Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[Cl:21])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[CH3:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(Cl)Cl>[Cl:21][C:15]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=1[O:13][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][C:7]=1[S:9]([N:26]1[CH2:27][CH2:28][CH:23]([CH3:22])[CH2:24][CH2:25]1)(=[O:11])=[O:10]
Reactant: N#Cc1ccc(Oc2cc(Cl)ccc2Cl)c(S(=O)(=O)Cl)c1
Reactant: CC1CCNCC1
Solvent: ClCCl
Product: CC1CCN(S(=O)(=O)c2cc(C#N)ccc2Oc2cc(Cl)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
Sulfonyl chloride 36 (0.20 g, 0.55 mmol) was combined with 4-methylpiperidine (0.16 g, 1.65 mmol) and TEA (0.17 g, 1.65 mmol) in DCM (5 mL). The solution was stirred overnight at room temperature. Upon consumption of starting material, as determined via TLC (75% EtOAc in hexanes), the reaction mixture was partitioned between DCM and water. After 3 extractions, the combined organic extracts were washed sequentially with saturated aqueous NaHCO3, water, and brine. The crude product was chromatographed on normal-phase silica to yield the desired product 87 (0.167 g, 71.4% yield, 97.1% pure). 1H NMR (500 MHz, DMSO-d6): δ 8.28 (d, J=2 Hz, 1H), 8.07 (dd, J1=9 Hz, J2=2 Hz, 1H), 7.72 (d, J=8 Hz, 1H), 7.46 (dd, J1=5 Hz, J2=2 Hz, 1H), 7.44 (d, J=2 Hz, 1H), 7.10 (d, J=9 Hz, 1H), 3.70 (d, J=12 Hz, 2H), 2.74 (ddd, J1=J2=12 Hz, J3=2 Hz, 2H), 1.65 (dd, J1=13 Hz, J2=2 Hz, 2H), 1.44 (m, 1H), 1.09 (ddd, J1=28 Hz, J2=13 Hz, J3=4 Hz, 2H), 0.87 (d, J=7 Hz, 3H); MS (ESI, EI+): m/z=425.11 (MH+); melting point: 127-130° C.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH2:23][CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])(=[O:21])=[O:20])=[CH:15][CH:14]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH2:23][CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])(=[O:20])=[O:21])=[CH:15][CH:14]=2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ccnc12
Reactant: CCN(CC)CCNS(=O)(=O)c1ccc(N)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCN(CC)CCNS(=O)(=O)c1ccc(Nc2ncc(Br)n3ccnc23)cc1
Temperature: 85 °C

Procedure:
A mixture of 5,8-dibromoimidazo[1,2-a]pyrazine (1.0 g, 3.6 mmol), 4-amino-N-(2-diethylaminoethyl)benzenesulfonamide (109 mg, 0.4 mmol), Pd2(dba)3 (7 mg, 0.007 mmol), Xantphos (8.4 mg, 0.015 mmol) and Cs2CO3 (167 mg, 0.52 mmol) in dioxane is heated at 85° C. under nitrogen for 18 hours. The reaction is cooled to room temperature then evaporated to dryness. The residue is chromatographed on silica gel, eluting with DCM then 98:2 DCM:NH3 (7N in MeOH), and the fractions containing the title compound are combined and evaporated to afford a dark oil. This oil contains an impurity, but is used in the subsequent step without further purification.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:4]1[CH:31]=[CH:30][C:7]2[N:8]([CH2:12][CH2:13][O:14][C:15]3[CH:29]=[CH:28][C:18]([O:19][C:20]([CH3:27])([CH3:26])[C:21]([O:23]CC)=[O:22])=[CH:17][CH:16]=3)[C:9](=[O:11])[S:10][C:6]=2[CH:5]=1.[OH-].[K+].Cl>C(O)C>[OH:1][N:2]=[C:3]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:4]1[CH:31]=[CH:30][C:7]2[N:8]([CH2:12][CH2:13][O:14][C:15]3[CH:29]=[CH:28][C:18]([O:19][C:20]([CH3:27])([CH3:26])[C:21]([OH:23])=[O:22])=[CH:17][CH:16]=3)[C:9](=[O:11])[S:10][C:6]=2[CH:5]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCn2c(=O)sc3cc(C(=NO)c4ccccc4)ccc32)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(Oc1ccc(OCCn2c(=O)sc3cc(C(=NO)c4ccccc4)ccc32)cc1)C(=O)O
Temperature: 25 °C

Procedure:
To a solution of the compound obtained in Example 32 (0.5 g) in 5 ml of ethanol 95° there is added potassium hydroxide (107 mg) dissolved in 1 ml of ethanol 95°. The reaction mixture is heated at reflux overnight. After cooling to ambient temperature, the solution is acidified using 1N HCl. The precipitate obtained is then filtered and purified on a reverse phase, RP18, eluant MeOH/H2O 6/4, to yield the title compound in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([I:36])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:12][CH2:13][C@H:14]([CH2:17][NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:15][CH2:16]3)=[N:9][C:10]=2[I:36])[CH:5]=[CH:6][N:7]=1
Reactant: O=C(NC[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1)OCc1ccccc1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NC[C@H]1CC[C@H](c2nc(I)c3c(Cl)nccn32)CC1)OCc1ccccc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of benzyl {[trans-4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}carbamate (1.49 g, 0.00374 mol) in DMF (0.6 mL) was added NIS (1.0 g, 0.0045 mol). The reaction mixture was stirred at 55° C. overnight then diluted with EtOAc (20 mL), washed with water (2×40 mL) and brine (20 mL), then dried over Na2SO4 and concentrated in vacuo. The crude mixture thus isolated was chromatographed over silica gel eluting with hexane → hexane:EtOAc 1:1 to afford 1.7 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([Sn](C)(C)C)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br[C:17]1[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=1>>[CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:17]3[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Cn1ccnc1Br
Reactant: COc1cccc2oc([Sn](C)(C)C)cc12
Product: COc1cccc2oc(-c3nccn3C)cc12
Yield: 53.4 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 87 using 4-methoxy-2-(trimethylstannyl)benzo(b)furan (5.26 g), 2-bromo-1-methylimidazole (2.72 g) and bistriphenylphosphinepalladium dichloride (593 mg), the title compound (2.06 g) was obtained as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:22](O)[CH3:23]>>[CH2:22]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([OH:1])[CH:3]=1)[CH3:23]
Reactant: CCO
Reactant: Cc1ccc(C(=O)O)cc1O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccc(C)c(O)c1

Procedure:
A mixture of 3-hydroxy-4-methylbenzoic acid (25.42 g, 167 mmol) (TCl US) and concentrated sulfuric acid (3 mL) in absolute ethanol (180 mL) was heated at reflux for 20 hours. After cooling, solid sodium bicarbonate (10 g) was added to neutralize the acid. Mixture was partitioned between diethyl ether (2×400 mL) and water (2×300 mL). Organic layers were washed with brine (300 mL), combined, dried (MgSO4), filtered, and concentrated. Residue was recrystallized from hexanes to give 3-hydroxy-4-methyl-benzoic acid ethyl ester as white crystals in two crops. (Yield 29.14 g, 96.8%).
Reaction SMILES: [CH:1]([S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)(=[O:5])=[O:4])=[CH2:2].[CH3:22][NH:23][CH3:24]>C1COCC1.O>[CH3:22][N:23]([CH3:24])[CH2:2][CH2:1][S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)(=[O:5])=[O:4]
Reactant: CNC
Reactant: C=CS(=O)(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCS(=O)(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.08 h
Yield: 86.9 %

Procedure:
A solution of the above vinylsulfonamide (3.10 g, 10 mmol) in 20 mL of THF was treated with an excess (10 mL, 80 mmol) of 40% aqueous dimethylamine. After 5 min, the mixture was diluted with water to give 3.09 g (87% yield) of benzyl 4-{[2-(dimethyl-amino)ethyl]sulfonyl}-1-piperazinecarboxylate as a white solid: mp (aq. MeOH) 101-103° C.; 1H NMR (CDCl3) δ 7.40-7.30 (m, 5H), 5.15 (s, 2H), 3.59 (m, 4H), 3.26 (m, 4H), 3.07 (dd J=8.1, 6.4 Hz, 2H), 2.74 (dd, J=8.0, 6.4 Hz, 2H), 2.25 (s, 6H); Anal. Calcd. for C16H25N3O4S: C, 54.1; H, 7.1; N, 11.8. Found: C, 53.8; H, 6.9; N, 11.8%.
Reaction SMILES: CC1C=CC(S(OCC2CC3C=CC=C(C4C=CC=CC=4F)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[N:33]([CH2:36][CH:37]1[CH2:41][C:40]2[CH:42]=[CH:43][CH:44]=[C:45]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[F:52])[C:39]=2[O:38]1)=[N+]=[N-].[N-]=[N+]=[N-]>[Pt]>[F:52][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[C:45]1[C:39]2[O:38][CH:37]([CH2:36][NH2:33])[CH2:41][C:40]=2[CH:42]=[CH:43][CH:44]=1
Reactant: [N-]=[N+]=NCC1Cc2cccc(-c3ccccc3F)c2O1
Agent: [Pt]
Agent: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccccc4F)c3O2)cc1
Agent: [N-]=[N+]=[N-]
Product: NCC1Cc2cccc(-c3ccccc3F)c2O1
Yield: 83 %

Procedure:
Treatment of (±)-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (3.13 g, 7.85 mmol) with sodium azide (2.04 g, 31.42 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.21 g, 5 wt. %) generally according to the procedure described for Example 1 provided 1.81 g (83%) of (±)-1-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 244-246° C.; Anal. calcd. for C15H14FNOHCl: C, 64.4; H, 5.4; N, 5.01. Found: C, 63.98; H, 5.4; N, 4.89.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][PH:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:20][C@H:21]([C:29]([NH:31][C@H:32]([C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]1([CH2:7][CH2:8][P:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([NH:20][C@H:21]([C:29]([NH:31][C@H:32]([C:37]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[PH](CCc1ccccc1)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NP(=O)(CCc1ccccc1)OCc1ccccc1)C(=O)OCc1ccccc1

Procedure:
(2-Phenylethyl)phosphinic acid, phenylmethyl ester is reacted with L-phenylalanyl-L-leucine, phenylmethyl ester, hydrochloride salt according to the procedure of Example 1(c) to yield N-[N-[(2-phenylethyl)(phenylmethoxy)phosphinyl]-L-phenylalanyl]-L-leucine, phenylmethyl ester.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([N:10]3[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[N:11]3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.C(O)C.O.[Cl-].[NH4+]>[Fe].CO.C(Cl)(Cl)Cl>[CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([N:10]3[CH:14]=[C:13]([NH2:15])[CH:12]=[N:11]3)[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1cnn(C2CCN(C3CC3)CC2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1cnn(C2CCN(C3CC3)CC2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 67.1 %

Procedure:
A mixture of 1-cyclopropyl-4-(4-nitro-1H-pyrazol-1-yl)piperidine (952 mg), ethanol (6 mL), water (2 mL), and ammonium chloride (108 mg) was heated to 80° C., and iron powder (1.13 g) was added thereto, followed by stirring at 80° C. for 3 hours. Chloroform and methanol were added thereto, followed by filtration through celite, and the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-95:4.5:0.5, NH2 type: eluent; hexane:ethyl acetate=3:7-0:1) to obtain 1-(1-cyclopropylpiperidin-4-yl)-1H-pyrazol-4-amine (558 mg) as a pale pink solid.
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS(O[CH2:22][CH2:23][F:24])(=O)=O>CN(C)C=O>[F:24][CH2:23][CH2:22][O:16][C:13]1[CH:12]=[CH:11][C:10]([O:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)OCCF
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FCCOc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.2 %

Procedure:
To a suspension of sodium hydride (60% oil dispersion; 4.0 g) in N,N-dimethylformamide (100 ml), 4-phenoxyphenol (18.6 g) was added at a temperature of 0 to 5° C., and the resultant suspension was stirred at room temperature for 1 hour. 2-Fluoroethyl methanesulfonate (14.2 g) was added thereto. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was subjected to post-treatment as in Example 1 to give 1-(2-fluoroethoxy)-4-phenoxybenzene (Compound No. 22) (20.0 g). nD25.0 1.5622.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10](=[O:13])([O-])[O-:11].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.F[B-](F)(F)F.C1(P(C2CCCCC2)C2C(OC)=CC(OC)=CC=2OC)CCCCC1>[CH3:6][C:1]1[C:10](=[O:13])[O:11][C@@H:3]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:2]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cc(OC)c(P(C2CCCCC2)C2CCCCC2)c(OC)c1
Solvent: Cc1ccccc1
Product: CC1=C(c2ccccc2)[C@H](c2ccccc2)OC1=O
Yield: 160.6 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 5. The difference is that, the reactans are (S)-3-methyl-4-chloride-5-phenyl-2(5H)— furanone (20.2 mg, 0.097 mmol), phenylboronic acid (19.0 mg, 98%, 0.15 mmol), palladium acetate (1.1 mg, 0.01 mmol), dicyclohexyl(2,4,6-trimethoxyphenyl)phosphine tetrafluoroborate (2.5 mg, 0.0055 mmol), potassium carbonate (62.3 mg, 0.45 mmol) are reacted in 2 mL of anhydrous toluene at 110° C. for 6 minutes and 20.1 mg (S)-3-methyl-4,5-diphenyl-2(5H)-furanone is obtained. The yield is 83%, 99% ee.
Reaction SMILES: Cl.[Si]([O:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[N:19][C:20]=1[CH:21](OC)[O:22]C)[N:17]([C:26]([NH:28][C:29]1[CH:34]=[C:33]([N:35]3[CH2:40][CH2:39][O:38][CH:37]([CH2:41][N:42]([CH3:44])[CH3:43])[CH2:36]3)[C:32]([C:45]#[N:46])=[CH:31][N:30]=1)=[O:27])[CH2:16][CH2:15][CH2:14]2)(C(C)(C)C)(C)C.C([O-])(O)=O.[Na+]>C1COCC1>[C:45]([C:32]1[C:33]([N:35]2[CH2:40][CH2:39][O:38][CH:37]([CH2:41][N:42]([CH3:44])[CH3:43])[CH2:36]2)=[CH:34][C:29]([NH:28][C:26]([N:17]2[C:18]3[C:13](=[CH:12][C:11]([CH2:10][OH:9])=[C:20]([CH:21]=[O:22])[N:19]=3)[CH2:14][CH2:15][CH2:16]2)=[O:27])=[N:30][CH:31]=1)#[N:46]
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Nc1cc(N2CCOC(CN(C)C)C2)c(C#N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CC1CN(c2cc(NC(=O)N3CCCc4cc(CO)c(C=O)nc43)ncc2C#N)CCO1

Procedure:
Aqueous hydrochloric acid (3 M, 1 ml) was added to a solution of 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-(2-((dimethylamino)methyl)morpholino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 76, 168 mg, 0.262 mmol) in THF (1.6 ml) at room temperature. After stirring for 1 h saturated aqueous NaHCO3 was added, the mixture extracted with DCM (3×), the organic layers dried over Na2SO4 and evaporated. The residue was sonicated with EtOAc (2 ml) and hexanes (3 ml) and then filtered to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:25][S:26]([C:29]1[CH:38]=[CH:37][C:32](/[CH:33]=[CH:34]/[CH:35]=O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][C@@H:19]1[CH2:20][O:21][C@@H:35](/[CH:34]=[CH:33]/[C:32]2[CH:37]=[CH:38][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=2)[O:23][CH2:22]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CS(=O)(=O)c1ccc(/C=C/C=O)cc1
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/c2ccc(S(C)(=O)=O)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 58 %

Procedure:
Reaction and treatment were carried out in the same manner as in Example 4 using (2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol and trans-4-(methylsulfonyl)cinnamaldehyde to obtain the title compound, a major product as an oil in a yield of 58%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH2:12].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[I:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1I
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(C(F)(F)F)cc1I
Temperature: 105 °C
Yield: 32.3 %

Procedure:
A mixture of 2-iodo-4-(trifluoromethyl)benzenamine (11.0 g, 0.0382 mol), pyridine (40 ml), methanesulfonylchloride (5.3 g, 0.046 mol) and DMAP (0.46 g, 0.0038 mol) in a 100 ml RB flask was heated slowly to 105° C. and maintained the same temperature for over night. The reaction mixture was concentrated to remove the pyridine. The crude product obtained was purified by column chromatography using 10% ethyl acetate in pet ether as eluent to get N-(2-iodo-4-(trifluoromethyl)phenyl)methanesulfonamide (4.5 g, 32%) as white solid. 1H NMR (400 MHz, CDCl3) δ 3.08 (s, 3H), 6.88 (bs, 1H), 7.65 (d, 1H), 7.75 (d, 1H), 8.07 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].[CH3:25][C:26]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=[C:28]([NH2:41])[N:27]=1>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18]([C:31]4[C:26]([CH3:25])=[N:27][C:28]([NH2:41])=[N:29][CH:30]=4)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: Cc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Product: Cc1nc(N)ncc1-c1ccc2c(c1)-c1nc(C(=O)N(CCO)C(C)C)sc1CCO2
Yield: 1.1 %

Procedure:
Following the procedure for 277, 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide (52.2 mg, 0.127 mmol) and 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (35.8 mg, 0.152 mmol) were reacted to give 278 (0.6 mg, 1% yield M+1 440.1)
Reaction SMILES: [Na].C([C:5]1[C:6](CC(C)C)=[C:7]([C:18]([O:20]C)=[O:19])[C:8](C(F)F)=[N:9][C:10]=1C(F)(F)F)(=O)C.N(OCCC(C)C)=O>CO>[N:9]1[CH:10]=[CH:5][CH:6]=[C:7]([C:18]([OH:20])=[O:19])[CH:8]=1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(C)=O)c1CC(C)C
Agent: CC(C)CCON=O
Agent: [Na]
Solvent: CO
Product: O=C(O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 313.5 %

Procedure:
This example illustrates the preparation of Compound 101 an examples of the formation of the heterocycle by cycloaddition reaction. Sodium (7.87 g, 0.35 mol) was cautiously added in portions to 250 mL methanol under nitrogen. Methyl 5-acetyl-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (20 g, 0.057 mol) was added at 25° C., followed by dropwise addition of isoamyl nitrite (33.15 g, 0.283 mol). The mixture was stirred overnight at 25° C., then quenched with ice/concentrated HCl slush, and extracted with ether. The combined ether layers were washed with saturated sodium bicarbonate and dried (MgSO4). The solvent was evaporated in vacuo and the residue purified by HPLC with 10% ethyl acetate-hexane to give 22 g (99%) of 3-pyridinecarboxylic acid, 2-(difluoromethyl)-5-((hydroxyimino)acetyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-, methyl ester, as a yellow solid. m.p. 84°-86° C.
Reaction SMILES: [F:1][C:2]1[C:21]([I:22])=[CH:20][C:5]2[C:6]3[N:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][C:7]=3[CH:16]3[CH2:19][CH:18]([C:4]=2[CH:3]=1)[CH2:17]3.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:32][C:33]1[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=1>CN(C)C=O>[F:1][C:2]1[C:21]([I:22])=[CH:20][C:5]2[C:6]3[N:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]([CH2:32][C:33]4[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=4)[C:7]=3[CH:16]3[CH2:19][CH:18]([C:4]=2[CH:3]=1)[CH2:17]3
Reactant: Cn1nccc1CCl
Reactant: CCOC(=O)c1nc2c([nH]1)C1CC(C1)c1cc(F)c(I)cc1-2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2c(n1Cc1ccnn1C)C1CC(C1)c1cc(F)c(I)cc1-2
Temperature: 50 °C
Yield: 61.8 %

Procedure:
To a mixture of ethyl 8-fluoro-9-iodo-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxylate (100 mg at 69% purity LCMS-UV215), potassium carbonate (50 mg, 0.36 mmol) and sodium iodide (73 mg, 0.48 mmol) was introduced a solution of 5-(chloromethyl)-1-methylpyrazole (64 mg, 0.48 mmol) in N,N-dimethylformamide (5 mL). After warming to 50° C. for 4 hr the reaction mixture was evaporated in vacuo. The residue was suspended in ethyl acetate (40 mL), washed with saturated aqueous sodium bicarbonate (2×10 mL), water (2×10 mL) and brine (10 mL) and the organic extract dried over sodium sulfate. Following filtration, the filtrate was evaporated onto silica gel in vacuo and the dry-loaded material purified by silica gel flash column chromatography (eluent: heptanes/ethyl acetate gradient). The title compound (78 mg, 0.15 mmol, 88%) was furnished as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 1.45 (t, J=7.3 Hz, 3H), 1.67-1.74 (m, 2H), 2.92 (dq, J=8.2, 2.8 Hz, 2H), 3.38 (dt, J=7.3, 3.8 Hz, 1H), 3.58 (dt, J=8.2, 3.8 Hz, 1H), 3.92 (s, 3H), 4.42 (q, J=6.9 Hz, 2H), 5.59 (d, J=1.6 Hz, 1H), 5.74 (s, 2H), 6.82 (d, J=8.9 Hz, 1H), 7.34 (d, J=1.8 Hz, 1H), 8.86 (d, J=6.9 Hz, 1H); M+1=507.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7](O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].CN(C=O)C.S(Cl)([Cl:18])=O.O>C1(C)C=CC=CC=1>[Cl:18][CH:7]1[CH2:8][CH2:9][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]1
Reactant: O=S(Cl)Cl
Reactant: CCCC1CCC(O)CC1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCC1CCC(Cl)CC1

Procedure:
100.0 g (0.70 mol) of 4-propylcyclohexanol are initially introduced in 1200 ml of toluene together with 2.7 ml of DMF, and the mixture is heated to reflux. 255 ml (3.52 mol) of thionyl chloride are carefully metered in, and the batch is heated for a further 4 h. After cooling, the mixture is added to water, and the organic phase is separated off. The aqueous phase is extracted with toluene, and the combined organic phases are washed with water and saturated sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography (SiO2, n-heptane), giving 1-chloro-4-propylcyclohexane as a colourless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[C:15](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[N:7]([CH3:15])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c2cc(Br)ccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cn(C)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.3 %

Procedure:
To a mixture of 25 g (98.39 mmol) of 6-bromo-1H-indole-3-carboxylic acid methyl ester and 27.20 g (196 mmol) of potassium carbonate in 300 mL of acetonitrile is added at room temperature Methyl Iodide (20.95 g, 147.6 mmol). The reaction mixture is stirred at room temperature for 3 days. The solvent is evaporated, 500 ml of water is added, and the organic layer is extracted with (3×300 ml) ethyl acetate. The organics are combined, dried over magnesium sulfate and evaporated. The crude is purified by silica gel chromatography eluting with hex/EtOAc 8:2. The title compound (23.3 g (88%)) is obtained as a brown solid. MS (m/e): 268 (M+1).