F:24])[C:21](I)=[C:20]([F:26])[CH:19]=3)=C(F)C=2)=CC=1)CC.[F:28][C:29]1[CH:30]=[C:31]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][CH3:46])=[CH:40][CH:39]=2)[CH:32]=[CH:33][C:34]=1I.OB(O)[C:49]1[CH:54]=[CH:53][C:52]([F:55])=[C:51]([F:56])[CH:50]=1>>[F:28][C:29]1[CH:30]=[C:31]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][CH3:46])=[CH:40][CH:39]=2)[CH:32]=[CH:33][C:34]=1[C:20]1([F:26])[CH2:19][CH:18]=[CH:23][C:22]([F:24])=[C:21]1[C:49]1[CH:54]=[CH:53][C:52]([F:55])=[C:51]([F:56])[CH:50]=1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CCCc1ccc(CCc2ccc(I)c(F)c2)cc1
Reactant: CCCc1ccc(CCc2ccc(-c3cc(F)c(I)c(F)c3)c(F)c2)cc1
Product: CCCc1ccc(CCc2ccc(C3(F)CC=CC(F)=C3c3ccc(F)c(F)c3)c(F)c2)cc1

Procedure:
The same procedures as in the fourth step were repeated with the exception that 4.3 g (8.9 mmol) of the 4′-(2-(4-propylphenyl)ethyl)-2′,3,5-trifluoro-4-iodobiphenyl obtained in the fifth step was used in place of the 3-fluoro-4-iodo-(2-(4-propylphenyl)ethyl)benzene used in the fourth step, and that 2.1 g (13.3 mmol) of dihydroxy(3,4-difluorophenyl)borane was used in place of dihydroxy(3,5-difluorophenyl)borane, to obtain 3.4 g of a crude 2″,2′,6′,3,4-pentafluoro-4″-(2-(4-propylphenyl)ethyl)terphenyl. This product was recrystallized from mixed solvent of ethanol/ethyl acetate (8/2) to obtain 2.6 g of the subject compound. (Yield: 62.3%) Phase transition temperatures of this product were as follows:
Reaction SMILES: [OH:1][C:2]1([CH3:33])[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:10]=2)[N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.O1CCOCC1>Cl>[CH3:33][C:2]1([OH:1])[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[N:10]=2)[NH:5][CH2:4][CH2:3]1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)C(C)(O)CCN3C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)C(C)(O)CCN3)cc1

Procedure:
A solution of tert-butyl 8-hydroxy-8-methyl-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 3) (310 mg, 0.696 mmol) in 4M HCl in dioxane (2 ml, 8.00 mmol) was stirred at room temperature for 30 mins. The reaction mixture was concentrated under reduced pressure and the residue partitioned between saturated aqueous sodium bicarbonate and DCM. The organic portion was separated and the aqueous portion extracted with DCM (30 ml). The combined organic layers concentrated under reduced pressure to afford the titled compound;
Reaction SMILES: [CH3:1][C:2](=[CH2:14])[C:3]#[C:4][CH2:5][O:6][SiH:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9].CC([O-])(C)C.[K+]>>[CH:8]([Si:7]1([CH:11]([CH3:13])[CH3:12])[C:3]([C:2]([CH3:1])=[CH2:14])=[CH:4][CH2:5][O:6]1)([CH3:10])[CH3:9]
Reactant: C=C(C)C#CCO[SiH](C(C)C)C(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: C=C(C)C1=CCO[Si]1(C(C)C)C(C)C

Procedure:
(4-Methylpent-4-en-2-ynyloxy)diisopropylsilane (1.662 g, 7.90 mmol) and KOtBu (0.092 g, 0.8199 mmol) were used according to the general procedure mentioned above. The light brown clear solution was subjected to column chromatography and yielded 8a as colorless, clear liquid (1.192 g, 5.666 mmol, 71.7%): Rf0.37 (hexanes/Et2O, 15:1); 1H NMR (500 MHz, CDCl3) δ 6.68 (t, J=1.9 Hz, 1H, H-4), 4.99 (s, 1H, H-9), 4.80 (s, 1H, H-9), 4.63 (dd, J=1.9, 0.9 Hz, 2H, H-5), 1.94 (s, 3H, H-10), 1.09-1.19 (m, 2H, H-6), 1.04 (d, J=7.3 Hz, 6H, H-7), 0.99 (d, J=7.3 Hz, 6H, H-7); 13C NMR (300 MHz, CDCl3) δ 142.4 (C-4), 142.1 (C-8), 139.8 (C-3), 116.3 (C-9), 72.7 (C-5), 20.6 (C-10), 17.3 (C-7), 17.0 (C-7), 13.3 (C-6); Anal. calcd for C12H22OSi: C, 68.51; H, 10.54. Found: C, 68.24; H, 10.61.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]1)[N:8]=[CH:7]2.C1(C)C=CC=CC=1.CCN(C(C)C)C(C)C.[CH3:36][S:37]([N:40]1[CH2:44][CH:43]=[CH:42][CH2:41]1)(=[O:39])=[O:38]>O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:36][S:37]([N:40]1[CH2:44][CH2:43][C:42]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[C:9]([NH:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]2)[N:8]=[CH:7]3)=[CH:41]1)(=[O:39])=[O:38]
Reactant: O[C@H]1CC[C@H](Nc2ncc3cccc(Br)c3n2)CC1
Reactant: CS(=O)(=O)N1CC=CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1C=C(c2cccc3cnc(N[C@H]4CC[C@H](O)CC4)nc23)CC1

Procedure:
To a shlenk tube was added trans-4-[(8-bromoquinazolin-2-yl)amino]cyclohexanol (322 mg, 1 mmol), followed by Pd(OAc)2 (48 mg, 0.2 mmol), (o-Tol)3P (60 mg, 0.2 mg), Ag2CO3 (192 mg, 0.7 mmol), toluene (8 mL) and iPr2NEt (516 mg, 4 mmol), followed by 1-(methylsulfonyl)-2,5-dihydro-1H-pyrrole (560 mg, 3.8 mmol). The mixture was refluxed overnight under Ar. TLC showed that several new spots were formed with small amount of starting material remaining. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (4×15 mL). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by chromatography (eluting with DCM, then DCM/EA 3/1, then DCM/EA=2/1) to afford the title compound (88 mg, 23%) as an off white solid. 1H-NMR (CDCl3, 400 MHz): δ 8.97 (s, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.55 (d, J=7.2 Hz, 1H), 7.21 (dd, J=8.8, 7.2 Hz, 1H), 6.60-6.58 (m, 1H), 5.51-5.49 (m, 1H), 5.22-5.19 (m, 1H), 5.16-5.11 (m, 1H), 4.36 (t, J=10.8 Hz, 1H), 3.99-3.94 (m, 1H), 3.58 (dd, J=10.8, 6.0 Hz, 1H), 2.85 (s, 3H), 2.30-2.24 (m, 2H), 2.12-2.08 (m, 2H), 1.41-1.26 (m, 4H).
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].C(N(CC)C(C)C)(C)C.[CH3:15][C:16]1[N+:21]([O-:22])=[C:20]([NH2:23])[CH:19]=[C:18]([N:24]([CH3:26])[CH3:25])[N:17]=1>C(Cl)(Cl)Cl.CN(C)C=O>[OH-:3].[CH3:15][CH:16]1[N:21]([O:22][S:2]([OH:5])(=[O:4])=[O:3])[C:20]([NH2:23])=[CH:19][C:18]([N:24]([CH3:25])[CH3:26])=[NH+:17]1
Reactant: Cc1nc(N(C)C)cc(N)[n+]1[O-]
Reactant: O=S(=O)(O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC1[NH+]=C(N(C)C)C=C(N)N1OS(=O)(=O)O
Product: [OH-]
Reaction time: 7 h
Yield: 44.3 %

Procedure:
133 ml (0.002 mol) of chlorosulphonic acid is added, with stirring, to a solution of 0.72 ml (0.0042 mol) of N,N-diisopropylethylamine in 12 ml of a 1/1 chloroform/dimethylformamide mixture, cooled in ice. After a waiting time of 30 minutes, 0. 168 g (0.001 mol) of 2-methyl-4-amino-6-dimethylaminopyrimidine 3-oxide prepared according to Example 2 is added and the mixture is kept at between 5° and 10° C. for 7 hours under nitrogen. The solvent is evaporated. The residue, taken up in a little water, allows a white product to crystallise, which is filtered off. After recrystallisation from a DMF/water mixture, 0.11 g of pure inner salt, which decomposes at 226° C., is obtained. The yield is 44.3%. Elementary analysis for C7H12N4O4S; molecular weight=248.
Reaction SMILES: C([O:9][C@@H:10]1[CH2:14][N:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C@@H:12]([CH2:25][N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][O:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)[CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>CCOCC.CO>[OH:9][C@@H:10]1[CH2:14][N:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C@@H:12]([CH2:25][N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][O:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)[CH2:11]1
Reactant: COc1ccc(CCN2C[C@@H](OC(=O)c3ccccc3)C[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: COc1ccc(CCN2C[C@@H](O)C[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To 870 mg (1.63 mmol) of (+)-5-[[(2R,4S)-4-benzoyloxy-1-(4-methoxyphenethyl)pyrrolidin-2-yl]methyl]-5,11-dihydrodibenzo[b,e][1,4]oxazepine in 15 ml of ether was added 460 mg (11.4 mmol) of NaOH in methanol (60 ml) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo, then water was added to the residue and the products were extracted with ether. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography (ethyl acetate) to give 680 mg (97.1%) of (+)-5-[[(2R,4S)-4-hydroxy-1-(4-methoxyphenethyl)pyrrolidin-2-yl]methyl]-5,11-dihydrodibenzo[b,e][1,4]oxazepine as yellow amorphous.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][Cl:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:17](O)[CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCCCCC.CCOCC>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2([CH2:12][CH2:13][CH2:14][Cl:15])[O:19][CH2:18][CH2:17][O:16]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)CCCCl)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Solvent: CCOCC
Product: CC(C)(C)c1ccc(C2(CCCCl)OCCO2)cc1

Procedure:
This compound was synthesized as described under 5.a) with 20.0 g (83.8 mmol) of 1-(4-tert-butylphenyl)-4-chloro-1-butanone (origin: Acros), 16 ml of ethylene glycol and ca. 1 g of p-toluenesulfonic acid in 120 ml of toluene for 16 h to give 24.1 g (99%) of the crude compound, which was used for further functionalization. Column chromatography of 3 g (SiO2, heptane/ether 4:1) afforded 2.48 g of a slightly yellow oil.