Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][C:12]2[CH:16]=[C:15]([CH:17]3[CH2:19][CH2:18]3)[NH:14][N:13]=2)=[N:4][C:5]([C:8](=[S:10])[NH2:9])=[N:6][CH:7]=1.Cl[CH:21]([C:25](=O)[CH3:26])[C:22](=[O:24])[CH3:23].CCN(CC)CC>CCO>[Cl:1][C:2]1[C:3]([NH:11][C:12]2[CH:16]=[C:15]([CH:17]3[CH2:18][CH2:19]3)[NH:14][N:13]=2)=[N:4][C:5]([C:8]2[S:10][C:21]([C:22](=[O:24])[CH3:23])=[C:25]([CH3:26])[N:9]=2)=[N:6][CH:7]=1
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: NC(=S)c1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)c1sc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)nc1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 19.5 %

Procedure:
A mixture of crude 5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-2-carbothioamide (1.2 g, 4.1 mmol), 3-chloropentane-2,4-dione (548 mg, 4.1 mmol, 1.0 eq) and Et3N (1.0 mL) in EtOH (30 mL) was stirred at 80° C. for 2 h, then, concentrated. The residue was recrystallized with EtOH to produce 1-(2-(5-Chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)-4-methylthiazol-5-yl)ethanone (Compound 297) (300 mg, 20%). LC-MS (m/z)=375.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.67-0.80 (m, 2H), 0.92-1.05 (m, 2H), 1.91-1.97 (m, 1H), 2.60 (s, 3H), 2.73 (s, 3H), 6.60 (s, 1H), 8.54 (s, 1H), 9.69 (s, 1H), 12.37 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[C:20]([F:32])[CH:19]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([S:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:8])=[C:20]([F:32])[CH:19]=1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Fc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1NSN1CCOCC1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)N(SN1CCOCC1)c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F)c1c(F)cccc1F
Reaction time: 2 h
Yield: 58.2 %

Procedure:
2,6-Difluorobenzoyl isocyanate (1.4 g) in a 1:1 (v/v) mixture of toluene and petroleum ether (10 ml) was added to a solution of the compound produced by Example 6 (3 g) in the same solvent (15 ml), at ambient temperature. The solution was stirred for two hours and placed in a freezer overnight (-5° to 0° C.). The solvent was removed by evaporation, and the residue was chromatographed twice on silica, firstly using dichloromethane as eluant and secondly using a 1:1 (v/v) mixture of diethyl ether and petroleum ether, to yield the title compound (2.5 g), m.p. 77°-80° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl>[OH:59][C:52]1[C:51]([CH2:50][NH:49][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([CH3:1])[CH:3]=2)=[C:56]([CH3:57])[CH:55]=[C:54]([CH3:58])[N:53]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1cc(C(=O)O)ccc1Oc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3ccccc3)c(C)c2)c(O)n1
Temperature: 25 °C
Yield: 27.6 %

Procedure:
A mixture of 3-methyl-4-phenoxybenzoic acid (114 mg, 0.5 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (285 mg, 0.75 mmol), triethylamine (0.2 mL) and dichloromethane (15 mL) were stirred at 25° C. for half an hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added. The mixture was stirred at 25° C. for 12 hours. The mixture was washed with water (30 mL). The organic phase was separated, dried over sodium, filtered, concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-3-methyl-4-phenoxybenzamide as a white solid (50 mg, 28%). LRMS (M+H+) m/z: calcd 362.16. found 362. HPLC purity (214 nm): 95%. 1H NMR (300 MHz, d6-DMSO): δ 11.47 (s, 1H), 8.24 (t, J=4.8 Hz, 1H), 8.83 (s, 1H), 7.68 (dd, J=9.6 Hz, J=2.1 Hz, 1H), 7.41-7.35 (m, 2H), 7.13 (t, J=7.5 Hz, 1H), 6.96-6.93 (m, 2H), 6.82 (d, J=8.4 Hz, 1H), 5.80 (s, 1H), 4.29 (d, J=4.8 Hz, 2H), 2.21 (s, 3H), 2.16 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:10]1[N:15]2[N:16]=[C:17]([NH2:19])[N:18]=[C:14]2[CH:13]=[C:12]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:11]=1>>[CH:3]1([N:2]([CH3:1])[C:10]2[N:15]3[N:16]=[C:17]([NH2:19])[N:18]=[C:14]3[CH:13]=[C:12]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Nc1nc2cc(-c3cccnc3)cc(Cl)n2n1
Reactant: CNC1CCCCC1
Product: CN(c1cc(-c2cccnc2)cc2nc(N)nn12)C1CCCCC1

Procedure:
A mixture of N-methyl-cyclohexylamine (4 mL) and 5-chloro-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine, which may be produced as in Example 1A, (300 mg, 1.22 mmol) was microwaved at 200° C. for 3 h. On cooling, the product was triturated with toluene/cyclohexane then taken up in CH2Cl2 and washed with aqueous Na2CO3. The organic layer was separated, dried (MgSO4), and concentrated to produce N5-cyclohexyl-N5-methyl-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine. MS m/z 323 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.[N+:9]([O-])([OH:11])=[O:10]>OS(O)(=O)=O>[OH:1][C:2]1[C:7]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccnc(O)c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(O)ccnc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
Following the general procedure of Norman (Norman, M. H., et al, J. Med. Chem., 2000, 43, 4288), 2,4-dihydroxypyridine (4.931 g, 44.4 mmol) and H2SO4 (20 mL) were combined and cooled to 0° C. HNO3 (20 mL, 44.4 mmol) was added dropwise. The sample was stirred for 30 minutes then poured onto ice. The resulting solid was stored at 4° C. for 1 hour then vacuum filtered to give 2,4-dihydroxy-3-nitropyridine (5.143 g, 32.9 mmol, 74%).
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)[C:6]([NH:8][C:9]1[CH:21]=[CH:20][C:12]([CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[CH3:1][Si:2]([CH3:30])([CH3:29])[C:3]1[CH:4]=[C:5]([C:6]([NH:8][C:9]2[CH:21]=[CH:20][C:12]([CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)=[S:40])[CH:22]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc(NC(=S)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1
Yield: 149.8 %

Procedure:
Compound 17a (293 mg) was dissolved in toluene (8.34 ml), and Lawesson's reagent (189 mg) was added thereto in a nitrogen atmosphere. The obtained mixture was stirred while refluxing under heating for 2 hours. The solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (10% ethyl acetate/n-hexane) to obtain Compound 17b (319 mg, 76%) as a yellow foam material.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([CH3:13])[CH:8]([CH3:14])[N:7]([CH:15]3[CH2:17][CH2:16]3)[C:6]=2[N:18]=1.I[CH3:20].[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:20])[C:10](=[O:12])[CH:9]([CH3:13])[CH:8]([CH3:14])[N:7]([CH:15]3[CH2:16][CH2:17]3)[C:6]=2[N:18]=1
Reactant: CI
Reactant: CC1C(=O)Nc2cnc(Cl)nc2N(C2CC2)C1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC1C(=O)N(C)c2cnc(Cl)nc2N(C2CC2)C1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a mixture of 0.266 g (0.001 mole) of (rac)-2-chloro-9-cyclopropyl-7,8-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-46) and 0.093 mL (0.0015 mole) of iodomethane at 0 degrees was added 0.06 g (0.0015 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.25 g of (rac)-2-chloro-9-cyclopropyl-5,7,8-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-46) as an yellow solid.
Reaction SMILES: Cl.[O:2]1[C@:14]2([CH3:20])[C@@:15]34[CH2:17][CH2:18][NH:19][C@@H:9]([C@:10]3([O:22][CH2:23][CH2:24][CH3:25])[CH2:11][CH2:12][C:13]2=[O:21])[CH2:8][C:7]2=[C:16]4[C:3]1=[C:4]([O:26][CH3:27])[CH:5]=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].[CH:34]1([CH2:37][Cl:38])[CH2:36][CH2:35]1>CN(C)C=O>[ClH:38].[CH:34]1([CH2:37][N:19]2[CH2:18][CH2:17][C@:15]34[C:16]5[C:3]6[O:2][C@@:14]3([CH3:20])[C:13](=[O:21])[CH2:12][CH2:11][C@@:10]4([O:22][CH2:23][CH2:24][CH3:25])[C@H:9]2[CH2:8][C:7]=5[CH:6]=[CH:5][C:4]=6[O:26][CH3:27])[CH2:36][CH2:35]1
Reactant: CCCO[C@@]12CCC(=O)[C@]3(C)Oc4c(OC)ccc5c4[C@@]31CCN[C@@H]2C5
Reactant: ClCC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCO[C@@]12CCC(=O)[C@]3(C)Oc4c(OC)ccc5c4[C@@]31CCN(CC1CC1)[C@@H]2C5
Temperature: 85 °C
Reaction time: 36 h
Yield: 55.4 %

Procedure:
A mixture of 4,5α-epoxy-3-methoxy-5-methyl-14-n-propyloxymorphinan-6-one hydrochloride (compound 12 of Example 7) (1.46 g, 3.71 mmol), potassium carbonate (2.24 g, 16.24 mmol), cyclopropylmethyl chloride (0.43 ml, 4.44 mmol), and 15 ml of anhydrous N,N-dimethyl formamide was stirred at 85° C. (bath temperature) for 36 h. The inorganic solid was filtered off and the filtrate evaporated. A solution of the residue in 30 ml of CH2Cl2 was washed with H2O (3×30 ml), dried over Na2SO4 and evaporated. The residue (1,69 g orange-yellow oil) was dissolved in diethyl ether and treated with ethereal HCl to give 920 mg (55%) of 17-(cydopropylmethyl)-4,5α-epoxy-3-methoxy-5-methyl-14-n-propyloxymorphinan-6-one hydrochloride (compound 16) as colorless powder. M.p. 156-158° C. IR (KBr): 3400 (+NH), 1723 (CO) cm-1. CI-MS: m/z 412 (M+ +1). 1H-MR (DMSO-d6): δ 8.57 (s, +NH), 6,85 (d, J=8.2 Hz, 1 arom. H), 6.75 (d, J=8.2 Hz, 1 rom. H), 3.79 (s, OCH3), 1.51 (s, CH3 --C(5)), 0.97 (t, J=7.4 Hz, CH3). Analysis calculated for C25H33NO4HCl. 0.6 H2O(458.81): C 65.45, H 7.73, N 3.05, Cl 7.73; found: C 65.45, H 7.85, N 3.08, Cl 7.84.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]1([C:14]2[N:15]=[CH:16][N:17]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:18]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][N:20]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[C:8]1([C:14]2[N:15]=[CH:16][N:17]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:18]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][N:20]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccccc3)c2-c2ccncn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(-c2ncn(C3CCNCC3)c2-c2ccncn2)cc1
Reaction time: 2 h
Yield: 52.3 %

Procedure:
TFA (2 mL) was added to a solution of tert-butyl 4-(4-phenyl-5-pyrimidin-4-yl-1H-imidazol-1-yl)piperidine-1-carboxylate (C22) (267 mg, 0.658 mmol) in dichloromethane (5 mL). After 2 hours, the reaction was concentrated in vacuo, and then treated with saturated aqueous sodium bicarbonate solution. The mixture was extracted with warm ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting light yellow oil solidified over the course of several days to provide 105 mg of product that was contaminated with approximately 20% of a related impurity. Fine white needles precipitated out of the aqueous layer; these were collected by filtration to provide additional product as a cream colored solid. Yield from aqueous layer: 54 mg, 0.18 mmol, 27%. 1H NMR (400 MHz, CDCl3) δ 1.83-1.93 (m, 2H), 2.12-2.18 (m, 2H), 2.72 (ddd, J=12.3, 12.3, 2.3 Hz, 2H), 3.20-3.25 (m, 2H), 4.85 (tt, J=12.0, 4.0 Hz, 1H), 7.19 (dd, J=5.3, 1.5 Hz, 1H), 7.30-7.36 (m, 3H), 7.42-7.45 (m, 2H), 7.85 (s, 1H), 8.54 (d, J=5.4 Hz, 1H), 9.30 (d, J=1.4 Hz, 1H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[NH:18][C:19]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)=[C:20]([C:24]#[N:25])[C:21](=O)[CH:22]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:41])=O>CN(C)C=O>[CH2:1]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[C:21]([Cl:41])[C:20]([C:24]#[N:25])=[C:19]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)[N:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)[nH]c(C2CCCN(C(=O)NCc3ccccc3)C2)cc1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1c(Cl)cc(C2CCCN(C(=O)NCc3ccccc3)C2)nc1-c1ccc(Oc2ccccc2)cc1
Yield: 82.9 %

Procedure:
A solution of N-benzyl-3-(5-cyano-4-oxo-6-(4-phenoxyphenyl)-1,4-dihydropyridin-2-yl)piperidine-1-carboxamide (167.9 mg, 0.333 mmol) and phosphorus oxychloride (0.093 mL, 0.998 mmol) in N,N-dimethylformamide (1 mL) was heated to 90° C. in a sealed tube for 50 min. The mixture was concentrated. The residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate and concentrated. Silica gel chromatography, eluting with 0-50% ethyl acetate in hexanes, gave N-benzyl-3-(4-chloro-5-cyano-6-(4-phenoxyphenyl)pyridin-2-yl)piperidine-1-carboxamide as white solid (144.4 mg, 83% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.92 (2H, δ, J=8.53 Hz), 7.28-7.46 (8H, m), 7.19 (1H, t, J=7.40 Hz), 7.06-7.14 (4H, m), 5.15 (2H, s), 4.36 (1H, hr. s), 4.12-4.25 (1H, m), 3.16 (1H, br. s), 2.92 (2H, br. s), 2.07 (1H, br. s), 1.84 (2H, hr. s), 1.58-1.70 (1H, m); MS (ES+) m/z: 524 (M+H); LC retention time: 4.330 min (analytical HPLC Method A).
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([O:5][C:6](=[O:37])[NH:7][C@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[N:19]=[N:20][N:21]([CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)[CH:22]=3)[CH:16]=2)[N:11]([C:33](=[O:35])[CH3:34])[C@@H:10]([CH3:36])[CH2:9]1)[CH3:4].CCOCC>O1CCOCC1>[ClH:1].[C:33]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([C:18]3[N:19]=[N:20][N:21]([CH2:23][CH2:24][NH2:25])[CH:22]=3)=[CH:14][CH:13]=2)[C@H:8]([NH:7][C:6](=[O:37])[O:5][CH:3]([CH3:2])[CH3:4])[CH2:9][C@@H:10]1[CH3:36])(=[O:35])[CH3:34]
Reactant: CC(=O)N1c2ccc(-c3cn(CCNC(=O)OC(C)(C)C)nn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3cn(CCN)nn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
HCl (4M in 1,4-dioxane, 2 mL, 8 mmol) was added to a solution of 1-methylethyl((2S,4R)-1-acetyl-6-{1-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-1H-1,2,3-triazol-4-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation, see intermediate 77) (108 mg, 0.22 mmol) in 1,4-dioxane (0.5 mL). The mixture was stirred at room temperature for 16 h. Et2O (5 mL) was added and the mixture stirred for 1 h. The solid formed was filtered off, washed with Et2O and dried under house vacuum to give 1-methylethyl {(2S,4R)-1-acetyl-6-[1-(2-aminoethyl)-1H-1,2,3-triazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate hydrochloride (75 mg, 0.172 mmol, 80%) as a colourless solid. LCMS (method G): Retention time 0.55 min, [M+H]+=401.1
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[CH3:8])=[CH:4][F:5].S(=O)(=O)(O)[OH:16]>O>[F:5][CH2:4][C:3]([OH:16])([C:6]([F:11])([F:12])[C:7]([F:10])([F:9])[CH3:8])[C:2]([F:13])([F:14])[F:1]
Reactant: CC(F)(F)C(F)(F)C(=CF)C(F)(F)F
Reactant: O=S(=O)(O)O
Solvent: O
Product: CC(F)(F)C(F)(F)C(O)(CF)C(F)(F)F

Procedure:
As another example, 2-fluoromethyl-1,1,1,3,3,4,4-heptafluoro-2-pentanol may be prepared by fluorinating commercially available 2,3-pentanedione to form 2,2,3,3-tetrafluoropentane which may then be dehydrogenated to form 3,3,4,4-tetrafluoro-1-pentene. CF3 may then be added to the 3,3,4,4-tetrafluoro-1-pentene to form 2-trifluoromethyl-1,3,3,4,4-pentafluoropentane which may then be dehydrogenated to form 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-pentene. The 2-trifluoromethyl-1,3,3,4,4-pentafluoro-1-pentene may then be reacted with sulfuric acid and then water to form 2-fluoromethyl-1,1,1,3,3,4,4-heptafluoro-2-pentanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:14][C:15]([CH:17]3[N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22][C:19]4([CH2:21][CH2:20]4)[CH2:18]3)=[O:16])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:4].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[CH2:20]1[C:19]2([CH2:22][CH2:23][NH:24][CH:17]([C:15]([NH:14][C:11]3([C:8]4[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=4)[CH2:12][CH2:13]3)=[O:16])[CH2:18]2)[CH2:21]1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC4(CCN3C(=O)OC(C)(C)C)CC4)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(C2(NC(=O)C3CC4(CCN3)CC4)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-butyl 5-((1-(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate (D55) (19.7 g) was dissolved in DCM (220 ml) before adding TFA (35 ml). The reaction was stirred at RT for 18 hrs. After solvent evaporation the title compound (D89) (27 g) was isolated.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1([NH:17][C:18]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[NH:27][CH:28]2[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:30]2[CH2:31][CH2:32][CH2:33][C@H:28]([NH:27][C@@H:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C@H:21]3[NH:20][C:18]([NH:17][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:19])[CH2:29]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1NC1CCCNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2ccc([N+](=O)[O-])cc2)C1
Yield: 13.6 %

Procedure:
1-((1R,2R)-2-((S)-1-(4-Nitrophenyl)piperidin-3-ylamino)cyclohexyl)-3-phenylurea (15 mg) was synthesized in 13% yield using the procedures as described in General Procedure A using 1-fluoro-4-nitrobenzene (39.2 mg, 0.278 mmol) and 1-phenyl-3-((1R,2R)-2-(piperidin-3-ylamino)cyclohexyl)urea (80 mg, 0.253 mmol). Anal. Calcd. for C24H31N5O3 m/z 437.5, found: 438.4 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 9.12 (s, 1H), 7.66 (d, J=8.8 Hz, 2H), 7.37 (br. s., 1H), 7.31 (d, J=8.2 Hz, 2H), 7.15 (t, J=7.7 Hz, 2H), 6.98 (t, J=6.9 Hz, 1H), 6.59 (d, J=8.8 Hz, 2H), 3.68 (br. s., 3H), 3.43-3.34 (m, 1H), 3.26-3.17 (m, 2H), 2.95 (br. s., 1H), 2.32 (br. s., 1H), 2.20-2.11 (m, 1H), 2.05 (br. s., 2H), 1.96 (br. s., 2H), 1.82-1.75 (m, 1H), 1.65 (d, J=15.9 Hz, 2H), 1.46 (br. s., 1H), 1.19 (d, J=9.9 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ ppm 158.96, 153.92, 138.94, 138.78, 128.79, 125.85, 122.92, 118.37, 113.48, 64.58, 53.54, 53.22, 49.48, 47.42, 45.94, 31.34, 29.50, 23.76, 21.69, 14.11, 8.63.
Reaction SMILES: [Br:1]Br.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]=2)[CH:5]=[CH:4]1.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Br:1][C:5]1[C:6]2[C:11](=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[NH:3][CH:4]=1
Reactant: BrBr
Reactant: Oc1ccc(-c2ccc3cc[nH]c3c2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc(-c2ccc3c(Br)c[nH]c3c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
A mixture solution of bromine (25 μL, 0.48 mmol) in DMF (1 mL) was added to a mixture solution of 4-(1H-indol-6-yl)phenol (100 mg, 0.48 mmol) in DMF (1 mL) at room temperature. After stirring for 1.5 hours at room temperature, followed by addition of icy water and addition of sodium thiosulfate, the mixture was stirred for 1 hour. Thus produced solid was filtered, washed with water and dried at room temperature. The target compound (136 mg) was obtained as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]O)[C:3]=1[OH:10].[C-:11]#[N:12].[Na+]>CN(C)C=O.O>[F:1][C:2]1[C:3]([OH:10])=[C:4]([CH2:8][C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cccc(F)c1O
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1cccc(F)c1O

Procedure:
A solution of 4.89 g of 2-fluoro-6-hydroxymethylphenol and 2.08 g of sodium cyanide in 120 ml of N,N-dimethylformamide is stirred at 120° C. over 24 hours. The reaction mixture is cooled, diluted with water and concentrated by evaporation. The residue is diluted with water and neutralized with conc. acetic acid (caution! hydrocyanic acid). The mixture is extracted with dichloromethane (3×). The combined organic phases are washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a violet solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.32 (1:2 EtOAc-heptane); Rt=3.12.
Reaction SMILES: C(OC([N:8]([C:10]1[N:15]=[C:14]([CH:16](O)[CH3:17])[CH:13]=[CH:12][CH:11]=1)[CH3:9])=O)(C)(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:33][C:34]1[CH:35]=[CH:36][C:37]2[CH2:43][CH:42]([CH2:44][C:45]([O:47]CC)=[O:46])[C:41]3[CH:50]=[CH:51][CH:52]=[CH:53][C:40]=3[O:39][C:38]=2[CH:54]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:9][NH:8][C:10]1[N:15]=[C:14]([CH2:16][CH2:17][O:33][C:34]2[CH:35]=[CH:36][C:37]3[CH2:43][CH:42]([CH2:44][C:45]([OH:47])=[O:46])[C:41]4[CH:50]=[CH:51][CH:52]=[CH:53][C:40]=4[O:39][C:38]=3[CH:54]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC(O)c1cccc(N(C)C(=O)OC(C)(C)C)n1
Reactant: CCOC(=O)CC1Cc2ccc(O)cc2Oc2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CNc1cccc(CCOc2ccc3c(c2)Oc2ccccc2C(CC(=O)O)C3)n1
Reaction time: 22 h
Yield: 57.3 %

Procedure:
A solution of 6-[N-(tert-butoxycarbonyl)-N-methylamino]-2-pyridylethanol (397 mg, 1.58 mmole) and diisopropyl azodicarboxylate (0.31 mL, 1.58 mmole) in anhydrous CH2Cl2 (8 mL) was added dropwise over 10 min to a solution of ethyl (±)-10, 11-dihydro-3-hydroxydibenzo[b,f]oxepine-10-acetate (186 mg, 0.63 mmole) and triphenylphosphine (413 mg, 1.58 mmole) in anhydrous CH2Cl2 (3.2 mL) at RT under argon. After 22 hr, the reaction was concentrated on the rotavap, and the residue was flash chromatographed on silica gel (2-13% EtOAc/hexanes) to give the title compound (146 mg,44%) as a clear oil: MS (ES) m/e 533.0 (M+H)+.
Reaction SMILES: [C:1]1([CH2:11][C:12](Cl)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:12](=[O:13])[CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(Cl)Cc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)NCCCCN
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCCCNC(=O)Cc1cccc2ccccc12
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A solution of 16.3 g of 1-naphthyl-acetic acid chloride in 80 ml of chloroform was added at +10° C. to a solution cooled to +10° C. of 15 g of N-(tert-butoxycarbonyl)-1,4-diamino butane, 100 ml of chloroform and 14 ml of triethylamine and after one hour of stirring at ambient temperature, the mixture was concentrated to dryness under reduced pressure. The residue was taken up in water, separated and dried under reduced pressure at 50° C. to obtain 27.8 g of the expected product.