Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:4]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[C:5]([O:7]CC)=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.O>[CH:1]1([CH:4]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(Oc1cccc2ccccc12)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(Oc1cccc2ccccc12)C1CC1
Temperature: 80 °C
Yield: 61 %

Procedure:
To a solution of 1-naphthol (170 mg, 1.18 mmol) in anhydrous DMF (10 mL) was added K2CO3 (510 mg, 3.53 mmol) and ethyl α-bromocyclopropaneacetate (295 mg, 1.41 mmol). The mixture was stirred at room temperature for 2 h and then diluted with water (50 mL) and then extracted with ethyl acetate (3×50 mL). The organic extracts were combined, washed with brine, dried over anhydrous MgSO4, filtered, concentrated in vacuo and purified by flash column chromatography using a mixture of ethyl acetate and n-hexane (1:9) to furnish ethyl 2-cyclopropyl-2-(1-naphthalenyloxy)acetate (8, R=c-Pr, 296 mg, 93%) as a white solid. The ester (250 mg, 0.92 mmol) was dissolved in 20 mL THF: H2O (2:1) and then 3M NaOH (111 mg, 2.77 mmol) was added. The reaction was heated at 80° C. for 6 h. After cooling, the reaction mixture was quenched with 1N HCL to a pH ˜7 and then extracted with chloroform. The organic extract was dried over anhydrous MgSO4, filtered, concentrated in vacuo and purified by flash column chromatography eluting with a mixture of ethyl acetate/n-hexane (a gradient of 2:1) to furnish 2-cyclopropyl-2-(1-naphthalenyloxy)acetic acid (41, R=c-Pr) (136 mg, 61%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[O:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][O:11][C:12]2[CH:13]=[C:14]3[N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19][N:15]3[C:16](=[O:18])[N:17]=2)=[CH:8][C:7]=1[C:31]([F:34])([F:33])[F:32]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[O:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][O:11][C:12]2[CH:13]=[C:14]3[NH:21][CH2:20][CH2:19][N:15]3[C:16](=[O:18])[N:17]=2)=[CH:8][C:7]=1[C:31]([F:33])([F:34])[F:32]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(F)c(F)c3)c(C(F)(F)F)c1)nc2=O
Solvent: CN(C)C=O
Product: O=c1nc(OCc2ccc(Oc3ccc(F)c(F)c3)c(C(F)(F)F)c2)cc2n1CCN2

Procedure:
Prepared in a manner similar to that described for E71 using tert-butyl 7-((4-(3,4-difluorophenoxy)-3-(trifluoromethyl)benzyl)oxy)-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylat in DMF (2 mL) and silica gel.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[O:15][CH2:14][C@@:13]([NH:24][C:25]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[S:26])([C:16]2[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:17]=2[F:23])[C@H:12]([CH2:36]O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[CH2:1]([O:8][CH2:9][C@@H:10]1[O:15][CH2:14][C@:13]2([C:16]3[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:17]=3[F:23])[N:24]=[C:25]([NH:27][C:28](=[O:35])[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[S:26][CH2:36][C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(=S)N[C@@]1(c2cc(Br)ccc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NC1=N[C@@]2(c3cc(Br)ccc3F)CO[C@@H](COCc3ccccc3)C[C@H]2CS1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of N-{[(3S,4R,6R)-6-[(benzyloxy)methyl]-3-(5-bromo-2-fluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide (C31) (9.49 g, 16.2 mmol) and pyridine (4.94 mL, 61.4 mmol) in dichloromethane (278 mL) was cooled to -50° C. Trifluoromethanesulfonic anhydride (5.44 mL, 32.3 mmol) was added drop-wise to the solution and the mixture was gradually warmed to 0° C. After 2 hours, the reaction mixture was partitioned between dichloromethane (1 L) and water (500 mL). The organic layer was washed with dichloromethane (2×250 mL) and the combined organics were then washed with brine (500 mL). The resulting organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to yield an orange oily residue. Purification via silica gel chromatography (Gradient: 0% to 60% ethyl acetate in heptane) afforded the product as an orange solid. Yield: 5.53 g, 60%. LCMS m/z 571.2 [M+H+]. 1H NMR (400 MHz, CD3OD) characteristic peaks: δ 8.12 (d, J=7.4 Hz, 2H), 7.43-5.58 (m, 5H), 7.12-7.32 (m, 6H), 4.51-4.60 (m, 2H), 4.10-4.13 (m, 1H), 3.87-3.91 (m, 1H), 3.55-3.63 (m, 2H), 3.18-3.21 (m, 1H), 2.94 (dd, J=13.2, 4.0 Hz, 1H), 2.74 (dd, J=13.1, 2.9 Hz, 1H), 1.90-1.99 (m, 1H), 1.67-1.72 (m, 1H).
Reaction SMILES: C([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18](=[O:21])[CH2:19][CH2:20][CH:11]([C:12]=23)[CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)C1C=CC=CC=1.Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[C:22]1([CH:10]2[CH:11]3[CH2:20][CH2:19][C:18](=[O:21])[C:13]4[C:12]3=[C:17]([CH:16]=[CH:15][CH:14]=4)[NH:9]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C1CCC2c3c1cccc3N(C(=O)c1ccccc1)C2c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1CCC2c3c(cccc31)NC2c1ccccc1
Yield: 111.1 %

Procedure:
A portion (4.25 g) of the compound obtained in Example 1 was dissolved in ethanol (40 ml). To the solution was added conc. hydrochloric acid (40 ml) and the resulting mixture was heated to reflux for 2 hours. After allowing to cool, the mixture was diluted with water, adjusted to pH 9 with potassium carbonate and extracted three times with ethyl acetate. The organic layers were combined, washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure and the residue was crystallized from an ether/hexane mixed solvent to yield 3.33 g (92%) of the titled compound as crystals.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[CH:6]=[CH:7][C:8]([I:15])=[C:9]([CH2:11][C:12](Cl)=[O:13])[CH:10]=1.CCOC(C)=O>CCOCC>[CH3:1][N:2]([CH3:3])[C:12](=[O:13])[CH2:11][C:9]1[CH:10]=[C:5]([Br:4])[CH:6]=[CH:7][C:8]=1[I:15]
Reactant: O=C(Cl)Cc1cc(Br)ccc1I
Reactant: CNC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CN(C)C(=O)Cc1cc(Br)ccc1I

Procedure:
Dimethylamine (200 mL of 2 M in THF) is added dropwise to a solution of the above 5-bromo-2-iodophenylacetyl chloride in Et2O (500 mL), cooled in an ice bath. After the addition is complete, EtOAc (350 mL) is added and the solution washed with water (350 mL), brine (250 mL) and dried (MgSO4). Evaporation by rotary evaporator and trituration with 1:1 Et2O/hexanes gives N,N-dimethyl-5-bromo-2-iodophenylacetamide (m.p. 127–129° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21](F)[CH:22]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:21]3[CH:20]=[N:19][CH:18]=[C:17]([F:16])[CH:22]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Fc1cncc(F)c1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cncc(F)c1

Procedure:
The title compound, MS: m/e=313.1 (M+H+), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3,5-difluoro-pyridine.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].[F-:22].[K+].C(#N)C.O>C1OCCOCCOCCOCCOCCOC1.C(OCC)(=O)C>[F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([S:16]([F:22])(=[O:18])=[O:17])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2CC1)C(F)(F)F
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: O=C(N1CCc2ccc(S(=O)(=O)F)cc2CC1)C(F)(F)F
Reaction time: 8 h
Yield: 96.4 %

Procedure:
A mixture of 3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl chloride (23 g, 67 mmol), potassium fluoride (12 g, 200 mmol), 18-crown-6 (0.1 g), and acetonitrile (100 mL) was stirred overnight. Water (200 mL) and ethyl acetate (200 mL) were added and the organic layer was washed with brine (100 mL), dried (MgSO4), and evaporated to give the title compound D1 as a white solid (21 g). 1H NMR 3 (d6-DMSO) 3.2 (4H, m), 3.7 (4H, m), 7.6 (1H, m), and 8.0 (2H, m).
Reaction SMILES: [NH:1]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31](OC)=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.O.[NH2:43][NH2:44]>CO>[NH:1]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:43][NH2:44])=[O:32])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: NN
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: O
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Reaction time: 24 h

Procedure:
43 g of Boc-Tyr-(D)-Ala-Gly-Phe-OCH3 are dissolved in 300 ml of methanol and 35 ml of hydrazine hydrate are added. After one day at room temperature, the mixture is evaporated and the residue is triturated with water which has been acidified to pH 3 with HCl. The precipitated product is filtered and dried to yield the title compound. M.P. 195° (decomp.). [α]D20 =-20.9 (C=1 in DMF).
Reaction SMILES: OC1[CH:7]([C:8]2[CH:13]=[CH:12][C:11](O)=[CH:10][CH:9]=2)CCN(C(OC(C)(C)C)=O)C1.ClCCCCOC1CCCCO1.BrCC1C=CC2C(=CC=CC=2)C=1.Cl.[OH:47][CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:58]=[CH:57][C:56]([CH:59]2[CH2:64][CH2:63][N:62]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:61][CH:60]2[O:72][CH2:73][C:74]2[CH:83]=[CH:82][C:81]3[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=3)[CH:75]=2)=[CH:55][CH:54]=1.C(Br)C1C=CC=CC=1>CO>[CH2:7]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:58]=[CH:57][C:56]([CH:59]2[CH2:64][CH2:63][N:62]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:61][CH:60]2[O:72][CH2:73][C:74]2[CH:83]=[CH:82][C:81]3[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=3)[CH:75]=2)=[CH:55][CH:54]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Agent: BrCc1ccc2ccccc2c1
Agent: BrCc1ccccc1
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
(bbb) In an analogous manner to that described in Example 44 (e), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate [Example 46 (b)] with 2-(4-chloro-butoxy)-tetrahydro-2H-pyran there was obtained a mixture of tert-butyl (3RS,4RS)- and (3SR,4SR)-3-hydroxy-4-[4-[4-[(RS)-tetrahydropyran-2-yloxy]-butoxy]-phenyl]-piperidine-1-carboxylate, alkylation of which with 2-bromomethyl-naphthalene analogously to Example 1 (g) gave a mixture of (3RS,4RS)- and (3SR,4SR)-3-(naphthalen-2-ylmethoxy)-4-[4-[4-[(RS)-tetrahydro-pyran-2-yloxy]-butoxy]-phenyl]-piperidine-1-carboxylate. Cleavage of the THP group with hydrogen chloride in methanol analogously to Example 53 (c) yielded tert-butyl (3RS,4RS)-4-[4-(4-hydroxy-butoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine1-carboxylate, alkylation of which with benzyl bromide analogously to Example 1 (g) gave tert-butyl (3RS,4RS)-4-[4-(4-benzyloxy-butoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 613 (M+NH4)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][OH:18]>C(N(CC)CC)C>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][OH:18])([O-:13])=[O:12]
Reactant: Nc1ccccc1CO
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Nc1ccccc1CO
Yield: 54.3 %

Procedure:
2.85 g (14 mmol) of 1-chloro-2,6-dinitrobenzene and 1.73 g (14 mmol) of 2-aminobenzyl alcohol. were dissolved in 30 ml of triethylamine and heated under reflux for 24 hours. After concentrating, the residue was purified by silica gel column chromatography. Thus 2.2 g of 2-[(2,6-dinitrophenyl)amino]benzyl alcohol was obtained. 0.29 g (1 mmol) of this powder was dissolved in 20 ml of dry dimethylformamide. After adding 40 mg (1 mmol) of sodium hydride (in oil, content: 60%), the reaction mixture was stirred at room temperature for 15 minutes and then at 150° C. for 2 hours. After cooling, 200 ml of ethyl acetate was added thereto and the mixture was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography. Thus 0.14 g of the title compound was obtained.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[CH3:14][NH2:15]>>[OH:1][C:3]1([CH2:2][NH:15][CH3:14])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CN
Reactant: CCOC(=O)N1CCC2(CC1)CO2
Product: CCOC(=O)N1CCC(O)(CNC)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.2 g (28 mmol) of ethyl 6-aza-1-oxaspiro[2,5]octane-6-carboxylate ) are added dropwise to 30 ml of methylamine solution (25% in water) and the mixture is stirred overnight at room temperature. It is then concentrated and recrystallized from petroleum ether (hygroscopic crystals).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][CH2:26][C:27]1[CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:31][CH:32]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:30]=[N:31][CH:32]=[C:27]([CH2:26][O:25][CH3:24])[CH:28]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: COCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Product: COCc1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 5-(methoxymethyl)pyridine-3-boronic acid pinacol ester (PepTeck, Burlington, USA, 32 mg, 0.128 mmol) to give the title compound as a white solid. (HPLC: tR 2.08 min (Method A); M+H=415 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.01 (s, 1H), 8.70-8.67 (m, 1H), 8.56-8.54 (m, 1H), 8.19-8.13 (m, 2H), 8.02-7.98 (m, 1H), 7.82-7.80 (m, 1H), 7.62-7.59 (m, 1H), 4.53 (s, 2H), 3.94 (s, 3H), 3.60 (s, 3H), 3.37 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Br:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].Cl[Sn]Cl.O.C([O-])(O)=O.[Na+]>C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:11])=[CH:4][C:3]=1[C:12]([F:15])([F:13])[F:14]
Reactant: Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(Br)cc(C(F)(F)F)c1N
Temperature: 90 °C
Yield: 62 %

Procedure:
To a stirred mixture of 2-amino-5-bromo-3-nitrobenzotrifluoride (261 mg, 0.949 mmol) in ethanol (4 mL) was added SnCl2.2 H2O (1.076 g, 4.745 mmol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) for 1 h. The solution was cooled to room temperature and ice water (20 g) was added. It was adjusted to pH=7 with NaHCO3 and extracted by ethyl acetate (2×4 mL). The extract was dried over Mg2SO4 and evaporated to give 150 mg (64.6%) of 2,3-diamino-5-bromobenzotrifluoride as a brown solid. 1H NMR (CDCl3): δ 3.503 (s, 2H); 3.898 (s, 2H); 6.987 (d, 1H, J=1.8 Hz); 7.123 (d, 1H, J=1.8 Hz).
Reaction SMILES: [CH3:1]C1C=C(O)C=CC=1O.C[O-].[Na+].CC1C(C)=C(C=CC=1O)O.[CH3:23][C:24]1[C:25]([OH:33])=[C:26]([CH3:32])[C:27]([CH3:31])=[C:28]([CH:30]=1)[OH:29]>CO>[CH3:23][C:24]1[C:25]([OH:33])=[C:26]([CH3:32])[C:27]([CH3:31])=[C:28]([OH:29])[C:30]=1[CH3:1]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: Cc1cc(O)ccc1O
Agent: C[O-]
Agent: Cc1c(O)ccc(O)c1C
Agent: [Na+]
Solvent: CO
Product: Cc1c(C)c(O)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into an autoclave (inner volume: 9 ml, made of SUS 316, equipped with a manometer) were charged 0.108 g of methylhydroquinone, 3.573 g of methanol and 0.2 mg of sodium methylate. The reaction was started by elevating the temperature up to 350° C. with sand bath. The pressure during the reaction was 16 MPa. After 4 hours, the autoclave was quickly cooled and the reaction solution was taken out from the autoclave when the temperature was cooled back to the room temperature. The measurement according to the process described above revealed that the conversion of methylhydroquinone was 86% by mole, the selectivity of dimethylhydroquinone was 38% by mole, the selectivity of trimethylhydroquinone was 37% by mole and no tetramethylhydroquinone was produced. As byproducts, methyl ethers of monomethylhydroquinone, dimethylhydroquinone and trimethylhydroquinone, represented by the formulae shown above, were formed with a selectivity of 6%, 4% and 3%, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:30][C:31]2[CH:32]=[CH:33][C:34]3[O:38][N:37]=[C:36]([CH3:39])[C:35]=3[CH:40]=2)[C:9]2[C:10]([C:27]([OH:29])=O)=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([C:17]4[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=4)[C:13]=3[CH:14]([CH3:15])[CH3:16])[C:27](=[O:29])[N:30]2[C:31]2[CH:32]=[CH:33][C:34]3[O:38][N:37]=[C:36]([CH3:39])[C:35]=3[CH:40]=2)=[CH:6][CH:7]=1
Reactant: COc1ncc(-n2nc(C(=O)O)c(C(Nc3ccc4onc(C)c4c3)c3ccc(Cl)cc3)c2C(C)C)c(OC)n1
Solvent: CCOC(C)=O
Product: COc1ncc(-n2nc3c(c2C(C)C)C(c2ccc(Cl)cc2)N(c2ccc4onc(C)c4c2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)((3-methylbenzo[d]isoxazol-5-yl)amino)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-isopropyl-1H-pyrazole-3-carboxylic acid (Step 54.2).; tR: 1.21 min (LC-MS 2); ESI-MS: 545 [M+H]+ (LC-MS 2); Rf=0.50 (EtOAc); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.48 (d, J=6.8 Hz, 3H) 1.17 (d, J=7.0 Hz, 3H) 2.54 (s, 3H) 2.61-2.71 (m, 1H) 3.96 (s, 3H) 4.01 (s, 3H) 6.71 (s, 1H) 7.31-7.42 (m, 4H) 7.67 (d, J=8.9 Hz, 1H) 7.80 (dd, J=8.9, 2.0 Hz, 1H) 8.04 (d, J=1.8 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[OH:9].C(OC(=O)C)(=O)C.[C:17]([NH:20]C1C=C(Cl)C(O)=C(Cl)C=1)(=[O:19])[CH3:18]>>[C:17]([NH:20][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([OH:9])=[C:4]([Br:8])[CH:5]=1)(=[O:19])[CH3:18]
Reactant: Oc1c(Br)cccc1Br
Reactant: CC(=O)Nc1cc(Cl)c(O)c(Cl)c1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(Br)c(O)c(Br)c1

Procedure:
4-Acetamido-2,6-dibromophenol (used as starting material in Example 54) was prepared from 2,6-dibromophenol and acetic anhydride, using the method described above for the preparation of 4-acetamido-2,6-dichlorophenol, as a solid, m.p. 155°-156° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:28]=2[NH2:29])[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[N:24]1([C:27]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:28]=2[NH:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:3]=2[CH3:20])[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (39.8 mg, 0.137 mmol) and 2,5-dimorpholinoaniline in toluene to give N-(2,5-di-4-morpholinylphenyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (CDCl3) δ ppm 8.71 (1H, d, J=4.7 Hz), 8.15 (1H, d, J=10.2 Hz), 7.82-7.97 (2H, m), 7.64 (1H, d, J=9.4 Hz), 7.38 (1H, ddd, J=6.7, 4.7, 2.3 Hz), 7.10 (1H, d, J=8.6 Hz), 6.99 (1H, ddd, J=13.3, 8.6, 2.7 Hz), 6.48 (1H, dd, J=8.4, 2.5 Hz), 6.22 (1H, d, J=2.3 Hz), 3.90 (4H, t, J=4.3 Hz), 3.76-3.85 (4H, m), 3.05-3.19 (4H, m), 2.92 (4H, br. s.), 2.22 (3H, s). Mass Spectrum (ESI) m/e=518.2 (M+1).
Reaction SMILES: C1(S([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:32]#[N:33])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:34]=[CH:35][CH:36]=[N:37][C:11]2=3)(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:31][S:28]([CH2:27][CH2:26][N:23]1[CH2:24][CH2:25][CH:20]([O:19][C:18]2[C:13]3[C:12]4[CH:34]=[CH:35][CH:36]=[N:37][C:11]=4[NH:10][C:14]=3[CH:15]=[N:16][C:17]=2[C:32]#[N:33])[CH2:21][CH2:22]1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)CCN1CCC(Oc2c(C#N)ncc3c2c2cccnc2n3S(=O)(=O)c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CS(=O)(=O)CCN1CCC(Oc2c(C#N)ncc3[nH]c4ncccc4c23)CC1
Yield: 47.2 %

Procedure:
To a solution of 9-benzenesulfonyl-5-[1-(2-methanesulfonylethyl)-piperidin-4-yloxy]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (6138 mg, 0.26 mmol) in methanol (10 mL) was added potassium carbonate (353 mg, 2.6 mmol) and the resultant suspension was heated to 40° C. for 3 hours. After this time, the reaction mixture was loaded directly onto a 5 g SPE NH2 cartridge, which was eluted with 1:1 methanol: dichloromethane. The appropriate fractions were concentrated in-vacuo and the resultant residue purified by flash chromatography (silica, 25 g column, Si-SPE, 0-5% 2N NH3 in methanol in dichloromethane) to afford the title compound as a pale yellow solid (49 mg, 47%). 1H NMR (400 MHz, DMSO-d6): 12.96 (s, 1H), 8.79 (s, 1H), 8.71 (dd, J=4.8, 1.6 Hz, 1H), 8.59 (dd, J=7.9, 1.6 Hz, 1H), 7.47 (dd, J=7.9, 4.8 Hz, 1H), 4.87-4.57 (m, 1H), 3.28-3.26 (m, 2H obscured by solvent peak), 3.04 (s, 3H), 3.02-2.77 (m, 2H), 2.73 (t, J=6.8 Hz, 2H), 2.20 (t, J=10.8 Hz, 2H), 2.21-1.97 (m, 2H), 1.96-1.89 (m, 2H).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[N:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:3]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>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.O>[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:2]1[N:7]2[N:8]=[N:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)n3nnnc23)CC1
Reactant: OB(O)c1cccs1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccs3)n3nnnc23)CC1
Temperature: 80 °C
Reaction time: 10 h
Yield: 69.5 %

Procedure:
A 1 L round bottom flask was charged with tert-butyl 4-(5-bromotetrazolo[1,5-a]pyrazin-8-yl)piperazine-1-carboxylate (50 g, 0.13 mol), thiophene-2-boronic acid (22 g, 0.17 mol), tetrakis(triphenylphosphine)palladium(0) (7.5 g, 6.5 mmol), Cs2CO3 (51 g, 0.16 mol), 1,4-dioxane (600 mL) and H2O (240 mL). After the air was purged by bubbling N2 into the solution, the resulting solution was stirred at 80° C. under N2 for 10 h. Work-up: the reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted with CH2Cl2, and then crystallized from methanol, to afford 35 g (70%) of the product as a yellow solid. MS m/z: 388 (M+H+).