Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12](O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].S(=O)(=O)(O)O.CC(=O)OCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Clc1ccc(C2CC=Cc3ccccc32)cc1Cl
Temperature: 100 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
To a solution of the crude alcohol 2 (53 g) in toluene (500 mL) was added silica gel coated with sulfuric acid (3%, 14 g). The mixture was heated to 100° C. and monitored by TLC (prod Rf (25 EA/hex)=0.58). After three hours, the mixture was filtered. The organic phase was washed with water and sodium bicarbonate solution, dried (Na2SO4), and evaporated to give the alkene 3 (42 g, 84%) as a pale-brown solid. TLC Rf (25 EA/hex)=0.58. GC-MS Rt=13.55 min, m/z=274 (M+). 1H NMR (CDCl3, δ): 7.4-6.7 (m, 7H), 6.54 (d, J=9.6 Hz, 1H), 6.0 (m, 1H), 4.08 (t, J=8.0 Hz, 1H), 2.7 (m, 1H), 2.5 (m, 1H). 13C NMR (CDCl3, δ, mult): 143.6, 136.3, 133.8, 132.2, 130.2, 130.2, 128.1, 127.7, 127.2, 126.4, 129.7, 127.4, 42.8(1), 31.6(2).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[N:3]1[CH2:10][CH2:11][S:12][C:13]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[N:14]=1.[H-].[Na+].I[CH3:26]>CN(C)C=O>[CH3:26][N:17]1[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[N:14]=[C:13]1[S:12][CH2:11][CH2:10][N:3]1[C:2]([CH3:22])([CH3:1])[CH2:7][CH2:6][CH2:5][C:4]1([CH3:8])[CH3:9]
Reactant: CI
Reactant: CC1(C)CCCC(C)(C)N1CCSc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(SCCN2C(C)(C)CCCC2(C)C)nc2ccccc21
Reaction time: 1 h
Yield: 97 %

Procedure:
In 5 ml of N,N-dimethylformamide was dissolved 200 mg of the compound obtained in Example 9, and 30.4 mg of 60% sodium hydride was added to the solution, followed by stirring for about 1 hour. To the mixture was added 0.48 ml of iodomethane, and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was extracted with 300 ml of chloroform, and the chloroform layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The residue was freed of the solvent by distillation under reduced pressure, and the resulting viscous brown liquid was purified by silica gel column chromatography (chloroform:methanol=50:1 to 10:1 by volume) to obtain 202 mg (97%) of the titled compound as a pale yellow powder.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:15]([OH:17])=O)[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:51]1[CH2:56][CH2:55][CH:54]([C:57]2[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=2)[C:60]#[N:61])[CH2:53][CH2:52]1>CN(C)C=O>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:15]([N:51]3[CH2:56][CH2:55][CH:54]([C:57]4[CH:58]=[C:59]([CH:62]=[CH:63][CH:64]=4)[C:60]#[N:61])[CH2:53][CH2:52]3)=[O:17])[CH:12]=[N:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1cccc(C2CCNCC2)c1
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(C2CCN(C(=O)c3cncc(C#Cc4ccccc4)c3)CC2)c1
Reaction time: 0.25 h
Yield: 45.1 %

Procedure:
A solution of 5-phenylethynyl-pyridine-3-carboxylic acid (0.75 g, 3.3 mmol) in anhydrous dimethylformamide (9 ml) is treated with HATU (1.27 g, 3.3 mmol) and diisopropylethylamine (1.1 ml, 6.1 mmol). The reaction mixture is stirred 15 mins. at ambient temperature before being treated with a solution of 3-(piperidin-4-yl)-benzonitrile (0.6 g, 3 mmol) in dimethylformamide (6 ml). The reaction mixture is stirred at ambient temperature 2 hours, concentrated under vacuum and the residue partitioned between ethyl acetate (200 ml) and saturated aqueous sodium bicarbonate ((45 ml). The organic layer is dried (magnesium sulfate), concentrated under vacuum and the residue chromatographed on silica gel (dichloromethane/methanol 39:1) to give the title compound as a yellow oil (0.53 g). 1H NMR (CDCl3, 500 MHz) δ8.80 (s, 1H), 8.63 (s, 1H), 8.00 (s, 1H), 7.50 (m, 9H), 4.90 (br m, 1H), 3.85 (br m, 1H), 3.28 (m, 1H), 2.90 (m, 2H), 1.91 (m, 1H), 1.75 (m, 3H). EI MS M++H: 392.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH:20]([CH3:22])[CH3:21]>C(OCC)(=O)C.CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:20]([CH3:22])[CH3:21])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(C=O)cc1Br
Temperature: 25 °C
Yield: 58.7 %

Procedure:
To a mixture of 3-bromo-4-hydroxybenzaldehyde (2.5 g, 12.4 mmol), potassium carbonate (2.57 g, 18.6 mmol), potassium iodide (0.21 g, 1.24 mmol) and N,N-dimethylformamide (30 mL) was added 2-bromopropane (1.46 mL, 15.5 mmol) under stirring at room temperature, and the mixture was stirred at 70° C. for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-3/1) to give the title compound (1.77 g, yield 59%) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@:13]([CH2:23][OH:24])([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:10]1[OH:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]1([CH3:45])[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@:13]([CH2:23][O:24][S:41]([C:38]2[CH:39]=[CH:40][C:35]([CH3:45])=[CH:36][CH:37]=2)(=[O:43])=[O:42])([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:10]1[O:34][S:41]([C:38]1[CH:39]=[CH:40][C:35]([CH3:45])=[CH:36][CH:37]=1)(=[O:43])=[O:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn([C@@H]2O[C@](CO)(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@]2(COCc3ccccc3)O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](OS(=O)(=O)c3ccc(C)cc3)[C@@H]2OCc2ccccc2)cc1
Yield: 79.4 %

Procedure:
A solution of 1-(3,5-di-O-benzyl-4-C-(hydroxymethyl)-β-D-ribofuranosyl)thymine 35 (1.48 g, 3.16 mmol), DMAP (1.344 g, 0.011 mol) and p-toluenesulphonyl chloride (1.45 g, 7.6 mmol) in dichloromethane (20 ml) was stirred for 3 h at room temperature. The reaction mixture was diluted with dichloromethane (30 ml) and washed with saturated aqueous solutions of sodium hydrogen carbonate (3×20 ml) and sodium chloride (2×25 ml). The organic phase was dried (Na2SO4), filtered and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography using methanol:dichloromethane (1:99, v/v) as eluent to give nucleoside 72 (1.95 g, 80%) as a white solid material. FAB-MS m/e 776. δC (CDCl3) 162.9, 149.8 (C-2, C-4), 145.8, 145.2 (2×Ts), 136.9, 136.8 (2×Bn), 134.3 (C-6), 132.1, 132.0, 130.0, 129.9, 129.0 128.9, 128.4, 128.3, 128.2, 128.0, 127.7 (2×Ts, 2×Bn), 111.2 (C-5), 85.3, 84.0 (C-1′, C-4′), 78.9, 78.3, 75.2, 74.3, 72.7, 69.1 (C-2′, C-3′, C-5′, C-1″, 2×Bn), 21.7 (2×CH3), 11.9 (CH3). Anal. Calcd. for C39H40N2S2O11: C, 60.30; H, 5.19; N, 3.61. Found: C, 59.95; H, 5.11, N, 3.81.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:12]1[CH2:16][CH2:15][C@@H:14]([NH2:17])[CH2:13]1.[H-].[Na+].[Cl:20][CH2:21][CH2:22][N:23]=[C:24]=[O:25]>C1COCC1>[Cl:20][CH2:21][CH2:22][NH:23][C:24]([NH:17][C@@H:14]1[CH2:15][CH2:16][O:12][CH2:13]1)=[O:25]
Reactant: N[C@@H]1CCOC1
Reactant: O=C=NCCCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCCl)N[C@@H]1CCOC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 70.2 %

Procedure:
A 0° C. suspension of (R)-(+)-tetrahydro-3-furylamine p-toluenesulfonate salt (1.00 g, 3.86 mmol) in THF (40 mL) was treated with NaH (60% in mineral oil, 0.170 g, 4.24 mmol), stirred at 0° C. for 1.5 h, treated with 2-chloroethyl isocyanate (0.362 mL, 4.24 mmol) and stirred at RT overnight as the cooling bath expired. The mixture was treated with satd. NH4Cl and water, extracted with EtOAc (2×) and the combined organics were washed with brine (2×), dried over Na2SO4 and concentrated to dryness. The residue was treated with 1:1 EtOAc/Hex and the resulting solid collected via filtration to afford (R)-1-(2-chloroethyl)-3-(tetrahydrofuran-3-yl)urea (522 mg, 70%). MS (ESI) m/z: 193.1 (M+H+).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=O)=O)=CC=1.[C-:19]#[N:20].[Na+]>CS(C)=O>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:12][CH2:11][C:19]#[N:20]
Reactant: Cc1ccc(S(=O)(=O)OCCc2cccs2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCc1cccs1
Temperature: 90 °C

Procedure:
A mixture was prepared from 20.8 g of 2-[2-(4-toluenesulfonyloxy)ethyl]thiophene, 5.4 g of sodium cyanide and 175 ml of dimethylsulfoxide and this mixture was heated to 90° C. The mixture was quenched by pouring it into saturated aqueous ammonium chloride solution and the resulting solution was extracted into ethyl acetate. The ethyl acetate solution was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give crude 2-thiophenepropionitrile. This product was mixed with 175 ml of 1M diborane in tetrahydrofuran and allowed to stir at room temperature. The reaction was quenched in ethanol and methanolic hydrogen chloride was added. The white solid which formed was separated by filtration, washed with ether and dried in a vacuum oven to give 3-(2-thienyl)propylamine hydrochloride melting at about 197°-198° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=1.[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20]([NH:1][C:2]2[S:3][C:4]([CH3:12])=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: COC(=O)Cc1nc(N)sc1C
Product: COC(=O)Cc1nc(NS(=O)(=O)c2cccc(Cl)c2C)sc1C

Procedure:
The title compound was prepared from methyl 2-(2-amino-5-methyl-1,3-thiazol-4-yl)acetate and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (23.2 mg) with purity >90%. LCMS (pos) m/z 375.2.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][C:4](OC)=[O:5].O.[NH2:11][NH2:12]>CCO>[CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][C:4]([NH:11][NH2:12])=[O:5]
Reactant: COC(=O)CC(C)(C)C
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)CC(=O)NN
Temperature: 80 °C
Yield: 18 %

Procedure:
To a mixture of methyl 3,3-dimethylbutanoate (500 mg, 3.84 mmol) in EtOH (12 ml) was added hydrazine monohydrate (1.87 ml, 38.4 mmol). The mixture was heated to 80° C. under reflux for overnight. The reaction was cooled back down to room temperature and concentrated to dryness affording a crude residue. The residue was dried under high vacuum to afford the title compound as crystalline solid (90 mg, 18% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.69-9.12 (s, 1H) 4.13 (br. s, 2H) 1.89 (s, 2H) 0.94 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][C:5]1[C:19]([OH:20])=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[N:16][CH:15]=[CH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1.Br[C:26]1[CH:27]=[CH:28][C:29]([C:32]#[N:33])=[N:30][CH:31]=1>>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][C:5]1[C:19]([O:20][C:26]2[CH:31]=[N:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)=[CH:18][C:8]2[NH:9][C:10]([C:12]3[CH:17]=[N:16][CH:15]=[CH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1
Reactant: Oc1cc2[nH]c(-c3cnccn3)nc2cc1Oc1ccccc1F
Reactant: N#Cc1ccc(Br)cn1
Product: N#Cc1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2ccccc2F)cn1

Procedure:
The entitled compound was obtained as a yellow solid in the same method as in Example 251 (step 2) or in accordance with the method or by combining it with an ordinary method but using 5-(2-fluorophenoxy)-6-hydroxy-2-pyrazin-2-yl-1H-benzimidazole obtained in Example 251 (step 1) and 5-bromo-2-cyanopyridine.
Reaction SMILES: N#N.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:13][C:14]1[N:22]=[C:21]([Cl:23])[C:20]([F:24])=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17].CN([CH:28]=[O:29])C>C1COCC1>[Cl:13][C:14]1[C:15]2[C:16](=[O:17])[NH:18][CH:28]([OH:29])[C:19]=2[C:20]([F:24])=[C:21]([Cl:23])[N:22]=1
Reactant: NC(=O)c1cc(F)c(Cl)nc1Cl
Reactant: CN(C)C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N#N
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1NC(O)c2c(F)c(Cl)nc(Cl)c21
Reaction time: 1 h
Yield: 90 %

Procedure:
A 22-L multi-neck RBF equipped with an overhead stirrer, temperature probe, and N2 inlet/outlet was charged with LiHMDS (10.65 L, 2.5 eq) by N2 pressure. The orange solution was cooled to <0° C. using an ice/brine bath. A separate 12-L RBF was sequentially charged with 2,6-dichloro-5-fluoronicotinamide (890 g, 1.0 eq), anhydrous THF (6.0 L), and anhydrous DMF (1.0 L, 3.0 eq). The resulting solution was added to the LiHMDS solution via a peristaltic pump over a 1 h period, which kept the internal temperature below 5° C. The 12-L flask was rinsed with THF (1.6 L), and the rinse was transferred to the reaction mixture. The mixture was stirred at a temperature <5° C. for 1 h, and the reaction was added to a pre-cooled 2N HCl aq solution via a peristaltic pump at a rate that kept the temperature of the mixture below 22° C. Following the quench, IPAc (14 L) was added and the mixture was stirred for 10 min. The biphasic mixture was separated and the organic layer was stored in a carboy at RT overnight. The organic layer was subsequently washed with water (8.9 L) and was concentrated under reduced pressure to a volume of about 4.5 L. The distillation was continued the next day. Isopropyl acetate (16 L) was added to the slurry and the distillation was continued until about 4.5 L of material remained. The off-white slurry was transferred into a 50-L multi-neck RBF to which was charged heptanes (18 L) via a peristaltic pump over a 45 min period. The resultant slurry was stirred at RT overnight and then filtered through a Buchner funnel with a Sharkskin filter paper. The filter cake was washed with heptanes (2×4.5 L) and then dried under high vacuum at RT for 24 h to afford title compound (913.0 g, 90%). 1H NMR (300 MHz, DMSO-d6) δ ppm 6.11 (dd, J=9.3 Hz, 1.5 Hz, 1H), 6.95 (d, J=9.3 Hz, 1H), 9.54 (s, 1H). [M+H] calc'd for C7H3Cl2FN2O2, 237. found, 237.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])=[N:4][CH:3]=1.[Cl:19][C:20]1[C:21]([F:31])=[CH:22][C:23]([F:30])=[C:24]([S:26](Cl)(=[O:28])=[O:27])[CH:25]=1>>[Cl:19][C:20]1[C:21]([F:31])=[CH:22][C:23]([F:30])=[C:24]([S:26]([N:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][N:4]=2)[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])(=[O:28])=[O:27])[CH:25]=1
Reactant: COc1ccc(CNc2ncc(Cl)s2)c(OC)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Product: COc1ccc(CN(c2ncc(Cl)s2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1

Procedure:
Prepared according to Preparation 207 using 5-chloro-N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation 208) and 5-chloro-2,4-difluorobenzenesulfonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[CH2:6][C:7](=[O:13])[N:8]([CH2:11][CH3:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[CH:28][C:27]=2[O:39][CH3:40])[C:22]([Cl:41])=[CH:21][N:20]=1>>[Cl:41][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[CH:28][C:27]=2[O:39][CH3:40])=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[CH2:6][C:7](=[O:13])[N:8]([CH2:11][CH3:12])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCc2cc(N)c(OC)cc2CC1=O
Product: CCN1CCc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCN(C)CC5)cc4OC)n3)c(OC)cc2CC1=O

Procedure:
The title compound was prepared from 7-Amino-3-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as a tan solid (0.060 g, 65%). MP: 222-233° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.16 (d, 1H, J=8.6 Hz), 8.08 (s, 1H), 8.02 (s, 1H), 7.48 (s, 1H), 7.42 (s, 1H), 6.61 (s, 1H), 6.57 (d, 1H, J=2.5 Hz), 6.55-6.51 (m, 1H), 3.91 (s, 3H), 3.85 (s, 3H), 3.84-3.80 (m, 2H), 3.70-3.64 (m, 2H), 3.48 (q, 2H, J=7.2 Hz), 3.25-3.17 (m, 4H), 3.03-2.97 (m, 2H), 2.65-2.57 (m, 4H), 2.38 (s, 3H), 1.17 (t, 3H, J=7.1 Hz). MS: 566 (MH)+.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=2)[C:18]=1[C:29](Cl)=[O:30]>C(Cl)Cl.[N+](C)([O-])=O>[CH3:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]=1[C:29]([C:8]1[CH:9]=[C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:10])[Cl:11])[NH:6][CH:7]=1)=[O:30]
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)Cl
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: Cc1onc(-c2ccccc2)c1C(=O)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.7 %

Procedure:
To a solution of 2.1 g (10 mmol) of 2-trichloroacetyl-1H-pyrrole (commercially available) in CH2Cl2 (35 mL) and nitromethane (17.5 mL), 1.66 g (12.5 mmol) of AlCl3 was added in one portion. Then 2.96 g (12.5 mmol) of 5-methyl-3-(4-fluoro-phenyl)-isoxazole-4-carboxylic acid chloride (example 2, step 1) in 5 mL of CH2Cl2 was added dropwise. The reaction mixture was stirred at room temperature for 18 h before poured onto ice-water. The organic phase was separated, and the aqueous phase was extracted with diethyl ether. The combined organic solution was dried over Na2SO4, and evaporated to dryness. The obtained solid was washed extensively with petroleum ether to give 2.93 g 4-(5-methyl-3-phenyl-isoxazole-4-carbonyl)-2-trichloroacetyl-1H-pyrrole in 70% yield as yellow solid. (m/e): 414.8 (M+; 100%).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1[O:4][C:5]([CH:19]([C:21]2[C:29]3[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH3:20])(C(OCC2C=CC=CC=2)=O)[C:6](=[O:8])[N:7]=1.C(O)C>[C].[Pd].O1CCCC1>[CH3:31][N:2]([CH3:1])[C:3]1[O:4][CH:5]([CH:19]([C:21]2[C:29]3[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH3:20])[C:6](=[O:8])[N:7]=1
Reactant: CC(c1c[nH]c2cc(F)ccc12)C1(C(=O)OCc2ccccc2)OC(N(C)C)=NC1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(c1c[nH]c2cc(F)ccc12)C1OC(N(C)C)=NC1=O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 99.5 %

Procedure:
Benzyl 2-dimethylamino-5-[1-(6-fluoroindol-3-yl)ethyl]-4-oxo-2-oxazolin-5-carboxylate (500 mg) was dissolved into 15 ml of a solution of ethanol and tetrahydrofuran in a ration of 5:1. 10% palladium-carbon (170 mg) was added. The whole was subjected to hydrogenation under normal temperature and normal pressure for 1.5 hours. The whole was stirred at 80° C. under nitrogen atmosphere for 1 hour and then filtered to remove the catalyst. The filtrate was concentrated to give 2-dimethylamino-5-[1-(6-fluoroindol-3-yl)ethyl]-2-oxazolin-4-one (340 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[NH:7][C:8](=[O:15])[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]=2[C:4]([CH:16]2[CH2:20][CH2:19][N:18](C(OCC3C=CC=CC=3)=O)[CH2:17]2)=[N:3]1>ClCCl.CO.[Pd]>[CH3:1][N:2]1[C:6]2[NH:7][C:8](=[O:15])[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]=2[C:4]([CH:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)=[N:3]1
Reactant: Cn1nc(C2CCN(C(=O)OCc3ccccc3)C2)c2c3c(c(=O)[nH]c21)CCCC3
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cn1nc(C2CCNC2)c2c3c(c(=O)[nH]c21)CCCC3
Yield: 110.2 %

Procedure:
A solution of EXAMPLE 24E (766 mg, 1.88 mmol) in a mixture of dichloromethane (30 mL) and methanol (30 mL) was treated with 10% palladium on carbon (150 mg) under hydrogen at ambient temperature for 6 hours. Solid material was filtered off and the filtrate concentrated to provide the title compound (564 mg, 100%). 1H NMR (DMSO-d6): 1.67-1.79 (m, 4H), 2.01-2.11 (m, 1H), 2.22-2.32 (m, 1H), 2.38-2.43 (m, 2H), 2.85-2.91 (m, 2H), 3.16-3.26 (m, 2H), 3.30 (dd, J=11.0, 8.0 Hz, 1H), 3.46 (dd, J=11.2, 7.5 Hz, 1H), 3.78 (s, 3H), 3.81-3.88 (m, 1H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]4[OH:35])=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([N:32]1[CH2:33][CH2:34][C@@H:29]([NH:28][C:26]([C:22]2[C:18]3=[N:19][CH:20]=[CH:21][C:16]([C:8]4[CH:9]=[C:10]([O:14][CH3:15])[C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)=[C:17]3[NH:24][C:23]=2[CH3:25])=[O:27])[C@H:30]([OH:35])[CH2:31]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CCN(C(C)=O)C[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f25) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:17](=[O:18])[CH2:16][Cl:15])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(Nc2ccccc2)c1
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Product: O=C(CCl)N(c1ccccc1)c1cccc(Cl)c1

Procedure:
N-(3-Chlorophenyl)aniline (25.1 g, 0.123 mole) and chloroacetyl chloride (19.6 ml, 0.246 mole) were refluxed in toluene (100 ml) for 4 hours, then stripped of toluene and excess acid chloride in vacuo to yield an oil which crystallized on scratching. Recrystallization from ethanol/H2O gave purified title product, 32.6 g, m.p. 94°-96.5°.
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]([CH3:38])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:17]([C:33]([F:36])([F:35])[F:34])=[N:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[CH:10][C:9]=1[CH3:37])[CH3:6])C.[Li+].[OH-]>>[CH3:38][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:17]([C:33]([F:35])([F:36])[F:34])=[N:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[CH:10][C:9]=1[CH3:37])([CH3:6])[C:4]([OH:39])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3ccc(OC(F)(F)F)cc3)nc2C(F)(F)F)cc1C
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(OCc2ccc(-c3ccc(OC(F)(F)F)cc3)nc2C(F)(F)F)ccc1OC(C)(C)C(=O)O

Procedure:
In analogy to the procedure described in example 26C], 2-methyl-2-{2-methyl-4-[6-(4-trifluoromethoxy-phenyl)-2-trifluoromethyl-pyridin-3-ylmethoxy]-phenoxy}-propionic acid ethyl ester was treated with 1 N aqueous LiOH solution to give the title compound as colorless oil.