Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])[CH:23]=[CH2:24].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C>[C:27]([O:26][C:22](=[O:25])[CH:23]=[CH:24][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:10][CH:11]=2)=[CH:16][CH:17]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)C=Cc1ccc(-c2ccc(OC(=O)OC(C)(C)C)cc2)cc1
Reaction time: 24 h
Yield: 93.9 %

Procedure:
To 7.4 g (21.2 mmol) of 4-(tert-butoxycarbonyloxy)-4′-bromobiphenyl synthesized in the Example 9, were added 2.85 g (22.2 mmol) of tert-butyl acrylate, 10 ml of triethylamine, 30 ml of acetonitrile, 50 mg (2.22×10−1 mmol) of palladium acetate [Pd(OAc)2], and 116 mg (4.42×10−1 mmol) triphenylphosphine. The reaction system was purged with argon, and the reaction was conducted for 24 hours with heating and refluxing. The reaction mixture was poured into 500 ml of an iced water, and hydrochloric acid was added to the resultant mixture with stirring. The solid formed by stirring was collected by filtration, washed with water, dried, and recrystallized from methanol to give 7.9 g (19.9 mmol) of tert-butyl-4-(4′-tert-butoxycarbonyloxyphenyl)cinnamate.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11]C=O)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[O:14][CH2:15][CH:16]1[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]1.[C:24](O)(=[O:26])C>C[O-].[Na+].CO>[NH2:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[O:14][CH2:15][CH:16]2[CH2:17][O:18][C:19]([CH3:22])([CH3:23])[O:20][CH2:21]2)=[C:2]([O:26][CH3:24])[N:10]=1
Reactant: CC1(C)OCC(COn2cnc3c(Cl)nc(NC=O)nc32)CO1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc2c1ncn2OCC1COC(C)(C)OC1
Yield: 69 %

Procedure:
6-Chloro-9-(2,2-dimethyl-1,3-dioxan-5-ylmethoxy)-2-formamidopurine (0.5 g, 1.46 mmol) in 1.2M sodium methoxide in methanol (3.38 ml) and methanol (5 ml) was heated at reflux temperature for 1.5 hours and then cooled. Acetic acid (0.16 ml) was added and the solution evaporated to dryness. The residue was suspended in water and extracted with ethyl acetate (2×50 ml). The combined ethyl acetate extracts were washed with water, dried (magnesium sulphate) and evaporated under reduced pressure. Chromatography on silica gel (eluted with chloroform-ethanol, 100:1) gave the title compound (310 mg, 69%). 1R: υmax (KBr) 3397, 3208, 1640, 1616, 1581, 1480, 1390 cm-1. 1H NMR: δH [(CD3)2SO] 1.32(3H,s,CH3), 1.35(3H,s,CH3), 2.00(1H,m,CH), 3.77(2H,dd, J=11.8, 6.1 Hz, 2×H(ax), 3.9 (3H,s,OCH3), 3.99 (2H,dd,J=11.8, 4.1 Hz, 2×H(eq)), 4.36(2H,d, J=6.8 Hz, CH2ON), 6.60(2H,br.s, D2O exchangeable, NH2), 8.14(1H,s,H-8). Found: C, 49.30; H, 6.12; N, 22.03%; M+ 309.1455. C13H19N5O4 0.5H2O requires: C, 49.04; H, 6.34; N, 22.00%; M+ 309.1437.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14](=[CH:21][C:22]2([CH2:28][CH3:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:15]3=[O:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][CH:14]([CH2:21][C:22]2([CH2:28][CH3:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[C:15]3=[O:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC1(C=C2Cc3c(cccc3-c3ccc(C(C)(C)C)cc3)C2=O)CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC1(CC2Cc3c(cccc3-c3ccc(C(C)(C)C)cc3)C2=O)CCCCC1
Yield: 97.1 %

Procedure:
25.0 g of crude 4-(4-tert-butyl-phenyl)-2-(1-ethylcyclo-hexylmethylene)-indan-1-one (GC: ˜83% purity) are dissolved in 250 ml of ethyl acetate in a flask with gas inlet and stirrer. 1.75 g of palladium on activated carbon (10 wt-% palladium) are added. The system is evacuated and refilled with argon three times to remove oxygen and then evacuated and refilled with hydrogen three times. The stirrer is started and the reaction mixture is vigorously stirred to help the diffusion of hydrogen gas into the liquid reaction mixture. The hydrogen uptake is monitored and stirring is continued until the hydrogen uptake ceases. Filtering the crude reaction mixture over a paper filter and removing the solvent in a vacuum leaves crude 4-(4-tert-butyl-phenyl)-2-(1-ethyl-cyclohexylmethyl)-indan-1-one (yield 24.4 g, GC: ˜82% purity). The obtained crude product was used without further purification for the subsequent reduction/elimination-sequence.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:36])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:34])([CH3:33])[CH:4]1[CH3:35].[CH2:37]([O:39][C:40]([C:42]1[CH:49]=[CH:48][C:45]([CH:46]=O)=[CH:44][CH:43]=1)=[O:41])[CH3:38]>>[CH2:37]([O:39][C:40](=[O:41])[C:42]1[CH:49]=[CH:48][C:45](/[CH:46]=[C:12](/[C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:3]([CH3:36])([CH3:2])[CH:4]([CH3:35])[C:5]3([CH3:33])[CH3:34])\[CH3:13])=[CH:44][CH:43]=1)[CH3:38]
Reactant: CC1C(C)(C)c2ccc(C(C)[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2C1(C)C
Reactant: CCOC(=O)c1ccc(C=O)cc1
Agent: [Br-]
Product: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)C(C)C3(C)C)cc1

Procedure:
In a manner analogous to that described in Example 1, from [1-(1,1,2,3,3-pentamethyl-5-indanyl)ethyl]-triphenylphosphonium bromide and 4-ethoxycarbonyl-benzaldehyde there can be obtained p-[(E)-2-(1,1,2,3,3,-pentamethyl-5-indanyl)propenyl]-benzoic acid ethyl ester of melting point 79°-80° C.
Reaction SMILES: [H-].[Na+].[C:3](OCC)(=[O:5])[CH3:4].[C:9]([C:12]1[CH:21]=[C:20]([F:22])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=2)[CH:13]=1)(=[O:11])[CH3:10].O>C(COC)OC>[F:22][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=2)[CH:13]=[C:12]([C:9]([OH:11])=[CH:10][C:3](=[O:5])[CH3:4])[CH:21]=1
Reactant: COc1ccc2cc(C(C)=O)cc(F)c2c1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc2cc(C(O)=CC(C)=O)cc(F)c2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
A mixture of sodium hydride (0.048 mol) and ethyl acetate (4.22 g, 0.048 mol) in dry dimethoxyethane (10 ml) under nitrogen, was treated over 30 minutes at room temperature with a solution of 2-acetyl-4-fluoro-6-methoxynaphthalene (5.33 g, 0.024 mol) in dry dimethoxyethane (25 ml). The reaction mixture was then stirred at 50° C. for 31/2 hours. After cooling it was treated with water (50 ml) then dilute hydrochloric acid (50 ml) and the orange precipitate collected by filtration, washed with petrol and dried. Recrystallisation from methanol/ether gave 3.2 g product m.p. 107°-8° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:39]1(=[O:49])[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][N:43]2[C:39](=[O:49])[C:40]3[C:41](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:42]2=[O:44])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc(Br)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)cc1)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 57 %

Procedure:
To a solution of 1,1-dimethylethyl [(1S)-2-(4-bromophenyl)-1-(hydroxymethyl)ethyl]carbamate (70.6 mmol), tripheylphosphine (84.7 mmol), and phthalimide (84.7 mmol) in anhydrous tetrahydrofuran (550 mL) at 0° C. was added dropwise diisopropyl azodicarboxylate (84.7 mmol) over 10 minutes. The reaction continued to stir allowing to warm to RT over 5 h. The reaction was then concentrated in vacuo and product was triturated out of solution using ethyl acetate (500 mL). The precipitate was filtered, washed with ethyl acetate (3×100 mL), and dried to afford the title product as a white solid (57%). ESMS [M+H]+: 460.4.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:13])[C:6]2=O.[BH4-].[Na+].Cl>C1COCC1.CO>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[CH2:6]2
Reactant: CC1Cc2c(Br)ccc(Br)c2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1=Cc2c(Br)ccc(Br)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 54.1 g (0.178 mol) of 4,7-dibromo-2-methyl-1-indanone in 240 ml of THF-methanol (2:1, vol.), 9.40 g (0.248 mmol) of NaBH4 was added in small portions for 2 hours at −5° C. (Caution: temperature must be lower 0° C.). The mixture was stirred overnight at ambient temperature. The resulting mixture was acidified with 10% HCl to pH=4. The organic layer was separated; the aqueous layer was extracted with 3×200 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and evaporated to dryness. To the residue 500 ml of toluene were added. This toluene solution was treated with 50.0 g pTolSO3H for 5 hours at reflux. The resulting mixture was cooled to room temperature and passed through a short Silica Gel 60 column (40-63 μm, d 60 mm, l 40 mm). This column was additionally eluted with 700 cm3 of toluene. The combined extract was evaporated to dryness to give a white solid of the title product. Yield 47.2 g (92%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10](Br)[CH:11]=1)[C:6]([OH:8])=[O:7])=[O:2].[CH2:13]([Zn]CC)[CH3:14]>O1CCOCC1.C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:13][CH3:14])[CH:11]=1)[C:6]([OH:8])=[O:7])=[O:2]
Reactant: CC[Zn]CC
Reactant: O=Cc1cc(Br)cc(C(=O)O)c1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCc1cc(C=O)cc(C(=O)O)c1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
Under nitrogen, Pd(dppf) (97 mg, 0.119 mmol) was added to a stirred solution of 3-formyl-5-bromo-benzoic acid (3.00 g, 11.92 mmol) in dioxane (100 mL). Diethyl zinc (14.7 g, 17.9 mmol, as a 15% solution in toluene) was added and the mixture was stirred at 75° C. for 1 h. The reaction was quenched by adding water (5 mL) and the solvent was evaporated to a volume of about 50 mL. The mixture was basified by adding sat. aq. ammonia (1 mL). The mixture was filtered and the filtrate was acidified by adding formic acid (4 mL) before it was separated by prep. HPLC to give the title compound as a colourless resin (1.17 g). LC-MS*: tR=0.44 min, [M−H]−=177.26; 1H NMR (D6-DMSO): δ 1.24 (t, J=7.8 Hz, 3H), 2.77 (q, J=7.5 Hz, 2H), 7.92 (t, J=1.8 Hz), 8.08 (t, J=1.8 Hz, 1H), 8.26 (t, J=1.5 Hz, 1H), 10.06 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[C:19]([C:13](=[CH:12][NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH3:3])[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C=CNc1ccccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1ccccc1OC)C(=O)c1ccccc1
Temperature: 5 °C
Yield: 46.8 %

Procedure:
50% Sodium hydride (2.4 g, 0.05 mol) was washed with petroleum ether, suspended in dry toluene (50 ml) and stirred at 5° C. Ethyl 3-(2-methoxyphenylamino)acrylate (8.7 g, 0.05 mol) in dry toluene (25 ml) was added and the mixture was stirred for 2.5 hours. Benzoyl chloride (6.8 g, 0.05 mol) in dry toluene (25 ml) was added dropwise and the mixture was heated under reflux for 2 hours. The mixture was cooled, washed with dilute hydrochloric acid, water and brine, then dried and evaporated. The residue was chromatographed (silica gel, dichloromethane) to afford ethyl 2-benzoyl-3-(2-methoxyphenylamino)acrylate (7.62 g, 46.8%) as a yellow oil.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: NCCc1ccccc1
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3cccnc3)nc(NCCc3ccccc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-3-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-phenethylamino-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][NH:14][C:15]1[C:16](=[O:26])[N:17]([CH2:22][C:23](O)=[O:24])[C:18]([CH3:21])=[CH:19][N:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([CH2:37][NH2:38])[CH:35]=2)[NH:30][CH:29]=1.C([O-])=O.[NH4+]>[Pd].ClCCl>[CH3:21][C:18]1[N:17]([CH2:22][C:23]([NH:38][CH2:37][C:34]2[CH:35]=[C:36]3[C:31](=[CH:32][CH:33]=2)[NH:30][CH:29]=[C:28]3[CH3:27])=[O:24])[C:16](=[O:26])[C:15]([NH:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:20][CH:19]=1
Reactant: Cc1c[nH]c2ccc(CN)cc12
Reactant: Cc1cnc(NC[C@H]2CCCN2C(=O)OC(C)(C)C)c(=O)n1CC(=O)O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1c[nH]c2ccc(CNC(=O)Cn3c(C)cnc(NC[C@H]4CCCN4C(=O)OC(C)(C)C)c3=O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
The title compound was prepared by a similar method to preparation 45 from 2-[3-({[(2R)-1-(tert-butoxycarbonyl)pyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2H)-pyrazinyl]acetic acid [see preparation 54] and (3-methyl-1H-indol-5-yl)methylamine (72 mg, 0.45 mmol) [see preparation 36]. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (100:0) changing to (95:5) in 1% increments 1H-NMR indicated starting chloro compound material. A mixture of this product with 10% palladium on charcoal (39.6 mg) and ammonium formate (439.5 mg,6.98 mmol) in dichloromethane (50 ml), was then stirred at room temperature overnight. Additional, 10% Palladium on charcoal (49 mg) was added and the mixture was heated under reflux for 48 hrs, after which time the catalyst was filtered off and the solvent evaporated under reduced pressure. The residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was separated and dried over MgSO4 and the solvent evaporated under reduced pressure to afford the title compound as a off-white solid, (44%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:9]2([CH3:19])[CH2:14][CH2:13][S:12][C:11]([NH:15][C:16](=[O:18])[CH3:17])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:20][C:21]1[C:26]([Sn](CCCC)(CCCC)CCCC)=[N:25][CH:24]=[CH:23][N:22]=1.[Cl-].[Li+]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C@:9]2([CH3:19])[CH2:14][CH2:13][S:12][C:11]([NH:15][C:16](=[O:18])[CH3:17])=[N:10]2)=[CH:3][C:2]=1[C:26]1[C:21]([F:20])=[N:22][CH:23]=[CH:24][N:25]=1
Reactant: CC(=O)NC1=N[C@](C)(c2ccc(F)c(Br)c2)CCS1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccnc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CC(=O)NC1=N[C@](C)(c2ccc(F)c(-c3nccnc3F)c2)CCS1
Reaction time: 3 h
Yield: 31 %

Procedure:
To solution of (S)-N-(4-(3-bromo-4-fluorophenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-yl)acetamide (500 mg, 1.5 mmoles, 1 equiv), 2-fluoro-3-(tributylstannyl)pyrazine (1.7 g, 4.3 mmoles, 3.0 equiv) in toluene (15 mL) is added bis(triphenylphosphine)palladium(II) chloride (51 mg, 72 μmoles, 0.05 equiv) and lithium chloride (92 mg, 2.2 mmoles, 1.5 equiv). The reaction is irradiated in a laboratory-grade microwave to a temperature of 130° C. and held for 3 h. The solvent is removed under reduced pressure and the residue is purified by silica gel chromatography eluting with a linear gradient of hexane to hexane:ethyl acetate (1:1) ramp 20 min to give the title compound (31% yield): MS (m/z): 363 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH:8]([C:10]([OH:12])=O)[CH2:9][C:4]=2[N:3]=[CH:2]1.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]=1[CH2:16][NH2:17]>>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]=1[CH2:16][NH:17][C:10]([CH:8]1[CH2:7][CH2:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH2:9]1)=[O:12]
Reactant: NCc1c(Cl)cccc1Oc1ccccc1
Reactant: O=C(O)C1CCc2[nH]cnc2C1
Product: O=C(NCc1c(Cl)cccc1Oc1ccccc1)C1CCc2[nH]cnc2C1

Procedure:
83 mg of the title compound was prepared from 4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid and 2-chloro-6-phenoxybenzylamine by a similar procedure as described in Example 1.
Reaction SMILES: CC[N:3]([CH:7]([CH3:9])[CH3:8])C(C)C.[NH:10]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11]1.C1(N)CC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:7]1([NH:3][C:15]([C:12]2[CH:13]=[CH:14][NH:10][CH:11]=2)=[O:17])[CH2:9][CH2:8]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc[nH]c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1cc[nH]c1

Procedure:
Following the same procedure in Example 31, step B, using DIPEA (0.87 mL, 0.65 g, 5.0 mmol), 1H-pyrrole-3-carboxylic acid (0.25 g, 2.3 mmol), cyclopropylamine (0.14 g, 2.5 mmol) and HATU (1.0 g, 2.7 mmol) in DMF (10 mL). The crude product was purified by MPLC using EtOAc on silica gel to 52 mg (15%) of the title product. 1H NMR (400 MHz, METHANOL-D4) δ 0.42-0.63 (m, 2 H), 0.66-0.83 (m, 2 H), 2.60-2.80 (m, 1 H), 6.49 (dd, J=2.93, 1.56 Hz, 1 H), 6.69 (dd, J=2.73, 1.95 Hz, 1 H), 7.30 (t, J=1.76 Hz, 1 H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH3:11])[NH2:10])=[N:7][CH:8]=1.[CH3:14][CH:15]([CH3:19])[C:16](=O)[CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH3:11])[N:10]=[C:16]([CH:15]([CH3:19])[CH3:14])[CH3:17])=[N:7][CH:8]=1
Reactant: CN(N)c1ccc(C(F)(F)F)cn1
Reactant: CC(=O)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(=NN(C)c1ccc(C(F)(F)F)cn1)C(C)C

Procedure:
A solution of 1-[5-trifluoromethylpyrid-2-yl]-1-methyl hydrazine (5.9 g; 0.031 mol), 3-methyl-2-butanone (5.6 g; 0.065 mol) and p-toluenesulphonic acid (0.1 g) in xylene (30 ml) was heated under reflux, with water removal (azeotrope), for 7 h. The solution was concentrated to yield an oil which was purified by distillation (70° C./72 mbar) to yield 3-methyl-2-butanone 1-[5-trifluoromethylpyrid-2-yl]-1-methyl hydrazone as a yellow oil (5.8 g; 72%). ##STR15##
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH:24]([CH2:36][CH3:37])[CH2:25][NH:26]CC2C=CC(OC)=CC=2)[C:5]1=[O:38])[CH:2]=[CH2:3]>C(#N)C.O>[CH2:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([CH:24]([CH2:36][CH3:37])[CH2:25][NH2:26])[C:5]1=[O:38])[CH:2]=[CH2:3]
Reactant: C=CCC1CC(c2cccc(Cl)c2)C(c2ccc(Cl)cc2)N(C(CC)CNCc2ccc(OC)cc2)C1=O
Solvent: CC#N
Solvent: O
Product: C=CCC1CC(c2cccc(Cl)c2)C(c2ccc(Cl)cc2)N(C(CC)CN)C1=O

Procedure:
To a solution of (3SR,5RS,6SR)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((SR)-1-(4-methoxybenzylamino)butan-2-yl)piperidin-2-one (88 mg, 0.160 mmol) in acetonitrile (1899 μL) and water (380 μL) was added ceric ammonium nitrate (350 mg, 0.638 mmol) at 25° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12.C([Mg]Cl)(C)C.[Cl:24][CH2:25][C:26](N(OC)C)=[O:27]>CCOCC.C1COCC1>[Cl:24][CH2:25][C:26]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12)=[O:27]
Reactant: CON(C)C(=O)CCl
Reactant: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(C(=O)CCl)ccnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 35 %

Procedure:
To a solution of 4-bromo-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (2.05 g, 0.00626 mol) in THF (10 mL, 0.123 mol) at 0° C. was added dropwise a solution of isopropylmagnesium chloride in ether (2.0 M, 9.4 mL). The mixture was allowed to warm to room temperature and stirred for 4 hours. This mixture was then transferred via cannula to a solution of 2-chloro-N-methoxy-N-methylacetamide (2.84 g, 0.0207 mol) in THF (10 ml). After 30 minutes reaction time, the solution was quenched by the addition of saturated ammonium chloride aqueous solution. The product was extracted with ethyl acetate, the combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography (0-20% ethyl acetate/hexanes) to afford 2-chloro-1-(1-[2-(trimethylsilyl)-ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)ethanone (711 mg, 35%). 1H NMR (400 MHz, CDCl3): 8.56 (d, 1H), 7.66 (d, 1H), 7.60 (d, 1H), 7.23 (d, 1H), 5.80 (s, 2H), 4.91 (s, 2H), 3.60 (dd, 2H), 0.98 (dd, 2H), 0.01 (s, 9H); MS(ES): 325 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl>>[ClH:1].[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:14][CH:15]=1
Reactant: C1CNCCN1
Reactant: O=Cc1c(Cl)n(-c2ccc(F)cc2)c2ccccc12
Agent: Cl
Product: O=Cc1c(N2CCNCC2)n(-c2ccc(F)cc2)c2ccccc12
Yield: 40 %

Procedure:
2-Chloro-1-(4-fluorophenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 and subsequently treated with hydrochloric acid as described in Example 44 to afford 1-(4-fluorophenyl)-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde hydrochloride (40% yield) as a cream solid. ESI/MS 324 (M+H); RT 2.44 min; NMR 10.15 (1H, s); 8.13 (1H, d, J=9 Hz); 7.71 (2H, m); 7.54 (2H, m); 7.23 (2H, m); 6.95 (1H, d, J=9 Hz); 3.33 (4H, br s); 2.95 (4H, br s).
Reaction SMILES: C([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][C:13]([OH:15])=[O:14])=[C:7]([CH3:16])[CH:6]=1)(C)(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH3:11][C:9]1[CH:10]=[CH:5][CH:6]=[C:7]([CH3:16])[C:8]=1[CH2:12][C:13]([OH:15])=[O:14]
Reactant: Cc1cc(C(C)(C)C)cc(C)c1CC(=O)O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cccc(C)c1CC(=O)O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
16.52 g [75 mmol] of 4-tert-butyl-2,6-dimethylphenylacetic acid and 100 ml of toluene are initially charged in a 250 ml autoclave. After cooling to 0° C., 40 ml of HF are added and the autoclave is closed. The reaction mixture is then stirred at 38-40° C. for 4 hours. Toluene and HF are then distilled off at 20° C./100 mbar. The residue is diluted with 65 ml of water and, with ice-cooling, made alkaline using 100 ml of 10% strength aqueous sodium hydroxide solution. The solution is extracted once with 65 ml of MTBE and once with 35 ml of MTBE, the aqueous phase is then, with ice-cooling, adjusted to pH 1 using 32% strength hydrochloric acid, then precipitate formed is dissolved in 130 ml of methylene chloride, the organic phase is dried and the solvent is removed under reduced pressure. This gives 11.91 g of a white solid which, according to GC(sil.), comprises 95.8% of 2,6-dimethylphenylacetic acid (92.6% of theory).