Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]1.O[N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O-])=O>O1CCCC1>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][N:12]2[C:13](=[O:22])[C:14]3=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]3[C:16]2=[O:17])[CH2:3][CH2:2]1
Reactant: OCCCN1CCOCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCCCN1CCOCC1
Temperature: 20 °C
Reaction time: 18 h
Yield: 28.8 %

Procedure:
N-(3-Morpholinopropoxy)phthalimide may be obtained in the following manner: solution of 3-morpholinopropanol (27.5 g), N-hydroxyphthalimide (30.2 g) and triphenylphosphine (47.2 g) in tetrahydrofuran (400 cc) is cooled to a temperature in the region of 0° C. and ethyl azodicarboxylate (37.65 g) is added in the course of 1 hour 30 minutes. The solution obtained is stirred at a temperature in the region of 20° C. for 18 hours and is then concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 40° C. The residue is taken up with ethyl acetate (500 cc) and the suspension obtained is filtered. The filtrate is extracted with N aqueous hydrochloric acid solution (200 cc). The aqueous phase is separated after settling has taken place and then extracted 3 times with ethyl acetate (600 cc in total). The aqueous phase is brought to a pH in the region of 10 by adding N aqueous sodium hydroxide solution and is extracted 3 times with ethyl acetate (300 cc in total). The organic extracts are combined, washed 3 times with distilled water (150 cc in total), dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 40° C. A crude product (25.8 g) is thereby obtained, which is chromatographed on a column 8 cm in diameter containing silica (0.060 mm) (1 kg). The column is eluted with pure ethyl acetate, collecting 500-cc fractions. The first 12 fractions are discarded; the next 48 fractions are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 40° C. N-(3-Morpholinopropoxy)phthalimide (15.5 g) is thereby obtained in the form of white crystals, m.p. 98° C. 3-Morpholinopropanol may be obtained according to O. HROMATKA, Ber., 75, 131, (1942).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.Cl.CN(C)[CH2:15][CH2:16][CH2:17][N:18]=C=NCC.C1(N)CC1.O>CN(C)C=O>[CH:17]1([NH:18][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=2)[CH2:15][CH2:16]1
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1I
Yield: 98 %

Procedure:
A solution of 3-iodo-4-methylbenzoic acid (10.5 g, 40 mmol), 1-(3-dimethlaminopropyl) -3-ethylcarbodiimide hydrochloride (9.2 g, 48 mmol) and cyclopropylamine (2.6 g, 45.6 mmol) in N,N-dimethylformamide (70 ml) was stirred at room temperature for 4 h. Water (250 mL) was added. The solution was extracted with ethyl acetate (200mL×2), washed with saturated K2CO3 solution (200 mL) and water (200 mL). Organic layer was dried over Na2SO4 and evaporated under reduced pressure to give the desired product (11.8 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH:26][C:14]([C:12]1[S:13][C:9]([S:8][C:7]2[C:6]([Cl:20])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=1)=[O:16]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCc1cccc(Cl)c1
Product: O=C(NCc1cccc(Cl)c1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (100 mg, 0.28 mmol) and 3-chloro benzylamine (45 mg, 0.32 mmol). The title compound was obtained as a solid (66 mg, 50% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.41 (1H, m), 8.98 (2H, m), 8.47 (1H, s), 7.34 (3H, m), 7.24 (1H, m), 4.39 (2H, m). MS m/z: 471.98, 473.99 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:19][N:20]1[C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:23][N:22]=[CH:21]1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:24]3[N:20]([CH3:19])[CH:21]=[N:22][CH:23]=3)[CH:10]=2)[CH:6]=[CH:7]1
Reactant: Cn1ccc2ccc(Br)cc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cn1cncc1-c1ccc2ccn(C)c2c1
Yield: 83.6 %

Procedure:
A solution of 6-bromo-1-methyl-1H-indole (6.2 g, 29.5 mmol) in toluene was degassed by bubbling argon through the solution for 10-20 min. Et3N (8.2 mL, 59 mmol), tetrakis(triphenylphosphine)palladium (0) (681 mg, 0.59 mmol) and 1-methyl-5-(tributylstannyl)imidazole (Gaare, K.; Repstad, T.; Benneche, T.; Undheim, K. Acta Chem. Scan. 1993, 47, 57.) (11.6 g, 31.2 mmol) in toluene (30 mL) were added and the mixture was heated to 120° C. for 18 h until Pd black appeared. The mixture was cooled, filtered through a pad of silica gel and the pad was washed well with EtOAc. The filtrate was evaporated and chromatography of the residue over silica gel using 0.5-1% methanol in EtOAc gave 1-methyl-6-(3-methyl-3H-imidazol-4-yl)-1H-indole (5.21 g, 84%) as an off white crystalline solid.
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:23])[N:12]([CH3:22])[C:13]3[C:18]([C:19]=2O)=[CH:17][C:16]([CH3:21])=[CH:15][CH:14]=3)=O)CCCCC1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:21])[CH:17]=2)[N:12]([CH3:22])[C:11](=[O:23])[C:10]=1[C:8]#[N:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2c(c1)c(O)c(C(=O)NC1CCCCC1)c(=O)n2C
Product: Cc1ccc2c(c1)c(Cl)c(C#N)c(=O)n2C
Yield: 54 %

Procedure:
A solution of Compound 20 (3 g, 9.5 mmol) in 30 mL neat phosphorus oxychloride was heated at 100° C. for 3 h. The solvent was evaporated under reduced pressure. The residue was suspended in ice water and neutralized by solid sodium bicarbonate. The solids formed were filtered, washed by water, and purified by flash chromatography eluting with 1% methanol in dichloromethane to yield 1.2 g (54%) of yellow solids. M.P. 241° C. 1H NMR (DMSO-d6): δ 2.44 (s, 3H), 3.64 (s, 3H), 7.62 (d, J=8.7 Hz, 1H), 7.73 (dd, J=1.5, 8.7 Hz, 1H), 7.85 (d, J=1.5 Hz, 1H). EIMS m/z 255 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]([CH:34]1[CH2:36][CH:35]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:13]1[C:14]2[N:25]=[N:24][N:23]([CH:26]3[CH2:30][CH:29]([OH:31])[CH:28]([OH:32])[CH:27]3[OH:33])[C:15]=2[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[N:18]=1.[C:43]1(C)[CH:48]=CC(S(O)(=O)=O)=C[CH:44]=1>CC(C)=O.COC(OC)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]([CH:34]1[CH2:36][CH:35]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:13]1[C:14]2[N:25]=[N:24][N:23]([CH:26]3[CH:27]4[O:33][C:43]([CH3:48])([CH3:44])[O:32][CH:28]4[CH:29]([OH:31])[CH2:30]3)[C:15]=2[N:16]=[C:17]([S:19][CH2:20][CH2:21][CH3:22])[N:18]=1
Reactant: CCCSc1nc(N(Cc2ccc(OC)cc2OC)C2CC2c2ccccc2)c2nnn(C3CC(O)C(O)C3O)c2n1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: CC(C)=O
Product: CCCSc1nc(N(Cc2ccc(OC)cc2OC)C2CC2c2ccccc2)c2nnn(C3CC(O)C4OC(C)(C)OC43)c2n1
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of product of example 12, step (f) (4.50 g) in acetone (100 ml), 2,2-dimethoxypropane (12.60 ml) and p-toluenesulphonic acid (2.34 g) were added and the reaction mixture stirred for 1 hour. Purification (SiO2, ethyl acetate:isohexane 2:7 as eluant) afforded the subtitle compound (4.34 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:34][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:28][CH:29]=1
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Reactant: NCCN1CCCC1
Product: O=C(NCCN1CCCC1)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (165 μM) and 0.0333 cm3 of 1-(aminoethyl)pyrrolidine. 39 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-pyrrolidin-1-ylethyl)benzamide are thus obtained in the form of a pale yelow powder [1H NMR spectrum (300 MHz, (CD3)2SO-d6 with addition of a few drops of CD3COOD-d4, δ in ppm): from 1.80 to 2.00 (mt, 4H), 2.97 (s, 3H), 3.20 (mt, 6H), 3.57 (t, J=6.5 Hz, 2H), 3.80 (mt, 2H), 4.23 (mt, 2H), 4.77 (s, 1H), 7.35 (d, J=8.5 Hz, 4H), 7.45 (d, J=8.5 Hz, 4H), from 7.50 to 7.65 (mt, 2H), 7.87 (broad s, 1H), 7.90 (broad d, J=7.5 Hz, 1H)].
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:29]2[N:28]=[C:26]([NH2:27])[NH:25][C:23](=O)[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:55])=O>[Cl-].C([N+](CC)(CC)CC)C.C(#N)C>[NH2:27][C:26]1[N:28]=[C:29]2[C:22]([N:21]=[CH:20][N:19]2[C@@H:6]2[O:7][C@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:5]2[O:4][C:1](=[O:3])[CH3:2])=[C:23]([Cl:55])[N:25]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC[N+](CC)(CC)CC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Cl-]
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 47.5 °C
Reaction time: 0.25 h

Procedure:
An 8-liter, 3-neck, round bottom flask equipped with a mechanical stirrer, a condenser, a thermometer, and an argon inlet is charged with dry acetonitrile (2.2 liters) and 2′,3′,5′-tri-O-acetyl-guanosine (550 g, 1.344 moles). Tetraethylammonium chloride (423 g, 2.55 moles), previously dried for 18 hours over P2O5 at 110° C./high vacuum is added to afford a clear, green solution. After heating to 45-50° C., N,N-dimethylaniline (179 g, 1.48 moles) is added, followed by phosphorus oxychloride (825 g, 5.38 moles) over 15 minutes, during which the temperature rose to 75±3° C. The mixture was kept at 75±3° C. for 15 minutes, flash evaporated (TBath<40° C.), and the dark red residue taken up in dichloromethane (4 liters). With vigorous stirring, the mixture is washed with ice water (2.5 L), the organic phase is collected, and the aqueous phase extracted with additional dichloromethane (2×1 L). The combined organic phases are washed with cold water (2×2 liters), saturated aqueous NaHCO3 (2×2 L), dried (Na2SO4), filtered, and concentrated to approximately 1.5 liters. Absolute ethanol (1.5 L) is added and the mixture concentrated to approximately 2 liters. Upon cooling to room temperature, the product crystallizes as a colorless solid (321 g, 56%) after drying in vacuo at 40° C. for 17 hours.
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:18][N:17]([CH3:26])[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.N1C=CC(CC(C2C=CC([CH2:42][O:43][Si:44]([CH:51]([CH3:53])[CH3:52])([CH:48]([CH3:50])[CH3:49])[CH:45]([CH3:47])[CH3:46])=CC=2)=O)=CC=1>>[CH3:26][N:17]1[CH:18]=[C:19]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:42][O:43][Si:44]([CH:45]([CH3:47])[CH3:46])([CH:51]([CH3:53])[CH3:52])[CH:48]([CH3:50])[CH3:49])=[CH:14][CH:13]=2)=[N:16]1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccccc3)cc2)n1
Reactant: CC(C)[Si](OCc1ccc(C(=O)Cc2ccncc2)cc1)(C(C)C)C(C)C
Product: CC(C)[Si](OCc1ccc(-c2nn(C)cc2-c2ccncc2)cc1)(C(C)C)C(C)C

Procedure:
Following the procedure for the preparation of 4-[3-(4-Benzyloxy-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyridine but substituting 2-Pyridin-4-yl-1-(4-triisopropylsilanyloxymethyl-phenyl)-ethanone provided the title compound. MS: (M+H m/z=422.2).
Reaction SMILES: [CH2:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.[C:25]([C:29]1[CH:30]=[C:31]([CH:52]=[C:53]([C:56]([CH3:59])([CH3:58])[CH3:57])[C:54]=1[OH:55])[C:32]([O:34][C:35]1[C:43]([C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][C:36]=1[C:48]([CH3:51])([CH3:50])[CH3:49])=[O:33])([CH3:28])([CH3:27])[CH3:26]>C1(C)C=CC=CC=1>[CH2:10]([N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:39](=[O:40])[C:38]1[CH:42]=[C:43]([C:44]([CH3:45])([CH3:47])[CH3:46])[C:35]([O:34][C:32](=[O:33])[C:31]2[CH:52]=[C:53]([C:56]([CH3:57])([CH3:59])[CH3:58])[C:54]([OH:55])=[C:29]([C:25]([CH3:27])([CH3:28])[CH3:26])[CH:30]=2)=[C:36]([C:48]([CH3:51])([CH3:49])[CH3:50])[CH:37]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CC(C)(C)c1cc(C(=O)Oc2c(C(C)(C)C)cc(C(=O)Cl)cc2C(C)(C)C)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCNCCCCCCCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCN(CCCCCCCC)C(=O)c1cc(C(C)(C)C)c(OC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4.83 grams of di-n-octylamine and 2.0 grams of triethylamine dissolved in 40 ml of toluene was added dropwise at 35° to 40° over a period of 10 minutes 10.0 grams of 4-(3,5-di-tert-butyl-4-hydroxybenzoyloxy)-3,5-di-tert-butyl-benzoyl chloride dissolved in 30 ml of toluene. The reaction mixture was stirred at 85° to 90°C for 2 hours. After cooling to room temperature, the reaction mixture was filtered to remove the precipitated triethylamine hydrochloride. The filtrate was washed with water and dried over anhydrous sodium sulfate. After removal of the toluene by distillation, the product was isolated as white crystals (m.p. 145°-146°) by successive crystallization from acetonitrile and isopropanol.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[F:25][C:26]([F:31])([F:30])[CH2:27][CH:28]=O>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[CH2:28][CH2:27][C:26]([F:31])([F:30])[F:25])=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=CCC(F)(F)F
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2CCC(F)(F)F)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was reductively alkylated with 3,3,3-trifluoropropionaldehyde in analogy to experiment L3 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(3,3,3-trifluoro-propyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 450.2 [M+H]+.
Reaction SMILES: [CH:1]12[C:9](=[O:10])[CH:6]([CH2:7][CH2:8]1)[CH2:5][CH:4]=[CH:3][CH2:2]2.[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:10]1[CH2:11][CH2:12][O:13][C:9]21[CH:6]1[CH2:7][CH2:8][CH:1]2[CH2:2][CH:3]=[CH:4][CH2:5]1
Reactant: O=C1C2CC=CCC1CC2
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C1=CCC2CCC(C1)C21OCCO1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture of bicyclo[4.2.1]non-3-en-9-one (10 g, 73 mmol), ethyleneglycol (12.3 ml, 220 mmol) and p-toluenesulphonic acid monohydrate (100 mg) in toluene (250 ml) was refluxed in a Dean-Stark apparatus for four hours. The reaction mixture was cooled to ambient temperature and sequentially washed with water (3×50 ml) and brine (100 ml). The organic extract was dried over MgSO4 and concentrated in vacuo, to afford spiro[bicyclo[4.2.1]non-3-ene-9,2′-[1,3]dioxolane] (13.12 g, 99.5%).
Reaction SMILES: [Mg].BrC(Br)C.Br[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18])=[CH:9][CH:8]=1.[B:19]([O:24]C)([O:22]C)[O:20]C.Cl>C1COCC1>[CH2:17]([O:16][CH2:15][CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:20][B:19]([OH:24])[OH:22])=[CH:8][CH:9]=1)[CH3:18]
Reactant: CCOCCCc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: CC(Br)Br
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOCCCc1ccc(OB(O)O)cc1
Temperature: 50 °C

Procedure:
A suspension of magnesium (0.37 g) in THF (5 ml) was stirred under a nitrogen atmosphere, and thereto was then added dibromoethane (a catalytic amount) and was subsequently added dropwise a solution of 1-bromo-4-(3-ethoxypropyl)benzene (3.4 g) in anhydrous THF (30 ml). The resulting mixture was heated at 50° C. for 1.5 hours and was then cooled to −78° C., and thereto was added dropwise trimethyl borate (3.1 ml). The reaction mixture was brought back to the room temperature and was stirred overnight. The reaction mixture was mixed with 1 N hydrochloric acid, was concentrated and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent, and the residue was purified by silica gel chromatography (ethyl acetate/triethylamine) to obtain 4-(3-ethoxypropyl)phenylboric acid (1.25 g) as a light yellow, oily substance.
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:33])[NH:28]2>[Ti](Cl)(Cl)(Cl)Cl>[CH3:19][C:8]1([CH3:18])[C:4]2[C:5](=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[O:20][CH3:21])[CH:11]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][C:27](=[O:33])[NH:28]3)[C:10]([OH:17])([C:13]([F:16])([F:14])[F:15])[CH2:9]1
Reactant: COc1c(F)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1cccc2[nH]c(=O)ccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COc1c(F)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2[nH]c(=O)ccc12
Yield: 2.7 %

Procedure:
Analogously to Example 3, the corresponding imine is produced starting from 500 mg of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and 260 mg of 5-aminoquinolin-2(1H)-one. By reaction of 80 mg of the imine with 0.5 ml of titanium tetrachloride (1 M in dichloromethane), 20 mg of the title compound is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8](B3OC(C)(C)C(C)(C)O3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:21].Br[C:23]1[CH:24]=[N:25][CH:26]=[C:27]([CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][C@H:31]2[C:35]([CH3:43])([CH3:42])[O:36][SiH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:28]=1>>[C:38]([SiH2:37][O:36][C:35]([CH3:43])([CH3:42])[C@@H:31]1[CH2:32][CH2:33][CH2:34][N:30]1[CH2:29][C:27]1[CH:28]=[C:23]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:2]([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]3)[CH:24]=[N:25][CH:26]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCCN1Cc1cncc(Br)c1
Product: CN1C(=O)CCc2cc(-c3cncc(CN4CCC[C@H]4C(C)(C)O[SiH2]C(C)(C)C)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of intermediate A-3 [C], 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) has been coupled to 3-bromo-5-[(S)-2-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-1-ylmethyl]-pyridine to give the title compound as an off white waxy solid. MS: 352.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O.C([O:23][CH2:24][CH3:25])(=O)C>O1CCOCC1.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:4][C:25]=1[CH2:24][OH:23]
Reactant: OB(O)c1cccnc1F
Reactant: CCOC(C)=O
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: OCc1cc(-c2cccnc2F)ccc1F
Temperature: 90 °C
Yield: 47 %

Procedure:
The crude oil was dissolved in dioxane (100 mL) and treated with 2-fluoropyridin-3-ylboronic acid (3.47 g, 24.63 mmol), potassium phosphate (5.23 g, 24.63 mmol), and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (0.25 g, 0.35 mmol). Water (10 mL) was added and the reaction heated to 90° C. for 10 min. Water (300 mL) and ethyl acetate (200 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification of the crude material using silica chromatography (hexane to ethyl acetate gradient) gave (2-fluoro-5-(2-fluoropyridin-3-yl)phenyl)methanol (2.54 g, 47%). MS m/z=222.1 [M+H]+. Calculated for C12H9F2NO: 221.05.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[C:11]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:20][CH3:21])=[CH:16][CH:17]=2)[C:12]1=[O:22])([OH:3])=[O:2]>C1COCC1.CCO.[Pd]>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:20][CH3:21])=[CH:16][CH:17]=2)[C:12]1=[O:22])([OH:3])=[O:2]
Reactant: COc1ccc2c(c1)C(=O)C(=Cc1ccccc1C(=O)O)C2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(c1)C(=O)C(Cc1ccccc1C(=O)O)C2
Reaction time: 5 h
Yield: 99.3 %

Procedure:
A mixture of the product of Step 1 (25 g, 85 mmol) and 10% Pd/C (2.5 g) in THF/EtOH (100 ml each) was hydrogenated at 40 psi for 5 hrs. The mixture was filtered through celite and concentrated to give 25 g of the title compound, which was used as such for the next step.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4([CH2:36][CH3:37])[CH2:33][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[C:28]4=[O:35])[CH:22]=3)[CH:13]=2)[C:9]([CH3:38])=[N:8][CH:7]=1.C(N(CC)CC)C.[C:46](Cl)(=[O:48])[CH3:47]>C(Cl)Cl>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([CH2:11][N:10]2[C:6]([CH2:5][CH2:4][NH:3][C:46](=[O:48])[CH3:47])=[CH:7][N:8]=[C:9]2[CH3:38])=[CH:13][C:14]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2([CH2:36][CH3:37])[CH2:33][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[C:28]2=[O:35])[CH:22]=1)#[N:17]
Reactant: CCC1(c2cccc(Oc3cc(Cn4c(CCN)cnc4C)ccc3C#N)c2)CCCCN(C)C1=O
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1(c2cccc(Oc3cc(Cn4c(CCNC(C)=O)cnc4C)ccc3C#N)c2)CCCCN(C)C1=O
Reaction time: 2 h

Procedure:
To a solution of 4-[5-(2-amino-ethyl)-2-methyl-imidazol-1-ylmethyl]-2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-benzonitrile dihydrochloride (as described in Example 11) (0.06 g, 0.108 mmol) in CH2Cl2 (3.0 mL) was added triethylamine (0.06 mL, 0.43 mmol) and acetyl chloride (0.010 mL, 0.14 mmol). After stirring for 2 hr, the solvents were removed in vacuo and the residue was partitioned with EtOAc and saturated NaHCO3. The EtOAc was dried with brine and MgSO4 and evaporated in vacuo to obtain the title compound.