Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:13][C:14]1[C:15]2[S:42][CH:41]=[CH:40][C:16]=2[C:17]2[CH:18]=[C:19]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:20]3[S:26][CH:25]=[CH:24][C:21]=3[C:22]=2[CH:23]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1COCC1.[Li+].CCC[CH2-].[CH3:53][Sn:54](Cl)([CH3:56])[CH3:55]>CCCCCC>[CH2:28]([O:27][C:19]1[C:20]2[S:26][C:25]([Sn:54]([CH3:56])([CH3:55])[CH3:53])=[CH:24][C:21]=2[C:22]2[CH:23]=[C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:15]3[S:42][C:41]([Sn:54]([CH3:56])([CH3:55])[CH3:53])=[CH:40][C:16]=3[C:17]=2[CH:18]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCCCOc1cc2c3ccsc3c(OCCCCCCCCCCCC)cc2c2ccsc12
Reactant: C[Sn](C)(C)Cl
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1cc2c3cc([Sn](C)(C)C)sc3c(OCCCCCCCCCCCC)cc2c2cc([Sn](C)(C)C)sc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
5,10-Bis-dodecyloxy-1,6-dithia-dicyclopenta[a,f]naphthalene (BB-3, 0.366 g, 0.6 mmol) was added into a 50 mL flask. The system was vacuumed and backfilled with argon 3 times before 17 mL of anhydrous THF was injected. N-Butyllithium (0.6 mL, 2.5 M in hexane, 1.5 mmol) was added after the mixture was cooled to −78° C. A white precipitate was observed after the mixture was stirred at −78° C. for 30 minutes. Stirring was continued at room temperature for one more hour before the mixture was cooled down to −78° C. again. Trimethyltin chloride (0.5 g, 2.5 mmol) was added in portions and stirring was continued overnight at room temperature. Hexane (100 mL) was added and the organic layer was washed with 150 mL of water. The aqueous layer was extracted with 50 mL of hexane twice. The combined organic layer was dried over anhydrous Na2SO4. Removal of the solvent under vacuum yielded a white solid. The colorless crystalline product (0.48 g, ˜85.7% yield) was obtained after recrystallization from a hexane/iso-propanol mixture. 1H NMR (CDCl3, 500 MHz): δ 7.80 (s, 2H), δ 7.51 (s, 2H), δ 4.37 (t, 4H, J=6.5 Hz), δ 2.00 (m, 4H), δ 1.63 (m, 4H), δ 1.46 (m, 4H), δ 1.30 (m, 28H), δ 0.90 (t, 6H, J=7.0 Hz), δ 0.51 (m, 18H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[CH:5]=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>>[Br:13][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2cccc(C)c12
Reactant: O=C1CCC(=O)N1Br
Product: Cc1cccc2cccc(CBr)c12

Procedure:
Using general procedure A (Exp. 1.3.), 1,8-dimethyl-naphthalene was reacted with N-bromosuccinimide to give 1-bromomethyl-8-methyl-naphthalene as white solid. MS: 234.1 ([M]+). Using general procedure B, ethyl 2-indole carboxylate was coupled with 1-bromomethyl-8-methyl-naphthalene to give 1-(8-methyl-naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 314.4 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]([CH3:26])([C:20]1[N:24]=[C:23]([CH3:25])[O:22][N:21]=1)[NH2:19]>>[CH3:17][C:18]([NH:19][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:20]1[N:24]=[C:23]([CH3:25])[O:22][N:21]=1)[CH3:26]
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Reactant: Cc1nc(C(C)(C)N)no1
Product: Cc1nc(C(C)(C)NC(=O)c2cccc(-c3cccc(Cl)c3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (Example 33 d, CAN 1153831-97-0) as starting materials, MS (LC/MS): 357.1 [M+H]+.
Reaction SMILES: [CH:1]([N:3]([C:12]([C:14]1[C:23]2[C:18](=[C:19]([C:26]([F:29])([F:28])[F:27])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:13])[CH2:4][C:5]([O:7]C(C)(C)C)=[O:6])=[O:2]>FC(F)(F)C(O)=O.O>[CH:1]([N:3]([C:12]([C:14]1[C:23]2[C:18](=[C:19]([C:26]([F:27])([F:29])[F:28])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:13])[CH2:4][C:5]([OH:7])=[O:6])=[O:2]
Reactant: COc1ccc2c(C(=O)N(C=O)CC(=O)OC(C)(C)C)cccc2c1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc2c(C(=O)N(C=O)CC(=O)O)cccc2c1C(F)(F)F
Yield: 45.8 %

Procedure:
A solution of N-formyl-N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine, 1,1-dimethylethyl ester (12.86 g, 31.3 mmole) in trifluoroacetic acid (100 mL) was stirred at room temperature for 5 minutes. The reaction was diluted with water (700 mL) and the resultant precipitate was collected by suction filtration. The solid was washed with water (2×25 mL) and recrystallized in 2:1 hexane:chloroform to provide the product as white needles (5.09 g, 46%), m.p. 142°-144° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][C:7]=1[S:15](=[O:18])(=[O:17])[NH2:16].[C:19]1([O:25][CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](=[O:11])[C:22]2[CH:23]=[CH:24][C:19]([O:25][CH3:26])=[CH:20][CH:21]=2)=[CH:8][C:7]=1[S:15]([NH2:16])(=[O:18])=[O:17]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen, aluminum chloride (1.95 g, 14.6 mmol) is slurried in dichloromethane (50 mL) then 4-chloro-3-sulfamoyl benzoyl chloride is added and allowed to stir at ambient temperature for 30 minutes. Anisole (683 mg, 6.3 mmol) is added in 2 mL methylene chloride. The reaction is allowed to stir at ambient temperature for 18 hours. The reaction mixture is poured over ice-cold 6 N HCl and extracted with dichloromethane to give a colorless oil. Purification by silica gel chromatography (gradient of ethyl acetate in hexanes 5-25%) yielded a white foam which is crystallized three times from ether to afford the title compound. 1H NMR (MeOD) δ 3.9 (s, 3H), 7.1 (d, 2H, J=8.84 Hz), 7.7-8.0 (m, 4H), 8.4 (d, 1H, J=1.96 Hz). MS (m/z): 326 (M+1). CHN Calc C, 51.62; H, 3.71; N, 4.3. Found C, 51.70; H, 3.76, N, 4.22. M.P. 156-158° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:21]([OH:22])=[CH:20][C:7]2[CH2:8][N:9]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1.[CH3:23][N:24]([CH3:28])[C:25]([Cl:27])=[O:26].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.ClCCl>[ClH:27].[CH3:2][O:3][C:4]1[C:21]([O:22][C:25](=[O:26])[N:24]([CH3:28])[CH3:23])=[CH:20][C:7]2[CH2:8][N:9]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: CN(C)C(=O)Cl
Reactant: COc1cc2c(cc1O)CN(Nc1ccncc1)CCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc2c(cc1OC(=O)N(C)C)CN(Nc1ccncc1)CCC2
Temperature: 25 °C
Yield: 52 %

Procedure:
To a solution of [7-methoxy-8-hydroxy-1,3,4,5-tetrahydrobenzo[c]azepin-2-yl]-4-pyridinylamine hydrochloride 0.25 hydrate (500 mg) in chloroform (10 ml) was added dimethylcarbamyl chloride (170 μl) and triethylamine (0.75 ml). The reaction mixture was heated under reflux for 3 hrs, then cooled to room temperature, and dichloromethane (200 ml) and saturated sodium bicarbonate solution (100 ml) were added. The aqueous phase was extracted with dichloromethane (2×5 ml), the organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed over silica gel eluting with dichloromethane:methanol (9:1). The appropriate fractions were collected and concentrated. The residue was dissolved in methanol (5 ml), and concentrated hydrochloric acid was added. The mixture was concentrated in vacuo, and the residue was crystallized from diethyl ether-dichloromethane to give 320 mg (52%) of product, mp 95-110° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl.CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:24][N:25]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:26]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(S(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (chiral intermediate from Example 261) (40 mg, 0.10 mmol) in dichloromethane (1 mL) was treated with triethylamine (35 μL, 0.25 mmol), cooled to 0° C., treated with methanesulfonyl chloride (9.3 μL, 0.12 mmol) and stirred at 0° C. for 1 h. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (20 mg, 42%). The product was isolated as a single enantiomer. 1H NMR (300 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.55 (s, 1H), 7.35 (br s, 2H), 6.25 (q, J=7.0 Hz, 1H), 4.54-4.40 (m, 1H), 4.27-4.12 (m, 4H), 3.68 (s, 3H), 3.01 (s, 3H), 2.55 (s, 3H), 1.74 (d, J=7.1 Hz, 3H). LCMS for C20H23ClN7O3S (M+H)+: m/z=476.1; Found: 476.1.
Reaction SMILES: [CH:1]1([CH2:4]Br)[CH2:3][CH2:2]1.[CH2:6]([NH:13][C:14]([C:16]1[S:17][C:18]([N:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]2=[O:29])=[CH:19][C:20]=1[CH3:21])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([NH:13][C:14]([C:16]1[S:17][C:18]([N:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[CH:24][C:23]2=[O:29])=[CH:19][C:20]=1[CH3:21])=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: BrCC1CC1
Product: Cc1cc(-n2ccc(OCC3CC3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 62 %

Procedure:
Following the procedure as described in Example 9, making variations only as required to use cyclopropylmethyl bromide in place of 2-cyclopropylethyl 4-methylbenzenesulfonate to react with N-benzyl-5-(4-hydroxy-2-oxopyridin-1(2H)-yl)-3-methylthiophene-2-carboxamide, the title compound was obtained as a colorless solid in 62% yield: mp 175-177° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.54 (t, J=6.0 Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.35-7.20 (m, 6H), 6.24 (dd, J=8.0, 2.7 Hz, 1H), 5.97 (d, J=2.7 Hz, 1H), 4.41 (d, J=6.0 Hz, 2H), 3.88 (d, J=7.2 Hz, 2H), 2.42 (s, 3H), 1.27-1.14 (m, 1H), 0.63-0.54 (m, 2H), 0.37-0.29 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 166.5, 162.4, 161.0, 139.6, 138.8, 137.2, 134.9, 128.2, 127.2, 127.1, 126.6, 120.4, 102.5, 96.6, 73.1, 42.3, 15.5, 9.5, 3.1; MS (ES+) m/z 395.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C.O>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([O:11][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: Cn1cnc2ccc(O)cc21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)COc1ccc2ncn(C)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.3 %

Procedure:
The mixture of 1-methyl-1H-benzo[d]imidazol-6-ol (600 mg, 4.03 mmol), BrCH2COOEt (372 mg, 4.03 mmol) and K2CO3 (1.1 g, 8.06 mmol) in DMF (8 mL) was stirred at room temperature for 16 h. DCM (100 mL) and water (100 mL) was then added to the reaction and the organic layer washed with water (50 mL), brine (50 mL) and dried over Na2SO4 before filtering and concentration to give the crude desired product (560 mg, Yield 60%). LCMS (m/z): 235.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[Br-:7].[CH2:8]([N+:4]1[CH:5]=[CH:6][N:2]([CH3:1])[CH:3]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCBr
Reactant: Cn1ccnc1
Product: CCCCCCCC[n+]1ccn(C)c1
Product: [Br-]
Temperature: 90 °C
Yield: 96.2 %

Procedure:
A 35 mL glass pressure tube (Ace Glass Cat#8648-07) containing a stir bar was charged with 4.105 g (0.050 moles) of 1-methylimdazole followed by 9.656 g (0.050 moles) of 1-bromooctane. The tube was sealed with a threaded Teflon plug and an O-ring and the tubes were placed in an oil bath on a VWR stirring hot plate. The temperature was raised to 90° C. and maintained at this temperature for 16 hours during which time the solution became viscous and the stir bar had stopped. The tube was removed from the bath and mixed vigorously on a vortexing mixer to completely mix the two layers and the tube replaced into the oil bath at 90° C. and the temperature raised to 90° C. The tube was heated for another hour and then mixed vigorously a second time followed by another hour of heating at 90° C. The cycle was repeated once more until the viscous liquid was homogeneous. The liquid was extracted with equal volumes of ethyl acetate three times followed by rotary evaporation to remove the residual ethyl acetate to give 13.239 g of the 1-hexyl-3-methylimidazolium bromide as a viscous lightly yellow colored oil. Compound is also available from loLiTec (Heilbronn, Germany).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([OH:13])=O)=[CH:8][C:9]=1[Br:10])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:55][CH2:56][C:57]1[CH:58]=[C:59]([OH:63])[CH:60]=[CH:61][CH:62]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:13])[NH:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([OH:63])[CH:58]=2)=[CH:8][C:9]=1[Br:10])=[O:4]
Reactant: NCc1cccc(O)c1
Reactant: COC(=O)c1sc(C(=O)O)cc1Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.5 %

Procedure:
To a solution of 3-Bromo-thiophene-2,5-dicarboxylic acid 2-methyl ester (204 mg, 0.76 mmol) in anhydrous DMF (7 mL) was added triethylamine (0.32 mL, 2.28 mmol), HBTU (0.43 g, 1.14 mmol), HOBT (123 mg, 0.91 mmol), and 3-Aminomethyl-phenol (110 mg, 0.91 mmol). The mixture was stirred at room temperature 15 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-50% EtOAc in hexane to afford the desired product (0.1647 g, 59% yield).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][S:40]([N:43]1[C:47]2=[N:48][CH:49]=[CH:50][C:51](B3OC(C)(C)C(C)(C)O3)=[C:46]2[CH:45]=[CH:44]1)(=[O:42])=[O:41].C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:51]4[CH:50]=[CH:49][N:48]=[C:47]5[N:43]([S:40]([CH3:39])(=[O:41])=[O:42])[CH:44]=[CH:45][C:46]=45)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: CC1(C)OB(c2ccnc3c2ccn3S(C)(=O)=O)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
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: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccnc5c3ccn5S(C)(=O)=O)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (150 mg, 0.25 mmol) was treated with 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.31 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) and aqueous solution 2M of sodium carbonate (200 μl, 0.4 mmol) in N,N-dimethylformide (5 ml) according to the method described in Preparation 186 but stirring at 100° C. overnight. The crude was purified using SP1® Purification System (hexane-ethyl acetate) to obtain 90 mg (50% yield) of the title compound as a oil. Purity 99%.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>C(#N)C>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[N:18]([C:34](=[O:35])[C:33]3[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=3[CH3:31])[C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccccc3C)c2=O)C[C@@H]1OC(C)=O
Reaction time: 1.5 h
Yield: 38.3 %

Procedure:
500 mg of 2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine and 0.76 ml of triethylamine were dissolved in 10 ml of dry acetonitrile, and the resulting solution was cooled with ice. To the solution was added 710 mg of 2-methylbenzoyl chloride, and the mixture was allowed to stand at room temperature for 90 minutes. The same procuedre as in Example 1 gave 260 mg (yield: 38.4%) of 2'-deoxy-3',5'-di-O-acetyl-5-fluoro-3-(2-methylbenzoyl)uridine as crystals having a melting point of 108° to 109° C. This was identical with the crystals obtained in Examples 1 by the mixed examination.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.O>CN(C=O)C>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([O:18][C:10]([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)=[CH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cc1ccncc1)c1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OC(=Cc1ccncc1)c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 152.9 %

Procedure:
To a suspension of NaH (0.81 g, 18.6 mmol) in DMF (30 mL) under argon atmosphere and cooled to 0° C., a solution of 1-(4-fluorophenyl)-2-(4-pyridyl)ethanone (2.00 g, 9.3 mmol, obtained in reference example 1) in DMF (15 mL) was added and stirred to room temperature for 30 minutes. It was then cooled to 0° C. and a solution of 4-fluorobenzoyl chloride (2.95 g, 1.9 mmol) in DMF (10 mL) was added. It was stirred at room temperature overnight. Water was added and the solvent was evaporated off. The residue was dissolved in a mixture of CHCl3 and water and the phases were separated. The aqueous phase was extracted with CHCl3 (×3). The organic phase was washed with water (×2), dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 0.98 g of the desired compound as a yellow solid (yield: 31%).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=O)=[CH2:3].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([NH2:20])[CH3:19])=[CH:14][CH:13]=1.O>CN1C(=O)CCC1>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([N:20]2[C:5](=[O:7])[CH2:4][C@@H:2]([C:1]([OH:9])=[O:8])[CH2:3]2)[CH3:19])=[CH:14][CH:13]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: COc1ccc([C@@H](C)N)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc([C@@H](C)N2C[C@H](C(=O)O)CC2=O)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a stirred solution of itaconic acid (35 g, 269 mmol) in NMP at 70° C. was added (R)-1-(4-methoxyphenyl)ethanamine (37 g, 245 mmol) via syringe. The mixture was heated at 80° C. for 1 hour and warmed to 120° C. for an additional 4 hours. The reaction was cooled to rt and poured into 550 mL of water with vigorous stirring. The mixture was aged for 1 hour over which time a slurry was formed. The solids were collected via filtration and washed with water. The solids were dried and transferred to a flask and recrystallized from iPrOH. Upon cooling and stirring, a thick slurry was obtained which was filtered to afford solids enriched in the major diastereomer. This material was again recrystallized from iPrOH to obtain (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carboxylic acid 1.01.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:6][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5]
Reactant: O=C(O)c1c(Cl)ccnc1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1c(Cl)ccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
A mixture of 2,4-dichloronicotinic acid (5.0 g, 26 mmol), benzyl bromide (3.7 mL, 31 mmol) and K2CO3 (7.2 g, 52 mmol) in DMF (50 mL) was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layers were combined and washed with water, brine, dried over sodium sulfate, evaporated and then purified by silica chromatography (0-7% ethyl acetate in hexanes) to give benzyl 2,4-dichloronicotinate (7.0 g, 96%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:22]OC(OC)(C)C.O>CO>[CH3:22][O:15][C:14]([C@H:10]1[CH2:11][C:12](=[O:13])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:9]1)=[O:16]
Reactant: COC(C)(C)OC
Reactant: O=C(O)[C@H]1CC(=O)N(c2ccc(O)cc2)C1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)[C@H]1CC(=O)N(c2ccc(O)cc2)C1
Yield: 86 %

Procedure:
A mixture of 26 g (117.5 mmol) of (S)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid, 0.66 ml of sulfuric acid, and 100 ml of dimethoxypropane in 700 ml of methanol are heated to reflux for 3 hours. For the working-up, the reaction mixture is reduced to ⅘ of its volume, then the residue is added under stirring to a mixture of ice and water. The precipitated product is collected on a filter funnel, washed with cold water and finally dried under high vacuum to yield 23.7 g (86% of theory) of (S)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid; MS: m/e=234 (M−H)+; optical integrity: 97.4% e.e. .