Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23]>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=2[N+:22]([O-:24])=[O:23])[CH2:4][CH2:3]1
Reactant: CN1CCC(O)CC1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 1-methylpiperidin-4-ol (0.542 g) in tetrahydrofuran (10 mL) at 0° C. was added NaH (60% in mineral oil) (0.753 g). After stirring for 15 minutes, 4-fluoro-3-nitrobenzenesulfonamide (1.036 g) was added as a solution in tetrahydrofuran (10 mL). The reaction was removed from the ice bath and allowed to warm to room temperature. After 1 hour, the reaction was poured into water and the pH adjusted to −7 with 1N aqueous HCl. The reaction was extracted with dichloromethane (3×100 mL), washed with brine, dried over magnesium sulfate, filtered, and concentrated. The product was suspended in dichloromethane (mL), sonicated and then filtered to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:22][CH2:21][C@@H:20]([OH:23])[C:12]2=[N:13][CH:14]=[C:15]([N:17]([CH3:19])[CH3:18])[CH:16]=[C:11]2[CH2:10]1.[H-].[Na+].[O:26]=[C:27]1[NH:35][C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[N:28]1[CH:36]1[CH2:41][CH2:40][N:39]([C:42](OC2C=CC([N+]([O-])=O)=CC=2)=[O:43])[CH2:38][CH2:37]1>C1COCC1>[O:26]=[C:27]1[NH:35][C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[N:28]1[CH:36]1[CH2:37][CH2:38][N:39]([C:42]([O:23][C@H:20]2[C:12]3=[N:13][CH:14]=[C:15]([N:17]([CH3:19])[CH3:18])[CH:16]=[C:11]3[CH2:10][C@H:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[CH2:22][CH2:21]2)=[O:43])[CH2:40][CH2:41]1
Reactant: CN(C)c1cnc2c(c1)C[C@H](c1cccc(F)c1F)CC[C@H]2O
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)c1cnc2c(c1)C[C@H](c1cccc(F)c1F)CC[C@H]2OC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reaction time: 8 h
Yield: 40.5 %

Procedure:
(6R,9R)-6-(2,3-Difluorophenyl)-3-(dimethylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (27.6 mg, 0.087 mmol) with stirring bar was azeotroped by benzene. Sodium hydride (20.80 mg, 0.867 mmol) was added to the THF (3 mL) suspension of (6R,9R)-6-(2,3-difluorophenyl)-3-(dimethylamino)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (27.6 mg, 0.087 mmol) and 4-nitrophenyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (43.2 mg, 0.113 mmol) at rt. The reaction was stirred at this temperature overnight. The reaction was quenched by water and partitioned between ethyl acetate and water. The ethyl acetate layer was washed by water two more times before dried (Na2SO4), filtered and concentrated. Flash column by methanol in CH2Cl2 from 0 to 4% to 8% gave the desired product (19.8 mg, 36%). MS (ESI)[M+H+]=563.35; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 10.30 (br. s., 1H) 8.08 (d, J=5.49 Hz, 1 H) 7.95-8.05 (m, 1H) 7.37-7.53 (m, 1H) 6.94-7.14 (m, 4H) 6.79 (br. s., 1H) 6.00 (d, J=10.38 Hz, 1H) 4.66 (br. m., 3H) 3.32 (t, J=12.67 Hz, 1H) 3.08 (br. m., 2 H) 2.91-3.02 (m, 6H) 2.29 (d, J=13.73 Hz, 2H) 2.13-2.24 (m, 2H) 1.86-2.07 (m, 2H) 1.20-1.40 (m, 3H) 0.75-0.98 (m, 1H).
Reaction SMILES: Br[C@H:2]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C@H:3]1[O:8][C:6](=[O:7])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4]1.[N-:19]=[N+:20]=[N-:21].[Na+]>>[N:19]([C@@H:2]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C@H:3]1[O:8][C:6](=[O:7])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4]1)=[N+:20]=[N-:21]
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](Br)CC2CCCCC2)OC1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CC(C)[C@@H]1C[C@@H]([C@H](CC2CCCCC2)N=[N+]=[N-])OC1=O
Temperature: 0 °C

Procedure:
42.5 g (0.135 mol) of 5(R)-bromo-6-cyclohexyl-2(S)-isopropyl-4(S)-hexanolide and 35 g (0.54 mol) of NaN3 in 480 ml of N,N'-dimethyl-N,N'-propylene urea (DMPU) are stirred at room temperature for 72 hours and then poured onto 1 liter of ice-cold 0.1N HCl. The mixture is then extracted three times with ether, and the combined organic phases are washed twice with 0.1N HCl and three times with brine and dried with MgSO4. After concentrating the solvent by evaporation, the residue is recrystallised from hexane: m.p. 38.5°-39°.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[O:6][CH2:5][C:4]=2[CH:3]=[C:2]1[C:14]([OH:16])=[O:15].C([Li])(C)(C)C.[F:22]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>C1COCC1.CCCCC>[F:22][C:3]1[C:4]2[CH2:5][O:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[S:1][C:2]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1cc2c(s1)-c1ccccc1OC2
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: O=C(O)c1sc2c(c1F)COc1ccccc1-2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 4H-thieno[3,2-c]chromene-2-carboxylic acid (1.65 g, 7.10 mmol) in THF (70 mL) at −78° C. was added a 1.5 M solution of tert-butyllithium in pentane (15 mL). The resulting solution stirred 1 hr at −78° C. N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (7.2 g, 23 mmol) was added and the reaction warmed to room temperature over 2 hr. The reaction was quenched by the addition of 1 M HCl to effect pH 3. The aqueous layer was extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to yield 3-fluoro-4H-thieno[3,2-c]chromene-2-carboxylic acid, which contained less than 40% 4H-thieno[3,2-c]chromene-2-carboxylic acid, which was utilized in the next step without purification (1.0 g). MS (Q1) 249 (M)+
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].Cl[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1>C(Cl)Cl>[C:3]1([O:4][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=1[O:2][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1
Reactant: Oc1ccccc1O
Reactant: Clc1ccc(Cl)nc1
Solvent: ClCCl
Product: Clc1ccc(Oc2ccccc2Oc2ccc(Cl)cn2)nc1

Procedure:
A mixture of 3.0 grams (0.027 mole) catechol and 9.0 grams (0.06 mole) 2,5-dichloropyridine was heated as a melt under nitrogen for 7 hours at 175° followed by heating at 200° for 5 hours. The black residue was dissolved in a minimum amount of methylene chloride and chromatographed through a silica gel column using methylene chloride as the eluent. From the initial fractions, the desired product was isolated. Yield 1.5 g, m.p. 82°-84°; NMR (CDCl3): δ6.70 (d, 2H, ArH), 7.30 (s, 4H, ArH), 7.60 (AB quartet, 2H, ArH), 8.05 (d, 2H, ArH); ir (Nujol): 6.30 (C=N), 9.90, 11.95, 13.10 microns.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][C@@H:7]([N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:12])[C:8](O)=[O:9])[C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]1=2.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:46][NH:47][C:48](=[O:59])[C@H:49]([NH:57][CH3:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:16]([O:15][C:13](=[O:14])[N:11]([C@@H:7]([C:8](=[O:9])[N:57]([CH3:58])[C@@H:49]([C:48](=[O:59])[NH:47][CH3:46])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:6][C:4]1[C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=2[S:1][CH:5]=1)[CH3:12])([CH3:17])([CH3:19])[CH3:18]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)NC
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1csc2ccccc12)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1csc2ccccc12)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.3 %

Procedure:
(2R)-3-(Benzo[b]thiophen-3-yl)-2-(tert-butoxycarbonyl-methylamino)propionic acid (2.00 g ; 5.96 mmol) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazole (0.81 g; 5.96 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.26 g ; 6.56 mmol) were added. The reaction mixture was stirred for 15 min at room temperature. (2R)-N-Methyl-2-methylamino-3-phenylpropionamide (1.15 g; 5.96 mmol) was dissolved in methylene chloride (10 mL) and added. Diisopropylethylamine (1.02 mL; 5.96 mmol) were added. The reaction mixture was stirred for 48 hours. Methylene chloride (10 mL) was added. The reaction was washed with water (30 mL), an aqueous solution of sodium hydrogen sulfate 10%; 30 mL), an aqueous solution of sodium hydrogen carbonate (saturated; 30 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (3×30 cm) using ethyl acetate/methylene chloride (1:1) as eluent to afford 0.89 g of ((1R)-2-(benzo[b]thiophen-3-yl)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)carbamoyl)ethyl)methyl carbamic acid tert-butylester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:12]([O:14][C:15](=[O:25])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:25])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[F:11])[CH:19]=1)[CH3:13]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: CCOC(=O)COc1cccc(N)c1
Product: CCOC(=O)COc1cccc(NC(=O)c2cc(Br)ccc2F)c1

Procedure:
5-Bromo-2-fluoro-benzoic acid (250 mg, 1.14 mmol) was coupled to aniline (64) (245 mg, 1.25 mmol) using Method D. The residue was purified by column chromatography eluting with a stepped gradient of 10-15% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH:1]1([CH:5]([C:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:18]=2[CH3:28])[O:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:5]([C:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:18]=2[CH3:28])[O:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC(c2cc(-c3ccccc3)oc2C)C2CCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of cyclobutyl(2-methyl-5-phenylfuran-3-yl)methanol (364 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (274 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (0.7 mL) and 1,1′-(azodicarbonyl)dipiperidine (757 mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 12% ethyl acetate/hexane) to give methyl 4-[cyclobutyl(2-methyl-5-phenylfuran-3-yl)methoxy]benzoate as an oil. The obtained methyl 4-[cyclobutyl(2-methyl-5-phenylfuran-3-yl)methoxy]benzoate was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). 2N Lithium hydroxide (1.0 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (276 mg, 47%) as an amorphous compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]([C:20]=1[CH2:21][OH:22])=[N:18][C:17]1[C:16]([CH2:23][OH:24])=[C:15]([O:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH:14]=[CH:13][C:12]=1[CH:11]=2)[CH3:2]>CS(C)=O.C(N(CC)CC)C>[CH2:31]([N:28]([CH2:29][CH3:30])[CH2:27][CH2:26][O:25][C:15]1[CH:14]=[CH:13][C:12]2[C:17]([C:16]=1[CH:23]=[O:24])=[N:18][C:19]1[C:10](=[CH:9][CH:8]=[C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:33][CH3:34])[CH2:1][CH3:2])[C:20]=1[CH:21]=[O:22])[CH:11]=2)[CH3:32]
Reactant: CCN(CC)CCOc1ccc2cc3ccc(OCCN(CC)CC)c(CO)c3nc2c1CO
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCN(CC)CCOc1ccc2cc3ccc(OCCN(CC)CC)c(C=O)c3nc2c1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a solution of 0.469 g of 3,6-bis[2-(diethylamino)ethoxy]-4,5-acridinedimethanol in a mixture of 5.0 ml of anhydrous dimethyl sulfoxide and 2.8 ml of triethylamine is added a solution of 0.96 g of sulfur trioxide-pyridine complex in 5 ml of anhydrous dimethyl sulfoxide. The reaction mixture is stirred at room temperature for one hour. Most of the dimethyl sulfoxide is removed under reduced pressure without heat. The residue is treated first with 50 ml of saturated sodium bicarbonate solution and then with 50 ml of water, giving 0.35 g of the desired product as a yellow solid.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C1(C)C=CC(S(O[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[CH2:30][CH2:29]2)(=O)=O)=CC=1>C(O)C>[CH2:37]([O:36][C:34]([N:31]1[CH2:32][CH2:33][CH:28]([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:29][CH2:30]1)=[O:35])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)OCCCCCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)OCC

Procedure:
In 80 ml of ethanol is dissolved 0.95 g of sodium, and 7.2 g of diethyl malonate is added to the solution, followed by stirring. 5(1-Benzyloxycarbonyl-4-piperidyl)pentyl p-toluenesulfonate (13.7 g) is added to the mixture, followed by refluxing with stirring for 2 hours. Further, a mixture of 0.25 g of sodium, 25 ml of ethanol and 1.8 g of diethyl malonate is added, and the reaction solution is refluxed with stirring for 2 hours. Ethanol is evaporated off under reduced pressure, and 200 ml of water is added to the residue, which is then extracted with 300 ml of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl 7-(1-benzyloxycarbonyl-4-piperidyl)-2-ethoxycarbonylheptanoate as an oily material. This product is dissolved in 30 ml of ethanol, and a solution of 6 g of sodium hydroxide in 50 ml of water is added dropwise to the solution with stirring. After the addition is completed, 150 ml of water is added to the reaction solution, which is then extracted with a mixture of ether and petroleum ether (1:1, 150 ml). The aqueous layer is made acidic with conc. hydrochloric acid and extracted with 300 ml of ethyl acetate, and the extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 7-(1-benzyloxycarbonyl-4-piperidyl)-2-carboxyheptanoic acid as an oily material. This product is heated at 160° to 165° C. with stirring for 1 hour, and the resulting oily material is purified by silica-gel column chromatography (hexane:ethyl acetate=3:1 to 1:1) to give 6.4 g of 7-(1-benzyloxycarbonyl-4-piperidyl)heptanoic acid as an oily material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH3:31].[CH2:32]([N:34](CC)CC)[CH3:33].ClCC#N>CO>[C:32]([CH2:33][N:18]1[CH2:19][CH2:20][CH:15]([CH2:14][O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([O:21][C:22]4[CH:23]=[C:24]5[C:28](=[CH:29][CH:30]=4)[NH:27][CH:26]=[C:25]5[CH3:31])=[N:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2][CH3:1])[CH2:16][CH2:17]1)#[N:34]
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCNCC1
Reactant: CCN(CC)CC
Agent: N#CCCl
Solvent: CO
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCN(CC#N)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35 %

Procedure:
A mixture of 6-methoxy-4-(3-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline (460 mg, 1.10 mmol), (prepared as described in Example 276), triethylamine (5 ml) and chloroacetonitrile (0.38 ml, 6.05 mmol) in methanol (5 ml) was stirred at ambient temperature for 24 hours. The solvents were removed in vacuo and the residue purified by silica column chromatography using gradient elution (dichloromethane, 5% methanol/95% dichloromethane, methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1)) and the product recrystallised from acetonitrile to give 7-(1-cyanomethylpiperidin-4-ylmethoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (178 mg, 35%).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][CH:9]([F:37])[CH2:10][NH:11][C:12]1[N:13]=[C:14]2[CH2:36][CH2:35][NH:34][CH2:33][C:15]2=[N:16][C:17]=1[N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:20][CH2:19]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:71][O:72][C@H:73]([CH3:77])[C:74](O)=[O:75]>CN(C=O)C>[F:37][CH:9]([F:8])[CH2:10][NH:11][C:12]1[N:13]=[C:14]2[CH2:36][CH2:35][N:34]([C:74](=[O:75])[C@H:73]([O:72][CH3:71])[CH3:77])[CH2:33][C:15]2=[N:16][C:17]=1[N:18]1[CH2:19][CH2:20][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:22][CH2:23]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CO[C@H](C)C(=O)O
Reactant: Fc1ccc(OC2CCN(c3nc4c(nc3NCC(F)F)CCNC4)CC2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CO[C@H](C)C(=O)N1CCc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2C1
Reaction time: 8 h

Procedure:
A solution of N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (17 mg, 0.032 mmol), DIPEA (12.2 mg, 0.095 mmol), and HATU (13.2 mg, 0.035 mmol) in DMF (158 μL) was stirred for 10 min at rt. To this was added (R)-2-methoxypropanoic acid (3.6 mg, 0.035 mmol), and the resulting reaction mixture stirred overnight. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (6 mg) as a clear oil. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.32 (d, J=6.8 Hz, 1.3H), 1.38 (d, J=6.6 Hz, 1.7H), 1.92-2.03 (m, 2H), 2.09-2.18 (m, 2H), 2.78 (t, J=6.2 Hz, 0.9H), 2.86 (m, 1.1H), 2.97-3.06 (m, 2H), 3.33 (s, 3H), 3.35-3.43 (m, 2H), 3.79 (td, J=14.5, 4.3 Hz, 2H), 3.85-3.97 (m, 2H), 4.36 (dq, J=12.7, 6.5 Hz, 1H), 4.42-4.49 (m, 1H), 4.58 (m, 0.9H), 4.68 (m, 1.1H), 5.90-6.22 (m, 1H), 6.84-6.91 (m, 1H), 6.98 (ddd, J=11.4, 8.5, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 512.4.
Reaction SMILES: B(C1CCCCC1)C1CCCCC1.[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].[Zn](CC)CC.[CH:25](=[O:30])[CH2:26][CH:27]([CH3:29])[CH3:28]>>[CH3:28][CH:27]([CH2:26][C@H:25]([OH:30])[CH:17]=[CH:16][C:15]([CH3:19])([CH3:18])[CH3:14])[CH3:29]
Reactant: C#CC(C)(C)C
Reactant: CC(C)CC=O
Agent: B(C1CCCCC1)C1CCCCC1
Agent: CC[Zn]CC
Product: CC(C)C[C@H](O)C=CC(C)(C)C
Yield: 86 %

Procedure:
The product was prepared by General procedure S using 196 mg (1.1 mmol) Cy2BH, 137 μL (1.1 mmol) 3,3-dimethyl-1-butyne, 1.1 mL (2.1 mmol, 2.0 M in hexanes) Et2Zn, 9.6 mg (0.04 mmol) (−)-MIB, and 107 μL (1.0 mmol) isovaleraldehyde. The crude product was purified by column chromatography (5% ethyl acetate in hexanes) to afford the title compound as a colorless oil in 86% yield (146 mg, 0.86 mmol). [α]D20=+16.7 (c=3.0, CHCl3, 85% ee); 1H NMR (CDCl3, 500 MHz): δ 0.88 (t, 6H, J=7.0 Hz), 0.97 (s, 9H), 1.26 (m, 1H), 1.43 (m, 1H), 1.50 (br s, 1H), 1.65 (m, 1H), 4.07 (dt, 1H, J=7.0, 6.8 Hz), 5.31 (dd, 1H, J=15.6, 7.2 Hz), and 5.61 (d, 1H, J=15.7 Hz) ppm; 13C{1H} NMR (CDCl3, 1.25 MHz): δ 22.5, 22.9, 24.6, 29.5, 32.5, 46.6, 71.5, 128.1, and 142.6 ppm; IR (neat): 3334, 3013, 2956, 2869, 2354, 2320, 1662, 1466, 1386, 1363, 1308, 1268, 1220, and 1202 cm−1; HRMS-CI m/z 170.1666 [M+; calcd for C11H22O: 170.1671].
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.CN(C)C=O>O>[O:1]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: OCc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 1.24 g (0.01 mole) of 4-hydroxymethylphenol, 1.8 g (0.012 mole) of tert-butyldimethylsilyl chloride, 1.7 g (0.025 mole) of imidazole and 3 ml of dimethylformamide was stirred under nitrogen at room temperature for 12 h. The reaction mixture was poured into water and extracted with three portions of ether. Ether extracts were combined and washed successively with water and saturated NaCl solution and then dried (Na2SO4). The ether solution was concentrated in-vacuo and the resultant crude product was purified by flash chromatography (silica; 10% ethyl acetate in hexanes) to give the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]([CH2:19][O:20][CH3:21])[CH2:17][CH3:18])[C:10]=2[N+:22]([O-])=O)=[C:5]([CH3:25])[CH:4]=1.Cl[Sn]Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]([CH2:19][O:20][CH3:21])[CH2:17][CH3:18])[C:10]=2[NH2:22])=[C:5]([CH3:25])[CH:4]=1
Reactant: CCC(COC)Nc1nccc(-c2ccc(OC)cc2C)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CCC(COC)Nc1nccc(-c2ccc(OC)cc2C)c1N
Temperature: 25 °C
Yield: 99 %

Procedure:
[4-(4-Methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine (0.43 g, 0.36 mmol) and SnCl2 (0.2 g, 1.08 mmol) in ethanol (2 mL) were heated to 70° C. for 4 h. The solution was cooled to room temperature and quenched with saturated aqueous NaHCO3 then extracted with EtOAc, washed with H2O, brine, dried (Na2SO4), filtered, and concentrated in vacuo to give a crude yield of 0.40 g (99%) of 4-(4-methoxy-2-methyl-phenyl)-N2-(1-methoxymethyl-propyl)-pyridine-2,3-diamine; MS(EI) m/z 316.28 [(M+H)+, 100]. The crude product was taken on to Part E.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][Si](C(C)(C)C)(C)C)=[CH:8][C:7](=[O:34])[CH2:6][CH2:5]1.O>C(O)(=O)C>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[CH:8][C:7](=[O:34])[CH2:6][CH2:5]1
Reactant: CC(C)(C)[Si](C)(C)OCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Solvent: CC(=O)O
Solvent: O
Product: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCO)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Yield: 115.1 %

Procedure:
A solution of 23.1 g of 11β-fluoro-7α-{5-tert-butyl-dimethylsilyloxypentyl)-estr-4-ene-3,17-dione in 115 ml of The and 64 ml of water are stirred with 128 ml of glacial acetic acid for 2.5 hours at 50° C. The reaction mixture is concentrated by evaporation in a vacuum, taken up in ethyl acetate, washed with water and dried. 20.4 g of 11β-fluoro-7α-(5-hydroxypentyl)-estr-4-ene-3,17-dione is obtained as foam.