Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:7]=1[O:15][CH3:16].O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH:9]=[CH:8][C:7]=1[O:15][CH3:16])[NH2:12]
Reactant: COc1ccc([N+](=O)[O-])cc1OCCCCl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(N)cc1OCCCCl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 39.8 %

Procedure:
A mixture of 2-(3-chloropropoxy)-1-methoxy-4-nitrobenzene (2.15 g, 8.77 mmol) and tin (II) chloride dihydrate (6.1 g, 27.11 mmol) in 50 mL of ethyl acetate was heated at reflux for 6.5 hours. The reaction mixture was cooled to room temperature and poured into 250 mL of saturated aqueous sodium bicarbonate. After stirring for 40 minutes, additional ethyl acetate was added and the layers were separated. The organic layer was washed with saturated sodium bicarbonate and water then dried over magnesium sulfate and filtered. The solution was concentrated in vacuo and purified by flash column chromatography, eluting with 1:1 hexane: ethyl acetate, to provide 753 mg of 3-(3-chloropropoxy)-4-methoxyaniline as a dark brown oil; 1H NMR (400 MHz, DMSO-d6) δ 2.13 (m, 2H), 3.62 (s, 3H), 3.78 (t, J=6 Hz, 2H), 3.96 (t, J=6 Hz, 2H), 4.77 (br s, 2H), 6.10 (dd, J=8, 2 Hz, 1H), 6.29 (d, J=2 Hz, 1H), 6.66 (d, J=8 Hz, 1H); MS (ES) m/z216.1, 218.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:12]=[C:11]([Cl:21])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O.C(N(CC)CC)C.C(N=C=NCCCN(C)C)C.[F:40][C:41]([F:51])([F:50])[O:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=1>ClCCl>[Cl:21][C:11]1[CH:12]=[C:13]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:14]=[C:2]([Cl:1])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8](=[O:10])[NH:47][C:46]1[CH:48]=[CH:49][C:43]([O:42][C:41]([F:40])([F:50])[F:51])=[CH:44][CH:45]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)CCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)Nc1ccc(OC(F)(F)F)cc1
Yield: 72 %

Procedure:
To a solution of 0.26 g of 4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyric acid and 0.07 g of triethylamine dissolved in 5 ml of dichloromethane was added dropwise 0.14 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC) hydrochloride, while stirring under ice cooling. After stirring for 30 minutes, a solution of 0.12 g of 4-trifluoromethoxyaniline dissolved in 5 ml of dichloromethane was added dropwise. After stirring at room temperature for 12 hours, the reaction mixture was concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.26 g of 3,5-dichloro-4-(3-(N-(4-trifluoromethoxyphenyl)carbamoyl)propyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (70% yield), m.p., 88.8° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][NH2:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][NH:36][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: COCCOCCN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 47 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-methoxy-ethoxy)-ethyl]-amide (44 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), 2-(2-methoxy-ethoxy)-ethylamine (24 mg), HBTU (84 mg), and DIEA (48 uL). LC/MS: m/z 511.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.40 (bs, 1H), 8.50 (t, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.78 (d, 1H), 7.74 (d, 1H), 7.50 (d, 1H), 7.36 (d, 1H), 3.64 (s, 3H), 3.59-3.53 (m, 4H), 3.49-3.41 (m, 4H), 3.25 (s, 3H).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:34])[C@H:5]([CH2:30][CH2:31][S:32][CH3:33])[NH:6][C:7](=[O:29])[C:8]1([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1>CCOC(C)=O>[ClH:1].[CH3:2][O:3][C:4](=[O:34])[C@H:5]([CH2:30][CH2:31][S:32][CH3:33])[NH:6][C:7](=[O:29])[C:8]1([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: COC(=O)[C@H](CCSC)NC(=O)C1(Cc2ccccc2C)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)C1(Cc2ccccc2C)CCNCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stream of anhydrous HCl gas was bubbled through a cold (0° C.) solution of (N-t-butoxycarbonyl-4-(2-methylbenzyl) isonipecotyl) L-methionine methyl ester (315 mg, 0.66 mmol) in 30 ml of EtOAc for 10 min. and the reaction solution stirred 1 h more at 0° C. The solution was then purged with argon for 10 min. and allowed to warm to room temp. Concentration of the solution in vacuo afforded the product as a colorless gum.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[C:4]([OH:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.[H-].[Na+].F[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1>CN(C=O)C>[CH3:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[C:4]([O:14][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1ccc(-c2c(C)cc3cc(OC)ccc3c2O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(C)cc3cc(OC)ccc3c2Oc2ccc(C=O)cc2)cc1
Yield: 81 %

Procedure:
3-Methyl-6-(methyloxy)-2-[4-(methyloxy)phenyl]-1-naphthalenol (45) (0.30 g, 1.00 mmol) was treated with NaH in DMF followed by addition of 4-fluorobenzaldehyde to give 0.32 g (81%) of the title compound (46) as a light yellow foam. 1H NMR (400 MHz, CDCl3): δ 2.26 (s, 3H), 3.76 (s, 3H), 3.93 (s, 3H), 6.71 (d, J=8.8 Hz, 2H), 6.79 (d, J=8.7 Hz, 2H), 7.02-7.07 (m, 3H), 7.14 (d, J=2.6 Hz, 1H), 7.58 (s, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.66 (d, J=9.1 Hz, 1H), 9.80 (s, 1H). LCMS (APCI): m/z 399 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([Br:20])[CH:18]=3)[NH:13][CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.N1C=CC=CC=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[S:36](Cl)(=[O:38])=[O:37].Cl>O1CCCC1>[Br:20][C:17]1[CH:18]=[C:19]2[C:11]([C:9]([C:4]3[C:3]([F:21])=[C:2]([NH:1][S:36]([C:30]4[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:29]=4[F:28])(=[O:38])=[O:37])[CH:7]=[CH:6][C:5]=3[F:8])=[O:10])=[CH:12][NH:13][C:14]2=[N:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(c1c(F)ccc(NS(=O)(=O)c2cc(F)ccc2F)c1F)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.9 %

Procedure:
Into a reaction flask, (3-amino-2,6-difluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (7, 140 mg, 0.40 mmol) is stirred in 3 mL of tetrahydrofuran and pyridine (0.3 mL, 4.0 mmol) is added, followed by 2,5-difluoro-benzenesulfonyl chloride (25, 127 mg, 0.596 mmol). The reaction is stirred at room temperature for 24 hours, then adjusted to pH 4 with addition of 1M aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with brine, dried with sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography to provide the desired compound (26, 190 mg, 90%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][N:5]([CH3:7])[CH3:6].C(O)(C)C.C(=O)=O.C([Li])CCC.[B:24](OC)([O:27][CH3:28])[O:25][CH3:26]>O1CCCC1>[CH3:6][N:5]([CH2:4][C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[B:24]([O:27][CH3:28])[O:25][CH3:26])[CH3:7]
Reactant: COB(OC)OC
Reactant: CN(C)Cc1ccccc1Br
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COB(OC)c1ccccc1CN(C)C
Temperature: -70 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
20.2 g (94.2 mmol) of the (2-bromobenzyl)dimethylamine prepared according to example 1 (2nd stage) were dissolved in 350 ml tetrahydrofuran and the solution was cooled to −70° C. in a cooling bath (isopropanol/dry ice). 68 ml (108 mmol) butyllithium solution (1.6 M in hexane) were added dropwise under nitrogen such that the temperature did not rise above −60° C. After the mixture had been stirred at −70° C. for two hours, 32 ml (282 mmol) trimethyl borate were also added dropwise such that the temperature did not rise above −60° C. The mixture was warmed to 25° C. in the course of 15 hours and the solution was concentrated on a rotary evaporator (500-10 mbar) without heat being supplied. The residue was taken up in 200 ml n-hexane, the mixture was stirred for one hour and filtered over an inert gas frit under nitrogen and the filtrate was concentrated on a rotary evaporator (500-10 mbar) without heat being supplied. 12.0 g dimethyl 2-(dimethylaminomethyl)benzeneboronate (61.5% of theory) were obtained in this manner.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1.[OH-].[Na+]>O1CCCC1>[CH:22]1([CH2:21][O:12][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=2[O:3][CH:2]([F:13])[F:1])[CH:8]=[O:9])[CH2:24][CH2:23]1
Reactant: BrCC1CC1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 0 °C
Reaction time: 7 h
Yield: 93.5 %

Procedure:
A mixture of 4-difluoromethoxy-3-hydroxybenzaldehyde (10 g, 53 mmol) and potassium carbonate (44 g, 105 mmol) in tetrahydrofuran (100 mL) is cooled to 0° C. and a solution of bromomethylcyclopropane (11 mL, 116.6 mmol) in tetrahydrofuran (50 mL) is added under vigorous stirring. The reaction mixture is heated to reflux under stirring for 7 hours, then fresh bromomethylcyclopropane (5.5 mL, 58.3 mmoles) is added and heating is continued for further 7 hours. The reaction mixture is cooled to room temperature and 2 N sodium hydroxide (100 ml) is added; the aqueous layer is extracted with dichloromethane (2×100 mL), the combined organic layers are dried over Na2SO4 and the solvent is removed under reduced pressure to afford 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (12 g), that is used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])[CH:7]=[CH:8][CH:9]=1.[C:21]1([CH3:30])[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>>[CH:18]([O:17][CH:11]([CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][CH2:2][O:1][C:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([CH3:30])=[CH:22][CH:23]=2)=[O:29])[CH:5]=1)[C:12]([OH:14])=[O:13])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C(Cc1cccc(CCO)c1)OC(C)C
Reactant: Cc1ccc(N=C=O)cc1
Product: Cc1ccc(NC(=O)OCCc2cccc(CC(OC(C)C)C(=O)O)c2)cc1

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([N:19]2[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]2)=[C:12]2[C:16]=1[C:15](=[O:17])[N:14]([CH3:18])[CH2:13]2.[Cl:28][C:29]1[CH:34]=[C:33](I)[C:32]([F:36])=[CH:31][N:30]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:28][C:29]1[CH:34]=[C:33]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([N:19]3[CH2:20][CH2:21][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:24]3)=[C:12]3[C:16]=2[C:15](=[O:17])[N:14]([CH3:18])[CH2:13]3)[C:32]([F:36])=[CH:31][N:30]=1
Reactant: CC(C)N1CCN(c2ccc(N)c3c2CN(C)C3=O)CC1
Reactant: Fc1cnc(Cl)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)N1CCN(c2ccc(Nc3cc(Cl)ncc3F)c3c2CN(C)C3=O)CC1
Temperature: 80 °C
Yield: 70.3 %

Procedure:
Cesium carbonate (960 mg, 2.95 mmol) was added to 7-amino-2-methyl-4-(4-propan-2-ylpiperazin-1-yl)-3H-isoindol-1-one (425 mg, 1.47 mmol), 2-chloro-5-fluoro-4-iodopyridine (379 mg, 1.47 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (51.2 mg, 0.09 mmol) and palladium(II) acetate (13.23 mg, 0.06 mmol) in dioxane (15 mL) under an atmosphere of nitrogen. The resulting suspension was heated at 80° C. for 18 hours and then allowed to cool to room temperature. The mixture was filtered and then filtrate evaporated. The residue was dissolved in EtOAc (150 mL), and the solution washed sequentially with a saturated solution of NaHCO3 (75 mL), water (75 mL), and finally with a saturated solution of NaCl (75 mL). The organic layer was dried over MgSO4 and then evaporated. The residue was triturated with Et2O and dried to afford 7-[(2-chloro-5-fluoropyridin-4-yl)amino]-2-methyl-4-(4-propan-2-ylpiperazin-1-yl)-3H-isoindol-1-one (432 mg, 70% yield); 1H NMR spectrum (300.132 MHz, CDCl3): δ 1.11 (6H, d), 2.70 (4H, m), 2.76 (1H, m), 3.07 (4H, m), 3.18 (3H, s), 4.37 (2H, s), 7.14 (1H, d), 7.33-7.41 (2H, m), 8.06 (1H, d), 9.40 (1H, d); Mass spectrum: m/z (ESI+) (M+H)+ =418.31.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.Cl.[NH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[CH3:26]>>[CH:14]1[C:5]2[CH2:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:3](=[CH:2][C:22]3[CH:23]=[CH:24][C:25]([CH3:26])=[C:20]([NH2:19])[CH:21]=3)[C:4]=2[CH:17]=[CH:16][CH:15]=1
Reactant: BrC=C1c2ccccc2CCc2ccccc21
Reactant: Cc1ccc(B(O)O)cc1N
Agent: Cl
Product: Cc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1N
Yield: 74.9 %

Procedure:
Following the procedure essentially as described for Example 219, below, and using 5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (300 mg, 1.05 mmol) and (3-amino-4-methylphenyl)boronic acid hydrochloride (217 mg, 1.16 mmol), yields 245 mg (75%) 5-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-2-methyl-phenylamine as a brown oil. Then, following procedures essentially as described in Example 90, below, and using 5-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-2-methyl-phenylamine (100 mg, 0.321 mmol), affords 35 mg (28%) of the title compound as a colorless oil. MS (ES) 407 (M+NH4), 388 (M−H); HPLC shows 98% purity.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:26]1([CH2:25][CH2:24][CH2:23][CH2:22][N:9]2[CH:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Reactant: BrCCCCn1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1CCCCn1ccnc1
Yield: 34.2 %

Procedure:
To a stirred solution of imidazole (500 mg, 7.35 mmol) and 1,4-dibromobutane (2.6 mL, 22.0) in THF (50 mL) was added 60% NaH (356 mg, 8.81 mmol), and the resultant mixture was refluxed for 2 h and stirred at room temperature overnight. The mixture was quenched with H2O (50 mL) and diluted with CH2Cl2 (75 mL). The aqueous phase was separated and extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to dryness. Purification by flash chromatography on silica gel (CH2Cl2/MeOH, 97:3) resulted in partial decomposition of 1-(4-Bromo-butyl)-1H-imidazole. This material was used without any further purification. Using General Procedure A: 3,3″-Dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (94.4 mg, 0.353 mmol), impure 1-(4-Bromo-butyl)-1H-imidazole (145 mg), KI (6.0 mg, 0.035 mmol), DIPEA (0.18 mL, 1.02 mmol), and DMF (3.5 mL) were stirred for 48 h at 60° C. Purification of the crude material by radial chromatography on a 1 mm TLC grade silica gel plate (CH2Cl2/MeOH/NH4OH, 96:2:2) afforded the free base of the title compound (47 mg, 34% over 2 steps) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25](I)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]([O-:31])=[O:30].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:29]([OH:31])=[O:30])[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2c1
Reactant: O=C[O-]
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2c1
Yield: 17.6 %

Procedure:
(1-Benzyl-1H-indazol-5-yl)-(6-iodoquinazolin-4-yl)-amine (0.48 g) in DMF under CO was treated with sodium formate (0.1 g) and catalytic quantities of triphenyl phosphine and bistriphenylphosphine palladium (II) chloride at 110° C. The mixture was cooled, added to 5% sodium hydroxide and extracted with ethyl acetate. The aqueous phase was treated with 2N HCl and the precipitated solid filtered and dried to give the title compound (0.07 g); δH [2H6]DMSO 13.35(1H,bs), 10.40(1H,s), 9.30(1H,s), 8.60(1H,s), 8.30(1H,d), 8.17(2H,d), 7.84(1H,d), 7.72(1H,s), 7.30(5H,m,), 5.70(2H,s); m/z (M+1)+396.
Reaction SMILES: Br[CH2:2][CH:3]([CH3:31])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11]([CH2:12][C@@H:13]([O:27][CH2:28][O:29][CH3:30])[CH2:14][C@@H:15]2[O:23][CH2:24][O:25][CH3:26])=[CH:10][CH:9]=3)[CH2:6][CH2:5]1.[C:32]1([CH3:41])[CH:37]=[CH:36][C:35]([S:38]([O-:40])=[O:39])=[CH:34][CH:33]=1.[Na+].BrCC(C)[C@@H]1[C@]2(C)[C@H](C3[C@H](CC2)[C@]2(C)C(C[C@@H](OC(OC)=O)C[C@@H]2OC(OC)=O)=CC=3)CC1.C1(S([O-])=O)C=CC=CC=1.[Na+]>>[CH3:31][CH:3]([C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11]([CH2:12][C@@H:13]([O:27][CH2:28][O:29][CH3:30])[CH2:14][C@@H:15]2[O:23][CH2:24][O:25][CH3:26])=[CH:10][CH:9]=3)[CH2:6][CH2:5]1)[CH2:2][S:38]([C:35]1[CH:36]=[CH:37][C:32]([CH3:41])=[CH:33][CH:34]=1)(=[O:40])=[O:39]
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CBr)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OCOC)C1
Agent: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CBr)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Product: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CS(=O)(=O)c5ccc(C)cc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OCOC)C1
Yield: 63.3 %

Procedure:
The procedure of Example 5 was repeated except that 59 mg of 21-bromo-20-methyl-1α,3β-bis(methoxymethoxy)pregna-5,7-diene and 95 mg of sodium p-toluenesulfinate were used in lieu of 65 mg of 21-bromo-20-methyl-1α,3β-bis(methoxycarbonyloxy) pregna-5,7-diene and 80 mg of sodium benzenesulfinate, respectively, to give 43 mg of 20-methyl-1α,3β-bis(methoxymethoxy)-21-p-tolylsulfonylpregna-5,7-diene.
Reaction SMILES: [CH2:1]([N:13]1[N:17]=[N:16][C:15]([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([OH:21])=O)=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:40][O:41][C:42]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[C:45]([O:51][CH3:52])[C:43]=1[NH2:44].Cl>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:13]1[N:17]=[N:16][C:15]([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([NH:44][C:43]2[C:45]([O:51][CH3:52])=[CH:46][C:47]([O:49][CH3:50])=[CH:48][C:42]=2[O:41][CH3:40])=[O:21])=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: CCCCCCCCCCCCn1nnc(C(C(=O)O)c2ccccc2)n1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCn1nnc(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound obtained in (d) above (6.58 g; 17.6 mmoles) was dissolved in tetrahydrofuran (50 mL), treated with carbonyldiimidazole (3.1 g; 19.1 mmoles), and stirred for 1 hour at room temperature under an atmosphere of N2. A solution of 2,4,6-trimethoxyaniline (3.2 g; 17.6 mmoles/50 mL THF) was then added in one portion and the solution was stirred at room temperature for overnight. Ethyl acetate (150 mL) was then added as well as aqueous HCl (1N). The layers were separated and the organic portion was washed with NaOH (1N), brine, and then dried over MgSO4. The drying agent was filtered and the filtrate concentrated in vacuo leaving a lavender colored solid which was purified by silica gel chromatography using chloroform (95%)/methanol (5%) as the eluent. Yield: 6.7 g (70%), mp 119°-120° C.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([NH:8][C:9](=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=1)[C:10]([OH:12])=[O:11])(=[O:7])[CH3:6].[OH-].[Na+].[H][H].CP(C1C=CC=CC=1)CC1C(OC)=CC=CC=1>C1C=CC=CC=1.[Rh].O.CO>[C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([NH:8][C@H:9]([C:10]([OH:12])=[O:11])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([O:21][CH3:22])[CH:15]=1)(=[O:7])[CH3:6]
Reactant: [H][H]
Reactant: COc1cc(C=C(NC(C)=O)C(=O)O)ccc1O
Agent: [Rh]
Agent: COc1ccccc1CP(C)c1ccccc1
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C[C@H](NC(C)=O)C(=O)O)ccc1O
Reaction time: 8 h

Procedure:
A one liter autoclave was charged with 100 grams (0.341 mole) of α-acetamido-4-hydroxy-3-methoxy-cinnamic acid acetate, 254 milliliters of methanol, 170 milliliters of water and 13.7 (0.341 mole) sodium hydroxide. The slurry obtained was brought to about 25° C. and 40 psig. hydrogen pressure and a catalyst solution in 6 milliliters of benzene that was made from 0.025 gram (0.115 milli-equivalents) of rhodium 1,5-hexadiene chloride [Rh-(1,5-hexadiene)Cl]2 (J. Am. Chem. Soc. 86, 217 (1964)), and 0.058 gram (0.250 milli-equivalents) (+) methylphenyl-o-anisylphosphine (while preventing intrusion of air) is added. (The catalyst charge is equivalent to 0.0118 gram rhodium metal.) Hydrogen is absorbed immediately and is complete in 8 hours, giving the compound, N-acetyl-3-(4-hydroxy-3-methoxyphenyl)-alanine acetate, with 80 percent of such compound being present as the L enantiomorph and 20 percent being present as a D enantiomorph.
Reaction SMILES: [CH2:1]([C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:25]([C:28]1[S:29][C:30]([C:33](O)=[O:34])=[CH:31][N:32]=1)[CH2:26][CH3:27].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:1]([C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][C:33]([C:30]3[S:29][C:28]([CH2:25][CH2:26][CH3:27])=[N:32][CH:31]=3)=[O:34])=[CH:22][CH:23]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCc1ncc(C(=O)O)s1
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCCc1cnc(-c2ccc(OC(=O)c3cnc(CCC)s3)cc2)nc1

Procedure:
4.9 g of 4-(5-undecyl-pyrimidin-2-yl)phenol, 1.7 g of 2-propyl-thiazole-5-carboxylic acid (prepared as described by Clemence et al., Eur. J. Med. Chem. Chimica Therapeutica 1976-11, no. 6, p. 567–570) and 2.1 g of dicyclohexylcarbodiimide are stirred for 24 h in 50 ml of dichloromethane at room temperature. Filtration, removal of the dichloromethane by distillation, purification by chromatography (silica gel; dichloromethane/heptane) and recrystallization from acetonitrile affords the target compound as colorless crystals.