Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C12BC(CCC1)CCC2.[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+].Cl[C:21]1[CH:29]=[C:28]2[C:24]([C:25]([NH:38][C:39](=[O:43])[CH2:40][CH2:41][CH3:42])=[N:26][N:27]2[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])=[CH:23][CH:22]=1.[F-].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C(OCC)(=O)C.O>[C:12]1([CH2:11][CH2:10][C:21]2[CH:29]=[C:28]3[C:24]([C:25]([NH:38][C:39](=[O:43])[CH2:40][CH2:41][CH3:42])=[N:26][N:27]3[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:35])[CH3:36])=[CH:23][CH:22]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)ccc12
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: B1C2CCCC1CCC2
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(CCc3ccccc3)ccc12
Temperature: 75 °C

Procedure:
27.2 cm3 of 9-borabicyclo[3.3.1]nonane are added by syringe to a solution of 0.8 cm3 of styrene in 35 cm3 of dioxane and the mixture is heated at 75° C. for 1 hour. 5.5 cm3 of 5N sodium hydroxide are added to the cooled solution, followed by successive addition of 1 g of N-[6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide prepared in Example 25, 1.2 g of caesium fluoride, 32.2 mg of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl and 12.3 mg of palladium acetate, and the mixture is heated at reflux for 3 hours. After cooling, 50 cm3 of water and 75 cm3 of ethyl acetate are added; the organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated under reduced pressure (2 kPa; 40° C.) to give 4.5 g of crude product, which is chromatographed under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (75/25 by volume). The fractions containing the expected product are combined and then evaporated under reduced pressure (2 kPa; 40° C.) to give 1.4 g of N-[6-(2-phenylethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide in the form of a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]([O:14][CH:15]2[CH2:32][CH:31]3[CH:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34](O)=[O:35])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:11]2[C:6](=[C:7]([CH3:41])[C:8]([O:39][CH3:40])=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:54]1([S:57]([NH2:60])(=[O:59])=[O:58])[CH2:56][CH2:55]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]([O:14][CH:15]2[CH2:32][CH:31]3[CH:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([NH:60][S:57]([CH:54]5[CH2:56][CH2:55]5)(=[O:59])=[O:58])=[O:35])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:11]2[C:6](=[C:7]([CH3:41])[C:8]([O:39][CH3:40])=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: NS(=O)(=O)C1CC1
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2) (182 mg, 0.32 mmol) and CDI (139 mg, 0.29 mmol) in dry THF (10 mL) was heated at reflux for 1.5 h under nitrogen. LCMS analysis showed one peak of the intermediate (2-1) (a stable intermediate, which can be isolated by purification on silica gel). The reaction mixture was cooled to room temperature and cyclopropyl-sulfonamide (93 mg, 0.76 mmol) was added. Then, DBU (138 mg, 0.91 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, then heated at 55° C. for 12 h. Next, the solvent was evaporated, and the residue partitioned between ethyl acetate and acidic water (pH=3). The organic layer was dried (Na2SO4) and evaporated. The crude material was purified by column chromatography (ethyl acetate/CH2Cl2, 1:9). The residue was sonicated in water for 1 h, filtered off and washed with isopropylether to give the title product (3) as a white powder: m/z=669 (M+H)+. 1H NMR (CDCl3): 0.90-1.30 (m, 5H), 1.31-1.52 (m, 6H), 1.61-1.72 (m, 1H), 1.73-1.99 (m, 3H), 2.09-2.20 (m, 1H), 2.30-2.42 (m, 2H), 2.48-2.62 (m, 5H), 2.70-2.83 (m, 1H), 3.01 (s, 3H), 3.30-3.41 (m, 2H), 3.94 (s, 3H), 4.50-4.73 (m, 3H), 5.05 (t, J=10.0 Hz, 2H), 5.62-5.69 (m, 1H), 5.95 (s, 1H), 6.35 (br s, 1H), 7.01 (d, J=9.1 Hz, 1H), 7.85 (d, J=9.1 Hz, 1H), 10.8 (br s, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:24][C:25]([C:27]1[C:28]([CH3:36])=[C:29]([C:32]([F:35])=[CH:33][CH:34]=1)[C:30]#[N:31])=[O:26]>C1COCC1>[C:30]([C:29]1[C:28]([CH3:36])=[C:27]([C:25](=[O:26])[CH2:24][N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]2=[O:1])[CH:34]=[CH:33][C:32]=1[F:35])#[N:31]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Cc1c(C(=O)CBr)ccc(F)c1C#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(C(=O)CN2CCN(C(=O)OC(C)(C)C)CC2=O)ccc(F)c1C#N
Reaction time: 0.25 h

Procedure:
To a THF solution of tert-butyl 3-oxopiperazine-1-carboxylate (0.080 g, 0.43 mmol) was added Lithium diisopropylamide (0.20 mL, 0.39 mmol) drop wise at −78° C. After stirring for 15 min., a THF solution of 3-(bromoacetyl)-6-fluoro-2-methylbenzonitrile (0.10 g, 0.39 mmol) was added to the reaction mixture slowly. Analysis of the reaction mixture by LC indicated formation of the desired product. To the reaction mixture was sat. NH4Cl followed by extraction of the aqueous layer with EtOAc. The extractions were combined and washed with brine, dried with Na2SO4, and concentrated under reduced pressure to provide a residue which was then subjected for purification by silica gel column chromatography (10% MeOH in DCM) to provide the title product. LC/MS (IE, m/z): [M+1]+=376.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:49][C:44]2[CH:45]=C[CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN1CC(N)C1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:49][CH:44]5[CH2:43][N:48]([CH3:47])[CH2:45]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN1CC(N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CN(C)C2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylazetidin-3-amine hydrochloride. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18-1.82 (m, 12 H) 2.32 (s, 3 H) 3.10 (s, 3 H) 3.62 (s, 2 H) 3.95 (s, 3 H) 4.06 (t, J=13.4 Hz, 2 H) 4.47 (m, 1 H) 4.45 (d, J=6.8 Hz, 1 H) 7.49 (d, J=8.1 Hz, 1 H) 7.53 (s, 1 H) 7.90 (s., 1 H) 8.21 (s, 1 H) 8.28 (d, J=8.1 Hz, 1 H) 8.65 (d, J=5.8 Hz, 1 H). [M+H] calc'd for C26H33F2N7O3, 530; found 530.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]#[N:7])=[N:2]1.[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>ClCCCl>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[N:1]1[CH:5]=[N:4][C:3]([C:6]#[N:7])=[N:2]1
Reactant: C1=COCCC1
Reactant: N#Cc1nc[nH]n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: N#Cc1ncn(C2CCCCO2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1H-1,2,4-triazole-3-carbonitrile (1.00 g, 10.63 mmol) in DCE (10 mL) was added 3,4-dihydro-2H-pyran (1.94 ml, 21.26 mmol) and p-toluenesulfonic acid (183 mg, 1.06 mmol). The resulting mixture was stirred at room temperature under nitrogen for 15 minutes. Saturated aqueous sodium bicarbonate solution (25 mL) was added and the product extracted into DCM (25 mL×3). The combined organics were washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography (Biotage, 0-10% methanol gradient in DCM) to give the title intermediate as a yellow oil: 1H NMR (500 MHz, CDCl3) delta 1.81-1.63 (3H, m), 2.11-1.95 (2H, m), 2.19 (1H, dd, J=8.1, 5.6 Hz), 3.87-3.65 (1H, m), 4.18-3.97 (1H, m), 5.53 (1H, dd, J=8.5, 2.9 Hz), 8.37 (1H, s).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:36]=[CH:37][CH2:38][CH3:39])=[C:13]([CH:35]=1)[O:14][CH2:15][CH2:16][C:17]1[N:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[O:20][C:21]=1[CH3:22])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:36]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:35][C:13]=1[O:14][CH2:15][CH2:16][C:17]1[N:18]=[C:19]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)[O:20][C:21]=1[CH3:22])[CH2:37][CH2:38][CH3:39]
Reactant: [H][H]
Reactant: CCC=Cc1ccc(OCc2ccccc2)cc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Agent: [Pd]
Solvent: CCO
Product: CCCCc1ccc(O)cc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C

Procedure:
A solution of 4-[2-(5-Benzyloxy-2-but-1-enylphenoxy)ethyl]-5-methyl-2-biphenyl-4-yl-oxazole (0.34 mmol) in ethanol (10 mL) was treated with 5% Pd/C (30 mg) under a balloon containing hydrogen at ambient temperature for 24 h. The mixture was filtered and concentrated in vacuo to give a white solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:14]([OH:16])=O)[C:8]=2[CH:7]=[CH:6]1)[CH3:2].[CH:17]1([NH2:20])[CH2:19][CH2:18]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1>[CH:17]1([NH:20][C:14]([C:9]2[C:8]3[CH:7]=[CH:6][N:5]([CH2:4][O:3][CH2:1][CH3:2])[C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:16])[CH2:19][CH2:18]1
Reactant: NC1CC1
Reactant: CCOCn1ccc2c(C(=O)O)cccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOCn1ccc2c(C(=O)NC3CC3)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 1-(ethoxymethyl)-1H-indole-4-carboxylic acid (123 g, 0.56 mol) in THF (1.5 L) is added cyclopropylamine (58 mL, 0.84 mol) and triethylamine (TEA, 167 mL, 1.12 mol), followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (240 g, 0.62 mol) at 0° C. The reaction mixture is stirred at ambient temperature overnight. The volatiles are removed in vacuo. The residue is stirred in EA (1.5 L) and HCl (0.5%, 1 L) for 10 minutes. The organic layer is separated, washed with aqueous saturated sodium chloride (3×100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified by chromatography on silica gel to give the title compound (110 g, 77%). MS (m/z): 259 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([I:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:17][C@H:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][OH:20]>C(#N)C.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C@H:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][OH:20])[C:5]([I:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: CC(C)[C@@H](N)CO
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC(C)[C@H](CO)Nc1nc(Cl)ncc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 10.05 g (36.6 mmol) of 2,4-Dichloro-5-iodo-pyrimidine and 5.6 ml (40.0 mmol) triethylamine in 30 ml of acetonitrile is mixed with 4.85 g (47.0 mmol) of (R)-2-Amino-3-methyl-butan-1-ol. The batch is stirred at room temperature for 16 hours and is finally diluted with water. The batch is filtered and the solid is washed with small amounts of acetonitrile and water. The solid is dried. 10.24 g (30.0 mmol, corresponding to 82% of theory) of the product is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:23]=[C:11]3[NH:12][C:13]([CH:16]4[CH2:21][CH2:20][NH:19][CH:18]([CH3:22])[CH2:17]4)=[N:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:4][C:3]=1[O:24]C.B(Br)(Br)Br.CCN(CC)CC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:23]=[C:11]3[NH:12][C:13]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=4)=[N:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:4][C:3]=1[OH:24]
Reactant: COc1ccc(-c2cc3[nH]c(C4CCNC(C)C4)ncc-3n2)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ncc3nc(-c4ccc(O)c(F)c4)cc-3[nH]2)ccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.2 %

Procedure:
To a −78° C. solution of 2-fluoro-1-methoxy-4-[2-methyl-4-piperidylpyrrolo[4,5-d]pyrimidin-6-yl]benzene (Example 119) (0.80 g, 2.35 mmol) in CH2Cl2 (40 mL) under a N2 atmosphere was added 1 M BBr3 (4.7 mL, 4.70 mmol). The reaction mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for an additional 20 h. The reaction mixture was then poured onto ice-water (200 mL) and the pH of the aqueous solution was adjusted to pH 9 with the addition of NEt3 (4 mL). The resulting mixture was stirred at room temperature for 2 h. The solid which formed was removed by filtration and dicarded. The remaining solution was transferred to a separatory funnel. The organic solution was separated, washed with H2O (100 mL), saturated NaCl (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure to afford 483 mg (62%) of 2-fluoro-4-(2-methyl-4-pyridylpyrrolo[4,5-d]pyrimidin-6-yl)phenol as a pale yellow colored solid. This compound (481 mg, 1.50 mmol) was dissolved in 4:2:1 EtOAc/MeOH/CH2Cl2 (50 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (1.50 mL, 1.50 mmol). The solution was allowed to cool to room temperature. The resulting solid was collected by filtration, washed with EtOAc (2×10 mL), Et2O (3×15 mL) and dried under vacuum at 60° C. to give 315 mg (37%) of the title compound as a pale yellow colored solid. Mp: >280° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.63 (br s, 6), 2.49 (s, 3), 3.96 (br s, 4), 6.76 (s, 1), 7.06 (dt, 1, J=1.9, 8.7), 7;58 (d, 1, J=8.5), 7.83 (dd, 1, J=1.9, 12.5), 10.47 (s, 1), 11.79 (s, 1), 14.12 (s, 1). MS m/z: 327 (M+1 for free base). Anal. Calcd for C18H19FN4O.HCl.1.5H2O: C, 55.45; H, 5.95; N, 14.37; Cl, 9.09. Found: C, 55.49; H, 5.87; N, 14.07; Cl, 9.03.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1.O.NN>CO.[Ni]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cc(F)ccc2F)cc1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccc(Oc2cc(F)ccc2F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.2 %

Procedure:
Into a 500 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of 1,4-difluoro-2-(4-nitrophenoxy)benzene (19.5 g, 77.63 mmol, 1.00 equiv) in methanol (200 mL), and Raney Nickel (2 g). This was followed by the addition of a solution of hydrazine hydrate (11.66 g) in methanol (50 mL) dropwise with stirring at 25° C. over 15 min. The resulting solution was stirred for 12 h at 25° C. and then filtrated and the filtrate was concentrated under vacuum. The residue was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 16 g (93%) of 4-(2,5-difluorophenoxy)aniline as a black oil.
Reaction SMILES: C([N:9]1[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[CH:12]=[CH:11]C1C#N)(=O)C1C=CC=CC=1.Br.[C:23]([OH:26])(=[O:25])[CH3:24]>>[CH3:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:9]=[C:24]([C:23]([OH:26])=[O:25])[CH:11]=[CH:12]2
Reactant: CC(=O)O
Reactant: Cc1ccc2c(c1)C=CC(C#N)N2C(=O)c1ccccc1
Agent: Br
Product: Cc1ccc2nc(C(=O)O)ccc2c1
Temperature: 25 °C

Procedure:
The resulting (±) 1-benzoyl-2-cyano-1,2-dihydro-6-methylquinoline thus obtained (155.2 g) was added to acetic acid (170 ml) and 48% hydrobromic acid (170 ml) and this mixture was stirred and refluxed for 0.5 hours. After cooling to room temperature, the solid was collected by filtration and then stirred in water (1000 ml) at 80°-90° while concentrated ammonium hydroxide was added until a pH of 8-9 was obtained. After cooling to 50°, acetic acid was added until a pH of 4-5 was reached. The 6-methyl-2-quinolinecarboxylic acid was collected by filtration and then recrystallized from acetic acid; yield 87 g, m.p. 208° (dec).
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.C(O)(=O)C>C1COCC1.O>[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
Solvent: C1CCOC1
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 THF 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.
Reaction SMILES: [C:1](=[O:19])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([OH:18])[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[CH2:20](O)[CH2:21][CH2:22][CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1](=[O:19])([O:2][C:3]([CH3:6])([CH3:5])[CH3:4])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([O:18][CH2:20][CH2:21][CH2:22][CH3:23])[CH:9]=1
Reactant: CC(C)(C)OC(=O)Oc1ccc(C(C)(C)C)c(O)c1
Reactant: CCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCOc1cc(OC(=O)OC(C)(C)C)ccc1C(C)(C)C
Yield: 55.4 %

Procedure:
tert-Butyl 4-tert-butyl-3-hydroxyphenyl carbonate (1.5 g, 5.6 mmol), n-butanol (0.5 mL, 5.4 mmol), triphenylphosphine (1.3 g, 5.0 mmol) and diethyl azodicarboxylate (DEAD) (0.78 mL, 5.0 mmol) were treated in the same procedure described in Example 31(a). The crude residue was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and ethyl acetate (19/1 to 9/1) to furnish 964 mg (66% yield) of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:14]OB(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.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>[CH3:14][C:2]1[CH:3]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(Br)cnc1OC
Reactant: COB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)cnc1OC
Temperature: 120 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
1.2 g of methyl 5-bromo-2-methoxy-3-pyridinecarboxylate was dissolved in 20 ml of N,N-dimethylformamide, 440 mg of methylboric acid, 4.79 g of anhydrous cesium carbonate, and 564 mg of tetrakis(triphenylphosphine)palladium were added thereto, and the mixture was stirred at 120° C. for 2 hours under a nitrogen atmosphere. Ice-water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (hexane:ethyl acetate=20:1), to give 461 mg of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][C:42]1[CH:62]=[CH:61][CH:60]=[CH:59][C:43]=1[CH2:44][N:45]1[CH2:49][CH2:48][N:47]([C@@H:50]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:51](O)=[O:52])[C:46]1=[O:58].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:51](=[O:52])[C@@H:50]([N:47]1[CH2:48][CH2:49][N:45]([CH2:44][C:43]2[CH:59]=[CH:60][CH:61]=[CH:62][C:42]=2[O:41][CH3:40])[C:46]1=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: COc1ccccc1CN1CCN([C@H](C(=O)O)C(C)(C)C)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2OC)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
A solution containing the product from Example 2C (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 75A (0.020 g, 0.062 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine (0.041 mL, 0.235 mmol) and the mixture was stirred at 25° C. for 2 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The product was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed brine, dried over MgSO4, filtered and concentrated to give the title compound (0.024 g, 59% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.83 (s, 9 H), 0.89 (s, 9 H), 1.26 (m, 1 H), 1.38 (m, 1 H), 1.54 (m, 2 H), 2.33 (m, 1 H), 2.83 (m, 5 H), 3.18 (m, 1 H), 3.50 (s, 3 H), 3.66 (m, 1 H), 3.83 (m, 4 H), 4.25 (m, 4 H), 4.53 (d, J=7.72 Hz, 1 H), 6.63 (d, J=9.93 Hz, 1 H), 6.95 (t, J=6.99 Hz, 1 H), 7.18 (m, 11 H), 7.45 (d, J=9.19 Hz, 1 H), 7.86 (m, 5 H), 8.63 (d, J=4.41 Hz, 1 H).