Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH2:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[C:10]([CH3:16])[CH:9]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1>O>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][CH:19]=[C:18]2[O:15][C:11]1[C:10]([CH3:16])=[CH:9][C:8]([NH2:7])=[C:13]([CH3:14])[CH:12]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cc(O)c(C)cc1N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60 wt %, 0.36 g) was added to dimethyl sulfoxide (10 ml), and the mixture was stirred at 50° C. for 30 min and was then cooled to room temperature. 4-Amino-2,5-dimethylphenol (1.23 g) was added to the cooled mixture, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added thereto, and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel by development with chloroform/acetone (1/1) to give the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[NH:6][CH:5]=1.C[N:18](C=O)C>>[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:14])[F:15])[CH:11]=2)[N:6]([NH2:18])[CH:5]=1
Reactant: CN(C)C=O
Reactant: Cc1c[nH]c2ccc(C(F)(F)F)cc12
Agent: [H-]
Agent: [Na+]
Product: Cc1cn(N)c2ccc(C(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
60% NaH (1.21 g, 30.2 mmol) is added to a stirred solution of 3-methyl-5-trifluoromethyl-1H-indole (400 mg, 2.01 mmol) in DMF (6 mL) at 0° C. in portions. The mixture is stirred at 0° C. for 1 h. HOSA (1.14 g, 10.0 mmol) is added in portions at 0° C. and the mixture is allowed to warm to rt over 2 h. The reaction is quenched with aqueous saturated ammonium chloride, extracted with extracted three times with DCM. The combined organic layer is dried (Na2SO4), filtered and concentrated. The residue is chromatographed through silica gel eluting with 0-40% EtOAc in heptane to afford 3-methyl-5-trifluoromethyl-indol-1-ylamine (223 mg, 52%). MS: 215 (M+H); 1H NMR (300 MHz, CDCl3): δ=7.84 (s, 1H), 7.48 (s, 2H), 7.04 (s, 1H), 4.77 (s, 2H), 2.34 (s, 3H).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][NH:12][CH3:13].O>C1COCC1>[CH3:11][N:12]([CH3:13])[S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CNC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A solution of benzenesulfonylchloride (10 ml; 78 mmol) in THF (100 ml) was added a 40% solution of dimethylamine in H2O (20 ml; 160 mmol) such that the reaction temperature was kept below 50° C. The reaction mixture was stirred 1 h at rt. The reaction mixture was added H2O and THF removed by evaporation. The precipitate formed was isolated by filtration and air dried to give 14 g (97%) of N,N-dimethylbenzenesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:23])=O)[C:9]=2[CH3:24])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:32]([NH:34][C:35]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH3:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:38]3[CH2:37][CH2:36][C:35]([NH:34][CH2:32][CH3:33])([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39]3)=[O:23])[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CCNC1(C(N)=O)CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC1(C(N)=O)CCN(C(=O)c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2C)CC1
Yield: 46.7 %

Procedure:
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carb oxylic acid (1 eq, 20 mg, 0.052 mmol), triethylamine (3 eq, 0.02 mL, 0.157 mmol), 4-(ethylamino)-4-piperidinecarboxamide (1 eq, 9 mg, 0.052 mmol), and benzotriazole-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (1 eq, 23 mg, 0.052 mmol) was stirred in tetrahydrofuran (5 mL) for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% CMA 80/ethyl acetate and precipitated from ethyl acetate with hexane to yield pure 1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-(ethylamino)piperidine-4-carboxamide (13 mg, 46%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.10 (t, J=6.97 Hz, 3H) 1.61-1.80 (m, 2H) 2.08-2.26 (m, 5H) 2.45-2.63 (m, 2H) 3.68 (td, J=8.85, 4.43 Hz, 2H) 3.96-4.19 (m, 2H) 5.40 (br. s., 1H) 7.07 (d, J=8.29 Hz, 2H) 7.12-7.19 (m, 1H) 7.20-7.36 (m, 3H) 7.44 (d, J=1.98 Hz, 1H).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH3:5][O:6][CH:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH:12]3[CH2:17][CH2:18][O:19][C:10]([C:11]=23)=[CH:9][N:8]1[O:20][CH3:21].[OH-].[Na+]>O1CCOCC1>[C:1]([CH2:2][CH2:3][CH:14]1[CH2:15][C:16]2[CH:7]([O:6][CH3:5])[N:8]([O:20][CH3:21])[CH:9]=[C:10]3[O:19][CH2:18][CH2:17][CH:12]([C:11]=23)[CH2:13]1)#[N:4]
Reactant: C=CC#N
Reactant: COC1C2=C3C(=CN1OC)OCCC3CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC1C2=C3C(=CN1OC)OCCC3CC(CCC#N)C2
Reaction time: 24 h

Procedure:
A solution of acrylonitrile (12 ml) and 1,2,3a,4,5,6-hexahydro-7,8-dimethoxypyrano[2,3,4-de]isoquinoline (11 g), described in Example 56, in dioxane (80 ml) and 10% NaOH solution (2.5 ml) is heated and stirred on the steam bath for 24 hr. The mixture is evaporated and the residue is dissolved in a mixture of ether and a little chloroform. The solution is extracted with 2N HCl and the extracts are washed (brine), dried and evaporated. The residue is crystallized from ether and then from benzene-hexane to give the title compound, m.p. 105°-107° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.C1CN([P+](O[N:38]2N=[N:45][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1(N)C=CC=CC=1N.CCN(CC)CC>CN(C=O)C>[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH:45][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([CH2:7][N:6]2[C:5]3[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=3[NH:3][C:2]2=[O:1])=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(Cn2c(=O)[nH]c3ccccc32)cc1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1ccc(Cn2c(=O)[nH]c3ccccc32)cc1
Temperature: 23 °C
Reaction time: 4 h

Procedure:
A solution of 4-(2-Oxo-2,3-dihydro-benzoimidazol-1 -ylmethyl)-benzoic acid (0.1 mmol) in DMF (1 mL) was sequentially treated with PyBOP (0.12 mmol), 1,2-phenylenediamine (0.12 mmol) and Et3N (0.3 mmol). After stirring at 23° C. for 4 h, the reaction was filtered and the crude material was purified by HPLC to yield N-(2-Amino-phenyl)-4-(2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-benzamide. 1H NMR (400 MHz, DMSO-D6) δ ppm 4.88 (s, 2H), 5.09 (s, 2H), 6.55-6.61 (m, 1H), 6.76 (d, J=8.08 Hz, 1H), 6.93-7.04 (m, 5H), 7.14 (d, J=7.58 Hz, 1H), 7.43 (d, J=8.08 Hz, 2H), 7.93 (d, J=8.08 Hz, 2H), 9.61 (s, 1H), 11.02 (s, 1H). ESI-MS: m/z 359.3 (M+H)+.
Reaction SMILES: C1(CO[C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)CCC1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][OH:29].C(OC(C1NC2C(C=1)=C(O)C=CC=2)=O)C>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][O:29][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]2
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Reactant: COc1ccccc1CCO
Agent: CCOC(=O)c1cc2c(O)cccc2[nH]1
Product: COc1ccccc1CCOc1cccc2[nH]c(C(=O)O)cc12

Procedure:
4-[2-(2-Methoxy-phenyl)-ethoxy]-1H-indole-2-carboxylic acid (16j) is synthesized analogous to 16a from 2-(2-methoxy-phenyl)-ethanol and 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [Cl:1]C1C(C#N)=NC(Cl)=C(Cl)C=1Cl.F[C:14]1[C:15]([C:23]#[N:24])=[N:16][C:17]([F:22])=[C:18]([F:21])[C:19]=1[F:20]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Cl:1][C:14]1[C:15]([C:23]#[N:24])=[N:16][C:17]([F:22])=[C:18]([F:21])[C:19]=1[F:20]
Reactant: N#Cc1nc(Cl)c(Cl)c(Cl)c1Cl
Reactant: N#Cc1nc(F)c(F)c(F)c1F
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: ClCCl
Product: N#Cc1nc(F)c(F)c(F)c1Cl
Temperature: 160 °C
Reaction time: 1 h

Procedure:
A mixture of 3,4,5,6-tetrachloropicolinonitrile (16.1 g, 66 millimoles (mmol)) and 3,4,5,6-tetrafluoropicolinonitrile (5.9 g, 33 mmol) were heated to 160° C. under nitrogen to form a solution. To this stirred solution was added tetrabutyl phosphonium chloride (Bu4PCl; 0.36 g, 1.2 mmol), and the solution was held at 160° C. for 1 h. An aliquot was dissolved in methylene chloride (CH2Cl2) and passed through a short pad of silica gel before GC analysis. The profile of halogenated picolinonitriles was: 11.2% Cl4-PN; 11.3% 4,6-F2—PN; 2.3% 5,6-F2—PN; 19% 3,6-F2—PN; 52.6% 6-F-PN and 3.6% 4-F-PN. About 80% of the mixture is useful in the halogen exchange reaction to produce 3-chloro-4,5,6-trifluoropicolinonitrile.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:25][S:26]([NH:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:28])=[O:27]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:34]4[CH:35]=[C:30]([NH:29][S:26]([CH3:25])(=[O:27])=[O:28])[CH:31]=[CH:32][CH:33]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(NS(C)(=O)=O)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 3.7 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(methylsulfonamido)phenylboronic acid (22 mg, 0.104 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and HPLC to give N-(3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)phenyl)methanesulfonamide (0.91 mg, 4%). 1H-NMR (MeOD): 2.46 (m, 1H), 2.62 (m, 1H), 2.97 (s, 3H), 3.29 (s, 3H), 5.86 (m, 1H), 6.94 (m, 2H), 7.13 (m, 1H), 7.18 (m, 1H), 7.41 (m, 6H), 7.62 (m, 1H), 7.81 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:21]=1[C:22](Cl)=O>C1(C)C=CC=CC=1>[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:21]=1[C:22]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Cc1ccc(N)c(C(=O)O)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc2nc(-c3c(Cl)cccc3Cl)oc(=O)c2c1
Temperature: 25 °C

Procedure:
2-Amino-5-methylbenzoic acid (0.5 g) and triethyl amine (10 ml) were mixed in dry toluene (20 ml). 2,6-Dichlorobenzoyl chloride (1.52 g) was added dropwise under cooling and stirring. The mixture was subsequently heated to RT for 24 h, then heated to 80° C. for 1 h. After cooling on ice the precipitate was filtered off and the filtrate evaporated to dryness. The residue was partitioned between methylene chloride and potassium carbonate (2N), the organic layers separated, dried over magnesium sulfate and evaporated to dryness. The raw product was purified by column chromatography on silicagel using heptane/ethyl acetate as eluent.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH:24]([N:27]([CH3:43])[C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][N:29]=1)([CH3:26])[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[CH:30][N:29]=[C:28]([N:27]([CH:24]([CH3:26])[CH3:25])[CH3:43])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC(C)N(C)c1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccnc(N(C)C(C)C)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and isopropyl-methyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-amine (Stage 130.1.1) to give the title compound as a white solid. (HPLC: tR 2.24 min (Method A); M+H=442 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.14-8.08 (m, 3H), 7.97-7.93 (m, 1H), 7.69-7.66 (m, 1H), 6.69-6.66 (m, 1H), 6.56-6.53 (m, 1H), 4.90 (hp, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 2.85 (s, 3H), 1.96 (s, 3H), 1.17-1.11 (m, 6H))
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([NH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(C(=O)O)cc1
Temperature: 0 °C

Procedure:
To 215.2 g (2.72 mole) of pyridine in 1250 ml of dichloromethane is added 238 g (1.44 mole) of ethyl 4-aminobenzoate. After cooling to 0° C., a solution of 177.6 g (1.55 mole) of methanesulfonyl chloride in 250 ml of dichloromethane is added with stirring. Upon completion of the addition, the ice bath is removed and the reaction is stirred for one hour at room temperature.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][Si:17]([CH3:19])([CH3:18])[C:20]#[C:21][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccc2c(c1)CC1(CC2)OCCO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2c(c1)CC1(CC2)OCCO1
Yield: 40.2 %

Procedure:
A solution of 7'-bromo-3',4'-dihydrospiro[1,3-dioxolane-2,2'(1H)-naphthalene] (3.40 g, 12.6 mmol), trimethylsilylacetylene (7.0 ml, 50 mmol) (Aldrich), triphenylphosphine (0.66 g, 2.50 mmol), and palladium acetate (0.28 g, 1.25 mmol) in triethylamine (18 ml) was stirred at 70° C. for 18 hours and then concentrated in vacuo. The residue was absorbed onto silica gel from a diethyl ether solution and partially purified by elution through silica gel (15 g) with diethyl ether: hexane (1:9). Further purification by chromatography on silica gel eluting with ethyl acetate:hexane (1:19) gave 3',4'-dihydro-7'[2-(trimethylsilyl)ethynyl]spiro[1,3-dioxolane-2,2'(1'H)-naphthalene] (1.45 g). 1H NMR (CDCl3 200 MHz) δ: 0.23 (s, 9H, SiMe3), 1.93 (t, J=7 Hz, 2 CH2), 2.95 (t, J=7 Hz, 2H, CH2), 4.02 (s, 4H, OCH2CH2O), 7.03 (d, J=8 Hz, 1H, Ar), 7.17 (s, 1H, Ar), 7.21 (d, J=8 Hz, 1H, Ar).
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[CH3:13][C:14]([NH2:28])([CH3:27])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[NH:18][CH:17]=1>C(O)C>[CH3:27][C:14]([NH:28][CH2:12][C@@H:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:4]([N:3]=[N:2][N:1]=2)[CH:9]=1)[OH:11])([CH3:13])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[NH:18][CH:17]=1
Reactant: COc1ccc2[nH]cc(CC(C)(C)N)c2c1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Solvent: CCO
Product: COc1ccc2[nH]cc(CC(C)(C)NC[C@H](O)c3ccc4nnnn4c3)c2c1

Procedure:
A solution of 598 mg of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane and 782 mg of (1,1-dimethyl-2-(5-methoxy-1H-indol-3-yl)ethyl amine (B. Heath-Brown and P. G. Philpott, J. Chem. Soc., 7165 (1965)) in 12 ml of absolute ethanol was heated at reflux for 44 hours. The reaction mixture was concentrated and the residue (1.15 g) was chromatographed on silica gel (95:5:0.5 CH2Cl2 :MeOH:NH4OH) to give 0.997 g of (R)-α-[[(1,1-dimethyl-2-(5-methoxy-1H-indol-3-yl)ethyl)amino]methyl]tetrazolo[1,5-a]pyridine-6-methanol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=1[C:18]([F:21])([F:20])[F:19].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=2[C:18]([F:19])([F:21])[F:20])[CH2:2][CH2:3]1
Reactant: OCC1CCNCC1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(N2CCC(CO)CC2)c(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 79.6 %

Procedure:
To a solution of piperidin-4-ylmethanol (2.19 g) in DMSO (40 mL) were added 4-fluoro-3-(trifluoromethyl)benzonitrile (3.00 g) and potassium carbonate (3.21 g). The reaction mixture was stirred at 100° C. for 4 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.59 g).
Reaction SMILES: [CH2:1]([CH2:8][N:9]=[C:10]([NH2:12])[NH2:11])[CH2:2][C@H:3]([NH2:7])[C:4]([OH:6])=[O:5].O.[CH2:14]([O:18][CH2:19][CH:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]1[O:17][CH2:16]1.[ClH:27]>C(O)C>[ClH:27].[OH:17][CH:15]([CH2:14][O:18][CH2:19][CH:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][NH:7][C@H:3]([C:4]([OH:6])=[O:5])[CH2:2][CH2:1][CH2:8][NH:9][C:10](=[NH:12])[NH2:11]
Reactant: NC(N)=NCCC[C@H](N)C(=O)O
Reactant: CCCCC(CC)COCC1CO1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCCC(CC)COCC(O)CN[C@@H](CCCNC(=N)N)C(=O)O
Temperature: 78 °C
Reaction time: 4 h

Procedure:
In a four-necked 200-mL flask equipped with a reflux cooling tube, a dropping funnel, a thermometer and a stirring blade, 9.4 g (53.7 mmol) of L(+)-arginine, 50.0 g of water and 50.0 g of ethanol were placed, and the mixture was heated to 78° C. while being stirred under a nitrogen atmosphere. Subsequently, the inside of the reaction system was maintained at 78 to 80° C., 10.0 g (53.7 mmol) of 2-ethylhexyl glycidyl ether was added dropwise thereto. Thereafter, the mixture was aged for 4 hours at 78 to 80° C., and then was returned to room temperature. Subsequently, 9.8 g (53.7 mmol) of a 6 mol/L aqueous solution of hydrochloric acid was added thereto to neutralize the mixture. Water and ethanol were completely distilled off from the reaction solution under reduced pressure, and thus 21.6 g of N-[2-hydroxy-3-(2-ethylhexyl)oxypropyl]-L-arginine hydrochloride was obtained as a white solid. This compound corresponds to the compound 2 of Table 1.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:28]2[O:29][C@@H:27]2[C@@:26]2([CH3:30])[C:7](=[CH:8][C@@H:9]([OH:32])[C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:21][CH2:20][CH2:19][O:18]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].[C:33]([O:36][C@H:37]1[C@@H]2O[C@@H]2[C@@]2(C)C(=C[C@@H](O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C2OCC(C)(C)CO2)C)C1)(=[O:35])C>>[C:1]([O:4][C@H:5]1[C@@H:28]2[O:29][C@@H:27]2[C@@:26]2([CH3:30])[C:7](=[CH:8][C@@H:9]([O:32][C:33]([O:36][CH3:37])=[O:35])[C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:18][CH2:19][CH2:20][O:21]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Reactant: CC(=O)O[C@@H]1CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C5OCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Product: COC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCCO4)CC[C@H]3[C@H]12
Yield: 74.9 %

Procedure:
The procedure of Example 12 was repeated except that 44.6 mg (0.1 mmole) of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxy-7α-hydroxypregna-5-en-3β-yl acetate was used in lieu of 49.0 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-hydroxypregna-5-en-3β-yl acetate to give 37.8 mg of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxy-7α-methoxycarbonyloxypregn-5-en-3β-yl acetate (yield: 75%)
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.IC1C=C(NC(=O)C2C=CC(N3CCOCC3)=NC=2)C=CC=1C>>[I:16][C:11]1[CH:10]=[C:9]([NH:8][C:6]([C:5]2[CH:17]=[CH:18][C:2]([N:31]3[CH2:32][CH2:33][CH:28]([C:24]4[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:34])[F:35])[CH:23]=4)[CH2:29][CH2:30]3)=[N:3][CH:4]=2)=[O:7])[CH:14]=[CH:13][C:12]=1[CH3:15]
Reactant: FC(F)(F)c1cccc(C2CCNCC2)c1
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1I
Agent: Cc1ccc(NC(=O)c2ccc(N3CCOCC3)nc2)cc1I
Agent: Cl
Product: Cc1ccc(NC(=O)c2ccc(N3CCC(c4cccc(C(F)(F)F)c4)CC3)nc2)cc1I

Procedure:
4-(3-Trifluoromethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (3-iodo-4-methyl-phenyl)-amide was prepared from 6-chloro-N-(3-iodo-4-methyl-phenyl)-nicotinamide and 4-(3 trifluoromethyl-phenyl)piperidine hydrochloride in a manner similar to the one described in the synthesis of N-(3-iodo-4-methyl-phenyl)-6-morpholin-4-yl-nicotinamide above. The product was isolated after silica gel column purification with 20-40% EtOAc in hexanes. HRMS m/z calcd for C25H23N3OF3I [M+H]+: 566.0911. Found: 566.0910. START