Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[N:18]#[C:19]Br>O1CCCC1>[C:19]([NH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3)#[N:18]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2
Reactant: N#CBr
Solvent: C1CCOC1
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC#N)C2
Temperature: 40 °C
Reaction time: 4 h
Yield: 38.5 %

Procedure:
2-Aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (1.0 g, 4.34 mmol) was dissolved in tetrahydrofuran (120 ml), to which cyanogen bromide (2.76 g, 26 mmol) was added and the mixture was stirred at 40° C. for 4 hours. After completion of the reaction, the precipitated crystals were collected by filtration, and washed with water. As a result, 0.427 g of the title compound was obtained as yellow crystals (38.5%). Recrystallization from chloroform-methanol yielded the title compound as pale yellow needles (mp: 227°-230° C. (dec.)).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][S:13][C:14]1[CH:19]=[N:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:15]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:38].[OH-].[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:32])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][S:13]([C:14]1[CH:19]=[N:18][C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:15]=1)=[O:38])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COCCCCSc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)COCCCCS(=O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reaction time: 2 h
Yield: 40 %

Procedure:
While stirring under ice cooling, to a solution of 350 mg of 2-{4-[(5,6-diphenylpyrazin-2-yl)thio]butyloxy}acetic acid tert-butyl ester obtained in Example 34 in 5 ml of chloroform, 191 mg of 70% m-chloroperoxybenzoic acid was added, followed by stirring for 2 hours. The reaction solution was combined with 20 ml of a 0.2N sodium hydroxide solution, extracted with chloroform and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 145 mg of the desired compound as a pale yellow oily substance.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8].[N:15]1C=CC=C[CH:16]=1>>[C:16]([C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8])#[N:15]
Reactant: c1ccncc1
Reactant: Cc1cc(-c2ccccc2)nnc1Cl
Product: Cc1cc(-c2ccccc2)nnc1C#N

Procedure:
Add 1.25 g (6.1 mol) 3-chloro-4-methyl-6-phenyl pyridazine, 0.99 g (11.0 mol) cuprous cyanide and 20 mL pyridine into 50 mL pressure reaction tube, allow the mixture react for 24 hours at 130° C. then cool down and filtrate, and wash the cake three times with 50 mL ethyl acetate, and the organic phase is washed twice with 100 mL 1N HCl, following by drying with anhydrous sodium sulfate, and brown solid compound, crude product 2, is obtained after concentration, the crude product can be directly used in the next step reaction without further purification, MS: 196.0 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[CH2:7][NH:8][C:9]([C@@H:11]1[CH2:15][C@@H:14]([S:16][C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][N:12]1[S:36]([C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)(=[O:38])=[O:37])=[O:10])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:60](Br)[CH:61]=[CH2:62]>C1COCC1>[C:1]([O:5][C:6](=[O:49])[CH:7]([NH:8][C:9]([C@@H:11]1[CH2:15][C@@H:14]([S:16][C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][N:12]1[S:36]([C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)(=[O:38])=[O:37])=[O:10])[CH2:62][CH:61]=[CH2:60])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)CNC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(NC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 20.7 %

Procedure:
A solution of 346 mg (0.5 mmol) (2S,4R)-{[1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carbonyl]-amino}-acetic acid tert-butyl ester in 10 ml THF at −78° C. was treated with 1.1 ml (1M in THF, 1.1 mmol) Lithium bis(trimethlsilyl)amide solution (LiHMDS). 0.127 ml (1.5 mmol) Allylbromide was added after 30 min and the reaction was warmed up to RT over night. The reaction was partitioned between aqueous 10% KHSO4/EtOAc (4×), the organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on silicagel (Hexane/EtOAc 2:1) and precipitation with Et2O/pentane gave 76 mg (21%) (2RS)-2-{(2S,4R)-[1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carbonyl]-amino}-pent-4-enoic acid tert-butyl ester, MS: 733 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:14].[CH3:15][S:16]([O-:18])=[O:17].[Na+]>C(O)C>[CH3:15][S:16]([CH2:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:14])(=[O:18])=[O:17]
Reactant: CS(=O)[O-]
Reactant: O=C1CCCc2c1ccc(O)c2CCl
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Cc1c(O)ccc2c1CCCC2=O

Procedure:
To 100 ml. of ethanol are added 10 g. of 5-chloromethyl-6-hydroxy-3,4-dihydro-1(2H)-naphthalenone and 5.4 g. of sodium methanesulfinate, and the mixture is heated on reflux for 2 hours. Then, the reaction mixture is concentrated and the residue is dissolved in chloroform and washed with water. The chloroform layer is dried in the conventional manner and the chloroform is distilled off. The procedure provides 5-methanesulfonylmethyl-6-hydroxy-3,4-dihydro-1(2H)-naphthalenone melting at 225° -230° C(decomp.).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)=[C:12]2[C:7]([C:8]([C:21]([F:24])([F:23])[F:22])=[CH:9][CH:10]=[CH:11]2)=[N:6]1.[NH:31]1[C:39]2[C:34](=[CH:35][C:36]([CH:40]=O)=[CH:37][CH:38]=2)[CH:33]=[CH:32]1.C([O-])=O.[Na+].C([BH3-])#N.[Na+]>CO>[NH:31]1[C:39]2[C:34](=[CH:35][C:36]([CH2:40][NH:20][C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([C:13]4[N:5]([CH2:4][C:3]5[C:2]([F:1])=[CH:28][C:27]([F:29])=[CH:26][C:25]=5[F:30])[N:6]=[C:7]5[C:12]=4[CH:11]=[CH:10][CH:9]=[C:8]5[C:21]([F:22])([F:23])[F:24])[CH:15]=3)=[CH:37][CH:38]=2)[CH:33]=[CH:32]1
Reactant: Nc1cccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2c(F)cc(F)cc2F)c1
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: O=C[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Fc1cc(F)c(Cn2nc3c(C(F)(F)F)cccc3c2-c2cccc(NCc3ccc4[nH]ccc4c3)c2)c(F)c1
Yield: 23.5 %

Procedure:
A solution of ({3-[2-(2,4,6-trifluorobenzyl)-7-(trifluoromethyl)-2H-indazol-3-yl]phenyl}amine (0.1 g, 0.24 mmol), indole 5-carboxaldehyde (0.035 g, 0.24 mmol), sodium formate (0.189 g, 3 mmol) and sodium cyanoborohydride (0.188 g, 3 mmol) in methanol (3 mL) was heated at 60° C. overnight. The reaction mixture was cooled, and concentrated in vacuo. The residue was partitioned with ethyl acetate and ammonium hydroxide. The organic phase was concentrated in vacuo to afford crude product, which was purified by flash chromatography (silic gel 60, methylene chloride) to afford the title compound (0.031 g, 24%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[C:32]([CH3:40])[CH:31]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:40][C:32]1[CH:31]=[C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=4)[N:16]=[CH:17]3)[N:21]=2)[CH:35]=[CH:34][C:33]=1[C:36]([F:39])([F:38])[F:37]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4cccc(S(=O)(=O)NC(C)(C)C)c4)c3)n2)ccc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4cccc(S(N)(=O)=O)c4)c3)n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.6 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[6-(3-methyl-4-trifluoromethylphenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.128 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (2.5 mL) and MeOH (2.5 mL) were added. The mixture was stirred at room temperature for 30 min, the precipitate was collected by filtration and washed with water. The crude product was further purified by crystallization (dichloromethane/heptane/MeOH) to yield the title compound as an off-white solid (0.077 g, 15%). MS (ISN) 526.4 [(M−H)−]; mp 180° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[N+:17]([C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[O:22][CH2:23][CH:24]1[CH2:26][O:25]1)([O-])=O.C([O-])=O.[NH4+]>CCO.[Pd]>[NH2:17][C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[O:22][CH2:23][CH:24]([OH:25])[CH2:26][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:5][CH2:6]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1OCC1CO1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccccc1OCC(O)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
A solution of 1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one (0.434 g, 2.0 mmol), 2-[(2-nitrophenoxy)methyl]oxirane (0.390 g g, 2.0 mmol) in EtOH (95%, 3 ml, was stirred for 2 hours at 78° C. The reaction mixture was cooled and Pd—C (5%, 0.20 g) was added. Then ammonium formiate (1.26 g, 20 mmol) was added in portions during 5 min. After 90 min the reaction mixture was filtered through Celite, concentrated, partioned between dichloromethane and ammonium hydoxide (25%) and purified on silica (dichloromethane-methanol, 12:1, containing 1% of NH4OH (25%)) to give the subtitle compound.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[C:8]([OH:14])=[C:7]([CH:15]([CH3:17])[CH3:16])[CH:6]=1)=[O:4].[I-:18].[Na+].CCCCCC>COCCOC>[OH:14][C:8]1[C:9]([CH:11]([CH3:13])[CH3:12])=[CH:10][C:5]([C:3](=[O:4])[CH2:2][I:18])=[CH:6][C:7]=1[CH:15]([CH3:17])[CH3:16]
Reactant: [I-]
Reactant: CC(C)c1cc(C(=O)CCl)cc(C(C)C)c1O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCCCCC
Product: CC(C)c1cc(C(=O)CI)cc(C(C)C)c1O
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution of 50.95 g (200 mmol) of 2-chloro-1-(4-hydroxy-3,5-di-isopropylphenyl)-ethanone in 250 ml of 1,2-dimethoxyethane, a solution of 30.94 g (206 mmol) of sodium iodide in 250 ml of 1,2-dimethoxyethane is added dropwise at room temperature. After the addition, stirring is continued for 16 hours at room temperature. Then 100 ml of hexane is added and, after stirring for additional 15 minutes, the precipitated salts are removed by filtration. The obtained solution is evaporated and the resulting residue is purified by recrystallization from hexane/dichloromethane to give 48.5 g (70%) of compound 201, m.p. 127-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:19])[C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]3[CH2:14][CH2:15][CH2:16][N:8]3[C:7](=O)[C:6]=2[CH:18]=1.B>>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:19])[C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]3[CH2:14][CH2:15][CH2:16][N:8]3[CH2:7][C:6]=2[CH:18]=1
Reactant: CN1C(=O)C2CCCN2C(=O)c2cc(Cl)cc(Cl)c21
Agent: B
Product: CN1C(=O)C2CCCN2Cc2cc(Cl)cc(Cl)c21

Procedure:
If 7,9-dichloro-1,2,3,11a-tetrahydro-10-methyl-5 H-pyrrolo[2,1-c] [1,4] benzodiazepin-5,11(10H)-dione (prepared by reaction of proline and 3,5-dichloro-N-methylisatoic anhydride as described in Example 1) is treated with borane as described in Example 1, the above compound is obtained.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[C:6]([CH3:8])[N:7]=1)[CH3:2].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C1COCC1>[CH2:12]([N:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:3]1[CH2:1][CH3:2])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCc1nc(C)c[nH]1
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCn1cc(C)nc1CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Hexyl-2-ethyl-4-methylimidazole was prepared in the following manner. All manipulations were performed under a nitrogen atmosphere. 2-Ethyl-4-methylimidazole (1.0 g) was dissolved in 10 mL THF. Sodium hydride (0.218 g) was added as a solid. An additional 10 mL of solvent was used to wash the hydride into the flask. There was a vigorous evolution of hydrogen. Mixture was stirred at room temperature overnight. 1-Bromohexane (1.568 mL) was added all at once. Mixture was stirred over weekend at room temperature and then refluxed for several hours. Reaction mixture was cooled and then filtered through Celite 545. Solvent was stripped under vacuum to yield viscous, yellow oil. Proton NMR spectrum (E102868-78) is consistent with indicated formulation and starting 1-bromohexane. This mixture was used without purification.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br[CH2:44][C:45]1C(C)=[N:48][O:47][N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:45]([CH3:44])=[N:46][O:47][N:48]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Cc1nonc1CBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)-4-methyl-1,2,5-oxadiazole and isolated as light yellow gum. MS (m/e): 379.3 (MH+).
Reaction SMILES: [C:1](=[O:18])(ON1C(=O)CCC1=O)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:19]([C:22]1[CH:23]=[C:24]([C@H:28]([NH2:30])[CH3:29])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]>C(Cl)Cl.CN(C=O)C>[N+:19]([C:22]1[CH:23]=[C:24]([C@H:28]([NH:30][C:1](=[O:18])[O:2][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:29])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: C[C@@H](N)c1cccc([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](NC(=O)OCc1ccccc1)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of benzyl 2,5-dioxopyrrolidin-1-yl carbonate (4.95 g, 19.9 mmol) and TEA (10 mL) in DCM (50 mL) was added a solution of (R)-1-(3-nitrophenyl)ethanamine (3 g, 18 mmol) in DMF (10 mL). The mixture was stirred 2 h and quenched with water (50 mL). The organic layer was separated and dried (MgSO4) before concentrating in vacuo. The residue was purified by flash chromatography (0-35% EtoAc/Hexane) to afford 64A (5 g, 93%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.50 (d, J=6.59 Hz, 3 H) 4.87-4.98 (m, 1 H) 5.00-5.15 (m, 2 H) 7.34 (s, 5 H) 7.49 (t, J=7.69 Hz, 1 H) 7.64 (d, J=7.03 Hz, 1 H) 8.11 (d, J=7.91 Hz, 1 H) 8.17 (s, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C=O)C>[N+:23]([C:22]1[C:17]([O:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])=[N:18][CH:19]=[CH:20][CH:21]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(Oc2ncccc2[N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
3-Cyanophenol (187 mg, 1.06 mmol) was dissolved in DMF (1 mL) and cesium carbonate (360 mg, 1.1 mmol) was added followed by a solution of 2-chloro-3-nitropyridine (158 mg, 1.0 mmol) in DMF (1 mL). The reaction mixture was heated with shaking at 80° C. for 18 h. The mixture was concentrated. The residue was dissolved in ethyl acetate (4 mL) and washed with water (0.6 mL), saturated NaHCO3 (0.5 mL) and water (2×0.5 mL). The organic phase was concentrated and the resulted mixture containing mainly 106a was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C:5](Cl)=[O:6])[CH3:2].[C:9]([SiH2:13][O:14][C:15]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:16]1[N:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([CH3:25])[N:24]=2)[CH:21]=1)([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:8])[C:5]([C:22]1[N:20]2[CH:21]=[C:16]([C:15]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:14][SiH2:13][C:9]([CH3:12])([CH3:11])[CH3:10])[N:17]=[CH:18][C:19]2=[N:24][C:23]=1[CH3:25])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cc1cn2cc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)ncc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(C)nc2cnc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cn12
Temperature: 120 °C
Yield: 64.3 %

Procedure:
In a reaction tube, chloro-oxo-acetic acid ethyl ester (0.51 ml, 4.5 mmol, 7.2 equiv) is added to a solution of 6-(tert-butyl-diphenyl-silanyloxymethyl)-2-methyl-imidazo[1,2-a]pyrazine (250 mg, 0.62 mmol) in anhydrous THF (5 ml) under an atmosphere of argon. The tube is sealed under argon, and the reaction mixture is heated under microwave irradiation for 30 minutes at 120° C. After cooling, the reaction mixture is carefully poured into an aqueous solution of sodium carbonate. After three extractions with EtOAc, the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (hexane/EtOAc 4:1) affords the title compound (200 mg, 64%). 1H NMR (400 MHz, d6-DMSO): δ=9.49 (d, J=1.4 Hz, 1H), 9.25 (d, J=1.4 Hz, 1H), 7.70-7.67 (m, 4H), 7.48-7.42 (m, 6H), 4.95 (s, 2H), 4.47 (q, J=7.4 Hz, 2H), 2.57 (s, 3H), 1.38 (t, J=7.4 Hz, 3H), 1.11 (s, 9H). MS (ES+): 502 (M+H)+.
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([C:40]3([C:43]#[N:44])[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)O1>>[C:1]1([C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4([C:43]#[N:44])[CH2:41][CH2:42]4)=[CH:36][CH:35]=3)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)OB(c2ccc(C3(C#N)CC3)cc2)OC1(C)C
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C#N)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonitrile.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[SH:23][CH2:24][CH2:25][C:26](O)=[O:27]>>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([O:11][C:26](=[O:27])[CH2:25][CH2:24][SH:23])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(O)CC1
Reactant: O=C(O)CCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)C1CCC(OC(=O)CCS)CC1

Procedure:
Into a 100 ml reaction flask equipped with reflux condenser, hot plate, spin bar and thermometer are placed 15.5 grams of 4-t-butylcyclohexanol; 0.5 grams paratoluene sulfonic acid and 15.5 grams of 3-mercapto-propionic acid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](O)=[O:10])=[CH:5][CH:4]=1.C(Cl)[Cl:17].S(Cl)(Cl)=O>CN(C=O)C>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([Cl:17])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)/C=C/c1ccc(C(F)(F)F)cc1

Procedure:
To a 500 mL round-bottomed flask was added 4-(trifluoromethyl)-cinnamic acid (231 mL, 116 mmol), DCM (7.44 mL, 116 mmol), thionyl chloride (17.7 mL, 243 mmol), and a few drops of DMF. The resulting mixture was stirred at reflux for about 1.5 hours and followed by LCMS (MeOH quench). Once no starting material was present, the solvents were reduced and the oil was used immediately in the next step.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][C:10]1=[O:18].C(N(CC)CC)C>ClCCl>[S:2]([O:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][C:10]1=[O:18])([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1oc2ccccc2n1CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCn1c(=O)oc2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methanesulfonyl chloride (2.21 ml, 3.265 g, 28.5 mmol) was added to a stirred solution of 3-(2-hydroxyethyl)benzoxazolin-2-one (5 g, 27.933 mmol) (J. Heterocyclic Chemistry 1988, 25, 1601) and triethylamine (5.947 ml, 4.318 g, 42.75 mmol) in dichloromethane (60 ml) and stirred for three days at room temperature. The solvent was evaporated in vacuo and the residue partitioned between water and ethyl acetate, washed with hydrochloric acid (2M, 5×50 ml), sodium hydrogen carbonate (2×20 ml), dried (MgSO4), filtered and the solvent removed in vacuo to give the title product.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].C(N(C(C)C)CC)(C)C.[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31](Cl)=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1>ClCCl>[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([NH:6][CH2:5][CH2:4][CH2:3][Br:2])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: NCCCBr
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCCBr)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of 3-bromopropylamine hydrobromide (5.0 g) and diisopropylethylamine (5.90 g) in dichloromethane (80 ml) was added portionwise 9-fluorenylmethoxycarbonyl chloride (5.91 g) and the mixture was stirred at ambient temperature for 3 hours and stand overnight. The resulting mixture was diluted with dichloromethane (50 ml) and the organic layer was washed successively with 1N hydrochloric acid and brine. Drying, filtering and removal of solvents afforded a crude product. The crude product was triturated with diethyl ether-hexane (1:5) to give 3-(9-fluorenylmethoxycarbonylamino)propyl bromide (7.82 g).