Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19]([C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(Br)c1
Reactant: OB(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(-c2cccs2)c1
Yield: 22.7 %

Procedure:
A mixture of 3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-5-bromo-6-chloropyridine from Example 69a (1.5 g, 3.8 mmol), 2-thienylboronic acid (1.46 g, 11.5 mmol), 2 M Na2CO3 (5 mL) and Pd(0) (190 mg) were mixed together in toluene (20 mL), and the mixture was heated at reflux for 48 h. The mixture was cooled and extracted with EtOAc. The EtOAc was removed under reduced pressure, and the residue was chromatographed (silica gel; hexane/EtOAc, 4:1) to afford the title compound (340 mg, 32% yield): 1H NMR (CDCl3, 300 MHz) δ 1.47 (s, 9H), 1.84-2.11 (m, 4H), 3.31-3.46 (m, 2H), 3.89 (m, 1H), 4.05-4.26 (m, 2H), 7.14 (dd, 1H, J=4.5, 6.0 Hz), 7.42-7.50 (m, 2H), 8.05 (d, 1H, J=3.0 Hz), 8.07 (m, 1H); MS (CI/NH3) m/z 395 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([S:16]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)(=[O:18])=[O:17])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13](=[S:15])[NH2:14])=[CH:9]2)[CH3:2].Br[CH:25]([CH:28]=O)[CH:26]=[O:27].CN(C)C(=O)C.[BH4-].[Na+]>O1CCCC1.CO.O>[CH2:1]([N:3]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:15][C:25]([CH2:26][OH:27])=[CH:28][N:14]=1)=[CH:9]2)[S:16]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)(=[O:17])=[O:18])[CH3:2]
Reactant: O=CC(Br)C=O
Reactant: CCN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCN(c1cccc2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 17 %

Procedure:
A mixture of 7-[ethyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (4.10 g), bromomalonaldehyde (3.55 g) and N,N-dimethylacetamide (30 mL) was stirred at 95° C. for 1.5 hr. To the reaction mixture was added water, and the obtained precipitate was dissolved in tetrahydrofuran (30 mL) and methanol (30 mL). After cooling in an ice bath, sodium borohydride (508 mg) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated and diluted with a mixture of ethyl acetate-tetrahydrofuran and washed successively with aqueous sodium bicarbonate and saturated brine. The organic layer was dried over magnesium sulfate and filtrated. The filtrate was concentrated, subjected to silica gel column chromatography, and eluted with an ethyl acetate-hexane (2:1) mixture to give the title compound (800 mg, yield 17%) as a solid.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=1)=[O:25].Cl>O1CCCC1>[Br:32][C:29]1[CH:30]=[CH:31][C:26]([C:24](=[O:25])[CH2:23][C:11]([CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:27][CH:28]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CCOC(=O)C(CCc1ccccc1)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCc1ccccc1)(CC(=O)c1ccc(Br)cc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 16 h
Yield: 60.5 %

Procedure:
To a 500 mL 3-neck round-bottom flask equipped with an argon inlet and an addition funnel, was added sodium hydride (95%, 1.40 g, 58.3 mmol) followed by tetrahydrofuran (30 mL). The resulting suspension was then cooled to 0° C. and diethyl 2-(2-phenylethyl)malonate (14.0 g, 53.0 mmol) in tetrahydrofuran (20 mL) was added dropwise over 20 minutes. The cooling bath was removed and the reaction mixture was allowed to warm to rt over 45 minutes. A solution of 2-bromo-1-(4-bromophenyl)ethanone (14.72 g, 58.26 mmol) in tetrahydrofuran (40 mL) was rapidly added and the resulting orange-red mixture was stirred at rt for 16 h. The mixture was carefully poured into 300 mL of 1N hydrochloric acid, and the resulting mixture was stirred for 10 minutes and extracted twice with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (Biotage flash 75, 10:90 ethyl acetate/hexane) to afford diethyl 2-[2-(4-bromophenyl)-2-oxoethyl]-2-(2-phenylethyl)malonate (14.8 g, 61%). LC-MS ret. time 3.89 min, m/z 461.2 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.26 (t, 6H), 2.41–2.45 (m, 2H), 2.56–2.59 (m, 2H), 3.67 (s, 2H), 4.23 (q, 4H), 7.14–7.22 (m, 3H), 7.22 (d, 2H), 7.61 (d, 2H), 7.79 (d, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C1COCC1.C(OCC)(=O)C>[C:31]([NH:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1)(=[O:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](N)C1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6R,7S)-6-amino-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (1.3 g) in THF (13 ml) were added triethylamine (0.752 ml) and acetyl chloride (0.385 mL) at 0° C., and the mixture was gradually warmed from 0° C. to room temperature, and stirred overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (0.965 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([SiH:16]([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1.C(OCC)(=O)C>C1COCC1.ClCCl>[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([SiH:16]([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:18])[CH3:19])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc([SiH](C(C)C)C(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[SiH](c1ccc(CO)cc1)C(C)C
Reaction time: 0.17 h
Yield: 101.2 %

Procedure:
LiAlH4 (1.2 g, 32 mmol) was dissolved in anhydrous THF (80 mL), and to this was slowly added dropwise the anhydrous THF solution (80 mL) 4-diisopropylsilanylbenzoic acid methyl ester (2) (8 g, 32 mmol). The resulting mixture was then stirred for 10 min and ethyl acetate (20 mL) was added slowly to it. The reaction mixture was diluted with dichloromethane (500 mL), and then extracted three times with 0.2 N hydrochloric acid aqueous solution (400 mL). An organic layer was collected and dehydrated with anhydrous sodium sulfate and filtered so that the resulting solvent was distilled out under a reduced pressure to give a desired product (7.2 g, quant). Its NMR data are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:18])[C:14]([O:16]C)=[O:15])[CH:7]=[CH:6]2.CO.[OH-].[K+].O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:18])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2
Reactant: COC(=O)C(C)c1ccc2cc(OC)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1

Procedure:
The crude methyl 2-(6-methoxy-2-naphthyl)propionate is hydrolyzed with methanol/potassium hydroxide/water until TLC indicates no remaining ester. Then the reaction mixture is poured into water and extracted with methylene chloride and acidified with hydrochloric acid. The mixture is filtered and the organic and aqueous layers are separated. The aqueous layer then is acidified and filtered to yield 13.5 g of 2-(6-methoxy-2-naphthyl)propionic acid (melting point: 153°-155° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[NH:4][C:5]([CH3:10])=[C:6]([CH2:8][CH3:9])[CH:7]=1.Cl[CH2:13][C:14]1[O:15][C:16]2[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]([CH3:24])[C:17]=2[N:18]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:24][C:19]1[C:17]2[N:18]=[C:14]([CH2:13][NH:1][C:2]3[C:3](=[O:11])[NH:4][C:5]([CH3:10])=[C:6]([CH2:8][CH3:9])[CH:7]=3)[O:15][C:16]=2[C:22]([CH3:23])=[CH:21][CH:20]=1
Reactant: CCc1cc(N)c(=O)[nH]c1C
Reactant: Cc1ccc(C)c2oc(CCl)nc12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(NCc2nc3c(C)ccc(C)c3o2)c(=O)[nH]c1C

Procedure:
A mixture of 3-amino-5-ethyl-6-methyl-2-(1H)-pyridinone (0.23 g, 1.5 mmol), 2-chloromethyl-4,7-dimethylbenzoxazole (0.29 g, 1.5 mmol), diisopropylethylamine (0.39 g, 3 mmol) in acetonitrile (50 mL) was refluxed under an atomosphere of nitrogen for 12 hours. The resultant mixture was concentrated under reduced pressure (15 torr). The residue was then subjected to column chromatography on silica gel (100 g, elution with 4% methanol in chloroform). Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([NH:22][C@@H:23]([C:25]([NH:27][CH2:28][C@H:29]([NH:37]C(OCC1C=CC=CC=1)=O)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:26])[CH3:24])=[O:21])[CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([NH:22][C@@H:23]([C:25]([NH:27][CH2:28][C@H:29]([NH2:37])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:26])[CH3:24])=[O:21])[CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH3:19])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NC[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NC[C@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.1 %

Procedure:
N-(tert-Butoxycarbonyl)-2,6-dimethyl-L-tyrosyl-N-{(2R)-2-[(benzyloxycarbonyl)amino]-3-phenylpropyl}-D-alaninamide (314 mg, 0.46 mmol) was dissolved in 5 mL of tetrahydrofuran and degassed by bubbling through argon gas for a few minutes. Palladium on charcoal (10% w/w, 5 mg) was added and the suspension stirred for 16 h at room temperature under 1 atmosphere of hydrogen pressure. The mixture was filtered through a short pad of celite, washed with 5 mL of tetrahydrofuran and evaporated under reduced pressure. The resulting residue was purified by column chromatography using 5% methanol in dichloromethane as eluant to provide the title compound as a clear oil (203 mg, 82%).
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].[CH2:38]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[CH3:39]>>[CH2:38]([N:40]1[CH2:45][CH2:44][N:43]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:42][CH2:41]1)[CH3:39]
Reactant: CCN1CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: CCN1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and N-ethylpiperazine according to conditions described in general procedure C. Mp: 86-87° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.96 (s, 3 H), 1.58-1.59 (m, 6 H), 2.26 (bs, 4 H), 3.26-3.31 (m, 8H), 3.46 (bs, 2 H), 6.21 (d, J=5.8 Hz, 1 H), 6.95 (d, J=12.4 Hz, 1 H), 7.15 (d, J=8.8 Hz, 1H), 7.40 (d, J=8.0 Hz, 1 H), 7.45 (s, 1 H), 7.55-7.61 (m, 3 H), 7.81-7.83 (m, 1 H), 7.97 (d, J=7.7 Hz, 1 H), 8.25 (d, J=5.5 Hz, 1 H), 10.43 (s, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[OH:14])([O-:3])=[O:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:15]([O:14][C:5]1[CH:6]=[C:7]([C:10]([F:11])([F:12])[F:13])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C(F)(F)F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-nitro-5-trifluoromethylphenol (730 mg, 3.5 mmol), benzyl bromide (0.42 mL, 3.5 mmol), and potassium carbonate (200 mg) in DMF (10 mL) is stirred at RT for 48 h. The mixture is partitioned between water and EtOAc, the organic layer is concentrated and the residue is chromatographed using a gradient of 5-20% EtOAc/hexane as eluent to afford the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:16]2[C:15](=O)[O:14][C:13](=[O:18])[C:12]=2[C:11]([O:19][CH2:20][CH3:21])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[CH:9]2)[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][C:24]=1[F:35]>C(O)(=O)C.CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:20]([O:19][C:11]1[C:12]2[C:13](=[O:18])[N:22]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][C:24]=3[F:35])[C:15](=[O:14])[C:16]=2[C:4]([O:3][CH2:1][CH3:2])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=12)[CH3:21]
Reactant: CCOC(=O)Cc1ccc(N)c(F)c1
Reactant: CCOc1c2c(c(OCC)c3ccccc13)C(=O)OC2=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2=O)c(F)c1
Temperature: 120 °C
Yield: 68.6 %

Procedure:
4,9-Bis(ethyloxy)naphtho[2,3-c]furan-1,3-dione (0.100 g, 0.35 mmol) in acetic acid (5 ml) was treated with DMAP (0.013 g, 0.11 mmol) then ethyl (4-amino-3-fluorophenyl)acetate (0.138 g, 0.70 mmol) and heated to reflux (120° C.) under argon overnight. The reaction mixture was cooled to room temperature and the solvent evaporated to afford a brown/orange oil which was diluted in DCM and washed with saturated NaHCO3 and then 2N HCl. The organics were dried over MgSO4 and evaporated to a brown oil which was purified by chromatography on silica gel eluting with ethyl acetate (0-20%) in hexane over 30 minutes. The evaporated fractions were triturated with hexane to give the title compound as a solid (0.110 g, 0.24 mmol, 69%).
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][C@@H:20]([OH:22])[CH2:19][CH2:18][NH:17]2)=[C:12]([OH:23])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:24](Br)#[C:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>>[CH2:26]([N:17]1[CH2:18][CH2:19][C@H:20]([OH:22])[CH2:21][C@@H:16]1[C:13]1[CH:14]=[CH:15][C:10]([C:2]([CH3:1])([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][C:12]=1[OH:23])[C:25]#[CH:24]
Reactant: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2)c(O)c1
Reactant: CC#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#CCN1CC[C@H](O)C[C@@H]1c1ccc(C(C)(C)CCCCCC)cc1O
Yield: 57 %

Procedure:
Employing the procedure of Example 10 with 321 mg (1.01 mmole) of cis-2-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-4-piperidinol, 82 microliter (1.06 mmole) or propynyl bromide and 292 mg (2.12 mmole) of potassium carbonate affords 205 mg (57%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([C:4]1([S:7](Cl)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[C:11]([O:15][C:16]([N:18]1[C:22]2=[C:23]([NH2:38])[C:24]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=3[F:37])=[C:25]([CH3:28])[C:26](=[O:27])[N:21]2[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(OC(=O)C)C>N1C=CC=CC=1>[C:11]([O:15][C:16]([N:18]1[C:22]2=[C:23]([NH:38][S:7]([C:4]3([CH2:1][CH:2]=[CH2:3])[CH2:6][CH2:5]3)(=[O:9])=[O:8])[C:24]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=3[F:37])=[C:25]([CH3:28])[C:26](=[O:27])[N:21]2[CH2:20][CH2:19]1)=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCN2C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=CCC1(S(=O)(=O)Nc2c(Nc3ccc(I)cc3F)c(C)c(=O)n3c2N(C(=O)OC(C)(C)C)CC3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.4 %

Procedure:
1-Allyl-cyclopropanesulfonyl chloride (259 mg, 0.001 mol) was added to a stirred solution of 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-carboxylic acid tert-butyl ester (350 mg, 0.001 mol) in pyridine (3 mL). The resulting mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was concentrated and partitioned between ethylacetate and water. The organic layer concentrated to afford the crude product. Purification by column chromatography on silica gel (75% ethylacetate in hexane) afforded 125 mg of the product (27.7% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[CH3:15][O:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[NH:19][CH:20]=[N:21]2.FC1C=C(F)C=CC=1[C@]1([C@H](N2C3C(=NC=NC=3OC)N=C2)C)CO1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([N:21]2[CH:20]=[N:19][C:18]3[C:22]2=[N:23][CH:24]=[N:25][C:17]=3[O:16][CH3:15])[CH3:13])[CH2:11][O:10]1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: COc1ncnc2nc[nH]c12
Agent: COc1ncnc2ncn([C@H](C)[C@@]3(c4ccc(F)cc4F)CO3)c12
Product: COc1ncnc2c1ncn2[C@H](C)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 21.1 %

Procedure:
Using (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl] ethanol (523 mg) and 6-methoxypurine 1/2 hydrate (415 mg), (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-[6-methoxy-7(7H)-purinyl]ethyl]oxirane (205 mg) and (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-[6-methoxy-9(9H)-purinyl]ethyl] oxirane (183 mg) were obtained as a white powder respectively by the same way as in Reference Example 2.
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12]2([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=3)[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5])[CH3:2].[N:34]([Si](C)(C)C)=[N+:35]=[N-:36]>C1(C)C=CC=CC=1>[CH2:32]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12]2([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[NH:36][N:35]=[N:34][N:31]=4)[CH:25]=3)[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5])[CH3:33]
Reactant: CCCC(C)CN1CCC(c2cccc(C#N)c2)(c2ncc(C(=O)N(CC)CC)cn2)CC1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCCC(C)CN1CCC(c2cccc(-c3nnn[nH]3)c2)(c2ncc(C(=O)N(CC)CC)cn2)CC1
Temperature: 100 °C
Yield: 46.3 %

Procedure:
To a stirring solution of 2-[4-(3-cyano-phenyl)-1-(2-methyl-pentyl)-piperidin-4-yl]-pyrimidine-5-carboxylic acid diethylamide (45 mg, 0.11 mmol) in 4 mL toluene at room temperature was added Bu2SnO (12 mg, 0.05 mmol) and azidotrimethylsilane (0.09 mL, 0.66 mmol). The reaction mixture was heated to 100° C. for 28 hours and cooled to room temperature. The reaction was quenched with water, neutralized with NaHCO3 and extracted with CH2Cl2. The combined organic layers were dried and concentrated. The resulting crude material was purified by flash chromatography with 5% MeOH/CH2Cl2 to afford 25 mg (51%) of the desired tetrazole. 1HNMR (400 MHz, CDCl3) δ 8.70 (s, 2H), 8.15 (s, 1H), 7.94 (d, 1H), 7.25-7.13 (comp, 2H), 3.53-3.51 (comp, 4H), 3.25-3.22 (comp, 4H), 2.70 (br s, 6H), 1.93 (br s, 1H), 1.40-1.12 (comp, 10H), 1.01 (d, 3H), 0.81 (t, 3H); MS (M+1) 491.4.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[O:8][C:9]([CH2:15][C:16]([F:19])([F:18])[F:17])([C:11]([F:14])([F:13])[F:12])[O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[N+:22]([O-])([OH:24])=[O:23]>S(=O)(=O)(O)O>[N+:1]([C:4]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:7]2[O:8][C:9]([CH2:15][C:16]([F:19])([F:18])[F:17])([C:11]([F:12])([F:13])[F:14])[O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)OC(CC(F)(F)F)(C(F)(F)F)O2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OC(CC(F)(F)F)(C(F)(F)F)O2
Temperature: 0 °C

Procedure:
317 g of the product of Example 15a were introduced, and a mixture of 250 ml of 100% strength by weight nitric acid and 350 ml of concentrated sulphuric acid were added dropwise, with stirring. The mixture was stirred for 2 hours at 55° C. The batch was then allowed to cool and poured into ice-water. The product was extracted using methylene chloride, and the methylene chloride phase was washed until neutral using sodium hydrogencarbonate solution, dried and freed from readily volatile components on a rotary evaporator. The yield was 339 g (=94% of theory), and the melting point was 101° to 103° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[F:24][C:25]([F:38])([F:37])[C:26]1[N:27]=[C:28]2[N:32]([C:33]=1[C:34](O)=[O:35])[CH:31]=[CH:30][S:29]2>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:33]2[N:32]3[C:28]([S:29][CH:30]=[CH:31]3)=[N:27][C:26]=2[C:25]([F:37])([F:24])[F:38])=[O:35])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1c(C(F)(F)F)nc2sccn12
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C(F)(F)F)nc3sccn23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 6-Trifluoromethyl-imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.92 min; [M+H]+=545.9.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13](F)[C:10]=1[C:11]#[N:12]>>[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]2)[C:10]=1[C:11]#[N:12]
Reactant: OC1C=CCCC1
Reactant: N#Cc1c(N)cccc1F
Product: N#Cc1c(N)cccc1OC1C=CCCC1

Procedure:
Prepared as in Example 22b from cyclohex-2-enol and 2-amino-6-fluorobenzonitrile as a colorless oil (78%). 1H NR (400 MHz, CDCl3) δ 1.64 (m, 1H), 1.96 (m, 4H), 2.15 (m, 1H), 4.39 (s, 2H), 4.82 (m, 1H), 5.87 (m, 1H), 5.98 (m, 1H), 6.30 (d, 2H), 7.20 (t, 1H). MS 215 (MH+).
Reaction SMILES: [CH:1]1([NH:7][CH:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16]([S:20][CH2:21][C:22](O)=[O:23])[CH2:17][CH2:18][CH3:19].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:8]([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:22](=[O:23])[CH2:21][S:20][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:9])[CH:11]=1
Reactant: CC(NC1CCCCC1)c1cccnc1
Reactant: CCCCSCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCSCC(=O)N(C1CCCCC1)C(C)c1cccnc1

Procedure:
N-[1-(3-pyridyl)ethyl]-N-cyclohexyl-α-(n-butylthio)acetamide was prepared by the method of Example 2 by reacting 5.0 g. of N-cyclohexyl-[1-(3-pyridyl)ethyl]amine with 3.6 g. of α-(n-butylthio)acetic acid and 5.0 g. of N,N'-dicyclohexylcarbodiimide in 200 ml. of dichloromethane. Oil.