Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:3]=1.[H-].[Na+].Cl[C:25]1[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=1>>[N:8]1([C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:1][C:25]3[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=3)[CH:3]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: N#Cc1cnc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cc(N)ncn2)CC1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cnc(Nc2cc(N3CCCNCC3)ncn2)s1

Procedure:
Tert-butyl 4-(6-aminopyrimidin-4-yl)-1,4-diazepane-1-carboxylate 15-2 (0.50 g, 1.70 mmol), sodium hydride (0.136 g, 3.4 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.246 g, 1.70 mmol) were treated as in Scheme 4 above. The product was purified on a C18 preparative column after treating the crude product with trifluoroacetic acid and then isolated via lyophilization. Hi-Res MS: calc: 302.1182 found: 302.1184. 1NMR (CD3OD): 8.45 ppm (s, 1H); 8.01 ppm (s, 1H); 6.16 ppm (s, 1H); 4.08 ppm (m, 2H); 3.73 ppm (m, 2H); 3.40 ppm (m, 2H); 3.32 ppm (m, 2H); 2.21 ppm (m, 2H).
Reaction SMILES: [CH3:1][C@@H:2]([NH2:6])[CH2:3][CH2:4][CH3:5].ClCCl.F[C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:13]([NH2:26])[N:12]=1>C(O)CO>[CH3:1][C@@H:2]([NH:6][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:13]([NH2:26])[N:12]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCC[C@@H](C)N
Reactant: Nc1nc(F)nc2c1ncn2C1CCCCO1
Solvent: ClCCl
Solvent: OCCO
Product: CCC[C@@H](C)Nc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 110 °C

Procedure:
A crude sample of (2R)-2-pentanamine containing dichloromethane (11.12 g containing ca 3.1 g, 35.6 mmol of amine) was added to a suspension of 2-fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (5.00 g, 21.08 mmol) in ethylene glycol (50 ml). The mixture was heated at 110° C. for 20 hours and then cooled to room temperature and partitioned between water (200 ml) and ethyl acetate (200 ml). The organic phase was separated, washed with saturated brine, dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was dissolved in dichloromethane and purified on a 110 g aminopropyl (NH2) cartridge using a 0-100% ethyl acetate-cyclohexane gradient over 40 mins. The appropriate fractions were combined and evaporated in vacuo and the residue triturated with diethyl ether and some insoluble starting material removed by filtration. Evaporation of the ether filtrate afforded the title compound as an off-white foam (2.34 g).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH3:34][CH:35]([CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])[CH2:36][CH:37]=O>>[CH3:34][CH:35]([CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])[CH2:36][CH:37]=[CH:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)=CCCC(C)CC=O
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(C)=CCCC(C)CC=CCc1ccccc1
Yield: 51.4 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (3.48 g, 7.78 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 4.9 mL, 7.78 mmol, 1.0 equiv.) and 3,7-dimethyloct-6-enal (1.80 g, 11.7 mmol, 1.5 equiv.), 0.97 g (51%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane).
Reaction SMILES: [CH:1](Br)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:21](#[N:23])[CH3:22]>O>[CH:1]([N:23]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:22]=[CH:21]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: c1ccc(C(c2ccccc2)n2ccc3ccccc32)cc1
Temperature: 25 °C
Yield: 45 %

Procedure:
(Step 4, 1 eq), Ph2CHBr (1.5 eq) and Cs2CO3 (1.5 eq) were mixed in dry acetonitrile (0.1M). The mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic phase was concentrated and the residue was chromatographed with CH2Cl2 as eluent to give the N-benzhydryl indole as an orange gum in 45% yield. m/z (M+H)+ 701.3
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([O:10][C:11]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]2[N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([CH:31]=O)=[CH:26][CH:25]=3)=[C:16]2[C:12]=1[CH2:13][NH:14][C:15]2=[O:40])(=[O:9])=[O:8].Cl.[CH3:42][NH:43][CH3:44].C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([O:10][C:11]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]2[N:23]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([CH2:31][N:43]([CH3:44])[CH3:42])=[CH:26][CH:25]=3)=[C:16]2[C:12]=1[CH2:13][NH:14][C:15]2=[O:40])(=[O:9])=[O:8]
Reactant: CNC
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccccn1)CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: COc1cc(-c2cc3cc(CN(C)C)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccccn1)CNC2=O
Yield: 40.1 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-(2-pyridinesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (0.455 g, 0.807 mmol) was dissolved in acetonitrile (16.0 mL), and the solution was treated with dimethylamine hydrochloride (1.31 g, 16.1 mmol), triethylamine (2.20 mL, 16.1 mmol), acetic acid (0.924 mL, 16.1 mmol) and sodium triacetoxyborohydride (0.513 g, 2.42 mmol), followed by purification of the residue by flash column chromatography (chloroform/methanol=80/20) to obtain 4-(2-pyridinesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(dimethylaminomethyl)indol-2-yl]isoindolinone (0.192 g, 40%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[N:23]([C:26](OCC)=O)=C=S.[Cl-].O[NH3+].C([N:37](CC)C(C)C)(C)C>CO.C(O)C.CS(C)=O>[NH2:37][C:26]1[N:1]=[C:2]2[CH:3]=[CH:4][C:5]([O:8][C:9]3[CH:10]=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH:12]=[CH:13][CH:14]=3)=[CH:6][N:7]2[N:23]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc(N)nc2)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)N=C=S
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CS(C)=O
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(N)nn3c2)c1
Yield: 61.8 %

Procedure:
In the same manner as in Example 17-1 and using tert-butyl {3-[(6-aminopyridin-3-yl)oxy]phenyl}carbamate (15.0 g, 49.8 mmol), ethyl isothiocyanatoformate (7.18 g, 54.8 mmol), DMSO (50 mL), hydroxylammonium chloride (11.8 g, 170 mmol), N,N-diisopropylethylamine (21.2 mL, 122 mmol), ethanol (70 mL) and methanol (70 mL) as starting materials, the title compound (10.5 g, 94%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C@H:10]([CH2:14][CH2:15][CH2:16][CH3:17])[C:11]([OH:13])=O)=[CH:4][C:3]=1[CH3:18].[C:19]([O:23][NH2:24])([CH3:22])([CH3:21])[CH3:20].C1C=CC2N(O)N=NC=2C=1.C[N+]1(C)[C@H]2CC3C=CC(O)=C4O[C@H]5[C@@H](O)C=C[C@@H]2[C@]5(C=34)CC1.CCN=C=NCCCN(C)C>ClCCl.O>[C:19]([O:23][NH:24][C:11](=[O:13])[C@H:10]([NH:9][C:5]1[CH:4]=[C:3]([CH3:18])[C:2]([F:1])=[C:7]([CH3:8])[CH:6]=1)[CH2:14][CH2:15][CH2:16][CH3:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)ON
Reactant: CCCC[C@@H](Nc1cc(C)c(F)c(C)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: C[N+]1(C)CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@@H]1C5
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCCC[C@@H](Nc1cc(C)c(F)c(C)c1)C(=O)NOC(C)(C)C
Temperature: 25 °C
Reaction time: 44 h
Yield: 38.4 %

Procedure:
To a solution of crude (R)-2-(4-fluoro-3,5-dimethyl-phenylamino)-hexanoic acid (ca. 6.0 mmol), O-tert-butyl-hydroxyamine (2.261 g, 18.0 mmol), HOBT (0.811 g, 6.0 mmol), and N-methyl morphine (3.036 g, 30.0 mmol) in 20 mL of dichloromethane, was added EDCI (1.725 g, 9.0 mmol). After stirring at room temperature under N2 for 44 h, the reaction mixture was diluted with 60 mL of water and extracted with dichloromethane (60 mL×3). The organic extracts were combined and dried over anhydrous Na2SO4 and the solvents removed under reduced pressure. The product was isolated by Flash chromatography (silica gel) eluting with 0-30% ethyl acetate/hexanes to give the title compound as a pale yellow semi-solid (0.747 g, 38% yield). LC-MS: tR=8.8 min; m/z 325 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].[H-].[Na+].Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1>>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:12]1[S:13][CH:14]=[CH:15][N:16]=1
Reactant: CN1CCC[C@H]1CO
Reactant: Brc1nccs1
Agent: [H-]
Agent: [Na+]
Product: CN1CCC[C@H]1COc1nccs1
Yield: 73.8 %

Procedure:
(S)-(-)-1-Methyl-2-pyrrolidine methanol (484 mg, 4.2 mmol) was reacted with NaH ((80% dispersion in mineral oil) 0.164 g 5.46 mmol) and 2-bromothiazole (0.417 g, 4.62 mmol) according to the procedure outlined in Example 3a to afford after column chromatography eluting with (10% MeOH/CHCl3 +1% NH3) (616.2 mg, 3.1 mmol, 74% yield) of 2-(1-methyl-2-(S)-pyrrolidinylmethoxy)-thiazole. The pure base was then converted to its hydrochloride salt by treating the amine (109.4 mg, 0.552 mmol) with a saturated solution of HCl in Et2O dropwise with stirring until no more precipitate formation was observed. This afforded 21.2 mg, 0.09 mmol, 16% of the title compound. mp=99° C. [α]d20 =+2.86° (c=0.021, MeOH). MS (DCI/NH3) m/e 199 (M+H)+. 1H NMR (CD3OD, 300 MHz) δ: 7.18 (d, J=4.04 Hz, 1H), 6.99 (d, J=4.04 Hz, 1H), 4.85 (dd, J=12.50, 3.31 Hz, 1H), 4.65 (dd, J=12.5, 6.62 Hz, 1H), 4.09-3.85 (m, 1H), 3.85-3.65 (m, 1H), 3.03 (br s, 3H), 2.45-2.3 (m, 1H), 2.3-1.95 (m, 3H). Analysis calculated for C9H15N2OSCl.0.6 H2O0.1Et2O: C, 44.63; H, 6.85; N, 11.07; Found: C, 44.68; H, 6.46; N, 10.68.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6]I.[CH3:17][O:18][CH2:19][CH2:20][NH:21][CH3:22].C(N(CC)CC)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][N:21]([CH2:20][CH2:19][O:18][CH3:17])[CH3:22]
Reactant: CNCCOC
Reactant: COC(=O)[C@H](CCI)NC(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COCCN(C)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 70 °C
Reaction time: 16 h
Yield: 492.8 %

Procedure:
A mixture of (S)-2-tert-butoxycarbonylamino-4-iodobutyric acid methyl ester (0.200 g, 0.58 mmol), (2-methoxyethyl)-methylamine (0.062 g, 0.70 mmol), and triethylamine (0.41 mL, 2.9 mmol) in dioxane (1 mL) was stirred at 70° C. for 16 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and dissolved in dichloromethane (20 mL). The solution was washed with water (3×10 mL), brine (10 mL), dried over MgSO4, filtered through Celite, and concentrated under reduced pressure. The tan oil was chromatographed eluting with ether to provide 0.87 g of pale yellow oil (49% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C[N:16]1C[CH2:19][CH2:18][C:17]1=O.C(N)CC>O>[CH2:17]([NH:16][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH2:18][CH3:19]
Reactant: CN1CCCC1=O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: CCCN
Solvent: O
Product: CCCNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5.23 g of 4-fluoro-3-nitro-benzo trifluoride and 25 ml of N-methylpyrrolidone was added 3.69 g of n-propylamine under ice cool, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was poured into water, and the deposited solid was collected by filtration. This solid was washed with water, then, dried under reduced pressure to obtain 2.78 g of N-propyl-2-nitro-4-trifluoromethylaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C@@:11]23[C:17]([CH3:19])([CH3:18])[C@@:14]([CH3:20])([CH2:15][CH2:16]2)[C:13](=[O:21])[O:12]3)=[O:10])=[C:4]([C@@:22]([OH:32])([C:27]#[C:28][CH:29]2[CH2:31][CH2:30]2)[C:23]([F:26])([F:25])[F:24])[CH:3]=1.ClCCl.C(N(CC)CC)C.Cl[C:44]([O:46][CH:47]([Cl:49])[CH3:48])=[O:45]>O>[C:44](=[O:45])([O:46][CH:47]([Cl:49])[CH3:48])[O:32][C@:22]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9]([C@@:11]12[C:17]([CH3:18])([CH3:19])[C@@:14]([CH3:20])([CH2:15][CH2:16]1)[C:13](=[O:21])[O:12]2)=[O:10])([C:27]#[C:28][CH:29]1[CH2:31][CH2:30]1)[C:23]([F:24])([F:25])[F:26]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CC1(C)[C@@]2(C)CC[C@]1(C(=O)Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F)OC2=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(Cl)OC(=O)O[C@@](C#CC1CC1)(c1cc(Cl)ccc1NC(=O)[C@@]12CC[C@@](C)(C(=O)O1)C2(C)C)C(F)(F)F
Temperature: 7.5 °C
Reaction time: 1 h

Procedure:
A solution of (1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (10, 20 g, 42.6 mmol), dichloromethane (100 mL) and triethylamine (5.17 g, 51.1 mmol) was stirred at 0-5° C. for 20 minutes, then 1-chloroethyl chloroformate (7.3 g, 51.1 mmol) was added dropwise. The mixture was stirred at 5-10° C. for 1 hour. Water (60 ml) was added with stirring and then the layers were separated. The organic solution was concentrated and MTBE (180 ml) was added. After washing with water twice, the system was concentrated to 30 ml and then MTBE (10 ml) and hexane (60 ml) were added. The suspension was stirred at 70° C. for 30 min and filtered to give (S)-2-(5-chloro-2-((1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamido)phenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-yl 1-chloroethyl carbonate (7, R1 is 4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptyl, R3 is 1-chloroethyl) as a white solid. 1H NMR (CDCl3) δ9.43, 9.30 (s, 1H), 8.17, 8.06 (d, J=8.7 Hz, 1H), 7.62, 7.54 (s, 1H), 7.42 (d, J=8.7 Hz, 1H), 6.36 (q, J=5.7 Hz, 1H), 2.60-2.50 (m, 1H), 2.09-1.93 (m, 2H), 1.89-1.86 (at, J=4.5 Hz, 3H), 1.77-1.61 (m, 2H), 1.16 (d, J=10.5 Hz, 6H), 1.01 (d, J=7.5 Hz, 3H), 0.97-0.92 (m, 2H), 0.88-0.84 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:17].[C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)(=[O:26])[CH3:25]>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24](=[O:26])[CH3:25])=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:15])([F:14])[F:13])=[O:17]
Reactant: CC(=O)c1ccccc1B(O)O
Reactant: O=C(c1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1Cl
Product: CC(=O)c1ccccc1-c1c(C(=O)c2ccccn2)cnc2c(C(F)(F)F)cccc12

Procedure:
This compound was prepared using the procedure of Example 1, step 5 using (4-chloro-8-trifluoromethyl-quinolin-3-yl)-pyridin-2-yl-methanone in place of [4-chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 2-acetylphenylboronic acid in place of phenyl boronic acid. MS (ESI) m/z 421 ([M+H]+); 1H NMR (CDCl3) δ 9.24 (s, 1H), 8.63 (d, J=4.16 Hz, 1H), 8.13 (d, J=7.03 Hz, 1H), 7.93 (m, 2H), 7.81 (m, 1H), 7.51 (m, 5H), 7.18 (m, 1H), 2.41 (s, 3H).
Reaction SMILES: Br[CH2:2]C1CCCCC1.C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:17]=1[CH2:18][N:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[S:22](=[O:30])(=[O:29])[N:21]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34]N=2)[C:20]1=[O:38]>>[Cl:15][C:16]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:17]=1[CH2:18][N:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[S:22](=[O:29])(=[O:30])[N:21]([CH2:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:2]2)[C:20]1=[O:38]
Reactant: O=C1N(Cc2c(F)cccc2Cl)c2ccccc2S(=O)(=O)N1Cc1ccccn1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1N(Cc2c(F)cccc2Cl)c2ccccc2S(=O)(=O)N1CC1CCCCC1

Procedure:
The title compound (25 mg, 0.06 mmol) was prepared from (IntE1) (0.3 g, 0.88 mmol), 2-(bromomethyl)cyclohexane (0.18 g, 1.05 mmol) and K2CO3 (0.36 g, 2.60 mmol) using the methods of (128).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([C:9]([OH:11])=[O:10])=[CH:4][N:3]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)Cl.[OH-].[Na+].O>[C:24]([NH:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([C:9]([OH:11])=[O:10])=[CH:4][N:3]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ncc(C(=O)O)c(O)n1
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ncc(C(=O)O)c(O)n1)c1ccccc1

Procedure:
2-Amino-4-hydroxypyrimidine-5-carboxylic acid (310 mg, 2 mmol) was suspended in chloroform (20 ml) and treated with triethylamine (880 μl, 6.2 mmol) and trimethylsilylchloride (850 μl, 6.2 mmol) at reflux for 4 hours. Benzoyl chloride (250 μl, 2 mmol) was added and the reaction mixture allowed to cool overnight. Water (10 ml) was added with very vigorous stirring and the solid product was dissolved in the aqueous layer by addition of 10% NaOH. After washing the aqueous layer with further chloroform, the product was precipitated by acidification to pH 0. The filtered product was washed with water and ether. Yield 374 mg (72%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=2)[CH:10]=1.IC.[C:31](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH3:31])[C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:22]=2)[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CCc1ccc(NCc2cccc(-c3c(C)cccc3C)c2)cc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)CCc1ccc(N(C)Cc2cccc(-c3c(C)cccc3C)c2)cc1
Yield: 47.9 %

Procedure:
To a solution of methyl 3-(4-{[(2′,6′-dimethylbiphenyl-3-yl)methyl]amino}phenyl)propanoate (0.598 g, 1.60 mmol) and iodomethane (0.498 mL, 8.00 mmol) in acetone (10 mL) was added potassium carbonate (0.332 g, 2.40 mmol), and the mixture was heated under reflux under a nitrogen atmosphere for 6 hr. After cooling, the reaction mixture was concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-25% ethyl acetate/hexane) to give the title compound (0.297 g, yield 48%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Br)=[CH:7]2.[CH2:14]([CH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH:24]=O)[CH2:19][CH2:18]1)[CH2:15][CH3:16].CC(C)([O-])C.[K+]>>[F:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:24][CH2:23][C@H:20]1[CH2:19][CH2:18][C@H:17]([CH2:14][CH2:15][CH3:16])[CH2:22][CH2:21]1)=[CH:7]2
Reactant: CCCC1CCC(CC=O)CC1
Reactant: Fc1ccc2cc(Br)ccc2c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCC[C@H]1CC[C@H](CCc2ccc3c(F)c(F)ccc3c2)CC1

Procedure:
The procedure of Example14 was followed except that 5,6-difluoro-2-bromonaphthalene was used instead of 6-fluoro-2-bromonaphthalene, 4-propylcyclohexaneethanal was used instead of 4-propylcyclohexanone and isomerization with potassium t-butoxide was not effected to obtain 5,6-difluoro-2-[2-(trans-4-propylcyclohexyl)ethyl]naphthalene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[H][H]>C(O)C.[Pt]=O>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: COc1ccc(N)c(F)c1

Procedure:
All of the product from Step A was placed in a Parr hydrogenation apparatus, and 0.35 g of platinum oxide in 200 mL of ethanol was added. This mixture was reacted with hydrogen until the theoretical amount of hydrogen was absorbed. The reaction was stopped, and the reaction mixture was filtered through Celite® filter aid. The solvent was then evaporated under reduced pressure, leaving 18.5 g of 2-fluoro-4-methoxyaniline as a solid residue.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]2[N:5]([CH:18]=[N:19][CH:20]=2)[C:6]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:7]([C:9](=[O:11])[CH3:10])[CH:8]=1.C(N(CC)C(C)C)(C)C.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[C:30]([N:15]1[CH2:16][CH2:17][N:12]([C:6]2[N:5]3[CH:18]=[N:19][CH:20]=[C:4]3[C:3]([Cl:2])=[CH:8][C:7]=2[C:9](=[O:11])[CH3:10])[CH2:13][CH2:14]1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: CC(=O)c1cc(Cl)c2cncn2c1N1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(Cl)c2cncn2c1N1CCN(C(C)=O)CC1
Reaction time: 0.08 h
Yield: 77 %

Procedure:
1-(8-Chloro-5-piperazin-1-ylimidazo[1,5-a]pyridin-6-yl)ethanone hydrochloride was dissolved in methylene chloride (1.0 mL) and N,N-diisopropylethylamine (45 μL, 0.26 mmol) was added. To the reaction mixture, acetyl chloride (5.5 μL, 0.077 mmol) was added and the mixture was stirred for 5 minutes. Evaporation and purification by preparative LCMS (pH 10) gave the desired compound (13 mg, 77%). LCMS calculated for C15H18ClN4O2 (M+H)+: m/z=321.1. found: 320.9.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([N:21]([CH3:23])[CH3:22])=[CH:13][CH:12]=1)=[O:10].Cl.[NH2:26][OH:27].C[O-].[Na+]>CO>[CH3:22][N:21]([CH3:23])[C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([NH:26][OH:27])=[O:2])=[O:10])=[CH:12][CH:13]=1
Reactant: NO
Reactant: COC(=O)CCCCNC(=O)c1ccc(N(C)C)c2ccccc12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)c1ccc(C(=O)NCCCCC(=O)NO)c2ccccc12
Reaction time: 0.5 h
Yield: 19.4 %

Procedure:
(Method J9B) To the solution of 5-[[[4-(dimethylamino)-1-naphthalenyl]carbonyl]amino]-pentanoic acid methyl ester (3/62) (0.31 g, 0.94 mmol) and hydroxylamine hydrochloride (0.26 g, 3.8 mmol) in absolute methanol was added NaOMe solution made by dissolving Na (0.18 g, 8 mmol) in absolute methanol. A white precipitate immediately appeared. After 0.5 h the reaction was complete (TLC), and the reaction mixture was evaporated, suspended in 1M phosphate buffer (pH 4), and extracted with 3 portions of methylene chloride. The organic phase became turbid, therefore the solvent was removed, and the residue was dried under reduced pressure yielding the crude product (0.27 g). Recrystallisation from acetonitrile gave the title product (0.06 g, 19%) of acceptable purity. Rf 0.50 (CHCl3—MeOH 4:1). M.p. 129° C. 1H NMR (DMSO-d6, TMS) δ: 1.53-1.57 (4H, m), 1.97-2.01 (2H, m), 2.84 (6H, s), 3.32-3.33 (m, overlapped with a signal from DMSO), 7.08 (1H, d, J=8.2 Hz), 7.46-7.56 (3H, m), 8.14-8.24 (2H, m), 8.39 (1H, br t, J=5.2 Hz), 8.69 (1H, br s), 10.37 (1H, br s). HPLC analysis on Symmetry 18 column: impurities <1% (column size 3.9×150 mm; mobile phase acetonitrile −0.1M phosphate buffer (pH 2.5), 10:90; detector UV 220 nm; flow rate 1.3 ml/min). Anal. Calcd for C18H23N3O3: C, 65.63; H, 7.04; N, 12.76. Found: C, 65.50; H, 6.90; N, 12.73.