Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2CCCCC2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:19](OC)=[CH:18][CH:17]=[CH:16][C:15]=2OC)CCCCC1.[C:30]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]([NH2:36])=[CH:32][CH:33]=[CH:34][CH:35]=1.IC1C=CC(C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:14]1([C:9]2[CH:8]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:17]([NH:36][C:31]2[C:30]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:18][CH:19]=1
Reactant: Nc1ccccc1-c1ccccc1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Ic1ccc(-c2ccccc2)cc1
Product: c1ccc(-c2ccc(Nc3ccccc3-c3ccccc3)cc2)cc1
Yield: 790.8 %

Procedure:
Xylene (250 mL) was bubbled with nitrogen for 15 min, followed by addition of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (3.0 g, 7.2 mmol) and Pd2(dba)3 (1.6 g, 1.8 mmol). The mixture was bubbled with nitrogen for 15 min, then [1,1′-biphenyl]-2-amine (10.1 g, 60.0 mmol), 4-iodobiphenyl (16.8 g, 60.0 mmol), sodium tert-butoxide (11.5 g, 120.0 mmol) were added. The mixture was bubbled with nitrogen for 15 min and refluxed for 12 h. After cooling, the reaction mixture was filtered through a silica pad and washed with toluene. The solvent was removed in vacuo and the residue was purified by flash chromatography using 30% toluene/hexane to afford N-([1,1′-biphenyl]-4-yl)-[1,1′-biphenyl]-2-amine (18.3 g, 95% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.Cl.[CH3:11][O:12][C:13]1[NH:17][N:16]=[C:15]([NH2:18])[CH:14]=1>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][C:15]2[CH:14]=[C:13]([O:12][CH3:11])[NH:17][N:16]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: COc1cc(N)n[nH]1
Agent: Cl
Solvent: CCO
Product: COc1cc(Nc2cc(Cl)nc(Cl)n2)n[nH]1
Temperature: 25 °C
Yield: 51 %

Procedure:
To a solution of 2,4,6-trichloro-pyrimidine (1.7 g) in absolute ethanol (100 mL) was added DIEPA (4.1 mL) and 5-methoxy-1H-pyrazol-3-amine hydrogen chloride salt (1.46 g). The resulting solution was stirred at room temperature for over night. The solvent was evaporated under reduced pressure. The crude compound was purified by Gilson (10-60% MeCN/H2O, 15 minutes) to give the titled compound as solid (1.23 g). 1H NMR δ 12.19 (s, 1H) 10.68 (s, 1H) 6.76 (s, 1H) 5.40 (s, 1H) 3.82 (s, 3H); m/z 260.
Reaction SMILES: [H+].[B-](F)(F)(F)F.CCOCC.[CH3:12][O:13][C:14](=[O:24])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.[Br:25]N1C(=O)CCC1=O.OS([O-])(=O)=O.[Na+]>C(#N)C>[CH3:12][O:13][C:14](=[O:24])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([Br:25])[CH:18]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: F[B-](F)(F)F
Agent: O=S(=O)([O-])O
Agent: [H+]
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)CCc1ccc(O)c(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Add HBF4-Et2O (4.4 mL, 27.7 mmol) to methyl-3-(4-hydroxyphenyl)-propionate (5.0 g, 27.7 mmol) in acetonitrile with stirring at 0° C. After 10 minutes, add N-bromosuccinimide (5.4 g, 30.5 mmol) and gradually allow to warm to room temperature. After 18 hours, pour into 38% NaHSO4 and extract with diethyl ether. Combine the organic extracts, wash with water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to provide the title compound.
Reaction SMILES: [CH:1]([O:6][CH3:7])([O:4][CH3:5])OC.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]([CH3:44])[C:34]2=[O:45])=[CH:29][C:28]=1C=O>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:41])([F:43])[F:42])[N:35]([CH3:44])[C:34]2=[O:45])=[CH:29][C:28]=1[CH:1]([O:4][CH3:5])[O:6][CH3:7]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=O)c2)c1=O
Reactant: COC(OC)OC
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(OC)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Reaction time: 0.5 h

Procedure:
170 ml of trimethyl orthoformate were added to a thoroughly stirred suspension of 136 g of montmorillonite K10 in 700 ml of anhydrous toluene, and stirring was carried out for 30 minutes. Thereafter, 68.0 g of 3-(4-chloro-3-formylphenyl)-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine were added dropwise while cooling with ice, and the batch was stirred overnight at 25° C. The montmorillonite K10 was filtered off and washed thoroughly with toluene. The solvent, excess ortho-ester and methyl formate were distilled off under reduced pressure from the combined filtrates. The remaining oil was crystallized with petroleum ether.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1.Cl[C:20]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:22][N:21]=1>C1(C)C=CC=CC=1>[C:26]1([C:24]2[C:23]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:22][N:21]=[C:20]([NH:7][C@H:8]3[CH2:9][CH2:10][C@H:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13]3)[N:25]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](N)CC1
Reactant: Clc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H]1CC[C@H](Nc2ncc(-c3ccccc3)c(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
550 mg (1.69 mmol) of cesium carbonate were added to a suspension of 175 mg (0.84 mmol) of ethyl trans-4-aminocyclohexanecarboxylate in 5 ml of toluene, and the mixture was stirred at room temperature. After 30 minutes, 150 mg (0.56 mmol) of 2-chloro-4,5-diphenyl-pyrimidine were added, and the mixture was stirred at 120° C. for 4 days. The solvent was removed in vacuo and the residue was partitioned between dichloromethane and water. The organic phase was dried and concentrated under high vacuum. An attempt was made to purify the residue on a silica gel column (heptane/isopropanol, gradient 100% to 5% in 15 minutes). A mixed fraction was obtained, and the product crystallized therefrom. The precipitate was filtered off with suction. 78 mg (34%) of the desired product were obtained in this way.
Reaction SMILES: [NH2:1][C@H:2]([C:12]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16](=[O:24])[C:15]2=[CH:25][CH:26]=[CH:27][N:14]2[N:13]=1)[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:28][C:29]1[C:34]([C:35]#[N:36])=[C:33](Cl)[N:32]=[CH:31][N:30]=1.C(N(CC)C(C)C)(C)C>>[NH2:28][C:29]1[C:34]([C:35]#[N:36])=[C:33]([NH:1][C@H:2]([C:12]2[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:16](=[O:24])[C:15]3=[CH:25][CH:26]=[CH:27][N:14]3[N:13]=2)[CH2:3][CH2:4][O:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:32]=[CH:31][N:30]=1
Reactant: N[C@@H](CCOc1ccccc1)c1nn2cccc2c(=O)n1-c1ccccc1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(N)ncnc1N[C@@H](CCOc1ccccc1)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 55 %

Procedure:
(S)-2-(1-Amino-3-phenoxypropyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one was treated with 4-amino-6-chloropyrimidine-5-carbonitrile (6 mg, 0.02 mmol) and N,N-diisopropylethylamine (16 μl, 0.09 mmol) according to the method described in Example 17. The residue was purified using SP1® Purification System (0% to 50%, dichloromethane-acetonitrile) to obtain 4 mg (55% yield) of the title compound as a yellow solid. Purity 89%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[S:11])[N:3]=1.[CH3:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24]>C(O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:16]([CH3:15])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH3:24])[N:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[S:11])[N:5]=1
Reactant: CCOC(=S)Cc1nc(Cl)cc(Cl)n1
Reactant: CNc1cccc(C)c1C
Solvent: CCO
Product: CCOC(=S)Cc1nc(Cl)cc(N(C)c2cccc(C)c2C)n1
Reaction time: 24 h

Procedure:
To a suspensione of ethyl 4,6-dichloro-2-pyrimidinylthioacetate (10.7 g) in ethanol (100 ml) anhydrous NaCO3 (4.66 g) and N-methyl-2,3-xylidine (6.2 g) are added; the mixture is refluxed under stirring for 24 hours.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[CH3:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34](O)=[O:35])=[N:32][CH:33]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:34]([C:31]3[CH:30]=[CH:29][C:28]([CH2:27][CH2:26][CH2:25][CH3:24])=[CH:33][N:32]=3)=[O:35])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: CCCCc1ccc(C(=O)O)nc1
Product: CCCCc1ccc(C(=O)NCCCCn2c(CCOC)nc3c(N)nc4ccccc4c32)nc1

Procedure:
According to the general method of Example 50, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine and fusaric acid were combined to provide N2-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-5-butyl-2-pyridinecarboxamide as a tan solid, m.p. 54.9-55.2° C. 1H NMR (300 MHz, DMSO-d6) δ 8.81 (t, J=6.1 Hz, 1H), 8.44 (m, 1H), 7.98 (d, J=7.3 Hz, 1H), 7.94 (dd, J=8.0, 0.7 Hz, 1H), 7.80 (dd, J=8.0, 2.2 Hz, 1H), 7.60 (dd, J=8.3, 1.2 Hz, 1H), 7.39-7.34 (m, 1H), 7.16-7.10 (m, 1H), 6.52 (broad s, 2H), 4.55 (t, J=6.9 Hz, 2H), 3.79 (t, J=6.7 Hz, 2H), 3.23 (s, 3H), 3.18 (t, J=6.7 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 1.83-1.72 (m, 4H), 1.63-1.53 (m, 2H), 1.34-1.24 (m, 2H), 0.90 (t, J=7.3 Hz, 3H); MS (EI) m/e 474.2750 (474.2743 calcd for C27H34N6O2).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:7]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:6]2[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)#[N:2].[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[NH4+]>CS(C)=O>[CH2:13]([C:8]1[C:7]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:6]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:1]3[N:33]=[N:34][NH:35][N:2]=3)[CH:4]=2)[N:9]=1)[CH:14]([CH3:15])[CH3:16]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(C#N)cc23)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(-c4nn[nH]n4)cc23)cc1
Temperature: 70 °C
Reaction time: 48 h
Yield: 57.4 %

Procedure:
A mixture of tert-butyl [6-cyano-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methylcarbamate (0.60 g, 1.4 mmol), sodium azide (0.18 g, 2.8 mmol), ammonium chloride (0.30 g, 3.6 mmol) and dimethyl sulfoxide (810 ml) was stirred at 70° C. for 2 days. The reaction mixture was partitioned between ethyl acetate and 0.1N hydrochloric acid. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from n-hexane-ethyl acetate to give tert-butyl [2-isobutyl-4-(4-methylphenyl)-6-(2H-tetrazol-5-yl)quinolin-3-yl]methylcarbamate (0.38 g, yield 57%) as a white powder.
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([N:10]2[C:15]3[CH:16]=[C:17]([C:20](O)=[O:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:2]=1.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:29]=1>>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][C:28]1[N:29]=[C:25]([NH:24][C:20]([C:17]2[CH:18]=[CH:19][C:14]3[O:13][CH2:12][CH2:11][N:10]([S:7]([C:3]4[CH:2]=[C:1]([CH3:23])[CH:6]=[CH:5][CH:4]=4)(=[O:8])=[O:9])[C:15]=3[CH:16]=2)=[O:21])[S:26][CH:27]=1)[CH3:35]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: Cc1cccc(S(=O)(=O)N2CCOc3ccc(C(=O)O)cc32)c1
Product: CCOC(=O)Cc1csc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(C)c2)CCO3)n1

Procedure:
The title compound, MS (ISP)=472.1 (M−H)−, was produced as described in example 1, steps 1-6. Step 3 was performed using 3-methylbenzenesulfonyl chloride, furnishing 4-(toluene-3-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, which was hydrolyzed in step 4, leading to 4-(toluene-3-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid. This was reacted with ethyl 2-amino-4-thiazoleacetate in step 5 and yielded (2-{[4-(toluene-3-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-acetic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:28]1[CH2:30][CH2:29]1)[O:5][C:6]1[CH:27]=[CH:26][C:9]2[C:10]3[N:14]([CH2:15][CH2:16][O:17][C:8]=2[CH:7]=1)[CH:13]=[C:12]([C:18]1[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=1)[N:11]=3.[NH3:32]>CO>[CH:28]1([CH:4]([O:5][C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH:13]=[C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)[N:11]=4)[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[C:3]([NH2:32])=[O:2])[CH2:29][CH2:30]1
Reactant: N
Reactant: COC(=O)C(Oc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2)C1CC1
Solvent: CO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(OC(C(N)=O)C3CC3)cc1OCC2
Yield: 50 %

Procedure:
A solution of cyclopropyl-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy]-acetic acid methyl ester (0.068 g, 0.16 mmol) and 7M ammonia in methanol (20 mL) was stirred at RT for 18 h then concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in ethyl acetate) to give 549 (0.033 g, 50%). LCMS: RT=3.52 min, [M+H]+=409. 1H NMR 400 MHz (DMSO-d6): δ 8.28 (1H, d, J=8.97 Hz), 7.89 (1H, d, J=0.64 Hz), 7.85 (1H, s), 7.54 (1H, s), 7.25 (1H, s), 6.73 (1H, dd, J=8.99, 2.59 Hz), 6.49 (1H, d, J=2.57 Hz), 5.89-5.88 (1H, m), 4.52-4.44 (4H, m), 3.97 (1H, d, J=8.20 Hz), 1.48 (3H, d, J=1.16 Hz), 1.46 (3H, d, J=1.16 Hz), 1.26-1.25 (1H, m), 0.61-0.54 (3H, m), 0.44-0.43 (1H, m)
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:15]([O:14][C:12]([N:10]1[CH2:11][CH:8]([C:3]2[C:2]([C:30]3[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2Cl)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2nccnc2C2CN(C(=O)OC(C)(C)C)C2)cc1
Yield: 96 %

Procedure:
To a solution of 3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (7) (100 mg, 0.37 mmol, as prepared in the above Preparation 2) in dioxane (8 mL) was added a solution of Na2CO3 (78 mg, 0.64 mmol) in 0.5 mL water, followed by additional of 4-methoxybenzeneboronic acid (20) (49 mg 0.40 mmol) and Pd(dppf)Cl2 (8 mg). The resulting mixture was heated to reflux overnight under N2 atmosphere. TLC showed that the starting material was consumed completely. The solution was filtered and the filtrate was concentrated to give the residue which was purified by column chromatography on silica gel to give the product compound (21) (120 mg, yield 96%) as solid. ESI-MS (M+1): 342 calc. for C19H23N3O3 341.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.[CH3:10][C:11]([S:14]([NH2:16])=[O:15])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1.[Cl-].[Na+].O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[N:16][S:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])[CH:5]=[N:6][CH:7]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)S(=O)N=Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-bromo-pyridine-3-carbaldehyde (2 g, 10.75 mmol), 2-methylpropane-2-sulfinamide (1.434 g, 11.83 mmol) and titanium(IV) isopropoxide (12.60 ml, 43.0 mmol) in toluene (53.8 ml) was stirred for 16 h at room temperature. Brine was added and the precipitate removed and washed with AcOEt. The organic layer was dried over MgSO4, filtered and concentrated to give the title compound that was used as is for the next step. LC-MS (M+1) 291.0.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:8](=[O:23])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=[O:5].C(N(CC)CC)C.[CH3:38][N:39]=[C:40]=[O:41]>O1CCCC1>[CH3:2][O:3][C:4]([C:6]1[N:7]([CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:40](=[O:41])[NH:39][CH3:38])[CH2:27][CH2:26]2)[C:8](=[O:23])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=[O:5]
Reactant: CN=C=O
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1CC1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)N1CCC(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 33 %

Procedure:
To a solution of 6-bromo-1-oxo-4-phenyl-2-(piperidin-4-ylmethyl)-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester hydrochloride (100 mg) in tetrahydrofuran (5 ml) were added triethylamine (0.06 ml) and methylisocyanate (0.018 ml), and the mixture was stirred at room temperature for 24 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative HPLC to give the title compound (34 mg, 33%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[O:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH3:37][O:38][C:39]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:40]=1[CH:41]=O>ClC(Cl)C>[CH3:37][O:38][C:39]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:40]=1[CH2:41][NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)=[O:11]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: COc1ccc(N)c(C(=O)c2cccc(F)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc(CNc2ccc(OC)cc2C(=O)c2cccc(F)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2-Amino-5-methoxyphenyl)(3-fluorophenyl)methanone (0.984 g, 4.01 mmol) in 15 mL of dichloroethane was added 4 Å powdered molecular sieves (1 g), followed by sodium triacetoxyborohydride (2.55 g, 12.0 mmol) and acetic acid (0.69 mL, 12.0 mmol). 2,4-Dimethoxybenzaldehyde was added (0.667 g, 4.01 mmol), and the reaction was stirred at room temperature for 3 hours. The reaction was partitioned between EtOAc and saturated NaHCO3 solution, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The titled product was isolated as a red oil (1.66 g) which was used in the next step without further purification. ESI+ MS: 396.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][CH2:20][C:21]([O:23]CC)=[O:22].Cl>[OH-].[Na+]>[C:21]([CH2:20][NH:19][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([C:8]([OH:17])([C:13]([F:15])([F:14])[F:16])[C:9]([F:10])([F:11])[F:12])=[CH:5][C:4]=1[CH3:18])([OH:23])=[O:22]
Reactant: CCOC(=O)CNc1c(C)cc(C(O)(C(F)(F)F)C(F)(F)F)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NCC(=O)O
Reaction time: 1 h

Procedure:
Dissolve ethyl N-[2,6-dimethyl-4-(hexafluoro-2-hydroxy-2-propyl)phenyl]glycinate (3.1 g, 8.3 mmol) in 25 ml 1.0 N NaOH. After 1 hour, add 25 ml 1.0 N HCl and extract with ethyl acetate. Dry and concentrate. Recrystallize from chloroform-benzene to give the title compound as beige solid, m.p. 153°-155° C. dec.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1Cl)=[O:11]>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[O:11])[CH2:9][CH:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:13][CH:14]=1
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)c1ccc(F)cc1Cl
Product: CCOC(=O)C(C#N)CC(=O)c1ccc(F)cc1

Procedure:
The compound of formula III, when n and p are equal to 1 and q is equal to 1, is prepared from ethyl cyanoacetate and 2-chloro-4-fluoroacetophenone. The ethyl 2-(4-fluorophenacyl)cyanoacetate thereby obtained is then reacted with anhydrous ethylene glycol to obtain 2-[2-(2-cyanoethoxycarbonyl) ethyl]-2-(4-fluorophenyl)-l,3-dioxolane. Hydrogenation of the latter compound leads to 2-[2-(2-aminomethylethoxycarbonyl)ethyl]-2-(4-fluorophenyl)- 1,3-dioxolane, which is reacted with methylmagnesium iodide to obtain 2 (4-fluorophenyl)-2-[(2-oxo-azetidin-3-yl) methyl]dioxolane. This compound is subjected to the action of lithium aluminum hydride to obtain the expected compound.
Reaction SMILES: C([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[NH:13][C:14]([CH3:23])=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[N:16]=2)=[C:7]([O:24][CH3:25])[CH:6]=1)(=O)C.O>Cl>[NH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[NH:13][C:14]([CH3:23])=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[N:16]=2)=[C:7]([O:24][CH3:25])[CH:6]=1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1-c1nc(-c2cccnc2)c(C)[nH]1
Agent: Cl
Solvent: O
Product: COc1cc(N)c(Cl)cc1-c1nc(-c2cccnc2)c(C)[nH]1
Yield: 71.4 %

Procedure:
A solution of 2-(4-acetamido-5-chloro-2-methoxyphenyl)-5-methyl-4-(3-pyridyl)imidazole (1.0 g) in 10% hydrochloric acid (30 ml) was stirred at 80° to 85° C. for 4 hours. The reaction mixture was poured into water (100 ml) and washed with ethyl acetate. The solution was adjusted to pH 8.0 with 20% potassium carbonate and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was crystallized from a mixture of ethyl acetate and diethyl ether to give 2-(4-amino-5-chloro-2-methoxyphenyl)-5-methyl-4-(3-pyridyl)imidazole (0.63 g).
Reaction SMILES: [F:1][C:2]1[C:12]([CH3:13])=[C:11](F)[C:10]([F:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N-:16]=[N+:17]=[N-:18].[Na+].C(OCC)(=O)C.O>CS(C)=O>[N:16]([C:11]1[C:10]([F:15])=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([F:1])[C:12]=1[CH3:13])=[N+:17]=[N-:18]
Reactant: CCOC(=O)c1cc(F)c(F)c(C)c1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(F)c(N=[N+]=[N-])c(C)c1F
Temperature: 55 °C
Reaction time: 14 h

Procedure:
In 308 ml of dimethyl sulfoxide was dissolved 61.7 g of ethyl 2,4,5-trifluoro-3-methylbenzoate, and 42.3 g of sodium azide was added to the solution, after which the resulting mixture was stirred at 55° C. for 14 hours. The reaction mixture was cooled to room temperature and thereafter added to a mixed solvent of 500 ml of ethyl acetate and 1200 ml of water. The organic layer formed was separated, washed with water and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure to obtain 65.3 g of pale yellow, oily ethyl 4-azido-2,5-difluoro-3-methylbenzoate.