Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([O:5][C:6]1[C:11](=[O:12])[N:10]([CH:13]([CH3:15])[CH3:14])[C:9](=[O:16])[N:8]2[CH:17]([CH2:30][CH2:31][NH:32][CH3:33])[CH2:18][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:20](=[O:21])[C:7]=12)(=O)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C.C[O-].[Na+].Cl.FC(F)(F)C(O)=O>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCOC(C)=O.CO>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:19]2[CH2:18][CH:17]([CH2:30][CH2:31][N:32]([CH3:33])[C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:8]3[C:9](=[O:16])[N:10]([CH:13]([CH3:14])[CH3:15])[C:11](=[O:12])[C:6]([OH:5])=[C:7]3[C:20]2=[O:21])=[CH:24][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNCCC1CN(Cc2ccc(F)cc2)C(=O)c2c(OC(C)=O)c(=O)n(C(C)C)c(=O)n21
Agent: CN(C)c1ccncc1
Agent: C[O-]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)n1c(=O)c(O)c2n(c1=O)C(CCN(C)C(=O)c1ccccc1)CN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-(4-Fluorobenzyl)-7-isopropyl-4-[2-(methylamino)ethyl]-1,6,8-trioxo-1,3,4,6,7,8-hexahydro-2H-pyrazino[1,2-c]pyrimidin-9-yl acetate hydrochloride (from Example 67, Step 2, 37 mg, 0.077 mmol) was suspended in CH2Cl2 and treated with benzoyl chloride (15 μL, 0.13 mmol), triethylamine (36 μL, 0.26 mmol) in CH2Cl2 (214 μL), and 4-dimethylaminopyridine (2.0 mg, 0.015 mmol) in CH2Cl2 (50 μL). The solution was stirred at ambient temperature for 18 h. The resulting material was suspended in EtOAc and filtered, washing with excess EtOAc. The filtrate was concentrated at 40° C. under a steady stream of nitrogen to yield a sticky solid which was dissolved in MeOH and treated with sodium methoxide in MeOH (25 wt %, 1.5 mL). The reaction was stirred for 30 min at ambient temperature and was then treated with aqueous HCl (1 M) and trifluoroacetic acid. The mixture was concentrated at 40° C. under a steady stream of nitrogen. The resulting residue was taken up in CH2Cl2, filtered, and concentrated. Purification of the remaining residue (dissolved in MeOH) by reverse phase chromatography [95:5 water (+0.1% TFA)/MeCN (+0.1% TFA) to 5:95 water (+0.1% TFA)/MeCN (+0.1% TFA)] afforded the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ 11.77 (br s, 1H), 7.47-7.30 (m, 5H), 7.29-7.22 (m, 3H), 4.41 (d, J=14.0 Hz, 1H), 3.93 (d, J=14.0 Hz, 1H), 3.77-3.73 (m, 1H), 3.65 (d, J=11.0 Hz, 1H), 2.98 (s, 3H), 2.77 (d, J=13.0 Hz, 1H), 1.87 (br s, 1H), 1.48 (d, J=6.0 Hz, 6H). HRMS (FT/ES) M+H: calcd for (C27H29FN4O5)+ 509.2195. found 509.2214.
Reaction SMILES: [OH-].[Na+:2].C([O:5][C:6](=[O:17])[CH2:7][C@@H:8]([CH2:13][N+:14]([O-:16])=[O:15])[CH2:9][CH:10]([CH3:12])[CH3:11])C>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Na+:2].[CH3:11][CH:10]([CH3:12])[CH2:9][C@H:8]([CH2:13][N+:14]([O-:16])=[O:15])[CH2:7][C:6]([O-:17])=[O:5]
Reactant: CCOC(=O)C[C@H](CC(C)C)C[N+](=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: CC(C)C[C@@H](CC(=O)[O-])C[N+](=O)[O-]

Procedure:
In a beaker 100 mg of EstC (lyophilized) were dissolved/suspended in 10 mL of potassium phosphate buffer (1 mM, pH 7.2). The pH drops to pH ˜6.8 and was adjusted to pH=7.4 with aqueous NaOH (0.1 M). Then 200 mg of 5-methyl-3-nitromethyl-hexanoic acid ethyl ester (VIII, R1=ethyl) were added and the pH was kept at 7.4 by continuous addition of aqueous NaOH (0.1M). After 45% conversion (corresponding to 4.0 mL of 0.1M NaOH consumption) the reaction was stopped by addition of 10 mL of ethyl acetate. The layers were separated and the aqueous layer was extracted once more with 10 mL of ethyl acetate. Then the aqueous layer was concentrated to give the title compound with an ee of 88%.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH3:21][C:22]1([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(OC)(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:25]3[CH2:26][CH2:27][C:22]([CH3:21])([OH:28])[CH2:23][CH2:24]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC1(O)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: COC(OC)OC
Product: Cn1c(CCN2CCC(C)(O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 16.8 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (200 mg, 0.68 mmol) in DCE (15 mL) was added 4-methylpiperidin-4-ol (117 mg, 1.01 mmol), trimethyl orthoformate (0.74 mL, 6.76 mmol) and acetic acid (0.04 mL, 0.68 mmol). The reaction mixture was stirred at room temperature for 1.5 h, sodium triacetoxyborohydride (187 mg, 1.35 mmol) was added and the resulting mixture stirred for a further 18 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by column chromatography (Si—PCC, 0-20% 2 M NH3/MeOH in DCM) to give the title compound as a colourless oil (45 mg, 17%). LCMS (Method H): RT=2.24 min, [M+H]+ 395.5
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]4[CH:22]=[N:23][N:24]([CH2:26][C@H:27]5[O:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]5)[CH:25]=4)[N:15]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Br-].[C:41]1([CH:47]([Zn+])[CH3:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1.C(OCC)(=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[C:41]1([CH:47]([C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]4[N:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]5[CH:22]=[N:23][N:24]([CH2:26][C@H:27]6[O:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]6)[CH:25]=5)[N:15]=4)[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH3:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC([Zn+])c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(N4CCN(c5ncc(Br)cn5)CC4)n3)cn2)C1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(c1ccccc1)c1cnc(N2CCN(c3ncnc(Nc4cnn(C[C@@H]5CN(C(=O)OC(C)(C)C)CCO5)c4)n3)CC2)nc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl 2-((4-(4-(4-(5-bromopyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (100 mg, 0.17 mmol) and Pd(Amphos)Cl2 (11.7 mg, 0.17 mmol) in THF (2 mL, dried) was dropwise added a solution of (1-phenylethyl)zinc(II) bromide in THF (7.0 mL, 0.5 M, 3.4 mmol). The reaction mixture was stirred at 70° C. for 1 hour under N2, then cooled to room temperature and diluted with ethyl acetate (50 mL). After filtration, the filtrate was concentrated to afford (2S)-tert-butyl 2-((4-(4-(4-(5-(1-phenylethyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate as a white solid (130 mg, crude), which was directly used in the next step without further purification. MS (ES+) C32H41N11O3 requires: 627, found: 628 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:15][CH:16]=2)[CH2:11][CH:10]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:15][CH:16]=2)[CH2:11][CH:10]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(NS(=O)(=O)c2ccccc2)Cc2cc(-c3ccccc3)ncc2N1Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(NC1Cc2cc(-c3ccccc3)ncc2N(Cc2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a suspension of 3I (80 mg, 0.17 mmol) in THF (1 mL) at RT under argon was added borane-tetrahydrofuran complex (0.85 mL, 0.85 mmol) dropwise. After the addition, the reaction became a clear solution. The reaction was allowed to stir at RT under argon for 1 h. After this time, no starting material was detected by LC-MS. MeOH (1 mL) was added carefully to the reaction and the reaction was stirred at RT for overnight. The solvent was concentrated. The resultant residue was partitioned between CH2Cl2 and saturated aqueous NaHCO3 (20 mL). The layers were separated. The aqueous layer was extracted with CH2Cl2 (20 mL×3). The combined organics were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. The resultant residue was purified by silica gel (10 g) column chromatography eluting with a gradient of EtOAc (0-60%) in hexane to give the title compound as a white foam (71 mg, 88%). LC/MS (method A): retention time=2.69 min, (M+H)+=456. 1H-NMR (CDCl3, 400 MHz): δ8.00 (s, 1H), 7.75-7.85 (m, 4H), 7.47-7.55 (m, 1H), 7.10-7.48 (m, 11H), 5.44 (d, J=8.2 Hz, 1H), 4.30 (dd, J1=90 Hz, J2=16.4 Hz, 2H), 3.80-3.90 (m, 1H), 3.35-3.45 (m, 1H), 3.10 (dd, J1=4.9 Hz, J2=1.8 Hz, 1H), 2.93 (dd, J1=16.7 Hz, J2=4.5Hz, 1H), 2.65 (dd, J1=4.9 Hz, J2=1.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][NH:39][CH2:40][C:41]#[CH:42]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:39]([CH3:38])[CH2:40][C:41]#[CH:42])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: C#CCNC
Product: C#CCN(C)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and methyl-prop-2-ynylamine according to conditions described in general procedure C. Mp: 116-117° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.58-1.61 (m, 6 H), 2.85 (m, 3 H), 3.27-3.30 (m, 5 H), 4.22 (s, 2 H), 6.30 (d, J=5.5 Hz, 1 H), 6.94-6.98 (m, 1 H), 7.15 (d, J=8.8 Hz, 1 H), 7.43 (d, J=8.0 Hz, 1H), 7.46 (s, 1 H), 7.55-7.60 (m, 3 H), 7.82-7.84 (m, 1 H), 7.98 (d, J=7.4 Hz, 1 H), 8.30 (d, J=5.5 Hz, 1 H), 10.44 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[OH-:15].[Na+].[Mn]([O-])(=O)(=O)=O.[K+].[OH2:23]>>[OH2:10].[O:12]=[C:7]1[NH:6][C:5]2[CH:13]=[CH:14][C:2]([C:1]([OH:23])=[O:15])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[NH:8]1
Reactant: [OH-]
Reactant: Cc1ccc2c(c1)S(=O)(=O)NC(=O)N2
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C1Nc2ccc(C(=O)O)cc2S(=O)(=O)N1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
7-Methyl-3-oxo-2,3-dihydro-4H-1,2,4-benzothiadiazine 1,1-dioxide (20 g) was suspended in hot water (2000 mL) and supplemented dropwise with a 10% aqueous solution of NaOH until complete dissolution. Potassium permanganate (60 g) was added portionwise and the reaction mixture was stirred for 3 h at 70° C. After cooling, the insoluble material was removed by filtration and the purple filtrate was treated with sodium hydrogen sulfite until complete discolouration of the excess of permanganate. The solution was treated with charcoal, filtered, and the filtrate was adjusted to pH 0 with 12N HCl. The resulting suspension was placed at +4° C. during 2 h and the crystalline precipitate was collected by filtration, washed with water and dried (yield: 14.5 g); m.p.: 305-308° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:13]=[CH:12][C:11]3[C:6](=[N:7][C:8](O)=[C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:10]=3)[N:5]2[N:21]=1.CN(C=O)C.O=S(Cl)[Cl:29]>C(Cl)(Cl)Cl>[Cl:29][C:8]1[N:7]=[C:6]2[C:11]([CH:12]=[N:13][C:4]3[N:5]2[N:21]=[C:2]([CH3:1])[CH:3]=3)=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc2ncc3nc(-c4ccccc4)c(O)nc3n2n1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1cc2ncc3nc(-c4ccccc4)c(Cl)nc3n2n1
Temperature: 70 °C

Procedure:
A 40 mL scintillation vial containing Compound (10-4) (220 mg, 0.8 mmol, 1 eq.), CHCl3 (12 mL), DMF (12 mg, 0.16 mmol, 2 eq.), and SOCl2 (0.56 g, 3.2 mmol, 4 eq.) was heated at 70° C. under nitrogen for 1.5 hours. Then the mixture was allowed to cool and the solvent was removed in vacuo. The residue was dissolved in CHCl3 (20 mL) and washed with saturated NaHCO3 (5 mL). The water solution was extracted with CHCl3 (2×5 mL). The combined organic phases were dried over MgSO4. After filtration and concentration, the residue was purified by silica gel chromatography using EtOAc and heptane as the mobile phases to furnish Compound (10-5) as a yellowish solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:27][O:28][CH2:29][C:30]([Cl:32])=[O:31].CS(C)=O>N1C=CC=CC=1>[ClH:32].[CH3:27][O:28][CH2:29][C:30]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]4)[CH2:20]3)=[O:18])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)=[O:31]
Reactant: COCC(=O)Cl
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: COCC(=O)Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1

Procedure:
A solution of 50 mg (0.13 mmol) of ((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) and 27.5 mg (0.25 mmol) of methoxyacetyl chloride in 1.0 ml of pyridine is stirred at room temperature for 18 h. The reaction mixture is mixed with 3 ml of DMSO and purified by preparative HPLC. The product fractions are concentrated, mixed with 5 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 16 mg (29.4% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[SH:9].N1C=CC=CC=1.[Cl:16][CH2:17][C:18](Cl)=[O:19]>C1C=CC=CC=1>[Cl:8][C:7]1[C:2]([NH:1][C:18](=[O:19])[CH2:17][Cl:16])=[C:3]([SH:9])[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1c(S)cccc1Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(CCl)Nc1c(S)cccc1Cl
Temperature: 25 °C
Yield: 84.5 %

Procedure:
2-Amino-3-chlorothiophenol (1.6 g) and pyridine (0.8 g) were dissolved in benzene (20 ml), and chloroacetyl chloride (1.2 g) was gradually added dropwise thereto at room temperature (25° C.) with stirring. After the addition was finished, the reaction mixture was stirred at room temperature for 30 minutes, and the solvent was removed under reduced pressure. The residue obtained was washed with water, dried and recrystallized from chloroform to obtain 2.0 g of 3-chloro-2-chloroacetylaminothiophenol (m.p. 186°-187° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]#[CH:12])=[CH:5][CH:4]=1.[F:13][C:14]([F:27])([F:26])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1I.C1C=CC=CC=1>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]#[C:12][C:16]2[CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:20][C:15]=2[C:14]([F:13])([F:26])[F:27])=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(C(F)(F)F)c(I)c1
Reactant: C#CC#Cc1ccc(OC)cc1
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc(C#CC#Cc2cc(C(F)(F)F)ccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 61.7 %

Procedure:
1100 mg of the 1-(4-methoxyphenyl)-1,3-butadiyne obtained and 2700 mg of 2,5-bis(trifluoromethyl) iodobenzene were then dissolved in 50 ml of triethylamine, and 50 mg of bis(triphenylphosphine)palladium (II) chloride and 14 mg of copper (I) chloride were then rapidly added to the reaction mixture. After the solution had been stirred at room temperature for 13 hours, 50 ml of benzene were added to the reaction mixture, and the precipitates produced were then filtered off. After the solvent had been evaporated, the residue was neutralized by 1N hydrochloric acid and subjected to extraction with 50 ml of benzene three times. The organic layer was dried over magnesium sulfate, and the solvent was then evaporated. The residue was purified by silica-gel column chromatography using hexane as an eluent to obtain 1600 mg of 1-(4-methoxyphenyl)-4-[2,5-bis(trifluoromethyl)phenyl]-1,3-butadiyne. This compound was a needle-like white crystal having a melting point of from 86° to 88° C.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH3:8][NH:9][CH3:10]>>[CH3:8][N:9]([CH3:10])[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[OH:7]
Reactant: CNC
Reactant: C1CCC2OC2C1
Product: CN(C)C1CCCCC1O
Reaction time: 8 h

Procedure:
A mixture of 50.0 g of cyclohexene oxide and 100 ml of 25 percent aqueous dimethylamine was heated with stirring at 145° in a small autoclave for 8 hours. While the mixture was being concentrated to dryness at 50° on a film evaporator, absolute ethanol was added periodically to aid in removal of water. The residue was distilled through a Nester-Faust spinning band column to give 53.0 g of 2-dimethylamino-1-cyclohexanol, b.p. 64.1 - 64.2/2.4 mm. The ir curve was consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]([P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])([F:12])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10]I.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:21]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][C:2]([P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])([F:12])[F:1])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOP(=O)(OCC)C(F)(F)CCOCCOCCI
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(F)(F)CCOCCOCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of diethyl 1,1-difluoro-3-(2-(2-iodoethoxy)ethoxy)propylphosphonate (1 eq) in DMF (0.5 M) was added sodium azide (3 eq). The reaction mixture was stirred at room temperature for 90 minutes. The mixture was diluted with ethyl acetate, and washed with water. The aqueous phases were back extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 10-50% EtOAc/Hex to give the product as a yellowish oil.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:32][CH:33]([F:35])[F:34])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[OH-].[Li+]>O1CCCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:36])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH2:17][CH3:18])[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](=[O:31])[C:27]([CH3:30])([CH3:28])[CH3:29])=[CH:24][CH:25]=1)=[C:8]2[O:32][CH:33]([F:35])[F:34]
Reactant: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(C(=O)C(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc2c(Cl)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(C(=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
A solution of {8-chloro-4-difluoromethoxy-3-[4-(2,2-dimethylpropionyl)benzyl]-2-ethylquinolin-5-yloxy}acetic acid methyl ester (0.071 g) in tetrahydrofuran (5.0 mL) was treated with 1.0 M aqueous lithium hydroxide solution (0.28 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated to low bulk under reduced pressure, acidified by the addition of 0.1 M aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and then concentrated under reduced pressure. Purification of the residue by preparative reverse-phase HPLC gave title compound as a yellow solid (0.040 g).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[NH2:4].[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([F:22])[C:20]=1[F:21])[C:15](Cl)=O.N>>[N:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:4]=[C:15]([C:14]3[CH:13]=[C:12]([F:11])[C:20]([F:21])=[C:19]([F:22])[CH:18]=3)[O:1][N:2]=2)=[CH:6][N:7]=1
Reactant: NC(=NO)c1ccnnc1
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1
Agent: N
Product: Fc1cc(-c2nc(-c3ccnnc3)no2)cc(F)c1F

Procedure:
The titled compound was prepared according to the procedure of Method D using the product of Example 83D and 3,4,5-trifluorobenzoyl chloride (Aldrich). 1H NMR (300 MHz, CD3OD) δ 8.04-8.16 (m, 2 H), 8.38 (dd, J=5.4, 2.2 Hz, 1 H), 9.46 (dd, J=5.4, 1.4 Hz, 1 H), 9.86 (dd, J=2.4, 1.2 Hz, 1 H) ppm; MS (DCI/NH3) m/z=279 (M+H)+.
Reaction SMILES: C[C@@H](NCCCC1C=CC=C(C(F)(F)F)C=1)C1C=CC=C2C=CC=CC=12.Cl.[F:28][C:29]([F:42])([F:41])[C:30]1[CH:31]=[C:32]([CH:38]=[CH:39][CH:40]=1)[CH:33]=[CH:34][C:35]([OH:37])=[O:36]>[OH-].[Pd+2].[OH-]>[F:28][C:29]([F:41])([F:42])[C:30]1[CH:31]=[C:32]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)C=Cc1cccc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: C[C@@H](NCCCc1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Agent: Cl
Product: O=C(O)CCc1cccc(C(F)(F)F)c1

Procedure:
Tetrahedron letters, (49), 13-15, (2008), discloses a synthetic sequence to Cinacalcet hydrochloride comprising reduction of 3-(trifluoromethyl)cinnamic acid in the presence of palladium hydroxide to obtain 3-(3-trifluoromethylphenyl)-propanoic acid, which is coupled with (R)-1-(1-naphthyl)ethylamine to the corresponding amide. The amide is then reduced in the presence of boron trifluoride-THF and sodium borohydride as reducing agents. After complete conversion, the resulting amine-borane complex is hydrolyzed by the addition of water and the crude Cinacalcet extracted into toluene is reacted with hydrochloric acid to give Cinacalcet hydrochloride, according to the following Scheme 5:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([OH:26])=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([NH:34][CH:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[O:26])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: CN1CCC(N)CC1
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.7 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (100 mg, 0.27 mmol) in DMF (2 mL) were added 1-methylpiperidin-4-amine (35 mg, 0.30 mmol), diisopropylethylamine (DIPEA) (105 μL, 0.60 mmol) and 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (125 mg, 0.33 mmol). The solution obtained was stirred at room temperature for 18 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by preparative HPLC yielding Compound 60 as a solid (22 mg).