Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9].[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23]Cl>CN(C=O)C>[CH3:3][O:4][CH2:5][CH2:6][N:7]([CH2:23][O:22][CH2:21][CH2:20][Si:19]([CH3:26])([CH3:25])[CH3:18])[S:8]([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COCCNS(=O)(=O)c1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN(COCC[Si](C)(C)C)S(=O)(=O)c1ccc(I)cc1
Reaction time: 1 h
Yield: 103.5 %

Procedure:
Sodium hydride (2.2 g, 55 mmol), was added to a solution of N-(2-methoxyethyl)-4-iodobenzenesulphonamide (Method 4; 15.8 g, 46.3 mmol), in DMF (250 ml), under nitrogen at 0° C. and the mixture stirred for 1 hour. 2-Trimethylsilylethoxymethyl chloride (10 g, 60 mmol), was added and the mixture stirred overnight at ambient temperature. The volatiles were removed by evaporation and the residue dissolved in ether, washed with water and then brine, dried (Na2SO4), and the solvent evaporated to give the title compound (22.6 g, 74%). NMR: 0.2 (s, 9H), 0.89 (t, 2H), 3.30 (s, 3H), 3.40-3.36 (m, 2H), 3.59-3.43 (m, 2H), 4.82 (s, 2H), 7.60 (d, 2H), 7.84 (d, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:14][OH:15])[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5][CH2:4]1.I([O-])(=O)(=O)=[O:17].[Na+]>CO.O>[OH:15][CH2:14][C:3]1([CH2:2][OH:1])[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5](=[O:17])[CH2:4]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C1c2ccccc2SCC1(CO)CO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1c2ccccc2S(=O)CC1(CO)CO
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3,3-bis(hydroxymethyl)thiochroman-4-one (200 mg, 0.9 mmol) in MeOH (5 ml) was admixed with a solution of sodium metaperiodate (206 mg, 0.96 mmol) in water (2 ml) and stirred at RT for 72 h. The reaction mixture was diluted with water (10 ml) and extracted with EtOAc (3×30 ml), the combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. After column chromatography purification of the residue (silica gel, EtOAc), the desired product was obtained as a white solid (113 mg, 52% of theory, m.p. 108-111° C.).
Reaction SMILES: [Br-].[N+:2]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:33]=1[CH:34]=O.[OH-].[Na+]>C(Cl)Cl>[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:33]=1/[CH:34]=[CH:9]/[C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:30][CH:29]=1
Reactant: O=[N+]([O-])c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1c(F)cccc1F
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(/C=C/c2c(F)cccc2F)cc1
Temperature: 50 °C
Yield: 68.9 %

Procedure:
To a solution of 956 mg (2 mmol) of (4-nitrobenzyl)triphenylphosphonium bromide and 284 mg (2 mmol) of 2,6-difluorobenzaldehyde in 20 mL of CH2Cl2 was added 5 mL of 0.48 M NaOH solution (2.4 mmol, 1.2 equiv) dropwise over a 10 min period. The red solution was heated at 50° C. for 1 h. The organic layer was separated, washed with a saturated aqueous NaHSO3 solution and water, and dried over anhydrous MgSO4. The residue was recrystallized from ethanol to afford 360 mg (69%) of 8 as light yellow crystals: mp 136-137° C. 1H NMR (DMSO-d6): δ 8.23 (d, 2H, J=8.8 Hz), 7.93 (d, 2H, J=8.8 Hz), 7.50 (d, 1H, J=16.8 Hz), 7.46-7.40 (m, 1H), 7.37 (d, 1H, J=16.8 Hz), 7.23-7.17 (m, 2H). 13C NMR (DMSO-d6): δ 160.79 (dd, J1=249.4 Hz, J2=7.3 Hz, two C), 147.27, 143.81, 133.35 (t, J=7.9 Hz), 130.82 (t, J=10.7 Hz), 128.21 (two C), 124.46 (two C), 119.70 (t, J=1.6 Hz), 113.79 (t, J=15.1 Hz), 112.65 (dd, J1=19.5 Hz, J2=5.9 Hz, two C). MS: m/z (%) 261 (61), 231 (67), 214 (45), 194 (34), 183 (100). Anal. Calcd for C14H9F2NO: C, 64.37; H, 3.47. Found: C, 64.56; H, 3.42.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C)C=O.C(OCC)(=O)C>[C:18]([Si:15]([CH3:17])([CH3:16])[O:14][CH2:13][CH2:12][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc([N+](=O)[O-])n1
Yield: 84.7 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 250 mg, 2.21 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL) and a 60% dispersion of sodium hydride in mineral oil (93 mg, 2.32 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min, (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (598 mg, 2.50 mmol) was added. The reaction continued to stir under nitrogen for 2 h. The solution was diluted with ethyl acetate (200 mL), washed with water (2×75 mL), saturated aqueous brine solution (75 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 5% ethyl acetate/hexanes to 25% ethyl acetate/hexanes) afforded 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-nitro-1H-pyrazole (508 mg, 84%) as a yellow oil: H1-NMR (400 MHz, DMSO-d6) δ 0.00 (6H, s), 0.86 (9H, s), 4.03 (2H, t, J=5.6 Hz), 4.40 (2H, t, J=5.2 Hz), 7.11 (1H, d, J=2.4 Hz), 8.06 (1H, d, J=2.4 Hz).
Reaction SMILES: [C:1]([O:4][C:5]([CH3:28])([CH3:27])[CH2:6][NH:7][C:8](=[O:26])[C@H:9]([N:17](C(OC(C)(C)C)=O)[CH3:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([O:4][C:5]([CH3:28])([CH3:27])[CH2:6][NH:7][C:8](=[O:26])[C@H:9]([NH:17][CH3:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)(C)CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccccc1)C(=O)NCC(C)(C)OC(C)=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
2-((2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-phenylpropionylamino)-1,1-dimethylethyl acetate (426 mg, 1.1 mmol) was dissolved in dichloromethane (2 ml) and cooled to 0° C. Trifluoroacetic acid (2 ml) was added and the reaction mixture was stirred for 15 min at 0° C. The solvent was removed in vacuo at 20° C. The residue was dissolved in dichloromethane (50 ml) and the solvent was removed in vacuo. This latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (45 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 312 mg of 1,1-dimethyl-2-((2R)-2-methylamino-3-phenylpropionylamino)ethyl acetate.
Reaction SMILES: [CH:1]1([N:6]([CH2:19][C:20]#[CH:21])[C@@H:7]2[CH2:11][CH2:10][N:9]([C:12](OC(C)(C)C)=O)[CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.ClC1[C:25]2[CH:32]=[CH:31][NH:30][C:26]=2[N:27]=[CH:28][N:29]=1.CCN(C(C)C)C(C)C>>[CH:1]1([N:6]([CH2:19][C:20]#[CH:21])[C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[C:25]4[CH:32]=[CH:31][NH:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: C#CCN(C1CCCC1)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCN(C1CCCC1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1

Procedure:
(R)-tert-butyl 3-(cyclopentyl(prop-2-ynyl)amino)pyrrolidine-1-carboxylate (80 mg, 0.27 mmol) was stirred with HCl (in MeOH, 6N, 1 mL) at ambient temperature for 2 h, and then concentrated under reduced pressure. The residue was dissolved in EtOH (3 mL) and treated with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (42 mg, 0.27 mmol) in the presence of DIPEA (53 mg, 0.41 mmol) at the refluxing temperature for overnight. The volatiles were removed and the residue was purified by preparative HPLC to give the title compound. MS (m/z): 310 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([CH:9]=[O:10])[C:7]([OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].O>CN(C=O)C>[CH2:30]([O:12][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]=1[CH:9]=[O:10])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20]
Reactant: CCCCCCCCCCCBr
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCOc1ccc([N+](=O)[O-])cc1C=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
5-Nitrosalicylaldehyde (1.7 g, 10 mm) was dissolved in 20 ml dry DMF and K2CO3 (2.2 g, 16 mm) was added cautiously. The reaction was stirred at room temperature for 20 minutes and 1-bromoundecane (2.6 g, 11 mm), in 20 ml dry DMF, was added dropwise to the mixture. The reaction was heated at 89° C. for 3 days, cooled and poured into 100 ml H2O. The product was extracted with diethyl ether, washed with 5% aqueous Na2CO3 and brine, and dried over MgSO4. Filtration and evaporation of the solvent yielded an oil which was chromatographed over silica gel using 10% ethylacetate/hexane. This yielded an oil which crystallized upon scratching. The resulting white solid melted at 47°-48° C.
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[O:10][C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37]>>[CH:1]1([CH:7]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([N:33]([CH3:32])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:29])=[CH:30][CH:31]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[O:10][C:9]=2[CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCNC
Reactant: Cc1oc(-c2ccc(Cl)cc2Cl)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Product: Cc1oc(-c2ccc(Cl)cc2Cl)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 85.6 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-({cyclohexyl[5-(2,4-dichlorophenyl)-2-methyl-3-furyl]methyl}amino)benzoic acid (458 mg) as well as ethyl 3-(methylamino)propanoate (157 mg) to give the title compound (465 mg, 85%) as an amorphous compound.
Reaction SMILES: [NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[C:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]1[NH:19][C:20]([NH:22][C:23]([O:25][CH3:26])=[O:24])=[S:21].[OH-].[Na+].[CH2:29](Br)[CH:30]=[CH2:31]>CC(C)=O.O>[NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[C:4]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:3]1[NH:19][C:20](=[N:22][C:23]([O:25][CH3:26])=[O:24])[S:21][CH2:31][CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: CCCSC1=C(Cc2ccccc2)C(NC(=S)NC(=O)OC)C(=N)C=C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: C=CCSC(=NC(=O)OC)NC1C(=N)C=CC(SCCC)=C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 1-iminophenylmethyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (1.0 g.) in acetone (30 ml.) and water (10 ml.) there is added aqueous sodium hydroxide (0.21 g.). The mixture is stirred at room temperature for one hour (a solution forms 20 minutes after the addition of sodium hydroxide) and to it there is added allyl bromide (0.36 g.). The solution is stirred at room temperature for two hours and is then poured into water (300 ml.). The mixture is stirred at room temperature for 24 hours and is vacuum filtered. The tacky yellow solid is stirred in hexane (50 ml.) and is filtered to yield 0.35 g. of 1-iminohexylmethyl-2-(3-carbomethoxy-S-isothioureido)-4-propylthiobenzene, m.p. 70°-72° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH:9]=[C:10](Br)Br)[C:3]=1[CH2:13][CH3:14].[CH2:15]([NH2:18])[CH2:16][NH2:17]>>[Cl:1][C:2]1[C:3]([CH2:13][CH3:14])=[C:4]([C:5]([F:8])=[CH:6][CH:7]=1)[CH2:9][C:10]1[NH:17][CH2:16][CH2:15][N:18]=1
Reactant: CCc1c(Cl)ccc(F)c1C=C(Br)Br
Reactant: NCCN
Product: CCc1c(Cl)ccc(F)c1CC1=NCCN1

Procedure:
2-(3-Chloro-2-ethyl-6-fluoro-benzyl)-4,5-dihydro-1H-imidazole was prepared from 1-chloro-3-(2,2-dibromo-vinyl)-2-ethyl-4-fluoro-benzene and ethylenediamine in analogy to Example 1e): yellow crystals; MS (ISP): 243.3 ([M+H]+, 30%), 241.2 ([M+H]+, 100%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][OH:16].[OH-].[Na+]>>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][CH2:14][CH2:15][OH:16])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: NCCO
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: [Na+]
Agent: [OH-]
Product: OCCNc1ccnc2cc(Cl)ccc12
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A mixture of 4,7-dichloroquinoline (50.0 g, 252 mmol) and of 2-aminoethanol (46.26 g, 757 mmol) is heated, with magnetic stirring, at 150° C. for 15 min and then at 185° C. for 30 min. After returning to ambient temperature, the solid is suspended in 250 ml of a 10%, w/v, aqueous sodium hydroxide solution. The precipitate obtained is filtered off through sintered glass, washed with water and then brought to reflux in 125 ml of methanol for 15 min. After returning to ambient temperature, the precipitate is filtered off through sintered glass, washed with 3 times 40 ml of methanol and then dried under vacuum. The product 5 is obtained in the form of a white powder: 52.28 g (yield=93%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)=[C:5]([CH3:17])[C:4]([C:18]([OH:20])=O)=[N:3]1.[N:21]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=2)=[C:5]([CH3:17])[C:4]([C:18]([N:29]2[CH2:30][CH2:31][CH:26]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:27][CH2:28]2)=[O:20])=[N:3]1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1c(C(=O)O)nn(C)c1-c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(C(=O)N2CCC(N3CCCC3)CC2)nn(C)c1-c1cccc(C(F)(F)F)c1

Procedure:
In analogy to the procedure described for Example 1, 1,4-dimethyl-5-(3-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid and 4-pyrrolidine-1-yl-piperidine with HATU/iPr2Net gave the title compound as yellow oil. MS: 421.1 (MH+).
Reaction SMILES: CO[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[C@:5]([NH2:16])([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH3:6].[CH3:20][NH:21][C:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=S>>[C:27]([O:26][C:25](=[O:31])[NH:24][C:22]1[N:21]([CH3:20])[C:3](=[O:19])[C:4]([CH3:17])([CH3:18])[C@@:5]([CH3:6])([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:16]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)C(C)(C)[C@](C)(N)c1cccc([N+](=O)[O-])c1
Reactant: CNC(=S)NC(=O)OC(C)(C)C
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cccc([N+](=O)[O-])c2)N=C1NC(=O)OC(C)(C)C

Procedure:
Starting from (R)-3-amino-2,2-dimethyl-3-(3-nitro-phenyl)-butyric acid methyl ester and tert-butyl [(methylamino)carbonothioyl]carbamate, the product [(R)-1,4,5,5-tetramethyl-4-(3-nitro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester was obtained as a white solid. MS (ESI): m/z=391.3 [M+H]+.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[C:35]([C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1)(=[O:37])[CH3:36]>O>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:18]1[C:13]([C:42]2[CH:43]=[C:38]([C:35](=[O:37])[CH3:36])[CH:39]=[CH:40][CH:41]=2)=[N:14][C:15]([CH3:34])=[CH:16][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: CC(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(C(C)=O)c3)c2cc1OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
N,N-dimethylformamide (1 ml) and a 2 M aqueous potassium carbonate solution (1 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 3-acetylphenylboronic acid (67 mg) under an argon atmosphere, and the mixture was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (49 mg, yield 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](SC)=[N:7][C:6]=2[CH:18]=1.[NH2:19][CH:20]1[CH2:24][CH2:23][N:22](NC(OC(C)(C)C)=O)[CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([NH:19][CH:20]3[CH2:24][CH2:23][NH:22][CH2:21]3)=[N:7][C:6]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)NN1CCC(N)C1
Reactant: CSC1=Nc2cc(Cl)ccc2Nc2ccccc21
Product: Clc1ccc2c(c1)N=C(NC1CCNC1)c1ccccc1N2
Yield: 11.2 %

Procedure:
8-Chloro-11-methylsulfanyl-5H-dibenzo[b,e][1,4]diazepine (166JO50) (100 mg, 0.22 mmol) and 3-amino-1-N-(tert-butoxycarbonylamino)pyrrolidine (73 mg, 0.4 mmol) were reacted according to GP8 to give 7.7 mg of the title compound (166JO74). MS (ESI) 313 (MH+). Purity for MH+ (UV/MS) 100/90.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=12)=[O:5].[CH2:29]([Mg]Cl)[C:30]([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[CH3:29][C:30]([CH3:33])([CH3:32])[CH2:31][C:4]([C:6]1[N:7]=[C:8]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:11][C:10]=12)=[O:5]
Reactant: CC(C)(C)C[Mg]Cl
Reactant: CON(C)C(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2
Solvent: C1CCOC1
Product: CC(C)(C)CC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
Compound 26A (0.10 g, 0.26 mmol) was dissolved in THF and cooled to 0° C. and neopentylmagnesium chloride (1M in diethyl ether, 0.35 mL) was added and the mixture was stirred for 2 hours. The mixture was quenched with NH4Cl saturated solution and extracted with EtOAc. The residue was purified by preparative flash chromatography on silica, eluting with 20-80% gradient of ethyl acetate in hexanes to provide intermediate 26B (0.08 g, 77%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[Br:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:9](=[O:11])[CH3:10])=[N:3][CH:4]=1
Reactant: Nc1cnc(Br)cn1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cnc(Br)cn1

Procedure:
2-Amino-5-bromopyrazine (500 mg, 2.87 mmol) is stirred in acetic anhydride (5 mL) for 12 h at RT. The resulting solid is filtered off, digested with toluene and dried.
Reaction SMILES: C(Br)C.[Mg].[CH3:5][CH:6]([OH:9])[C:7]#[CH:8].[CH3:10][CH:11]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH3:20])[CH2:12][CH2:13][OH:14]>O1CCCC1>[CH3:10][CH:11]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH3:20])[CH2:12][CH:13]([OH:14])[C:8]#[C:7][CH:6]([OH:9])[CH3:5]
Reactant: C#CC(C)O
Reactant: CCC/C=C\CC(C)CCO
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCC/C=C\CC(C)CC(O)C#CC(C)O
Reaction time: 1.5 h
Yield: 81.6 %

Procedure:
A solution of 10.4 g (95.6 mmol) of ethyl bromide in 40 mL of dry tetrahydrofuran was added dropwise over a period of 30 min to a vigorously stirred suspension of 2.32 g (95.6 mmol) of magnesium turnings in 15 mL of dry tetrahydrofuran, with the reaction being initiated by occasional heating with a heat gun. After stirring the reaction mixture for 90 min under reflux, it was allowed to cool down to room temp., and a solution of 2.95 g (42.1 mmol) of but-3-yn-2-ol in 40 mL of dry tetrahydrofuran was added dropwise with stirring. The reaction mixture was then again refluxed for 3 h, the heating bath removed and a solution of 6.50 g (42.2 mmol) of (5Z)-3-methylnon-5-en-1-ol (vide supra) in 40 mL of dry tetrahydrofuran added at room temp. with stirring over a period of 30 min. The reaction mixture was refluxed with stirring overnight, allowed to cool to room temp., and quenched by pouring into 100 mL of an aqueous satd. NH4Cl solution. The organic layer was separated, and the aqueous one extracted three times with 500 mL of ether each. The combined organic extracts were dried with sodium sulphate, and concentrated to dryness in a rotary evaporator. The resulting residue (8.85 g) was purified by flash chromatography (200 g of silica gel, pentane/ether, 1:1, Rf=0.21) to furnish 7.71 g (82%) of (9Z)-7-methyltridec-9-en-3-yne-2,5-diol as a colourless oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15]Br)=[CH:8][CH:7]=1.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>C(O)C>[CH2:17]([N:19]([CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][N:19]([CH2:20][CH3:21])[CH2:17][CH3:18])=[CH:8][CH:7]=1)[CH3:18]
Reactant: BrCCCCc1ccc(CCCCBr)cc1
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)CCCCc1ccc(CCCCN(CC)CC)cc1
Yield: 69.8 %

Procedure:
First, 1.05 g of 1,4-bis(4-bromobutyl)benzene and 1.1 g of diethylamine were dissolved in absolute ethanol, and the mixture was refluxed for an hour and then evaporated under a reduced pressure to remove the solvent. After adding chloroform, the mixture was evaporated under a reduced pressure. After adding ethyl acetate the mixture was extracted with 15 ml of 1N hydrochloric acid. The aqueous extract was alkalized with 10% sodium hydroxide, and extracted with total 70 ml of chloroform. The organic extract was washed with water and a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated under a reduced pressure to obtain 0.70 g of the title compound as a colorless liquid.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[H-].[Na+].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]>O1CCCC1>[C:1]([CH:3]([CH2:12][C:13](=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: O=C(CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a solution of ethyl 2-cyanoacetate (10 g, 88.4 mmol) in tetrahydrofuran (50 ml) at 0° C. was added sodium hydride (4.2 g, 60% in mineral oil, 105 mmol) portionly. The reaction mixture was stirred for 30 minutes, and 2-bromoacetophenone (20 g, 100 mmol) in tetrahydrofuran (20 ml) was added dropwisely. After warming the mixture to room temperature, it was stirred for 4 hours. The resulting solution was quenched with water and normal work-up accomplished with diethyl ether. The organic layer was dried with MgSO4, and purified by silica gel column chromatography (EtOAc:Hx=1:3) to produce desired compound (19 g, 98%) as light yellow color oil.