Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:15][CH2:14][CH2:13][C:12]3=[O:16])=[CH:9][N:10]=2)[N:7]=1.[NH2:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>>[O:16]=[C:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:8]1[N:6]2[N:7]=[C:2]([NH:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: O=C1CCCN1c1cnc2ccc(Cl)nn12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccc2ncc(N3CCCC3=O)n2n1
Yield: 73 %

Procedure:
The 1-(6-chloroimidazo[1,2-b]pyridazin-3-yl)pyrrolidin-2-one was reacted with (S)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate using the amine displacement conditions described in example 5.6.42, Part A to afford the desired product in 73% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.38-1.46 (m, 10H) 1.71 (br. s., 1H) 1.80-1.91 (m, 2H) 1.95-2.08 (m, 1H) 2.22 (quin, J=7.55 Hz, 2H) 2.50-2.58 (m, 2H) 3.22-3.41 (m, 4H) 3.90 (q, J=6.69 Hz, 2H) 4.16 (br. s., 1H) 6.40 (d, J=9.70 Hz, 1H) 7.44 (s, 1H) 7.54 (d, J=9.70 Hz, 1H); LRMS (ESI) m/401.0 [(M+H)+, calcd for C20H28N6O3 400.0].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:36])[CH3:35])[C:29]=1[N:37]=[C:38]=[O:39])([CH3:27])[CH3:26]>>[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:35])[CH3:36])[C:29]=1[NH:37][C:38](=[O:39])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=1)([CH3:26])[CH3:27]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCc1ccc(NCc2ccc(OC)cc2)cc1
Product: CCCCCCCCc1ccc(N(Cc2ccc(OC)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 48.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(4-methoxyphenyl)methyl](4-octylphenyl)amine (2.2 g) and 2,6-diisopropylphenyl isocyanate (1.2 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-methoxyphenyl)methyl]-N-(4-octylphenyl)urea (1.5 g) was obtained.
Reaction SMILES: [CH:1]([O:14][NH:15][C:16]([CH:18]1[CH:24]([C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23][CH:22]=[CH:21][CH2:20][N:19]1[S:33]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34])=[O:17])([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.[BH4-].[Na+]>CO.ClCCl>[CH:1]([O:14][NH:15][C:16]([CH:18]1[CH:24]([CH:25]([OH:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:23][CH:22]=[CH:21][CH2:20][N:19]1[S:33]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34])=[O:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(C(=O)c3ccccc3)C2C(=O)NOC(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CC=CCC(C(O)c3ccccc3)C2C(=O)NOC(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
3-Benzoyl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid benzhydryloxy-amide (32 mg, 0.054 mmoL) was dissolved in a methanol:dichloromethane (3:1, 1.3 mL) mixture and cooled to 0° C. This solution was treated with sodium borohydride and stirred 5 hrs at 0 to 25° C. The solvents were removed in vacuo and the residue was reconstituted in dichloromethane. This solution was washed with 1 M aqueous HCl, and H2O, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 1.25% methanol in dichloromethane) to give 3-(hydroxy-phenyl-methyl)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid benzhydryloxy-amide; MS: (M+H)+ 598.8, (M+NH4)+ 615.7.
Reaction SMILES: C([O:5][C:6]([CH:8]1[C:13]([OH:15])([CH3:14])[CH2:12][CH2:11][CH2:10][N:9]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:7])(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][O:25][C:22]2[CH:21]=[CH:20][C:19]([S:16]([N:9]3[CH2:10][CH2:11][CH2:12][C:13]([OH:15])([CH3:14])[CH:8]3[C:6]([OH:7])=[O:5])(=[O:17])=[O:18])=[CH:24][CH:23]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)C1N(S(=O)(=O)c2ccc(OCc3ccc(F)cc3)cc2)CCCC1(C)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(O)CCCN(S(=O)(=O)c2ccc(OCc3ccc(F)cc3)cc2)C1C(=O)O

Procedure:
A solution of 1-[4-(4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid tert-butyl ester in 2 mL of 1:1 trifluoroacetic acid-CH2Cl2 was stirred for 15 min-2 h at room temperature. Concentration in vacuo afforded 1-[4-(4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid as a colorless syrup:
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].[CH3:7][O:8][C:9]1[S:13][C:12](=[O:14])[N:11]([CH2:15][C:16](=O)[CH3:17])[N:10]=1>CO>[CH3:6][O:5][C:1]([NH:2][N:3]=[C:16]([CH3:17])[CH2:15][N:11]1[N:10]=[C:9]([O:8][CH3:7])[S:13][C:12]1=[O:14])=[O:4]
Reactant: COC(=O)NN
Reactant: COc1nn(CC(C)=O)c(=O)s1
Solvent: CO
Product: COC(=O)NN=C(C)Cn1nc(OC)sc1=O
Temperature: 25 °C
Reaction time: 36 h
Yield: 78.8 %

Procedure:
9.1 g of methyl carbazate are added to a solution of 18.8 g of 5-methoxy-3-(2-oxo-propyl)-3H-[1,3,4]thiadiazol-2-one (Comp. 7.001) in 150 ml of methanol and the mixture is then stirred at room temperature for 36 hours. The reaction mixture is concentrated by evaporation and the residue is stirred with isopropanol and filtered with suction to yield 20.5 g of crystals of the title compound having a melting point of 142-143°.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]2[CH:5]=[CH:6][C:7]([NH:13][CH2:14][C:15]3[O:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[N:8][C:9]=2[CH:10]=[CH:11][CH:12]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:2]([CH3:1])[C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][C:7]([NH:13][CH2:14][C:15]2[O:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[N:8]3)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: CNc1cccc2nc(NCc3ccc(C)o3)ccc12
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: Cc1ccc(CNc2ccc3c(N(C)S(=O)(=O)c4ccc(F)cc4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=426.1 (M+H+), was prepared from N5-methyl-N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,5-diamine and 4-fluorobenzene sulphonylchloride as described in example 39.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1CCCC1>CO>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]2([CH2:1][C:2](=[O:3])[C:4]3[C:5](=[CH:6][CH:7]=[C:8]([Br:10])[CH:9]=3)[O:11]2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: CO
Solvent: C1CCNC1
Product: O=C1CC2(CCN(Cc3ccccc3)CC2)Oc2ccc(Br)cc21
Reaction time: 11 h
Yield: 66.6 %

Procedure:
A mixture of 2-hydroxy-5-bromoacetophenone (5.85 g, 27.2 mmol), N-benzyl-4-piperidone (5.14 g, 27.21 mmol) and pyrrolidine (1.11 ml, 13.60 mmol) in MeOH (100 ml) was heated to reflux. After 11 h, the solvent was removed under vacuum and the crude mixture was purified by column chromatography (eluent: hexane/AcOEt 90:10 to 70:30) to give 1′-benzyl-6-bromo-spiro[chromane-2,4′-piperidine]-4-one (7.0 g) as a yellow solid.
Reaction SMILES: O[C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]2[N:21]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)=[O:26])[CH2:22][CH2:23][N:24]=2)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:69]([SH:72])(=[O:71])[CH3:70]>O1CCCC1.C(OCC)(=O)C>[C:69]([S:72][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:20]2[N:21]([C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=3)=[O:26])[CH2:22][CH2:23][N:24]=2)[CH2:3]1)(=[O:71])[CH3:70]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCN=C1[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)S
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)S[C@H]1C[C@@H](C2=NCCN2C(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.5 h

Procedure:
(2S, 4R) -4-Hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-[1-(4-nitrobenzyloxycarbonyl)-2-imidazolin-2-yl]-pyrrolidine (655 mg) and triphenylphosphine (0.51 g) were dissolved in tetrahydrofuran (20 ml) at 0° C. To this solution was added dropwise a solution of diethyl azodicarboxylate (0.30 ml) in tetrahydrofuran (5 ml) with stirring for 30 minutes, followed by addition of a solution of thioacetic S-acid (0.14 ml). Stirring was continued at ambient temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The obtained oily residue was subjected to a column chromatography on silica gel and eluted with a mixture of dichloromethane and acetone (20:1, V/V) to give (2S, 4S )-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-[1-(4-nitrobenzyloxycarbonyl)-2-imidazolin-2 -yl]-pyrrolidine (1.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:19](Cl)(Cl)=[S:20]>>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:12][N:13]=2)=[CH:6][CH:7]=1)=[C:19]=[S:20]
Reactant: S=C(Cl)Cl
Reactant: CCCCCc1cnc(-c2ccc(N)cc2)nc1
Product: CCCCCc1cnc(-c2ccc(N=C=S)cc2)nc1

Procedure:
2-(4-Aminophenyl)-5-pentylpyrimidine (prepared from 4-aminophenylamidine and 2-pentylpropane-1,3-diol) is reacted with thiophosgene as described in Example 3, affording 2-(4-isothiocyanatophenyl)-5-pentylpyrimidine; m.p. 46°, c.p. 85.5°.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([C:9](Cl)=[O:10])[S:7][CH:8]=2)[CH2:3][CH2:2]1.[NH2:12][C:13]1[C:18]([Cl:19])=[C:17]([O:20][CH3:21])[CH:16]=[CH:15][C:14]=1[C:22](=[O:24])[CH3:23].O>O1CCOCC1>[C:22]([C:14]1[C:13]([NH:12][C:9]([C:6]2[S:7][CH:8]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:5]=2)=[O:10])=[C:18]([Cl:19])[C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:24])[CH3:23]
Reactant: COc1ccc(C(C)=O)c(N)c1Cl
Reactant: O=C(Cl)c1nc(C2CC2)cs1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C3CC3)cs2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of compound 267a (3.4 g, 1.2 eq.) in dioxane (60 mL) was added 6-acetyl-2-chloro-3-methoxy aniline 201d (3.01 g, 1 eq.) in dioxane. The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate) to yield compound 268a as a brown solid in 66% yield. 1H NMR (CDCl3, 400 MHz): δ (ppm) 1-1.06 (m, 4H), 2.08-2.15 (m, 1H), 2.58 (s, 3H), 3.99 (s, 3H), 6.87 (d, J=8.78 Hz, 1H), 7.16 (s, 1H), 7.67 (d, J=8.78 Hz, 1H), 10.27 (br s, 1H); MS (ESI, EI+): m/z=351 (MH+).
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:8]=1)[CH3:4].C(=O)(O)[O-].[Na+]>ClCCl.O>[CH2:3]([O:5][C:6](=[O:20])[C:7]1[C:12]([Br:1])=[CH:11][N:10]=[C:9]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:8]=1)[CH3:4]
Reactant: CCOC(=O)c1ccnc(N2CCN(C)CC2)c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc(N2CCN(C)CC2)ncc1Br
Reaction time: 1 h
Yield: 37.4 %

Procedure:
A solution of 0.91 ml (17.7 mmol) Br2 was added dropwise to a solution of 2.95 g (11.8 mmol) 2-(4-methyl-piperazin-1-yl)-isonicotinic acid ethyl ester in 20 ml dichloromethane at 0° C.-4° C. Stirring was continued at room temperature for 1 h and 50 ml saturated sodium bicarbonate solution in water was added. The aqueous layer was separated and washed twice with dichloromethane. The combined organic layers were dried (magnesium sulfate) and evaporated. The residue was purified by chromatography to give 1.45 g (37%) of the title compound as a pale yellow oil.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([OH:10])=[N:2]1.[F:11][C:12]([F:23])([F:22])[CH:13]1[CH2:18][CH2:17][N:16]([C:19](Cl)=[O:20])[CH2:15][CH2:14]1>>[F:22][C:12]([F:11])([F:23])[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:10][C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[S:1][N:2]=2)=[O:20])[CH2:15][CH2:14]1
Reactant: O=C(Cl)N1CCC(C(F)(F)F)CC1
Reactant: Oc1nsc2ncccc12
Product: O=C(Oc1nsc2ncccc12)N1CCC(C(F)(F)F)CC1

Procedure:
In analogy to example 1, 2.99 g (9.82 mmol) of isothiazolo[5,4-b]pyridin-3-ol were reacted with 2.33 g (10.81 mmol) of 4-trifluoromethylpiperidine-1-carbonyl chloride. Yield: 1.3 g (40%), M+H+: 332.09.
Reaction SMILES: [CH2:1]([N:4]1[CH:9]=[C:8]([O:10]CC2C=CC=CC=2)[C:7](=[O:18])[CH:6]=[C:5]1[CH:19]([F:21])[F:20])[CH:2]=[CH2:3].B(Br)(Br)Br>ClCCl>[CH2:1]([N:4]1[CH:9]=[C:8]([OH:10])[C:7](=[O:18])[CH:6]=[C:5]1[CH:19]([F:21])[F:20])[CH:2]=[CH2:3]
Reactant: C=CCn1cc(OCc2ccccc2)c(=O)cc1C(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C=CCn1cc(O)c(=O)cc1C(F)F
Reaction time: 0.33 h
Yield: 131.7 %

Procedure:
An alternative debenzylation procedure was used for the allyl derivative in order to avoid reduction of the allyl double bond. Thus, a clear yellow/brown solution of 1-allyl-5-benzyloxy-2-difluoromethyl-1H-pyridin-4-one (2.91 g, 10 mmol) in dichloromethane (30 mL) was cooled in an ice-salt bath under a positive nitrogen atmosphere. Then, a pre-mixed 1.0 M boron tribromide solution (10 mL) and dichloromethane (10 mL) was added dropwise. After 20 min, the reaction mixture was quenched with 25 mL of methanol. The solution was concentrated to dryness. The obtained solid was suspended in ether. The solid was collected by filtration to afford the title product (2.65 g, 94% yield) as the hydrobromide salt. HPLC purity (peak area percent) is 99.4% at λ=267 nm using HPLC Method 1 as described above. 1H NMR (400 MHz, DMSO-D6+D2O) δ (ppm): 8.10 (s, 1H), 7.29 (t, J=53.0 Hz, 1H, CF2H), 6.26 (s, 1H), 5.07-6.00 (m, 1H), 5.36 (d, J=10.3 Hz, 1H), 5.20 (d, J=17.1 Hz, 1H), 4.95 (d, J=5.1 Hz, 2H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:10][O:11]C(Cl)Cl.C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1
Reactant: COC(Cl)Cl
Reactant: BrCCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=Cc1ccc(CCBr)cc1
Reaction time: 0.17 h
Yield: 40.8 %

Procedure:
To a solution of (2-bromoethyl)benzene (100 mmol, 18.5 g) in methylene chloride (185 ml) at 0° C. was added dropwise titanium tetrachloride (200 mmol, 22 ml). The mixture was stirred for 10 minutes and alpha,alpha-dichloromethyl methyl ether (100 mmol, 9 ml) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour and poured into saturated NaHCO3 (1 liter). Ethyl acetate (750 ml) was added and the solution was filtered through diatomaceous earth, the organic layer separated, dried (Na2SO4) and solvent removed in vacuo. The residue was triturated with hexane to afford 8.7 g of title product; m.p. 49°-52° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:8]([C@@H:18]([NH:20][C:21]1[N:29]=[CH:28][N:27]=[C:26]3[C:22]=1[N:23]=[CH:24][NH:25]3)[CH3:19])=[CH:7]2.[CH3:30][N:31](C=O)C>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-]#N.[C-]#N.[Zn+2]>[N:29]1[C:21]([NH:20][C@H:18]([C:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[C:30]#[N:31])[CH3:19])=[C:22]2[C:26]([NH:25][CH:24]=[N:23]2)=[N:27][CH:28]=1
Reactant: CN(C)C=O
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2nc1-c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(C#N)c2nc1-c1ccccn1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A mixture of N—((S)-1-(8-chloro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (80 mg, 0.2 mmol), Pd(PPh3)4 (23 mg, 0.1 eq) and Zn(CN)2 (117 mg, 5.0 eq) in DMF (5 mL) was purged with N2 for 5 min before heating to 130° C. After 3 h, LCMS showed formation of trace amount of 2. The reaction was then heated to 165° C. over night. After cool to rt, the reaction was filtered through Celite™ and purified by reverse HPLC (MeCN/H2O, 0.1% TFA) to give a white solid. 1H-NMR (400 Hz, DMSO-d6) δ 8.83 (s, 1H), 8.72 (s, 1H), 8.52 (s, 1H), 8.42-8.37 (m, 3H), 8.14 (d, J=8.0 Hz, 1H), 8.08 (t, J=8.0 Hz, 1H), 7.79 (t, J=8.0 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 6.24 (s, 1H), 1.72 (d, J=8.0 Hz, 3H). Mass Spectrum (ESD m/e=393 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:30]=[C:31]([CH3:38])[C:32]3[N:36]=[CH:35][NH:34][C:33]=3[CH:37]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([O:28][C:29]5[CH:30]=[C:31]([CH3:38])[C:32]6[N:36]=[CH:35][NH:34][C:33]=6[CH:37]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]cnc12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5nc[nH]c5c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
47 mg (0.17 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 45 mg (0.17 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-4-methyl-1H-benzimidazole and 0.06 mL (0.34 mmol) DIPEA were combined in 2.0 mL DMF and stirred for 48 h at RT. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and the acetonitrile was evaporated down. The residue was made alkaline with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [F:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:3]=1[CH2:4][C:5]([OH:7])=O.[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][NH2:20]>>[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][NH:20][C:5](=[O:7])[CH2:4][C:3]1[CH:8]=[CH:9][C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:2]=1[F:1]
Reactant: COC(CN)OC
Reactant: COc1ccc(CC(=O)O)c(F)c1OC
Product: COc1ccc(CC(=O)NCC(OC)OC)c(F)c1OC

Procedure:
Following the procedures outlined in Examples 1 and 2, the 2-fluorohomoveratric acid is reacted with aminoacetaldehyde dimethylacetal to form N-(2,2-dimethoxyethyl)-3,4,-dimethoxy-2-fluorophenylacetamide which is ring closed with hydrochloric acid and glacial acetic acid to obtain 2,3-dihydro-7,8-dimethoxy-6-fluoro-2-oxo-1H-3-benzazepine. The dihydrobenzazepine is reduced first with hydrogen and palladium-on-carbon, then with diborane to give 7,8-dimethoxy-6-fluoro-2,3,4,5-tetrahydro-1H-3-benzazepine. The latter is treated with formaldehyde/formic acid to give the corresponding 3-methyl derivative which is demethylated with 48% hydrobromic acid. The resulting catechol is oxidized with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and the dione is treated with a methanolic solution of thiophenol to furnish the product 7,8-dihydroxy-9-fluoro-3-methyl-6-phenyl-thio-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:10]([C:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=1)#[CH:11]>C1(C)C=CC=CC=1>[N:7]1[CH:8]=[CH:9][C:4]([N:1]2[CH:11]=[C:10]([C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=3)[N:3]=[N:2]2)=[CH:5][CH:6]=1
Reactant: C#CC1=CCN(C(=O)OC(C)(C)C)CC1
Reactant: [N-]=[N+]=Nc1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(c2cn(-c3ccncc3)nn2)CC1
Yield: 13.5 %

Procedure:
4-Azidopyridine (140 mg) prepared in the above 1) and 207 mg of tert-butyl 4-ethynyl-1,2,3,6-tetrahydropyridine-1-carboxylate were dissolved in 3 ml of toluene and the solution was heated to reflux for 20 hours. The reaction solution was returned to room temperature and the solvent was evaporated in vacuo. The resulting residue was separated and produced by a silica gel chromatography (chloroform/methanol=100/1) to give 44 mg of the title compound as a white solid.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH2:21]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)[CH2:22][CH3:23]>>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH2:21][CH2:22][CH3:23])=[CH:26][CH:27]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1)[CH3:20]
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Reactant: CCCOc1ccc(C=O)cc1
Product: CCCOc1ccc(CN2C(=O)C(C)CC2c2c(F)cccc2OCC)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with commercially available 4-propoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.97 min.; [M+H]+: 385.81 g/mol.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]([CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:8].[C:35]([NH2:38])(=[O:37])[CH3:36]>O>[C:35]([NH:38][C:10]([CH:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:18][CH:19]=1)[C:7]([O:6][CH3:5])=[O:8])=[O:12])(=[O:37])[CH3:36]
Reactant: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Reactant: CC(N)=O
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)NC(C)=O
Temperature: 60 °C
Yield: 37.3 %

Procedure:
Thionyl chloride (1.0 ml) was added to 2-methoxycarbonyl-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionic acid (2.63 g, 6.43 mmol) obtained in Example 1, and the mixture was stirred with heating at 60° C. for 1 hr. Excess thionyl chloride was evaporated under reduced pressure and acetamide (504 mg, 8.54 mmol) was added to the residue. The mixture was stirred with heating at 120° C. for 30 min. Tetrahydrofuran-ethyl acetate (1:1, 100 ml) and water (50 ml) were added to the reaction mixture for partition. The organic layer was washed with saturated brine (50 ml), dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent; n-hexane:ethyl acetate=1:1) to give the title compound (1.08 g, yield 34%) as a white solid.