Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>ClCCl>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:7][C:6]2[CH:8]=[CH:9][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[CH:20][CH:19]=1
Reactant: CSc1ccc(N)cc1
Reactant: Fc1ccc(CBr)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ccc(NCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.2 %

Procedure:
To 5.0 mL (40.19 mmol) of 4-(methylthio)aniline and 8.4 mL (60.28 mmol) triethylamine dissloved in 30 mL dichloromethane was added 5.0 mL (40.19 mmol) 4-fluorobenzyl bromide. The mixture was stirred at room temperature for 12 h, partitioned between dichloromethane and sat. aqueous ammonium chloride, dried over MgSO4 and concentrated. Purification by column chromatography, eluting with ethyl acetate/hexane, provided 3.10 g of 4-[(4-fluorobenzyl)amino]thioanisole, along with recovered starting material.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:33]1([C:39]2[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][CH:40]=2)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:36]1[CH2:37][CH2:38][N:33]([C:39]2[CH:40]=[CH:41][C:42]([C:43]#[N:44])=[CH:45][CH:46]=2)[CH2:34][CH2:35]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Product: N#Cc1ccc(N2CCN(C(=O)[C@@H]3C[C@H](NCc4ccc(F)cc4F)CN3Cc3ccccc3)CC2)cc1
Yield: 17 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 4-piperazine-1-yl benzonitrile instead of 2-piperazin-1-yl-benzonitrile, to the title compound (11.8 mg, 17%) as light yellow oil. MS m/e=516.5 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH2:16])=[O:5])[CH3:2].[F:17][C:18]1[CH:23]=[C:22]([Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:21]=[CH:20][C:19]=1OS(C(F)(F)F)(=O)=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:19]1[CH:20]=[CH:21][C:22]([Si:24]([CH3:26])([CH3:25])[CH3:27])=[CH:23][C:18]=1[F:17])=[O:5])[CH3:2]
Reactant: C[Si](C)(C)c1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1
Reactant: CCOC(=O)c1c(N)c2cnccc2n1C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(Nc2ccc([Si](C)(C)C)cc2F)c2cnccc2n1C
Yield: 85.1 %

Procedure:
3-Amino-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (25 g, 114 mmol), trifluoro-methanesulfonic acid 2-fluoro-4-trimethylsilanyl-phenyl ester (47.0 g, 149 mmol), Pd2(dba)3 (5.0 g, 5.5 mmol), Xantphos (6.5 g, 11.3 mmol) and cesium carbonate (74.5 g, 228 mmol) were suspended in toluene (500 mL) and the flask evacuated and purged with argon. The reaction mixture was heated at reflux for 18 hours. The mixture was cooled and filtered through Celite® washing through with toluene. The filtrate was evaporated in vacuo and the residue subjected to flash chromatography (SiO2, gradient 0-10% MeOH in DCM) to give the title compound (37.4 g, 85%) as a yellow solid. 1H NMR (CDCl3) 8.79 (1H, d, J=1.1 Hz), 8.39 (1H, d, J=6.1 Hz), 7.60 (1H, s, br), 7.25 (0.5H, s), 7.22 (1H, s), 7.21 (0.5H, d, J=1.0 Hz), 7.14-7.10, (2H, m), 4.42 (2H, q, J=7.0 Hz), 3.97 (3H, s), 1.44 (3H, t, J=7.0 Hz), 0.26 (9H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(N(CC)CC)C.[Cl:21][C:22]1[C:27]([C:28](Cl)=[O:29])=[C:26]([Cl:31])[N:25]=[CH:24][N:23]=1>O1CCCC1.ClCCl>[Cl:21][C:22]1[C:27]([C:28]([O:8][C:6]2[CH:5]=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=[C:2]([OH:1])[CH:7]=2)=[O:29])=[C:26]([Cl:31])[N:25]=[CH:24][N:23]=1
Reactant: CS(=O)(=O)Nc1cc(O)cc(O)c1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(O)cc(OC(=O)c2c(Cl)ncnc2Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.8 %

Procedure:
N-(3,5-Dihydroxyphenyl)methanesulfonamide (260 mg, 1.28 mmol) was dissolved in tetrahydrofuran (5 ml) and triethylamine (214 μl, 1.52 mmol) was added. Then a solution of 4,6-dichloropyrimidine-5-carbonyl chloride (298 mg, 1.40 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was dropwise added. The reaction mixture was stirred at room temperature over 48 hours. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. The product was purified by reverse phase using SP1® Purification System to give 280 mg (18% yield) of the title compound. Purity 100%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].[NH2:14][OH:15].O.CCOCC>CCO>[NH2:2][C:1](=[N:14][OH:15])[C:3]1[CH:4]=[CH:5][C:6]([F:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: NO
Reactant: COC(=O)c1cc(C#N)ccc1F
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: COC(=O)c1cc(C(N)=NO)ccc1F
Temperature: 25 °C
Yield: 98 %

Procedure:
To a suspension of methyl 5-cyano-2-fluorobenzoate, obtained in step 2 (804.60 mg; 4.49 mmol; 1 eq.) in EtOH (8.05 mL) was added hydroxylamine (50% in water) (1.35 mL; 22.46 mmol; 5 eq.). The reaction mixture was stirred at RT for 1 h40. Water (25 mL) was added followed by Et2O (25 mL). Aqueous layer was extracted with Et2O (2×25 mL). The combined organic layers were then washed with NaCl sat. solution and dried over magnesium sulfate, filtered and concentrated to afford the title compound as a yellow solid (931 mg; 98%). 1H NMR (DMSO-d6, 300 MHz) δ 9.78 (br s, 1H), 8.21 (dd, J=7.1, 2.4 Hz, 1H), 7.96-7.91 (m, 1H), 7.38 (dd, J=10.8, 8.8 Hz, 1H), 5.97 (br s, 2H), 3.87 (s, 3H). HPLC (Method A), Rt 0.92 min (purity: 90.6%). LC/MS (Method B): 211.1 (M−H)−; 213.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][OH:12])[CH2:3]1.CC1C(C)=NC=CC=1.[C:22](O)(=[O:24])[CH3:23]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][O:12][C:22](=[O:24])[CH3:23])[CH2:3]1
Reactant: CC1(C)CC(CO)c2ccccc21
Reactant: CC(=O)O
Agent: Cc1cccnc1C
Solvent: Cc1ccccc1
Product: CC(=O)OCC1CC(C)(C)c2ccccc21
Temperature: 30 °C
Reaction time: 5 h
Yield: 75.7 %

Procedure:
To a mixture of 12.3 g (70 mmol) of 1,1-dimethyl-3hydroxymethylindane (IX), 12.8 g of dimethylpyridine, and 20 ml of toluene, 8.6 g (84 mmol) of acetic acid was added dropwise over 10 minutes at room temperature. After the addition, the mixture was stirred for 5 hours at 30° C. to complete the reaction. After extraction with ether and removal of dimethylpyridine with 10% sulfuric acid, the residue was dried over anhydrous magnesium sulfate. The solvent was removed from the organic layer and the residue was distilled under reduced pressure to produce 11.6 g (53 mmol) of (1,1-dimethylindane-3-yl)methylacetate at a yield of 76%. The product was a colorless, transparent liquid having a woody, floral odor with a weak fruity sensation.
Reaction SMILES: OCCCN1C=C(C2C=CC(N[C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=C3C=2CN(C)C3=O)C=N1.[NH2:50][C:51]1[C:52]([C:67]([NH:69][CH3:70])=[O:68])=[N:53][C:54]([C:57]2[C:58]([Cl:66])=[N:59][N:60]([CH2:62][CH2:63][CH2:64][OH:65])[CH:61]=2)=[CH:55][CH:56]=1>>[Cl:66][C:58]1[C:57]([C:54]2[N:53]=[C:52]([C:67](=[O:68])[NH:69][CH3:70])[C:51]([NH:50][C:26]3[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:25]=3)=[CH:56][CH:55]=2)=[CH:61][N:60]([CH2:62][CH2:63][CH2:64][OH:65])[N:59]=1
Reactant: CNC(=O)c1nc(-c2cn(CCCO)nc2Cl)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cn(CCCO)nc4Cl)nc3C(=O)NC)n2)c(OC)c1)OCC
Yield: 59 %

Procedure:
Prepared analogously to Compound 1B using 3-amino-6-[3-chloro-1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-N-methylpyridine-2-carboxamide (Compound 49C, 365 mg, 1.18 mmol) to afford 480 mg of the title compound (59%). 1H NMR (400 MHz, CD3OD) δ 9.06 (br. s., 1H), 8.51 (s, 1H), 8.35 (s, 1H), 7.89 (d, J=9.1 Hz, 1H), 7.82 (d, J=8.1 Hz, 1H), 7.04 (t, J=2.0 Hz, 1H), 6.91 (td, J=2.3, 8.1 Hz, 1H), 4.26 (t, J=6.9 Hz, 2H), 4.00-4.11 (m, 4H), 3.89 (s, 3H), 3.59 (t, J=6.1 Hz, 2H), 3.35 (s, 1H), 3.23 (s, 1H), 2.98 (s, 3H), 2.11 (quin, J=6.5 Hz, 2H), 1.22-1.29 (m, 6H). MS (ESI): m/z=727.38/729.32 [M+H]+. UPLC: tR=1.35 min (UPLC-TOF: polar—2 min).
Reaction SMILES: O.[OH-].[Li+].O.C([O:7][C:8]([C:10]1[CH:11]=[N:12][N:13]([C:15]2[NH:24][C:23](=[O:25])[C:22]3[C:21]4[CH2:26][CH2:27][CH2:28][CH2:29][C:20]=4[CH:19]=[CH:18][C:17]=3[N:16]=2)[CH:14]=1)=[O:9])C>C1COCC1>[O:25]=[C:23]1[C:22]2[C:21]3[CH2:26][CH2:27][CH2:28][CH2:29][C:20]=3[CH:19]=[CH:18][C:17]=2[N:16]=[C:15]([N:13]2[CH:14]=[C:10]([C:8]([OH:9])=[O:7])[CH:11]=[N:12]2)[NH:24]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc4c(c3c(=O)[nH]2)CCCC4)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnn(-c2nc3ccc4c(c3c(=O)[nH]2)CCCC4)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85471152 %

Procedure:
Lithium hydroxide monohydrate (9.3 mg, 0.22 mmol) and water (0.19 mL) were added to 1-(1-oxo-1,2,7,8,9,10-hexahydro-benzo[f]quinazolin-3-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (25.0 mg, 73.9 pmol) in THF (0.28 mL). The reaction mixture was stirred at room temperature for 18 h and was then concentrated. The residue was redissolved in water (3 mL) and this solution was brought to pH 1 with 1M aqueous HCl. The resulting precipitate was collected and dried to yield the titled compound (19.6 mg, 85% yield). MS (ESI/Cl): mass calcd. for C16H14N4O3, 310.1; m/z found, 311.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.98 (s, 1H), 12.42 (s, 1H), 8.92 (s, 1H), 8.23 (s, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.41 (d, J=8.3 Hz, 1H), 3.37 (t, J=5.8 Hz, 2H), 2.83 (t, J=5.3 Hz, 2H), 1.84-1.67 (m, 4H).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.[Br:10]Br.O.[OH-].[Na+]>C(O)(=O)C>[Br:10][C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:1][N:2]=1
Reactant: BrBr
Reactant: c1cc2cn[nH]c2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Brc1n[nH]c2cnccc12
Yield: 66.7 %

Procedure:
1H-pyrazolo[3,4-c]pyridine (1 g), bromine (1.33 g), and water (40 mL) were stirred for 1 h. Basification with 20% sodium hydroxide solution, and adjustment to pH 7 by addition of acetic acid, yielded 3-Bromo-1H-pyrazolo[3,4-c]pyridine (1.1 g, 67%). ESI MS m/z=275 (M+1)
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1([CH3:14])[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13])([CH3:4])([CH3:3])[CH3:2].[OH-:15].[K+]>>[C:10]([NH:11][C@:7]([CH3:14])([C:8]([OH:15])=[O:13])[CH2:6][S:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:12])[NH2:9]
Reactant: CC(C)(C)SCC1(C)NC(=O)NC1=O
Reactant: [OH-]
Agent: [K+]
Product: CC(C)(C)SC[C@](C)(NC(N)=O)C(=O)O
Temperature: 95 °C
Reaction time: 22 h
Yield: 92 %

Procedure:
First, 5-tert-butylthiomethyl-5-methylhydantoin (5 g, 23 mmol) was mixed with a 58% aqueous potassium hydroxide solution (9.2 g), and the mixture was heated to 95° C. and stirred for 22 hours. The HPLC analysis of the reaction solution showed the production of the title compound in a reaction yield of 92%.
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12]([C:18]1[N:19]=[CH:20][N:21]2[CH:25]=[CH:24][S:23][C:22]=12)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].[CH2:26]([Sn:30](Cl)([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH3:29].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:12]([C:18]1[N:19]=[CH:20][N:21]2[CH:25]=[C:24]([Sn:30]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:26][CH2:27][CH2:28][CH3:29])[S:23][C:22]=12)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)c1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)C(C)(C)C)c2s1
Reaction time: 0.33 h

Procedure:
A 1.6 N n-butyllithium/n-hexane solution (2.9 ml) was added to a solution of 0.92 g of 7-pivaloylimidazo[5,1-b]thiazole in 20 ml of dry THF in an argon atmosphere at −50° C. The mixture was stirred at the same temperature for 20 min. Tri-n-butylstannyl chloride (1.3 ml) was added thereto, followed by stirring for 20 min. A saturated aqueous ammonium chloride solution was added to the reaction mixture. Ethyl acetate was added thereto. The mixture was washed with water and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:3) to give 0.82 g of the title compound.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].Br[C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:16])[CH:7]=1>O1CCCC1.[Zn+2].[Br-].[Br-].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]>[CH2:1]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:16])[CH:7]=1)[CH3:2]
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: CC[Mg+]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)OC)c(C)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a stirred mixture of ZnBr2 (4.50 g, 20.0 mmol, 2.00 equiv) in tetrahydrofuran (50 mL) under nitrogen at 0° C. was added EtMgBr (6.6 mL, 2.00 equiv, 3M in THF) dropwise. After stiffing for 30 min at 0° C., the temperature was lowered to −78° C. and Pd(dppf)Cl2 (1.08 g, 1.48 mmol, 0.30 equiv) was added followed by a solution of methyl 4-bromo-2-methylbenzoate (compound 152.1, 2.30 g, 10.0 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). The resulting mixture was stirred for 30 min at −78° C., warmed to room temperature, and stirred overnight. The reaction mixture was carefully quenched with 60 mL of NH4Cl (aq.) and extracted with 3×50 mL of ethyl acetate. The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:100-1:5) as eluent to furnish 1.50 g (84%) of methyl 4-ethyl-2-methylbenzoate as a brown oil.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([C@@H:9]2[CH2:12][C@H:11]([O:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10]2)[CH:8]=1)([O-])=O.CCN(CC)CC.[C:31]1([CH2:41][C:42](O)=[O:43])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>C(OCC)(=O)C.[Pd]>[C:31]1([CH2:41][C:42]([NH:1][C:4]2[N:5]=[CH:6][N:7]([C@H:9]3[CH2:12][C@H:11]([O:13][S:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)(=[O:16])=[O:15])[CH2:10]3)[CH:8]=2)=[O:43])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](n3cnc([N+](=O)[O-])c3)C2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@H](n3cnc(NC(=O)Cc4cccc5ccccc45)c3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
trans-Toluene-4-sulfonic acid 3-(4-nitro-imidazol-1-yl)-cyclobutyl ester (Preparation 4, Step 2; 590 mg, 1.75 mmol) was mixed with 10% Pd on carbon (500 mg) in ethyl acetate (30 mL). The mixture was then reacted under 50 psi H2 at room temperature for 6 h. The mixture was filtered through celite into a flame-dried flask which was kept under a nitrogen atmosphere. Et3N (1.22 mL, 8.75 mmol) was added followed by 1-naphthylacetic acid (326 mg, 1.75 mmol) and tripropylphosphonic anhydride (1.1 mL, 1.7 M solution in ethyl acetate, 1.75 mmol). The mixture was stirred at room temperature for 1 h and was then diluted with ethyl acetate and was washed with water and brine. The organic layer was dried (MgSO4), was filtered, and was concentrated in vacuo The resulting residue was purified by silica gel chromatography (50:1 chloroform-methanol) to afford 600 mg (72% yield) of trans-toluene-4-sulfonic acid 3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl ester; 1H NMR (400 MHz, CDCl3) δ7.9 (m, 2H), 7.85 (m, 2H), 7.76 (d, J 8.3 Hz, 2H), 7.48 (m, 2H), 7.42 (m, 2H), 7.33 (m, 2H), 7.04 (s, 1H), 4.96 (m, 1H), 4.73 (m, 1H), 2.7 (m, 4H), 2.44 (s, 3H); MS (AP/Cl): 476.2 (M+H)+.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][C:2]=1[C:15]([OH:17])=O.Cl.Cl.[NH2:20][CH:21]1[CH:26]2[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]2)[CH2:22]1>>[N:23]12[CH2:28][CH2:27][CH:26]([CH2:25][CH2:24]1)[CH:21]([NH:20][C:15]([C:2]1[CH:3]=[CH:4][C:5]3[C:14](=[N:13][C:12]4[C:7]([N:6]=3)=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:1]=1)=[O:17])[CH2:22]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(O)c1ccc2nc3ccccc3nc2c1
Agent: Cl
Product: O=C(NC1CN2CCC1CC2)c1ccc2nc3ccccc3nc2c1
Yield: 25.2 %

Procedure:
Prepared in analogy to the method for Example 1 starting from 236 mg of phenazine-2-carboxylic acid and 200 mg of 3-aminoquinuclidine dihydrochloride. 84 mg (25% yield) of the free base were obtained after chromatographic separation.
Reaction SMILES: [F-:1].[Cs+].F.[K].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:18])([CH3:17])[C:13]#[C:14][C:15]#[N:16])=[CH:8][CH:7]=1.C(OCC)(=O)C.CCCCCC>CN(C)C=O.O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([CH3:18])([CH3:17])[C:13]([F:1])=[CH:14][C:15]#[N:16])=[CH:10][CH:11]=1
Reactant: CC(C)(C#CC#N)c1ccc(Cl)cc1
Reactant: [F-]
Agent: F
Agent: [Cs+]
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C(F)=CC#N)c1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 76.6 %

Procedure:
A mixture of cesium fluoride (41.38 g, 0.272 mol), potassium hydrogen fluoride (10.64 g, 0.136 mol) and water (13.07 g, 0.726 mol) in N,N-dimethylformamide is stirred for 10 minutes, treated with a solution of 4-(p-chlorophenyl)-4-methyl-2-pentynenitrile (18.5 g, 0.091 mol) in N,N-dimethylformamide, stirred at 80-85° C. for 4 hours, stirred at room temperature overnight and diluted with water. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Column chromatography of the residue using silica gel and a 1:9 ethyl acetate/hexane solution gives the title product as an oil (15.6 g, 76.8% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:20](=[O:21])[C:19]3[N:11]([C:12]4[C@H:13]5[CH2:22][C@@H:16]([C:17]=4[CH:18]=3)[CH2:15][CH2:14]5)[CH2:10][CH2:9]2)[C:3]=1[CH:23]=[O:24].[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:51]=[C:45]3[CH2:46][N:47]([CH3:50])[CH2:48][CH2:49][N:44]3[N:43]=2)[C:27]1=[O:52].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Pd].O.C(#N)C>[CH3:25][N:26]1[C:27](=[O:52])[C:28]([NH:41][C:42]2[CH:51]=[C:45]3[CH2:46][N:47]([CH3:50])[CH2:48][CH2:49][N:44]3[N:43]=2)=[CH:29][C:30]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N:8]3[C:20](=[O:21])[C:19]4[N:11]([C:12]5[C@H:13]6[CH2:22][C@@H:16]([C:17]=5[CH:18]=4)[CH2:15][CH2:14]6)[CH2:10][CH2:9]3)[C:3]=2[CH:23]=[O:24])=[CH:31]1
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c(cc3c2[C@@H]2CC[C@H]3C2)C1=O
Reactant: CN1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6[C@@H]6CC[C@H]7C6)C5=O)c4C=O)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 58.8 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 170b (150 mg, 0.44 mmol), 1-methyl-3-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-5-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 135a (169 mg, 0.44 mmol), sodium acetate (72 mg, 0.88 mmol), K3PO4 (234 mg, 0.88 mmol), Pd (dppf) Cl2 (36 mg, 0.044 mmol), acetonitrile (20 mL), and water (1 mL). After bubbling nitrogen through the reaction mixture for 30 minutes, it was heated at 100° C. for 3 hours. The reaction mixture was evaporated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 170c (146 mg, 52%) as a brown solid. MS-ESI: [M+H]+ 565.3
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18](Cl)[N:17]=[C:16]([CH:30]3[CH2:32][CH2:31]3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[NH2:33][CH2:34][CH2:35][OH:36]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:18]([O:36][CH2:35][CH2:34][NH2:33])[N:17]=[C:16]([CH:30]3[CH2:32][CH2:31]3)[N:15]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccccc1Oc1c(Cl)nc(C2CC2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1
Reactant: NCCO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(C2CC2)nc1OCCN

Procedure:
According to the procedure described in Example 4b) 5-i-propyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide was reacted with 2-aminoethanol to give 950 mg 5-i-propyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide. LC-MS: tR=3.66 min, [M−1]−=498.37.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:19][CH3:20])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[C:6]([C@H:9]2[CH2:11][O:10]2)[C:7]=1[F:8].[CH3:21][C:22]([NH2:33])([CH3:32])[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[CH3:32][C:22]([NH:33][CH2:11][C@H:9]([C:6]1[CH:5]=[C:4]([CH:12]([CH2:19][CH3:20])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:3]=[C:2]([F:1])[C:7]=1[F:8])[OH:10])([CH3:21])[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(N)CCCc1ccccc1
Reactant: CCOC(=O)CC(CC)c1cc(F)c(F)c([C@H]2CO2)c1
Solvent: CCO
Product: CCOC(=O)CC(CC)c1cc(F)c(F)c([C@H](O)CNC(C)(C)CCCc2ccccc2)c1
Yield: 68.6 %

Procedure:
Ethyl 3-{3,4-difluoro-5-[(2S)-2-oxiranyl]phenyl}pentanoate (8.56 g, 0.0301 mol) and (1,1-dimethyl-4-phenylbutyl)amine (5.39 g, 0.0304 mol) in ethanol (50 mL) was heated at 70° C. overnight. The reaction was concentrated and purified by column chromatography (0-40% ethyl acetate:hexane) yield the desired product (9.53 g, 69%). MS (m/z): 434.2 (M+H).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[OH:27][C:28]([CH3:33])([CH3:32])[C:29](N)=[O:30]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:29](=[O:30])[C:28]([OH:27])([CH3:33])[CH3:32])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CC(C)(O)C(N)=O
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: CC(C)(O)C(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, white solid (65 mg, 63%), MS (ISP) m/z=413.4 [(M+H)+], mp 169° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 2-hydroxy-2-methyl-propionamide.