Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)#[N:2].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:23]=1)=[O:25])#[N:2]
Reactant: COC(=O)CBr
Reactant: N#Cc1ccccc1Sc1ccccc1NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.3 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 1.0 g of N-[2-(2-cyanophenylthio)phenyl]-4-hydroxybenzamide and 0.49 g of methyl bromoacetate followed by addition of 0.6 g of potassium carbonate, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was then diluted with water and crystals separated out therefrom were collected by filtration and washed with water and aqueous ethanol in that order to give 1.2 g of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH2:28][CH2:29]O)[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[CH2:31]([N:33]([CH:37](C)C)[CH:34](C)[CH3:35])[CH3:32].CS(Cl)(=O)=O.[Cl-].[NH4+:46]>O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH2:28][CH2:29][N:46]5[CH2:35][CH2:34][N:33]([CH3:37])[CH2:31][CH2:32]5)[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2cc1OCCO
Reactant: CCN(C(C)C)C(C)C
Reactant: [NH4+]
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2cc1OCCN1CCN(C)CC1
Reaction time: 1 h

Procedure:
To a mixture of 0.070 g (0.15 mmole) of 4-(3-chloro-phenyl)-2-[6-(2-hydroxy-ethoxy)-5-methoxy-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.44a), 0.041 g (0.242 mmole) of ethyldiisopropylamine and 3 mL of dimethylformamide 0 degrees was added 0.027 g (0.24 mmole) of methanesulfonyl chloride. Stirring was continued for 1 hour and then 1 mL of saturated ammonium chloride solution was added dropwise. The mixture was poured into 25 mL of water and extracted three times with 20 mL of ethyl acetate. The combined organic extracts were washed three times with 25 mL of water, once with 25 mL of saturated sodium bicarbonate solution, once with 25 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was heated at 80 degrees for 1 hour with 2 mL of dimethylformamide and 0.080 g of N-methylpiperazine. The mixture was poured into 25 mL of water and extracted three times with 20 mL of ethyl acetate. The combined organic extracts were washed three times with 25 mL of water, once with 25 mL of saturated sodium bicarbonate solution, once with 25 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 12:88-17:83) to give 0.023 g of 4-(3-chloro-phenyl)-2-{5-methoxy-6-[2-(4-methyl-piperazin-1-yl)-ethoxy]-benzoimidazol-1-yl}thiazole-5-carboxylic acid amide (I.44) as a pink solid. MH+/Z=527
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([I:13])[C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[N:3]=1.[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1>CC(O)C>[I:13][C:7]1[C:8]([CH3:12])=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:14])[N:3]=[C:2]2[NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([O:17][C:16]([F:15])([F:25])[F:26])[CH:19]=1
Reactant: Cc1nc(Cl)c2ccc(C)c(I)c2n1
Reactant: Nc1cccc(OC(F)(F)F)c1
Solvent: CC(C)O
Product: Cc1nc(Nc2cccc(OC(F)(F)F)c2)c2ccc(C)c(I)c2n1
Temperature: 170 °C
Yield: 74.1 %

Procedure:
4-Chloro-8-iodo-2,7-dimethylquinazoline (0.30 g, 0.94 mmol) and 3-(trifluoromethoxy)benzenamine (0.20 g, 1.1 mmol) were placed in a microwave vial containing 3 mL of IPA. The vial was capped and heated in a microwave reactor at 170° C. for 10 min. The mixture was concentrated in vacuo and the residue was taken up in ethyl acetate and washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was dried with sodium sulfate, concentrated and purified by column chromatography on silica gel using a gradient of 20 to 60% EtOAc in hexanes to give a 8-iodo-2,7-dimethyl-N-(3-(trifluoromethoxy)phenyl)quinazolin-4-amine (0.32 g, 74%) as an off-white solid. MS (M+H)+ 460.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:34](=[O:35])[N:6]2[C:7]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19][CH3:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Br:36]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.ClCCl>C1C=CC=CC=1.[Cl-].[Na+].O>[Br:36][C:18]1[N:13]2[C:14]([S:15][C:11]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:34](=[O:35])[N:6]4[C:7]=3[C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:22])=[CH:12]2)=[C:16]([S:19][CH3:20])[N:17]=1
Reactant: CSc1ncn2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: c1ccccc1
Product: CSc1nc(Br)n2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
4-Nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo-[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (77 mg) was dissolved in 5 ml of benzene at room temperature. N-bromosuccinimide (33 mg) and 5 mg of 2,2′-azobis(isobutyronitrile) were added to the solution. The mixture was stirred for 10 min. Dichloromethane (10 ml) and 10 ml of semisaturated brine were added thereto, followed by separation. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) to give 70 mg of 4-nitrobenzyl(1S,5R,6S)-2-(5-bromo-7-methylthioimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=O)[CH3:11].[CH2:23]([O:25][C:26](=[O:31])/[CH:27]=[C:28](\[NH2:30])/[CH3:29])[CH3:24]>C(O)C>[CH2:23]([O:25][C:26]([C:27]1[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)[C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:22])=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:30][C:28]=1[CH3:29])=[O:31])[CH3:24]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=Cc1cccc(Cl)c1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C1=C(C(=O)OCC)C(c2cccc(Cl)c2)C(C(=O)OCC)=C(C)N1

Procedure:
14 g of 3-chlorobenzaldehyde, 19 g of oxalacetic acid diethyl ester and 13 g of β-aminocrotonic acid ethyl ester in 60 ccs of ethanol are heated to the boil for several hours and subsequently evaporated in vacuo. Oil (orange). a. In the same way, 2-methyl-4-(2'-chlorophenyl)-1,4-dihydropyridine-3,5,6-tricarboxylic acid triethyl ester is prepared from 14 g of 2-chlorobenzaldehyde, 19 g of oxalacetic acid diethyl ester and 13 g of β-aminocrotonic acid ethyl ester in 60 ccs of ethanol.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[I-:1].[CH:4]1([CH2:3][CH2:2][P+:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: ICCC1CCCCC1
Solvent: Cc1ccccc1
Product: [I-]
Product: c1ccc([P+](CCC2CCCCC2)(c2ccccc2)c2ccccc2)cc1
Temperature: 80 °C

Procedure:
Dissolve (2-iodo-ethyl)-cyclohexane (3.0 g, 12.5 mmol) in toluene, add triphenyl-phosphine (3.1 g, 11.9 mmol) and stir at 80° C. over night. Cool the reaction mixture down to room temperature and isolate the product by filtration as a white solid (4.75 g). 1H-NMR (CDCl3) δ=0.78-0.96 (m, 2H), 1.01-1.34 (m, 3H), 1.44-1.74 (m, 2H), 3.56-3.70 (m, 2H), 7.66-7.90 (m, 15H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:20]([C:22]3[CH:27]=[CH:26][C:25](SC4CC4)=[CH:24][CH:23]=3)[OH:21])=[N:8][C:9]=2[O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:3][CH2:2]1.ClC1C=CC=[C:35]([C:39](OO)=O)[CH:34]=1.[S:43]([O-:47])([O-])(=[O:45])=S.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:20]([C:22]3[CH:23]=[CH:24][C:25]([S:43]([CH:39]4[CH2:35][CH2:34]4)(=[O:47])=[O:45])=[CH:26][CH:27]=3)[OH:21])=[N:8][C:9]=2[O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Reactant: COc1ccc(COc2nc(C(O)c3ccc(SC4CC4)cc3)ccc2C2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(COc2nc(C(O)c3ccc(S(=O)(=O)C4CC4)cc3)ccc2C2CC2)cc1
Reaction time: 3.5 h
Yield: 80 %

Procedure:
A solution of {5-cyclopropyl-6-[(4-methoxybenzyl)oxy]pyridin-2-yl}[4-(cyclopropylsulfanyl)phenyl]methanol (469 mg) in chloroform (15 mL) was stirred in an ice bath, and m-chloroperbenzoic acid (560 mg) was added as powder. The mixture was returned to room temperature and stirred for 3.5 hours. The reaction solution was stirred again in an ice bath, and sodium thiosulfate and a potassium carbonate solution were added, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=92:8→34:66) to give {5-cyclopropyl-6-[(4-methoxybenzyl)oxy]pyridin-2-yl}[4-(cyclopropylsulfonyl)phenyl]methanol as a light yellow oil (403 mg, 80%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([Se:16][C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=O)=[CH:19][N:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:35])=O>CN(C=O)C>[CH3:1][C:2]1[C:3]([Se:16][C:17]2[CH:25]=[CH:24][C:20]([CH2:21][Cl:35])=[CH:19][N:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: Cc1cc2c(cc1[Se]c1ccc(C(=O)O)cn1)C(C)(C)CCC2(C)C
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1[Se]c1ccc(CCl)cn1)C(C)(C)CCC2(C)C

Procedure:
2 g (5 mmol) of 6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanyl)nicotinic acid, 20 ml of toluene, 100 μl of DMF and 450 μl of thionyl chloride are introduced into a round-bottomed flask. The reaction medium is refluxed for one hour and evaporated. 100% of the expected acid chloride are collected, this product being used for the rest of the synthesis without further purification.
Reaction SMILES: [I:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:5]2[NH:6][C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[Br:22]Br.CCOC(C)=O>C(O)(=O)C>[Br:22][C:3]1[C:4]2[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:13][CH:14]=3)[NH:6][C:5]=2[C:18]([O:20][CH3:21])=[CH:19][C:2]=1[I:1]
Reactant: COc1cc(I)cc2nc(-c3ccc(C(C)C)cc3)[nH]c12
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(I)c(Br)c2nc(-c3ccc(C(C)C)cc3)[nH]c12
Reaction time: 0.75 h
Yield: 52.4 %

Procedure:
To a solution of 200 mg (0.51 mmol) 5-iodo-2-(4-isopropyl-phenyl)-7-methoxy-1H-benzoimidazole in 3 ml glacial acetic acid is slowly added 82 mg (0.51 mmol) bromine. The reaction mixture is stirred for 45 min. 30 ml EtOAc are added and this solution is washed 2n NaOH, water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) and recrystallized from EtOAc/diethyl ether to afford 126 mg of the title compound as off-white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15]Br)[CH:13]=2)[N:8](C(=O)C)[C:7]=1[C:20]([F:23])([F:22])[F:21])[CH3:2].[CH3:25][NH:26][CH3:27]>C1COCC1.C(O)C>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][N:26]([CH3:27])[CH3:25])[CH:13]=2)[NH:8][C:7]=1[C:20]([F:23])([F:22])[F:21])[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)Cc1c(C(F)(F)F)n(C(C)=O)c2ccc(CBr)cc12
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)Cc1c(C(F)(F)F)[nH]c2ccc(CN(C)C)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
To a solution of (1-acetyl-5-bromomethyl-2-trifluoromethyl-1H-indol-3-yl)-acetic acid ethyl ester (378 mg, 0.93 mmol) in THF (16.0 mL) is added a 33% solution of dimethylamine in ethanol (8.0 mL). The resulting reaction mixture is stirred for 15 h at room temperature, followed by removal of the volatiles in vacuo. The residue is purified by flash column chromatography (silica gel, CH2Cl2/MeOH 9:1) to afford the title compound as a yellow solid (303 mg, 0.92 mmol, 99%). 1H NMR (400 MHz, CDCl3, 298 K): δ=12.31 (s, 1H), 7.71 (s, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.42 (d, J=8.6 Hz, 1H), 4.15 (q, J=7.1 Hz, 2H), 4.11 (s, 2H), 3.90 (s, 2H), 2.64 (s, 6H), 1.24 (t, J=7.1 Hz, 3H). MS (ES+): 329 (M(C16H19F3N2O2)+H)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH:7]([CH3:9])[CH3:8])[N:6]=1.[Li]CCCC.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>CCOCC>[CH:7]([C:5]1[N:6]=[C:2]([Sn:19]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH3:18])[S:3][CH:4]=1)([CH3:9])[CH3:8]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)c1csc(Br)n1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1nc(C(C)C)cs1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-bromo-4-isopropyl-thiazole (6.79 mmol) in anhydrous Et2O (30 mL) under nitrogen at −78° C. was added dropwise nBuLi (7.47 mmol). The reaction was stirred for 30 min and the temperature reached to −40° C. The reaction mixture was cooled down to −78° C. and tri-n-butyltinchloride (8.15 mmol) was added slowly. The reaction mixture was allowed to warm up to room temperature and stirred during 36 hrs. Et2O was added and the reaction was quenched with saturated NH4Cl. The organic layer was washed with saturated NH4Cl and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 219 as a pale yellow oil in quantitative yield.
Reaction SMILES: [O:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.O.O[CH2:8][CH2:9][CH2:10][CH:11]=[O:12]>[Cr].[Co].O1CCCC1>[O:1]1[CH:2]=[CH:3][CH2:4][CH2:5]1.[O:12]1[CH:8]=[CH:9][CH:10]=[CH:11]1
Reactant: C1=CCOC1
Reactant: O=CCCCO
Agent: [Co]
Agent: [Cr]
Solvent: C1CCOC1
Solvent: O
Product: C1=COCC1
Product: c1ccoc1
Temperature: 120 °C

Procedure:
A 300 ml stirred Hastelloy C autoclave was charged with 16 g 2,5-dihydrofuran, 80 g water and 5 g of the catalyst described in Example III. The autoclave was heated for 3 hours at 120° C. After cooling the resulting liquid was analysed by means of gas-liquid chromatography. The conversion of 2,5-dihydrofuran amounted to 55% gamma-hydroxy butyraldehyde having been formed with a selectivity of 65%. 2,3-Dihydrofuran, tetrahydrofuran and furan had also been formed in minor amounts.
Reaction SMILES: C(OC(=O)[N:7]([C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]=O)=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:29]=2)=[O:26])=[CH:20][CH:19]=1)[CH3:8])(C)(C)C.C(O)(=O)C.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.C([BH3-])#N.[Na+]>C(O)C>[CH3:8][NH:7][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][N:49]3[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]3)=[C:30]([C:36]([F:37])([F:38])[F:39])[CH:29]=2)=[O:26])=[CH:22][CH:23]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(C=O)c(C(F)(F)F)c2)cc1
Reactant: CN1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CNc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
In 2 mL of ethanol, 40 mg (0.07 mmol) of (9-{4-[3-(4-formyl-3-(trifluoromethyl)phenyl)ureido]phenyl}-9H-purin-6-yl)-methyl-carbamic acid tert-butyl ester was dissolved, and 15 μL of acetic acid and 20 mg (0.20 mmol) of 1-methylpiperazine were added thereto, and the mixture solution was stirred at room temperature for 30 minutes. To the reaction solution, 10 mg (0.26 mmol) of sodium cyanoborohydride was further added and the resulting solution was stirred at room temperature for one hour. The reaction solution was concentrated and partitioned between water and ethyl acetate and the organic layer was washed with a saturated sodium chloride solution, concentrated under reduced pressure and purified by a silica gel column (ethyl acetate:methanol=4:1). The obtained intermediate was dissolved in 1 mL of trifluoroacetic acid and stirred for one hour. The reaction solution was concentrated and partitioned between a saturated sodium bicarbonate solution and ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution, concentrated under reduced pressure, and purified by trituration with ethyl acetate to obtain 27.4 mg (70%) of a target product as a white solid.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:42][C:43]3[CH:48]=[C:47]([CH3:49])[C:46]([OH:50])=[C:45]([CH3:51])[CH:44]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:34][CH2:33][CH:32]([O:35][CH2:36][C:37]([O:39]CC)=[O:38])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:52]=[CH:53][CH:54]=[CH:55][C:6]=2[NH:5]1.Cl>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@H:20]([CH2:42][C:43]3[CH:48]=[C:47]([CH3:49])[C:46]([OH:50])=[C:45]([CH3:51])[CH:44]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:30][CH2:31][CH:32]([O:35][CH2:36][C:37]([OH:39])=[O:38])[CH2:33][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:52]=[CH:53][CH:54]=[CH:55][C:6]=2[NH:5]1
Reactant: CCOC(=O)COC1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC(OCC(=O)O)CC3)CC2)cc(C)c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 15 mg (0.63 mmol) LiOH in 5 mL water was added to a solution of 180 mg (0.25 mmol) (R)-2-(4-ethoxycarbonylmethoxy-1,4′-bipiperidinyl-1′-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 15 mL THF and the reaction mixture was stirred for 4 h at RT. 0.66 mL of 1 M HCl were added and the mixture was concentrated by evaporation i. vac. The residue was taken up in a little DCM/MeOH (7:3) and filtered through silica gel. The filtrate was concentrated by evaporation i. vac., the residue was triturated with diethyl ether, suction filtered and dried.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[CH2:16][CH2:17][CH3:18].[NH2:19][C@@H:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41])[CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[O:31]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:32])[N:22]1[CH2:21][C@@H:20]([NH:19][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][C:11]=2[CH2:16][CH2:17][CH3:18])[CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:42])([F:41])[F:43]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: CCCc1cnn(C)c1-c1cc(C(=O)O)sc1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)sc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
To a solution of 5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (206 mg, 0.78 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (300 mg, 0.78 mmol)[prepared according to Preparation 6] and diisopropylethylamine (0.68 ml, 3.90 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (400 mg, 0.86 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (283 mg, 0.46 mmol, 60% yield) as a yellow oil: LCMS (ES) m/e 595 (M+H)+.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([OH:7])=O.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:22]3[C:23]4[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][C:24]=4[S:30][C:21]=3[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[Cl:15].Cl.[O:32]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:22]3[C:23]4[CH2:29][CH2:28][CH2:27][N:26]([C:5](=[O:7])/[CH:4]=[CH:3]/[CH2:2][N:35]5[CH2:36][CH2:37][CH2:38][O:32][CH2:33][CH2:34]5)[CH2:25][C:24]=4[S:30][C:21]=3[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: Clc1ccc(Nc2ncnc3sc4c(c23)CCCNC4)cc1Cl
Reactant: C1CNCCOC1
Reactant: O=C(O)/C=C/CBr
Agent: Cl
Product: O=C(/C=C/CN1CCCOCC1)N1CCCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1

Procedure:
In analogy to Example 130, the title compound was prepared from (2E)-4-bromobut-2-enoic acid (85 mg, 0.41 mmol), N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-4-amine from Example 82A (100 mg, 0.27 mmol) and 1,4-oxazepane hydrochloride (60 mg, 0.44 mmol) to yield 41 mg (26%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.CCN(CC)CC.[CH3:16][OH:17].CN([CH:21]=[O:22])C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:8][C:4]1[N:5]=[CH:6][N:7]=[C:2]([C:16]([O:22][CH3:21])=[O:17])[CH:3]=1
Reactant: CO
Reactant: CN(C)C=O
Reactant: Nc1cc(Cl)ncn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(N)ncn1
Temperature: 100 °C
Yield: 42 %

Procedure:
A mixture of 6-chloropyrimidin-4-amine (10.0 g, 77.2 mmol), PdCl2(dppf) (6.0 g, 8.2 mmol), Et3N (30 mL), MeOH (30 mL) in DMF (100 mL) was heated 100° C. for 24 h under 20 atm CO (g) atmosphere. The solvents were removed under reduced pressure, and the residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL) three times. The combined organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel column chromatography (0-10% MeOH/DCM) to give the desired product as a gray solid (5.0 g, 42% yield). 1H-NMR (500 MHz, DMSO-d6): δ 8.44 (d, J=0.5 Hz, 1H), 7.27 (s, 2H), 7.03 (d, J=1.5 Hz, 1H), 3.84 (s, 3H). LCMS (ESI) m/z: 154.1 [M+H+].