Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)=[CH:19][CH:18]=1
Reactant: CSc1ccc(C2=C(Br)CCC2)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CSc1ccc(C2=C(c3ccc(C(F)(F)F)cc3)CCC2)cc1
Yield: 80.6 %

Procedure:
Following the synthetic procedure outlined in Step 3 of Example 1, 240 mg (0.89 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio)benzene (Example 1, Step 2) was reacted with 360 mg (1.8 mmol) of 4-trifluoromethylphenylboronic acid (Step 1). Purification by silica gel chromatography (MPLC) with hexane gave 240 mg (81%) of 1-[2-(4-trifluoromethylphenyl)cyclopenten-1-yl]-4-(methylthio)benzene as a colorless solid: mp 60.0°-61.5° C.; NMR (CDCl3) δ2.06 (m, J=7 Hz, 2H), 2.46 (s, 3H), 2.89 (t, J=7 Hz, 4H), 7.06 (d, J=6 Hz, 2H), 7.10 (d, J=6 Hz, 2H), 7.27 (d, J=8 Hz, 2H), 7.46 (d, J=8 Hz, 2H).
Reaction SMILES: Br.[N:2]1([C:8]([NH2:10])=[NH:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[C:20](=[CH:25]N(C)C)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].CC(C)([O-])C.[K+].C(O)(C)(C)C>CCO>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21]2[N:9]=[C:8]([N:2]3[CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)[N:10]=[CH:25][C:20]=2[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: N=C(N)N1CCOCC1
Agent: Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2nc(N3CCOCC3)ncc2C1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To a 500 ml round bottom flask charged with anhydrous EtOH (150 ml) under nitrogen at 0° C. are added morpholine-4-carboxamidine hydrobromide (10.50 g, 50 mmol), tert-butyl-3-[(dimethylamino)methylene]-4-oxo-1-piperidinecarboxylate (12.7 g, 50 mmol, 1.0 eq.), and potassium t-butoxide in t-butanol (11.0M, 100 ml, 100 mmol, 2.0 eq.). The resulting mixture is stirred at 75° C. for 16 hr. The solvent is evaporated under reduced pressure, and the residue is taken up in DCM (300 ml), washed with water and brine, dried (Na2SO4) and concentrated. The residue is purified by silica gel chromatography (Hexane/EtOAc 1:1) to give the title compound. MS (+VE) m/z 321.1 (M++1).
Reaction SMILES: [CH2:1]([O:4][CH:5]1[NH:9][C:8](=[O:10])[CH:7]=[CH:6]1)[CH2:2][CH3:3].[Li+].CCC[CH2-].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.CCCCCC>[C:16]1([S:22]([N:9]2[CH:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:6]=[CH:7][C:8]2=[O:10])(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCOC1C=CC(=O)N1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCOC1C=CC(=O)N1S(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
To a solution of 3 g of 1,5-dihydro-5-n-propyloxy-2H-pyrrol-2-one, in 80 cm3 of tetrahydrofuran, cooled to -45° C., there is added 13.25 cm3 of a 1.6M solution of N-butyllithium in n-hexane, while maintaining the temperature between -35° and -45° C. After 30 minutes, a solution of 3.74 g of benzenesulphonyl chloride in 12 cm3 of tetrahydrofuran is added at a temperature between -45° and -35° C., then the temperature is allowed to return to the ambient over two hours, followed by evaporating to dryness and chromatographing on silica (eluent: ethyl acetate-n-hexane, 1--1). 2.2 g of the expected product is recovered. m.p. 56°-58° C., crystallized from a mixture of ethyl ether-n-hexane, 1-2. By crystallizing from isopropanol, 1.4 g of the expected product is obtained, m.p. 66°-67° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[N:7]=1.[C:12](OC(=O)C)(=[O:14])C.C(O)=O>O1CCCC1>[CH3:1][N:2]([C:3]1[S:4][C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[N:7]=1)[CH:12]=[O:14]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1nc(C)c(C(C)=O)s1
Solvent: C1CCOC1
Solvent: O=CO
Product: CC(=O)c1sc(N(C)C=O)nc1C
Reaction time: 2 h

Procedure:
To a solution of 2-methylamino-4-methyl-5-acetylthiazole (35 g) in tetrahydrofuran (700 ml) were added a mixture of acetic anhydride (94.5 ml) and formic acid (37.7 ml) at ambient temperature and the mixture was stirred for two hours. The reaction mixture was evaporated in vacuo. The residue was added to water and the resultant precipitate was collected by filtration and dried over phosphorus pentoxide to give 2-(N-methylformamido)-4-methyl-5-acetylthiazole (39.59 g).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][N:18]([CH2:20][C:21]([O-:23])=[O:22])[C:17](=[O:24])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].O>CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][N:18]([CH2:20][C:21]([OH:23])=[O:22])[C:17](=[O:24])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C2CC(=O)N(CC(=O)[O-])C2)cc1OC1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C2CC(=O)N(CC(=O)O)C2)cc1OC1CCCC1
Reaction time: 10 h
Yield: 100.8 %

Procedure:
4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone-1-acetate (250 mg, 0.72 mmol) was treated with 8 ml of a 1M solution of potassium hydroxide in 95% methanol. After 10 hours, the reaction solution was acidified with 2NHCl to pH 3 and 30 ml of water was added and the resulting mixture was extracted with 60 ml of ethyl acetate twice. The organic layer was concentrated and chromatographed (methanol/dichloromethane 5:100) to give 242 mg (quantitative yield) of 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone-1-acetic acid: 1H NMR (300 MHz, CDCl3) δ 6.85-73 (m, 3H), 4.84-4.74 (m, 1H), 4.20 (d, J=12.0 Hz, 1H), 4.12 (d, J=12.0, 1H), 3.82 (s, 4H), 3.66-3.46 (m, 2H), 2.89 (dd, J=16.8, 8.7 Hz, 1H), 2.58 (dd, J=16.8, 8.4 Hz, 1H), 2.00-1.72 (b, 6H), 1.70-1.50 (b, 2H).
Reaction SMILES: N1C=CC=CC=1.[O:7]([Si:15]([CH3:18])([CH3:17])[CH3:16])S(C(F)(F)F)(=O)=O.[CH2:19]([C:21](O)([CH2:52][CH3:53])[C:22]#[C:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([CH2:49][CH3:50])([C:33]2[CH:38]=[CH:37][C:36]([B:39]3[O:43][C:42]([CH3:45])([CH3:44])[C:41]([CH3:47])([CH3:46])[O:40]3)=[C:35]([CH3:48])[CH:34]=2)[CH2:31][CH3:32])=[CH:26][C:25]=1[CH3:51])[CH3:20].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:31]([C:30]([C:33]1[CH:38]=[CH:37][C:36]([B:39]2[O:40][C:41]([CH3:46])([CH3:47])[C:42]([CH3:45])([CH3:44])[O:43]2)=[C:35]([CH3:48])[CH:34]=1)([C:27]1[CH:28]=[CH:29][C:24]([C:23]#[C:22][C:21]([CH2:19][CH3:20])([O:7][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH2:52][CH3:53])=[C:25]([CH3:51])[CH:26]=1)[CH2:49][CH3:50])[CH3:32]
Reactant: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C)CC
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(C#Cc1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C)(CC)O[Si](C)(C)C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
Pyridine (0.116 mL, 1.432 mmol) and trimethylsilyl triflate (0.129 mL, 0.716 mmol) were added to a solution of 3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-pentyn-3-ol (Example 125-(2); 175 mg, 0.358 mmol) in dichloromethane (5 mL) at 0° C., and the mixture was stirred for one hour. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 70:30) to give the target compound as a colorless oil (158 mg, 79%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][NH:16][C:13]4=[N:14][CH:15]=[C:10]3[NH:9][N:8]=2)[CH2:2]1.Cl[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CCO>[C:7]1([CH:3]2[CH2:4][CH2:5][CH2:6][N:1]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=3)[CH2:2]2)[C:11]2=[C:12]3[CH:18]=[CH:17][NH:16][C:13]3=[N:14][CH:15]=[C:10]2[NH:9][N:8]=1
Reactant: c1cc2c(ncc3[nH]nc(C4CCCNC4)c32)[nH]1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: N#Cc1ccc(N2CCCC(c3n[nH]c4cnc5[nH]ccc5c34)C2)nc1
Temperature: 120 °C
Yield: 5.4 %

Procedure:
A mixture of 1-(piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.16 g, 0.65 mmol, Example #26, Step E) and 6-chloronicotinonitrile (0.090 g, 0.65 mmol) with DIEA (0.37 mL, 2.12 mmol) in EtOH (3 mL) was heated at about 120° C. for about 15 min in a microwave reactor. The crude material was purified by RP-HPLC (Table 2, Method h) to give 6-(3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)piperidin-1-yl)nicotinonitrile (0.012 g, 6%): LC/MS (Table 2, Method a) Rt=1.96 min; m/z: 344 (M+H)+.
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[C:16]([O:20][CH3:21])(=[O:19])[CH2:17][SH:18].CN1C(=O)CCC1.O.[OH-].[Li+]>O>[C:16]([C:17]1[S:18][C:4]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=2[C:6]=1[NH2:7])([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CS
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1sc2cc(C(F)(F)F)ccc2c1N
Temperature: 2 °C
Reaction time: 0.67 h
Yield: 84.8 %

Procedure:
A 22-L, 3-necked, round-bottom flask equipped with a mechanical stirrer, nitrogen bubbler, and a thermocouple probe, was charged with 1.20 kg (5.55 mole) of 2-nitro-4-trifluoromethylbenzonitrile, 589.3 g (496 mL, 5.55 mole) of methyl thioglycolate, and 4.3 L of NMP. After the resulting yellow solution was cooled to 2° C., a solution prepared from 466.0 g (11.11 mole, 2.0 eq) of lithium hydroxide monohydrate in 3.36 L of water was slowly added over a period of 78 min while maintaining a temperature of 2-20° C. The brown slurry was allowed to warm to 21° C. over a 2 h period, then was diluted with 8.0 L of water (Texo->27° C.). After stirring for 40 min and cooling to 18° C., product was collected by filtration, rinsing with 10 L of water, then air-drying at ambient temperature to give 1.295 kg (84.7% yield) of 2-carbomethoxy-3-amino-6-trifluoromethylbenzo[b]thiophene, as a light-yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.CN(C)C=O.[O-:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na+].[OH-].[Na+]>O>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cncc(Oc2ccccc2)c1
Temperature: 110 °C
Reaction time: 44 h
Yield: 79.3 %

Procedure:
Sodium phenoxide trihydrate (7.50 g, 44.1 mmol) was dried under vacuum at 65° C. for 18 h at 0.6 mm Hg to yield 5.08 g of sodium phenoxide. Under a nitrogen atmosphere, 3,5-dibromopyridine (4.00 g, 16.9 mmol) and anhydrous N,N-dimethylformamide (40 mL) were added to the sodium phenoxide (5.08 g, 43.8 mmol). The resulting mixture was stirred at 110° C. for 44 h. After cooling to ambient temperature, water (75 mL) was added, and the pH was adjusted to 13.0 using 30% NaOH solution. The solution was extracted with diethyl ether (4×60 mL). The combined ether extracts were washed with saturated NaCl solution (50 mL), dried (NaSO4), filtered and concentrated by rotary evaporation to a brown oil (4.0 g). The oil was vacuum distilled, collecting a forerun (317 mg), bp 48°-65° C. at 0.05 mm Hg. Further distillation afforded 3.35 g (79.8%) of 3-bromo-5-phenoxypyridine as a pale-yellow oil, bp 75-112° C. at 0.05 mm Hg (lit. bp 110°-115° C. at 1.7 mm Hg, see K. Fujikawa, et al. Agr. Biol. Chem. 34:68 (1970).
Reaction SMILES: Cl[CH2:2][Si:3]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])([CH3:5])[CH3:4].[Na].[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1>CN(C)C=O.O>[Cl:13][C:7]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1[Si:3]([CH3:5])([CH3:4])[CH2:2][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: c1nc[nH]n1
Reactant: C[Si](C)(CCl)c1ccc(Cl)cc1Cl
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reaction time: 2 h
Yield: 80.4 %

Procedure:
A mixture of 5.1 g (0.020 mol) of chloromethyl(2,4-dichlorophenyl)dimethysilane and 2.0 g (0.022 mol) of 1,2,4-triazole sodium salt in 10 ml of dry dimethylformamide was stirred at 80°-90° for 2 hours. The resulting slurry was cooled, diluted with water, and washed with ether. The ether extracts were washed with several portions of water and once with brine, dried over magnesium sulfate, and evaporated to leave 4.6 g (81%) of the title compound as a pale yellow liquid: nD23 1.5580; ir (neat) 1550, 1485, 1440, 1345, 1260, 1240, 1130, 1085, 1025, 1005, 835 cm-1 ; nmr (CDCl3) 0.5 (6H, s), 4.1 (2H, s), 7.2-7.5 (3H, m), 7.8 (1H, s), 7.9 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH3:13])[C:7]=1[CH3:14])[CH3:2].[CH3:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1F)[C:20]#[N:21].[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][C:28]=1[Cl:37]>C(OC(=O)C)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH3:13])[C:7]=1[CH3:14])[CH3:2].[Cl:37][C:28]1[CH:29]=[C:30]([S:33](=[O:34])(=[O:35])[NH2:36])[CH:31]=[CH:32][C:27]=1[NH:26][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:24]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=2[CH3:16])=[C:8]([CH3:13])[C:7]=1[CH3:14]
Reactant: Cc1cc(C#N)ccc1F
Reactant: Nc1ccc(S(N)(=O)=O)cc1Cl
Agent: CCOC(=O)Cc1ccc(O)c(C)c1C
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)ccc1Oc1ccc(CC(=O)Nc2ccc(S(N)(=O)=O)cc2Cl)c(C)c1C

Procedure:
(4-Hydroxy-2,3-dimethyl-phenyl)-acetic acid ethyl ester (45c) was prepared as described in Example 13. N-(2-Chloro-4-sulfamoyl-phenyl)-2-[4-(4-cyano-2-methyl-phenoxy)-2,3-dimethyl-phenyl]-acetamide (I-25) was prepared starting with 45c utilizing the procedure from example 1 except in step 1, 45c was used in place of 3-bromo-4-hydroxy-phenyl)-acetic acid ethyl ester and 3-methyl-4-fluoro-benzonitrile was used in place of 3-chloro-5-fluoro-benzonitrile and in step 4, 4-amino-3-chloro-benzenesulfonamide was used in place of 4-amino-benzenesulfonamide.
Reaction SMILES: [F:1][C:2]([F:17])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-])=O)[C:3]([F:6])([F:5])[F:4].[H][H]>[Ni].O1CCOCC1>[F:1][C:2]([F:17])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14])[C:3]([F:4])([F:6])[F:5]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1OC(F)(F)C(F)(F)F
Agent: [Ni]
Solvent: C1COCCO1
Product: Nc1ccccc1OC(F)(F)C(F)(F)F
Yield: 85.3 %

Procedure:
A mixture of 27.2 g of crude 2-pentafluoroethoxy-nitrobenzene, 2.6 g of Raney-nickel catalyst and 250 ml of dioxane is agitated in a hydrogen atmosphere for 24 hours at a temperature of 20°-25° C. The hydrogen consumption is 6.54 liters. After filtering off the catalyst, the solution is evaporated to dryness, yielding 20.5 g of 2-pentafluoroethoxy-aniline in form of a yellowish oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][CH2:13][OH:14])[CH:6]=[CH:5]2.[N:15]1[NH:16][C:17](=[O:21])[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1.[Cu]>[OH:14][CH2:13][CH2:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([N:16]1[C:17](=[O:21])[CH:18]=[CH:19][CH:20]=[N:15]1)[CH:11]=[CH:10]2
Reactant: O=c1cccn[nH]1
Reactant: OCCc1ccc2cc(Br)ccc2c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=c1cccnn1-c1ccc2cc(CCO)ccc2c1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A mixture of the product from Example 31E (500 mg, 1.87 mmol), 2H-pyridazin-3-one (180 mg, 1.87 mmol), copper powder (120 mg, 1.87 mmol), and K2CO3 (775 mg, 5.61 mmol, 3 equiv.) in pyridine (75 mL) was stirred at reflux under a dry nitrogen atmosphere for 20 hr. The reaction mixture was cooled to room temperature then concentrated under reduced pressure. Residual pyridine was removed by repeated evaporation with toluene. The residue was partitioned between ethyl acetate (350 mL) and saturated aqueous Na2CO3. The organic layer was washed twice with aqueous NH4OH, dried (MgSO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (75:25 ethyl acetate/hexane) to provide the title compound (270 mg, 54% yield). 1H NMR (CDCl3, 300 MHz) δ 8.11 (d, J=2 Hz, 1H), 7.97-7.93 (m, 1H), 7.88 (t, J=9 Hz, 2H), 7.75-7.68 (m, 2H), 7.41 (dd, J=2, 12 Hz, 1H), 7.31-7.24 (m, 1H), 7.10 (dd, J=2, 12 Hz, 1H), 3.97 (t, J=6 Hz, 2H), 3.06 (t, J=6 Hz, 2H). MS (DCl-NH3) [M+H]+ at 267, [M+NH4]+ at 284.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH3:23])[C:12](=[O:22])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[C:14]=1[F:21])(C(C)(C)C)(C)C.OC1C=C(C=C(O[C@@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)C=1)C(NC1C=CN(C)N=1)=O.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Cl:20][C:15]1[C:14]([F:21])=[C:13]([CH:18]=[CH:17][C:16]=1[F:19])[C:12]([N:11]([CH2:10][CH2:9][OH:8])[CH3:23])=[O:22]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(F)c(Cl)c1F
Agent: CC(C)[Si](OC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(CCO)C(=O)c1ccc(F)c(Cl)c1F
Temperature: 160 °C
Yield: 728.3 %

Procedure:
N-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-2,4-difluoro-N-methylbenzamide (100 mg, 0.275 mmol) was added to 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzamide (123 mg, 0.275 mmol) and potassium carbonate (76 mg, 0.551 mmol) in dry dimethylacetamide. The mixture was heated in a Smith Creator microwave at 160° C. for 2 hours. Water (25 mL) was added to the reaction mixture and extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried (MgSO4), filtered and evaporated. Purification by column chromatography on silica, eluting with 50-100% ethyl acetate in hexanes, gave the title compound as a pale yellow oil (500 mg). 1H NMR δ (CDCl3): 1.29 (d, 3H), 2.09 (t, 1H), 3.23 (s, 3H), 3.59 (t, 2H), 3.71-3.76 (m, 2H), 3.79 (s, 3H), 4.54 (t, 2H), 4.50-4.57 (m, 1H), 6.74 (t, 1H), 6.77 (d, 1H), 6.80 (d, 1H), 7.04 (t, 1H), 7.23 (t, 1H), 7.28 (d, 1H), 7.70 (d, 1H), 8.52 (s, 1H)
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C@@H:3]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[NH2:4].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]([CH3:13])([CH3:12])[C@@H:3]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[NH:4][S:22]([CH3:21])(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)[C@@H](N)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H](NS(C)(=O)=O)C(C)(C)C
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A solution of tert-butyl 3-methyl-L-valinate (50 mg, 0.223 mmol) in dichloromethane (1 mL) at 0° C. was treated with 4-(dimethylamino)pyridine (5.4 mg, 0.045 mmol), triethylamine (93.4 μL, 0.67 mmol), and methanesulfonyl chloride (34.5 L, 0.45 mmol), and the mixture was warmed to 25° C. for 1 h. The mixture was washed with 5% potassium bisulfate, saturated sodium bicarbonate, brine, and dried over MgSO4, filtered, and the solvents were evaporated to give the crude title compound (59 mg, 100%).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[S:14][C:15]([C:18]([OH:27])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[CH:16][N:17]=1.CN(C)[CH:30]=[O:31]>C(OCC)C>[F:20][C:19]([F:22])([F:21])[C:18]([C:15]1[S:14][C:13]([CH:30]=[O:31])=[N:17][CH:16]=1)([OH:27])[C:23]([F:26])([F:25])[F:24]
Reactant: OC(c1cnc(Br)s1)(C(F)(F)F)C(F)(F)F
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
To a nitrogen purged three-necked flask was added n-butyl lithium in hexane (2.5M, 9.09 mmol, 3.64 mL) and diethyl ether (8 mL). The solution was cooled to −78° C. and 2-(2-bromothiazol-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (3.03 mmol, 1 g) in diethyl ether (7 mL) added drop wise over a period of 15 minutes. The mixture was stirred at −78° C. for 20 minutes before the drop wise addition of N,N-dimethylformamide (4.54 mmol, 0.332 g) in diethyl ether (4 mL). The mixture was stirred at −78° C. for 1 hour then was allowed to warm to −60° C. and stir for 1 hour. The mixture was slowly quenched with 4M hydrochloric acid at −60° C. and allowed to warm to room temperature. The mixture was extracted with diethyl ether (100 mL), washed with 4M hydrochloric acid (50 mL), followed by water (50 mL) and then brine (50 mL). The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with a gradient of heptane to 50% ethyl acetate/50% heptane) to afford the title compound (500 mg).
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:11].[C:12]([OH:21])(=[O:20])[C@@H:13]([C@H:15]([C:17]([OH:19])=[O:18])[OH:16])[OH:14]>CO.O>[NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].[CH3:13][OH:14].[C:17]([C@@H:15]([C@H:13]([C:12]([OH:21])=[O:20])[OH:14])[OH:16])([OH:19])=[O:18]
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: O
Solvent: CO
Product: N[C@H]1c2ccccc2C[C@H]1O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Racemic cis-1-amino-2-indanol (66.6 g, water wet, content 81.1%) was dissolved in 390 ml of methanol with 10 ml of water. 65 g of (R,R)-tartaric acid were added in portions at 60° C. Stirring of the mixture was continued for one hour at reflux and then it was cooled down again to 20° C. The solid was isolated by filtration and washed twice with 120 ml of methanol. After drying, 56.2 g of (1S,2R)-1-amino-2-indanol-(R,R)-tartrate methanol solvate were obtained with an e.e. of 97.2%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]1[NH:20][CH2:21][CH2:22][N:23]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]1[N:23]([C:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])[CH2:22][CH2:21][N:20]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Clc1ccccc1CC1=NCCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccnc1Cl)N1CCN=C1Cc1ccccc1Cl
Reaction time: 2 h

Procedure:
Dissolve 2-chloro-3-pyridinylcarbonyl chloride (4.69g) in dichloromethane (25 ml), and add the solution to a stirred, cooled (ice bath) solution of 2-(2-chlorophenyl)methyl-imidazoline (4.30g) and diisopropylethylamine (7.69 ml) and dichloromethane (25 ml). Allow the resulting solution to stir 2 hours, then wash it with water, 1 M sodium bicarbonate solution, and with water. Dry the dichloromethane solution, using sodium sulfate, then filter and evaporate the solvent. Crystallize the residue from ethyl acetate to obtain 2-[(2-chlorophenyl)methyl]-1-[(2-chloro-3-pyridinyl) carbonyl]-4,5-dihydro-1H-imidazole, mp 128.5°-130° C.