Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[CH2:9].[Na].C1(C=CC(O)=CC=1)O>O>[CH2:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:9][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: C=Cc1ccccn1
Reactant: Cc1ccccn1
Agent: Oc1ccc(O)cc1
Agent: [Na]
Solvent: O
Product: c1ccc(CCCc2ccccn2)nc1
Yield: 18.9 %

Procedure:
To a flask were added 93 g of 2-picoline, 21 g of 2-vinylpyridine, 1 g of sodium and a trace of hydroquinone. The mixture was heated to 130 C under nitrogen for 2 hours. After cooling to 22 C, 200 ml of water were added and the mixture was extracted with 150 ml diethyl ether. After washing the diethyl ether layer twice with 100 ml of water, and twice with 50 ml of 10% sodium sulfite, the solvent was removed and the product was purified by vacuum distillation to give 7.5 g of a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12](O)=O)=[CH:7]2.CS(Cl)(=O)=O.[N:20]1C=CC=CC=1>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]#[N:20])=[CH:7]2
Reactant: O=C(O)c1ccc2c(Br)cccc2c1
Reactant: c1ccncc1
Agent: CS(=O)(=O)Cl
Product: N#Cc1ccc2c(Br)cccc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-2-naphthoic acid (4.3 g, 17 mmol)) in dry pyridine (75 mL) at 0° C. was added methanesulfonyl chloride (1.4 mL, 18 mmol). After stirring at 0° C. for 1 h, ammonia gas was bubbled through the solution for 10 min, whilst maintaining the temperature below 5° C. During the gas addition the solution became viscous, so additional dry pyridine (˜30 mL) was added. Excess ammonia was removed in vacuo, the solution again cooled to 0° C., then treated with additional methanesulfonyl chloride (12.5 mL) and allowed to warm to room temperature overnight. The solution was poured onto ice cold water, the mixture stirred for 30 min and the brown precipitate collected by filtration, washed on the sinter with ice cold water, then dried in vacuo. The crude product was dissolved in hot chloroform (˜35 mL) and insoluble material filtered off. The chloroform was removed and the residue dissolved in a minimum volume of ether at reflux. Hexane was added until the solution remained turbid at reflux, the solution filtered rapidly into a pre-heated flask, and allowed to cool slowly to room temperature. The precipitate was collected by filtration, washed with hexane, and dried in vacuo, to yield 5-bromo-2-naphthonitrile. Further crops were obtained by cooling the filtrate at −18° C. overnight.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[C:14]1([C:20]2[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:28][SiH:29]([Cl:31])[Cl:30]>>[C:14]1([C:20]2[CH:27]=[CH:26][C:23]([CH2:24][Si:29]([Cl:31])([Cl:30])[Cl:28])=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: CCCCP(CCCC)CCCC
Product: Cl[Si](Cl)(Cl)Cc1ccc(-c2ccccc2)cc1
Yield: 88.4 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.15 g (0.75 mmol) of tri-n-butylphosphine, 1.52 g (7.5 mmol) of 4-phenylbenzyl chloride, and 5.08 g (37.5 mmol) of trichlorosilane were reacted at 150° C. for 2 hrs. The resulting mixture was distilled to give 2.0 g of (4-phenylbenzyl)trichlorosilane (mp; 60-65° C., yield; 90%).
Reaction SMILES: [CH:1]1([CH2:10][CH2:11][NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][C:14]1([CH3:27])[C:18]2([CH2:22][S:23](Cl)(=[O:25])=[O:24])[C:19]([CH2:21][CH:15]1[CH2:16][CH2:17]2)=[O:20].C(N(CC)CC)C>C(Cl)Cl>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([CH2:10][CH2:11][NH:12][S:23]([CH2:22][C:18]23[C:14]([CH3:13])([CH3:27])[CH:15]([CH2:16][CH2:17]2)[CH2:21][C:19]3=[O:20])(=[O:25])=[O:24])=[CH:2]1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)Cl)C(=O)C2
Reactant: NCCC1C=Cc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CCC1(CS(=O)(=O)NCCC1=CCc3ccccc31)C(=O)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-(1H-Indene-1-yl)ethyl)amine (190 mg, 1.19 mmol) and (+)-10-camphorsulfonyl chloride (299 mg, 1.19 mmol) were combined in CH2Cl2 (2 ml), treated with triethylamine (87 μl, 120 mg, 1.19 mmol), and the mixture was stirred at ambient temperature overnight. The mixture was chromatographed on a silica gel column eluted with 25% EtOAc in hexane and the product fractions were evaporated to dryness in vacuo to give N-(2-(1H-inden-3-yl)ethyl)-7,7-dimethyl-2-oxobicyclo(2.2.1)heptane-1-methanesulfonamide.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[O:6][C:7]=1[CH3:8].[C-:18]#[N:19].[Na+]>>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:10]=[CH:9][C:5]1[O:6][C:7]([CH3:8])=[C:3]([CH2:2][C:18]#[N:19])[N:4]=1
Reactant: [C-]#N
Reactant: Cc1oc(C=Cc2ccccc2Cl)nc1CCl
Agent: [Na+]
Product: Cc1oc(C=Cc2ccccc2Cl)nc1CC#N
Yield: 96.9 %

Procedure:
4-Chloromethyl-2-(2-chlorostyryl)-5-methyloxazole was reacted with sodium cyanide in the same manner as Example 1-(5) to give 2-(2-chlorostyryl)-4-cyanomethyl-5-methyloxazole. Yield 96.9%. Light-yellow needles (recrystallized from ethanol). Mp 89°-90° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f8) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.CO[CH:17](OC)[CH2:18][CH:19](OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[N:1]1[C:2]2=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]2[CH:19]=[CH:18][CH:17]=1
Reactant: COC(CC(OC)OC)OC
Reactant: COC(=O)c1c(N)[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: COC(=O)c1c2ccccc2n2cccnc12

Procedure:
A stirred solution of methyl 2-aminoindole-3-carboxylate (I. Forbes et al, J. Chem. Soc. Perkin I, 1992, 275) (0.5 g, 0.0026 mole) in xylene (10 ml) was treated with 1,1,3,3-tetramethoxypropane (0.43 g, 0.0026 mole) and a few crystals of 4-toluenesulphonic acid and heated under reflux for 2.5 h. The mixture was concentrated in vacuo and the residue dissolved in chloroform (25 ml), washed with water (2×10 ml), dried (MgSO4) and concentrated in vacuo to leave a dark orange solid. This was purified by chromatography on silica gel eluting with ethyl acetate to afford the title compound (D19) as an orange solid (0.23 g, 35%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13](OC(Cl)(Cl)Cl)=[O:14]>O1CCOCC1>[CH3:11][C:10]1[C:2]2[NH:1][C:13](=[O:14])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Cc1cccc2c(=O)oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-3-methylbenzoic acid (6 g) in dry 1,4-dioxane (50 mL) was added dropwise a solution of trichloromethyl chloroformate (8 mL) in dry 1,4-dioxane (25 mL), with ice-water cooling to keep the reaction temperature below 25° C. A white precipitate began to form during the addition. The reaction mixture was stirred at room temperature overnight. The precipitated solids were removed by filtration and washed with 1,4-dioxane (2×20 mL) and hexane (2×15 mL) and air-dried to yield 6.51 g of off-white solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[CH2:9]([NH:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:22]3[CH2:23][CH2:24][C:25](=[O:28])[NH:26][N:27]=3)[CH:19]=2)[CH2:14]1)[CH2:10][CH3:11].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:9]([N:12]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:22]3[CH2:23][CH2:24][C:25](=[O:28])[NH:26][N:27]=3)[CH:19]=2)[CH2:14]1)[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3])[CH2:10][CH3:11]
Reactant: CC(C)COC(=O)Cl
Reactant: CCCNC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCN(C(=O)OCC(C)C)C1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reaction time: 1 h
Yield: 67.3 %

Procedure:
Under ice cooling, 2.46 g of isobutyl chloroformate was added to 4.07 g of 2-propylamino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane and 2.02 g of triethylamine dissolved in 40 ml of chloroform, and the mixture was stirred for 1 hour. The organic layer was washed with water and dried, and the solvent was removed. The resulting crude crystals were recrystallized from ethyl acetate to obtain 3.75 g of 2-(N-propyl-N-isobutoxycarbonylamino)-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22]=O)[CH:6]=1.[CH2:25]([NH2:27])[CH3:26]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:13]=2[CH2:22][NH:27][CH2:25][CH3:26])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2C=O)c1
Reactant: CCN
Product: CCNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 2, using the following starting materials: [3-(2-formyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and ethylamine (2M in THF).
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3].[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[CH:15]=[C:14]2[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33].CN1CCOCC1.Cl>ClCCl>[CH:5]1([O:4][C:2]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[CH:15]=[C:14]3[CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=2[O:32][CH3:33])=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(N)cc23)c(OC)c1
Reactant: O=C(Cl)OC1CCCC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Reaction time: 2 h
Yield: 77.4 %

Procedure:
Cyclopentyl chloroformate (0.11 g.) was added to a stirred solution of methyl 4-(5-amino-1-methylindol-3-ylmethyl)-3-methoxybenzoate (D) (0.25 g.) and N-methylmorpholine (0.23 g.) in dichloromethane (3 ml.), under an atmosphere of nitrogen. The mixture was stirred for 2 hours and then poured into 1M hydrochloric acid (20 ml.). This acid mixture was extracted with ethyl acetate (2×30 ml.). The combined extracts were washed with saturated brine (20 ml.), dried (MgSO4), and evaporated to give a viscous oil. This was purified by flash chromatography on silica gel (50 ml.), eluting with 3:7 v/v ethyl acetate:hexane, to give the title compound as a foam (0.25 g., 74%): NMR: 1.62 [m,8 H, (CH2)4 ], 3.68 (s,3 H, NCH3), 3.83 (s,3 H, CO.OCH3), 3.91 (s,3 H, OCH3), 3.95 (s, 2 H, CH2.Ar), 5.05 (m,1 H, --CHO--), 7.11 (m,2 H), 7.26 (d, 1 H), 7.43 (m,2 H), 7.59 (br,1 H), 9.18 (br,1 H, NH).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CI.[C:14](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][O:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2c1CCCC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cccc2c1CCCC2
Reaction time: 72 h

Procedure:
5,6,7,8-Tetrahydro-1-naphthol (9.85 g, 66 mM), methyl iodide (30.6 g, 215 mM) and potassium carbonate (15 g, 90.8 mM) in acetone (500 ml) were heated under reflux with stirring for 3 days. The mixture was evaporated and the residue was extracted with 2M sodium hydroxide and ether. The organic layer was washed and dried to give 1-methoxy-5,6,7,8-tetrahydronaphthalene as as oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C([O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:34])[C:18]([CH3:33])=[C:19]([CH:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:32])[CH2:30][CH3:31])[CH2:25][CH2:24]3)[O:20]2)=[CH:15][CH:14]=1)C=C.O>CN(C)C=O>[Br:1][C:22]1[C:13]([OH:12])=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19]([CH:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:32])[CH2:30][CH3:31])[CH2:25][CH2:24]1)=[C:18]([CH3:33])[C:17]2=[O:34]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCOc1ccc2c(=O)c(C)c(C3CCN(C(=O)CC)CC3)oc2c1
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)N1CCC(c2oc3c(Br)c(O)ccc3c(=O)c2C)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.9 %

Procedure:
N-Bromosuccinimide (171 mg, 0.96 mmol) was added to a solution of 7-hydroxy-3-methyl-2-(1-propanoylpiperidin-4-yl)-4H-chromen-4-one (304 mg, 0.96 mmol) obtained in Example 31-3 in N,N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane/methanol=98/2→67/33) to obtain 204 mg of the title compound (yield: 54%).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=2)[CH:10]=1.[CH3:44][N:45]1[CH2:51][CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:44][N:45]1[CH2:51][CH2:50][CH2:49][N:48]([CH2:35][C:31]2[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=2)[C:28]([NH:27][C:16]2[CH:17]=[CH:18][C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:20][C:15]=2[C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][N:12]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[C:3]([C:2]([F:43])([F:42])[F:1])[CH:4]=2)=[O:38])=[O:37])[CH2:47][CH2:46]1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CBr)c2)c1
Reactant: CN1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 38.9 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(bromomethyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (100 mg, 0.15 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL), 1-methyl-1,4-diazepane (65.4 mg, 0.57 mmol, 3.74 equiv), KI (12.7 mg, 0.08 mmol, 0.50 equiv), and potassium carbonate (42.4 mg, 0.31 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 70° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 40 mg (23%) of a yellow solid. 1H-NMR (400 MHz, CD3OD, ppm): δ 8.95-8.93 (d, J=4.2 Hz, 1H), 8.75-8.73 (d, J=6.6 Hz, 1H), 8.46 (s, 1H), 8.18-8.17 (d, J=4.2 Hz, 1H), 8.09 (s, 1H), 8.02-8.00 (d, J=8 Hz, 1H), 7.90-7.88 (m, 1H), 7.75-7.55 (m, 1H), 4.72 (s, 2H), 4.19 (s, 2H), 3.70-3.67 (t, J=5.6 Hz, 4H), 3.55-3.49 (m, 4H), 3.18-3.16 (t, J=5.6 Hz, 2H), 2.95 (s, 3H), 2.22-2.18 (m, 2H), 2.07-2.05 (t, J=5.2 Hz, 4H), 1.84-1.83 (d, J=5.2 Hz, 1H). MS (ES, m/z): 685 [M+H]+.
Reaction SMILES: I[C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[CH:11]=[C:12]([N:16]([CH3:18])[CH3:17])[CH:13]=[CH:14][CH:15]=3)=[N:8]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]([C:34]([F:37])([F:36])[F:35])[C:30]([NH2:33])=[N:31][CH:32]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:17][N:16]([CH3:18])[C:12]1[CH:11]=[C:10]([C:7]2[S:6][C:5]3=[N:4][CH:3]=[C:2]([C:27]4[CH:28]=[C:29]([C:34]([F:37])([F:36])[F:35])[C:30]([NH2:33])=[N:31][CH:32]=4)[N:9]3[N:8]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)c1cccc(-c2nn3c(I)cnc3s2)c1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(C)c1cccc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)c1
Temperature: 110 °C
Yield: 16.4 %

Procedure:
A mixture of [3-(5-Iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-phenyl]-dimethyl-amine (0.084 g, 0.226 mmol, 1 eq), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (0.098 g, 0.339 mmol, 1.5 eq), 2M aq Na2CO3 (1 mL) and PdCl2(PPh3)2 (0.032 g, 0.045 mmol, 0.2 eq) was heated at 110° C. for 24 h. The solvent was removed in vacuo and the residue was redissolved in DCM/water (150 mL) and extracted with DCM (2×80 mL). The organic layer was dried (MgSO4), filtered and evaporated. The residue was triturated from MeOH and filtered off. The solid was purified by column chromatography (0-5% MeOH in DCM) to give the desired product (15 mg, 16%) as a yellow solid. HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=5.97 min, [M+H]+ m/z 405.1; 1H NMR (300 MHz, DMSO) δ 8.86 (d, J=1.8 Hz, 1H), 8.45 (d, J=2.0 Hz, 1H), 7.80 (s, 1H), 7.40 (t, J=8.1 Hz, 1H), 7.20 (m, 2H), 6.99 (dd, J=9.1, 2.0 Hz, 1H), 6.75 (s, 2H), 3.00 (s, 6H).
Reaction SMILES: CC(C)(OC([NH:7][C@@H:8]([C:27](=[O:36])OCC1C=CC=CC=1)[CH2:9][CH2:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C@H:14]1[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:12])=O)C.[C:38]1(OC)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[NH2:7][C@@H:8]([C:27](=[O:36])[CH2:47][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:9][CH2:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C@H:14]1[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:12]
Reactant: COc1ccccc1
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)CC[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)CC[C@@H](N)C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the ester product from part (e) (0.39 mmole, 0.2 g.), anisole (0.2 ml.) and trifluoroacetic acid (1.95 ml.) is allowed to stir at room temperature for two hours. The trifluoroacetic acid is stripped in vacuo to yield (S)-1-[(R)-4-amino-1,5-dioxo-5-(phenylmethyl)-pentyl]-2,3-dihydro-1H-indole-2-carboxylic acid, ethyl ester, trifluoroacetate salt as a yellow oil.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:32]([O:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][C:47](Cl)=[O:48])=[CH:42][CH:41]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:32]([O:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:46][C:47]([NH:21][C:18]2[C:17]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)=[N:16][C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[CH:10][CH:11]=3)=[CH:20][N:19]=2)=[O:48])=[CH:44][CH:45]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3cccc4ccccc34)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2cccc3ccccc23)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 55.9 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(naphthalen-1-yl)pyrazin-2-amine (7d) (500 mg, 1.17 mmol) and 4-(dimethylamino)pyridine (15.3 mg, 125 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) at 0° C. and the mixture was heated with stirring at 50° C. for 16 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11d (442 mg, 653 μmol, 55.9%) as a yellow foamy solid. Rf=0.26 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.13 (s, 6H), 0.19 (s, 6H), 0.91 (s, 9H), 0.92 (s, 9H), 3.24 (s, 2H), 6.54-6.60 (AA′BB′, 2H), 6.65-6.72 (AA′BB′, 2H), 6.91-6.98 (AA′BB′, 2H), 7.36-7.54 (m, 4H), 7.61-7.69 (m, 1H), 7.87-8.08 (m, 4H, includes AA′BB′), 9.09 (s, 1H), 10.27 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.6 (4C), 17.90, 17.94, 25.48 (3C), 25.55 (3C), 119.4 (2C), 120.4 (2C), 125.0, 125.4, 125.7, 126.2, 126.8, 128.0, 128.15, 128.21 (2C), 128.6, 128.9 (2C), 129.9, 130.7, 133.4, 134.8, 138.2, 144.4, 147.9, 148.3, 153.5, 156.7, 169.3 (one carbon at the benzyl position was unobservable due to overlapping with the septet peak of DMSO); IR (KBr, cm−1) 492, 538, 675, 718, 779, 806, 839, 914, 1007, 1080, 1115, 1169, 1260, 1362, 1420, 1441, 1472, 1510, 1605, 1670, 2857, 2886, 2930, 2955, 3046, 3223; HRMS (ESI+) m/z 698.3205 ([M+Na]+, C40H49N3NaO3Si2+ requires 698.3205).
Reaction SMILES: CN(C)/C=[CH:4]/[C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16].I([O-])(=O)(=O)=[O:20].[Na+]>O.O1CCCC1>[CH3:14][O:13][C:11]([C:8]1[CH:9]=[CH:10][C:5]([CH:4]=[O:20])=[C:6]([N+:15]([O-:17])=[O:16])[CH:7]=1)=[O:12]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)c1ccc(/C=C/N(C)C)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 119.5 g (0.478 mol) of (E)-1-(dimethylamino)-2-[4-(methoxycarbonyl)-2-nitrophenyl]-ethene and 1.3 l of water/tetrahydrofuran mixture (1/1 v/v) were added, in batches, 308.0 g (1.44 mol) of sodium metaperiodate, whilst the reaction temperature was regulated at under +30° C. by external cooling with ice water. The mixture was stirred for a further 2.5 hours at room temperature and then filtered. The precipitate was thoroughly washed with ethyl acetate. The organic phase was separated off, the aqueous phase was thoroughly extracted with ethyl acetate. The combined ethyl acetate phases were dried over sodium sulphate and evaporated down in vacuo. The oil which crystallised after one day was further processed without any more purification. Yield: 87 g (87% of theory).