Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C1COCC1.[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[C:19]=1[Mg]Br>CCCCCC>[CH2:2]([C:19]1[C:20]([CH3:25])=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=1[CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCBr
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCc1c(C)cc(C)cc1C

Procedure:
1-Bromodecane (110.8 mg, 0.5 mmol) and a THF solution (0.66 mL, 1.14 M, 0.75 mmol) of 2,4,6-trimethylphenylmagnesium bromide were used as starting materials, and reacted as in Entry 1. Conditions: The THF solution of 2,4,6-trimethylphenylmagnesium bromide was added dropwise at 40° C. over 3 hours. After thin-layer chromatography (hexane), the title compound was obtained as a colorless liquid (0.099 g, yield 76%).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:43])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[S:32][C:31]5[C:26](=[N:27][CH:28]=[CH:29][C:30]=5[O:33][CH3:34])[CH:25]=4)[N:22]=3)[N:17](COCC[Si](C)(C)C)[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2].C(C1CN(C(=O)[C@H](NC(C2C3C(=NC=C(C4SC5C(=NC=CC=5Cl)C=4)N=3)N(COCC[Si](C)(C)C)C=2)=O)C2CC2)C1)#N>>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:43])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[S:32][C:31]5[C:26](=[N:27][CH:28]=[CH:29][C:30]=5[O:33][CH3:34])[CH:25]=4)[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:6]1)#[N:2]
Reactant: COc1ccnc2cc(-c3cnc4c(n3)c(C(=O)N[C@@H](C(=O)N3CC(C#N)C3)C3CC3)cn4COCC[Si](C)(C)C)sc12
Agent: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3cc4nccc(Cl)c4s3)cnc21
Product: COc1ccnc2cc(-c3cnc4[nH]cc(C(=O)N[C@@H](C(=O)N5CC(C#N)C5)C5CC5)c4n3)sc12

Procedure:
Prepared according to the procedure outlined in Example 154, step 3 substituting 2-(7-methoxy-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide for 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide. MS: (M+H)+=488.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7].Cl.[CH2:15]=O>O>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[C:6](=[O:8])[O:7][CH2:15]2
Reactant: C=O
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: Cl
Solvent: O
Product: COc1cc2c(cc1OC)C(=O)OC2
Reaction time: 8 h
Yield: 29.7 %

Procedure:
A suspension of 3,4-dimethoxybenzoic acid (10 g, 54.9 mmol) in aqueous 37% HCl (126 ml, 1522 mmol) and a 37% solution in water of formaldehyde (25 ml, 54.9 mmol) were heated to 90 to 100° C. for 6 hours. Stirring was prolonged overnight at room temperature, and then the obtained insoluble material was removed by filtration. The filtrate was quenched with water (200 ml) and extracted with ethyl acetate (200 ml×3). The combined organic layers were washed with aqueous 1N NaOH (100 ml) and then with brine (2×100 ml). The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The obtained yellow solid was triturated with ethyl acetate to afford 5,6-dimethoxyisobenzofuran-1(3H)-one as a white solid (3.171 g, 16.33 mmol, 30% yield). MS/ESI+ 195.0 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:18][CH2:17]3)=[CH:12][N:11]=[C:10]([C:19]([OH:21])=O)[N:9]=2)=[CH:4][CH:3]=1.[CH:22]1([C:25]2[N:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=2)[CH2:24][CH2:23]1>>[CH:22]1([C:25]2[N:29]=[C:28]([CH2:30][NH:31][C:19]([C:10]3[N:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:13]([O:14][CH2:15][CH:16]4[CH2:17][CH2:18]4)=[CH:12][N:11]=3)=[O:21])[O:27][N:26]=2)[CH2:24][CH2:23]1
Reactant: NCc1nc(C2CC2)no1
Reactant: O=C(O)c1ncc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Product: O=C(NCc1nc(C2CC2)no1)c1ncc(OCC2CC2)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic acid (example T) and (3-cyclopropyl-1,2,4-oxadiazol-5-yl)methane amine (CAS Registry No. 428507-31-7) as starting materials; LC-MS (UV peak area/ESI) 100%, 426.1324 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:9]1[C:14]([CH2:15][O:16]C2CCCCO2)=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:23][O:24]C1CCCCO1)[OH:8]>C(O)(=O)C.C1COCC1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:9]1[C:10]([CH2:23][OH:24])=[CH:11][CH:12]=[CH:13][C:14]=1[CH2:15][OH:16])[OH:8]
Reactant: OC(c1ccccn1)c1c(COC2CCCCO2)cccc1COC1CCCCO1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc(CO)c1C(O)c1ccccn1
Yield: 43.8 %

Procedure:
A solution of 1 g (2.42 mmol) of 1-(2-pyridyl)-1-[2,6-di(tetrahydro-2H-2-pyranyloxymethyl)phenyl]-methanol in 14 ml of acetic acid/THF/water (4:2:1) was heated at 100° C. under nitrogen for 6 hours. The mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate and concentrated in vacuo. The residual solid was triturated with ether to afford 0.26 g of 1-(2-pyridyl)-1-[2,6-di(hydroxymethyl)-phenyl]methanol (Formula X: R1 =R2 =H; R7 =6-hydroxymethyl) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13](OCC)=[O:14])=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O=[Mn]=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]=[O:14])=[CH:11][N:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cncn1-c1ccc(Br)cc1
Agent: O=[Mn]=O
Agent: [Al+3]
Agent: [H-]
Product: O=Cc1cncn1-c1ccc(Br)cc1

Procedure:
Ethyl 1-(4-bromophenyl)-1H-imidazole-5-carboxylate (4) was constructed through the condensation of tosylmethyl isocyanide and hemi-aminal 3, which in turn was produced by the addition of 4-bromoaniline (2) to ethyl glyoxalate (1). Ester 4 was reduced with LiAlH4 at −40° C. and the resulting alcohol 5 oxidised with MnO2 to furnish 1-(4-bromophenyl)-1H-imidazole-5-carbaldehyde (6), which was condensed with ethyl azidoacetate to give the α,β-unsaturated ester 7. The pyrrolo[2,3-d]imidazole core 8 was then formed by thermal cyclisation of 7 in refluxing in p-xylene. Hydrolysis of 8 provided 1-(4-bromophenyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylic acid (9) which could be coupled with various amines, for example, with 2-methoxyethylamine to give amide 10.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][CH:55]([C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)[CH3:56])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]([CH2:54][CH:55]([C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)[CH3:56])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:45])([CH3:46])[CH3:47]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(CNCc1ccc(C(C)(C)C)cc1)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(CN(Cc1ccc(C(C)(C)C)cc1)C(=O)c1cccc2cc[nH]c12)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.4 %

Procedure:
To a solution of 81 mg of 1H-indole-7-carboxylic acid (0.5 mmol) and 161 mg of TBTU (0.5 mmol) in 2 ml DMF, were added 0.43 ml (2.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 158 mg (0.5 mmol) [rac]-(4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-propyl]-amine in 3.5 ml DMF was added. After stirring for 22 h at rt, the reaction mixture was diluted with 50 ml water and extracted twice with EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; heptane/EtOAc 2:1) to give 203 mg (86%) of a off-white solid. MS(ISP) 459.4 (M+H)+.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:13][CH2:14][CH:15](N)[CH3:16].[C:18]([C:20]1[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[C:21]=1[N+:27]([O-:29])=[O:28])#[N:19]>ClC1C=CC=CC=1Cl>[CH3:25][N:24]1[C:20]([C:18]2[NH:13][CH2:14][CH:15]([CH3:16])[N:19]=2)=[C:21]([N+:27]([O-:29])=[O:28])[C:22]([CH3:26])=[N:23]1
Reactant: Cc1nn(C)c(C#N)c1[N+](=O)[O-]
Reactant: CC(N)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: Cc1nn(C)c(C2=NC(C)CN2)c1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
p-Toluenesulfonic acid monohydrate (15.2 g, 0.08 mol) is added in portions with stirring to 6 g (0.08 mol) of 1,2-diaminopropane under nitrogen. To the resulting melt (ca 100° C.) is added in portions 12.6 g (0.076 mol) of 5-cyano-1,3-dimethyl-4-nitropyrazole (mp 93° C.); the mixture is stirred and heated to 120° C. and 25 ml of o-dichlorobenzene is added; stirring is continued at 120°-130° for 0.5 hours then at 160° C. for three hours. The cooled mixture is extracted with 75 ml of 3N HCl. The aqueous extract is made strongly basic with a large excess of concentrated NH4OH and the mixture is extracted thoroughly with methylene dichloride. Evaporation of the extract gives 14.3 g (84%) of 2-(1,3-dimethyl-4-nitropyrazol-5-yl)-4-methylimidazoline, mp 98°-101°.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH3:31])[S:5]([C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][CH2:21][N:22]3[C:26]([CH3:28])([CH3:27])[C:25](=[O:29])[NH:24][C:23]3=[O:30])[N:14]=2)=[CH:11][CH:12]=1)(=[O:7])=[O:6].[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.[I-].[Na+]>CN1CCCC1.[Cl-].[Na+].O>[CH3:27][C:26]1([CH3:28])[N:22]([CH2:21][CH2:20][NH:19][C:15]2[N:14]=[C:13]([C:10]3[S:9][C:8]([S:5]([N:4]([CH3:31])[CH2:3][CH2:2][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)(=[O:7])=[O:6])=[CH:12][CH:11]=3)[CH:18]=[CH:17][N:16]=2)[C:23](=[O:30])[NH:24][C:25]1=[O:29]
Reactant: CN(CCCl)S(=O)(=O)c1ccc(-c2ccnc(NCCN3C(=O)NC(=O)C3(C)C)n2)s1
Reactant: C1CCNC1
Agent: CN1CCCC1
Agent: [Cl-]
Agent: [I-]
Solvent: O
Product: CN(CCN1CCCC1)S(=O)(=O)c1ccc(-c2ccnc(NCCN3C(=O)NC(=O)C3(C)C)n2)s1
Temperature: 25 °C

Procedure:
A mixture of N-(2-chloroethyl)-5-(2-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)ethylamino)pyrimidin-4-yl)-N-methylthiophene-2-sulfonamide (200 mg, 0.41 mmol), pyrrolidine (59 mg, 0.82 mmol) and a catalytic amount of sodium iodide in N-methyl-pyrrolidine (5 mL) was heated at 90° C. overnight. After cooling to rt, 50 mL of brine was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×80 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the product purified by flash chromatography eluting with methanol (1 M, ammonia)/dichloromethane (1:20) to afford the title compound as a slightly yellow solid (98 mg, 46%). MS (M+H)+ 522.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]3([CH2:16][NH:17][C:18](=[O:20])[CH3:19])O[CH:9]3[C:8]=2[CH:21]=1)([O-:3])=[O:2].[NH:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27].O.C(OCC)(=O)C>C(O)C.O1CCOCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])=[C:9]([N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])[C:8]=2[CH:21]=1)([O-:3])=[O:2]
Reactant: CC(=O)NCC12OC1c1cc([N+](=O)[O-])ccc1OC2(C)C
Reactant: O=C1CCCN1
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)NCC1=C(N2CCCC2=O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Temperature: 50 °C
Yield: 22.6 %

Procedure:
A solution containing 6-nitro-3-acetamidomethyl-3,4-dihydro-3,4-epoxy-2,2-dimethyl-2H-1-benzopyran (0.5 g, 1.72 mmol), 2-pyrrolidinone (0.3 g, 3.48 mmol) and Triton B (40% in ethanol, 0.1 ml) in dioxane (10 ml) was heated at 50° C. for eighteen hours. Water and ethyl acetate were added, and the organic phase separated and evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with dichloromethane/methanol (95/5), to give crude product which on triturating with diethyl ether afforded 0.14 g of 6-nitro-2,2-dimethyl-3-acetamidomethyl-4-(2-oxopyrrolidin-1-yl)-2H-1-benzopyran, m.p. 205° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[C:20]([O:24][C:25](=[O:50])[CH2:26][N:27]1[C:31]2[CH:32]=[CH:33][C:34]([NH:36][S:37]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])=[CH:35][C:30]=2[N:29]=[C:28]1[CH2:47][CH2:48][CH3:49])([CH3:23])([CH3:22])[CH3:21]>CC#N.CCOC(C)=O.O>[C:20]([O:24][C:25](=[O:50])[CH2:26][N:27]1[C:31]2[CH:32]=[CH:33][C:34]([N:36]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([O:3][C:2]([F:13])([F:12])[F:1])=[CH:5][CH:6]=3)[S:37]([C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)(=[O:38])=[O:39])=[CH:35][C:30]=2[N:29]=[C:28]1[CH2:47][CH2:48][CH3:49])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc2cc(N(Cc3ccc(OC(F)(F)F)cc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Trifluoromethoxybenzyl bromide (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH2:21][CH3:22])[CH:5]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:12]=2[CH2:21][CH3:22])[CH:5]=1
Reactant: CCc1[nH]c2cc(Cl)ccc2c1Sc1cccc(C(=O)OC)c1
Reactant: BrCc1ccccc1
Product: CCc1c(Sc2cccc(C(=O)OC)c2)c2ccc(Cl)cc2n1Cc1ccccc1

Procedure:
Prepared according to the procedure described in Example 10, Step 3, using the following starting materials: 3-(6-chloro-2-ethyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and benzyl bromide.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.[C:18](OCC)(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(OCC)(=O)C>[O:25]=[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:12]=1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)Nc1cccc(-c2cnc3ccccc3n2)c1
Yield: 19.8 %

Procedure:
A slurry of (3-quinoxalin-2-ylphenyl)amine (200 mg, 0.904 mmol) and dietyl malonate (1.4 mL, 9.04 mmol) was heated at 160° C. in a Dean-Stark vial (Glass Solutions) for 5 hrs. The reaction mixture was diluted with ethyl acetate (25 mL), the organic phase was washed with water (20 mL) and brine (20 mL), dried over sodium sulphate, the solvent evaporated in vacuo and the residue dissolved in DCM (2 mL). The solution was loaded on a Isolute 20 g silica gel column and purified by flash chromatography (Flash Master, 5 g Isolute Silica column, gradient 0 to 5 min hexane, then ethyl acetate up to 50% over 20 min) to afford ethyl 3-oxo-3-(3-(quinoxalin-2-yl)phenylamino)propanoate (60 mg, 20% yield). LCMS calculated for C19H17N3O3 (M+H): 336.35. found 336. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.41 (1H, br.), 9.52 (1H, s), 8.52 (1H, m), 8.15-8.10 (2H, m), 8.05-8.08 (1H, m), 7.82-7.95 (3H, m), 7.55-7.60 (1H, m), 4.16 (2H, q, J=8 Hz), 3.54 (2H, s), 1.23 (3H, t, J=8 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:2]([Cl:1])=[CH:3][C:4]3[O:5][CH2:6][CH2:7][C:8]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: Nc1ccc(-c2cc3c(cc2Cl)OCC3)cn1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-c2cc3c(cc2Cl)OCC3)cn1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a solution of 5-(6-chloro-2,3-dihydrobenzo[3,4-b]furan-5-yl)-2-pyridylamine (144) (41 mg, 0.166 mmol) in 2 ml DCM was added 2,6-difluorobenzoyl chloride (42 μl, 2 eq) followed by addition of DIEA (145 μl). The resulting solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (330 μl) at r.t. for 2 h and before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished (2,6-difluorophenyl)-N-[5-(6-chloro(2,3-dihydrobenzo[b]furan-5-yl))(2-pyridyl)]carboxamide (145) (52.7 mg, yield: 82.1%, purity>95%) as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C@H:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][C@@H:9]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(N)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
To 2.35 g (4.3 mmol) di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-(4-nitrobenzyl)-L-glutamate in 50 mL methanol and under argon atmosphere palladium (10% on charcoal) was added and the suspension hydrogenated overnight at room temperature. The reaction mixture was filtered, the solvent evaporated and the residue was chromatographed on silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:22])[CH2:13][CH2:12][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:14]#[N:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH:26]1[CH2:28][CH2:27]1.[H-].[Na+].O>CN(C=O)C>[CH:26]1([CH2:25][CH2:24][O:22][C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:13][CH2:12][C:11]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([C:14]#[N:15])[CH2:10][CH2:9]2)[CH2:28][CH2:27]1
Reactant: N#CC1(c2ccccc2)CCC(O)(c2ccc(F)cc2)CC1
Reactant: BrCCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1(c2ccccc2)CCC(OCCC2CC2)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 47.1 %

Procedure:
500 mg of the compound of Example 1, 760 mg of (2-bromoethyl)cyclopropane (Chorvat et al., J. Med. Chem. 28, 194-200 (1985)) and 122 mg of sodium hydride in 20 ml of anhydrous DMF were stirred at room temperature for 19 h. 760 mg of (2-bromoethyl)cyclopropane and 122 mg of sodium hydride were then added and the mixture was stirred at room temperature for 4 days. The reaction mixture was then treated with 100 ml of water and extracted three times with 50 ml each of EA. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. 290 mg of the title compound were obtained as a pale yellow oil.
Reaction SMILES: [N:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2)=[N+:2]=[N-:3].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C[C-]1C(C)=C(C)C(C)=C1C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru+].C1COCC1>[C:4]12([N:1]3[C:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:21][N:3]=[N:2]3)[CH2:5][CH:6]3[CH2:12][CH:10]([CH2:9][CH:8]([CH2:7]3)[CH2:13]1)[CH2:11]2
Reactant: [N-]=[N+]=NC12CC3CC(CC(C3)C1)C2
Reactant: C#Cc1ccccc1
Agent: Cl[Ru+]
Agent: Cc1c(C)c(C)[c-](C)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(-c2cnnn2C23CC4CC(CC(C4)C2)C3)cc1
Yield: 52 %

Procedure:
1-Azidoadamantane (177 mg, 1 mmol), phenylacetylene (113 mg, 1.1 mmol), Cp*RuCl(PPh3)2 (8 mg, 0.01 mmol, 1 mol %). Solvent: THF, 10 mL, 60° C., 12 hours. Product obtained as off-white powder in 52% yield (145 mg). ESI-MS: m/z 280, [M+H].
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[AsH3:5]>CCCCCCCC.CS(O)(=O)=O>[CH3:4][C:2]([AsH:5][C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:3])[CH3:1]
Reactant: [AsH3]
Reactant: C=C(C)C
Agent: CS(=O)(=O)O
Solvent: CCCCCCCC
Product: CC(C)(C)[AsH]C(C)(C)C
Temperature: 8 °C
Yield: 6.3 %

Procedure:
An autoclave reactor having approximately 3.8 liter capacity is charged with 400 grams of isobutylene reactant, 600 grams of n-octane solvent and 1000 grams of aqueous 70% methanesulfonic acid catalyst. The reactor is pressurized to about 12.3 atmospheres at room temperature by addition of arsine reactant in molar excess with respect to isobutylene. The autoclave is sealed and its contents are heated at 80°-95° C. with constant agitation for four hours reaction time. The contents are then cooled to 8° C. before the reactor is opened. Unreacted arsine is vented from the reactor. By gas chromatographic analysis of the liquid reaction product mixture, yields of 350 grams mono-1,1-dimethylethylarsine (36.6% yield) and 85 grams bis(1,1-dimethylethyl)arsine (6.3% yield) are measured. The organic phase separated from the liquid product mixture is washed with water, dried and then distilled at 68°-69° C. to separate the mono-1,1-dimethylethylarsine. The bis(dimethylethyl)arsine is separated by further distillation of the reaction product.
Reaction SMILES: [C:1]([O:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:21])[C:16]([O:18]CC)=[O:17])[N:14]=1)=[O:8])([CH2:4][CH3:5])([CH3:3])[CH3:2].C(O)C.[OH-].[Na+]>O>[C:1]([O:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:21])[C:16]([OH:18])=[O:17])[N:14]=1)=[O:8])([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)OC(C)(C)CC)n1
Agent: CCOC(=O)C(=O)c1csc(=NC(=O)OC(C)(C)CC)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylate, (2.8 g.) and ethanol (10 ml.) was mixed with a solution of sodium hydroxide (0.54 g.) in water (20 ml.), and the mixture was stirred for 1 hour at room temperature. After the reaction, a small amount of ethanol was distilled off. The remaining reaction mixture was washed with diethyl ether and then the aqueous layer was separated therefrom. To the aqueous layer was added ethyl acetate, and the mixture was adjusted to pH 1 to 2 with 10% hydrochloric acid and then the ethyl acetate layer was separated therefrom. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then treated with activated charcoal. The solvent was distilled off from the ethyl acetate layer to give yellow brown powder of 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylic acid, which can be represented as 2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylic acid, (1.75 g.).