Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:25](OC(=O)C)(=[O:27])[CH3:26].B(F)(F)F.CCOCC>>[C:25]([C:22]1[S:21][C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:24][CH:23]=1)(=[O:27])[CH3:26]
Reactant: CCCCCCCCCCCCCCCCCCOc1cccs1
Reactant: CC(=O)OC(C)=O
Agent: FB(F)F
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(C)=O)s1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
When in Example 3, 1-bromooctadecane is substituted for 1-bromohexadecane, 2-octadecyloxythiophene is obtained. A mixture of 35.3 g (0.1 mole) of 2-octadecyloxythiophene and 12.3 g (0.12 mole) of acetic anhydride is cooled in an ice bath. While rapidly stirring this mixture, 1.4 g of boron trifluoride etherate is added, and the mixture is heated to 100° C with stirring for 1 hour after which it is cooled to room temperature. Ice water is added, and the mixture is extracted with chloroform. The chloroform solution is evaporated to dryness under reduce pressure to give 2-acetyl-5-octadecyloxythiophene. In 500 ml of 10% aqueous potassium hydroxide 2-acetyl-5-octadecyloxythiophene is combined with 35.0 g (0.6 mole) of lithium hypochlorite. The mixture is stirred vigorously on a steam bath overnight, then allowed to cool to room temperature and extracted with ether. The aqueous extract is acidified with hydrochloric acid to precipitate 5-octadecyloxy-2-thiophenecarboxylic acid
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH2:36](I)[CH3:37]>>[CH2:36]([O:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH3:37]
Reactant: CCI
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1O
Product: CCOc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1OC

Procedure:
prepared by reaction of 2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with ethyl iodide
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[F:7][C:8]1([CH:20]([CH3:24])[C:21](O)=[O:22])[CH2:13][CH:12]=[CH:11][CH:10]=[C:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O.C(Cl)Cl>[F:7][C:8]1([CH:20]([CH3:24])[C:21]([Cl:4])=[O:22])[CH2:13][CH:12]=[CH:11][CH:10]=[C:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C(=O)O)C1(F)CC=CC=C1c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C(=O)Cl)C1(F)CC=CC=C1c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (3.8 g, 30 mmol) was combined with methylene chloride (30 mL). The resulting mixture was cooled to 0° C. and dimethylformamide (10 drops) was added. After 5 minutes of stirring a solution of 2-fluoro-α-methyl-biphenylacetic acid (3.0 g, 12 mmol) in methylene chloride (30 mL) was added dropwise over a 30 minute period. The reaction mixture was allowed to warm to room temperature and stirred overnight The solvent was evaporated to give the product in a quantitative yield as a yellow solid. 1H NMR (CDCl3) δ: 1.58 (d, 3 H), 4.20 (q, 1 H), 7.11 (t, 2 H), 7.33-7.47 (m, 4 H), 7.54 (d, 2 H).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[NH2:11][C:12]1[CH:13]=[C:14]([C:19]2[S:23][C:22]([NH:24][C:25](=[O:27])[CH3:26])=[N:21][C:20]=2[CH3:28])[N:15]=[N:16][C:17]=1[Cl:18].[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O.C1COCC1>[CH3:28][C:20]1[N:21]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:23][C:19]=1[C:14]1[N:15]=[N:16][C:17]([Cl:18])=[C:12]([NH:11][S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])[CH:13]=1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(N)c(Cl)nn2)s1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2cc(NS(=O)(=O)c3ccccc3)c(Cl)nn2)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Lithium hexamethyldisilazane (1M solution in THF; 0.81 mL) was added to a mixture of N-[5-(5-amino-6-chloropyridazin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (77 mg) and THF (1.3 mL) that had been cooled to 0° C. The reaction mixture was allowed to warm and was stirred at room temperature for 30 minutes. Benzenesulfonyl chloride (0.069 mL) was added and the reaction mixture was stirred at room temperature for 2 hours. Water (2 drops) was added to the reaction mixture. The mixture was evaporated and the residual solid was purified by preparative HPLC. The material so obtained was purified further by column chromatography on silica using a solvent gradient of 0% to 20% methanol in dichloromethane as eluent. There was thus obtained the title compound as a solid (2.5 mg); 1H NMR Spectrum: (DMSOd6) 2.15 (s, 3H), 2.40 (s, 3H), 7.05 (s, 1H), 7.45 (m, 3H), 7.80 (m, 2H); Mass Spectrum: M+H+ 424.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].Cl[CH2:17][C:18](=[O:20])[CH3:19]>CN(C=O)C>[NH2:5][C:4]1[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[O:1][C:17]=1[C:18](=[O:20])[CH3:19]
Reactant: N#Cc1ccccc1O
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1oc2ccccc2c1N
Temperature: 120 °C
Yield: 63.9 %

Procedure:
To a solution of 2-hydroxy-benzonitrile (1000 mmol) in DMF (dimethylformamide, 80 mL) was added K2CO3 (207 g, 1.5 mol) portionwise under stirring, followed by 1-chloro-propan-2-one (139 g, 1.5 mol). After addition, the mixture was heated to 120° C. and stirred at that temperature for 2 hours. TLC showed the reaction was completed. The reaction mixture was cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate, washed with brine, dried and concentrated. The residue was washed with dichloromethane, filtered and dried to give 112 g of 1-(3-amino-benzofuran-2-yl)-ethanone (1A).
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH2:38])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.CN1CCOCC1.[CH3:46][O:47][C:48]([NH:50][C@H:51]([C:55](O)=[O:56])[CH:52]([CH3:54])[CH3:53])=[O:49].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C>CN(C=O)C>[S:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][N:13]([NH:38][C:55](=[O:56])[C@H:51]([CH:52]([CH3:53])[CH3:54])[NH:50][C:48]([O:47][CH3:46])=[O:49])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C:32]([CH3:34])([CH3:35])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1)C(C)(C)C
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under an argon atmosphere, 344 mg of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane and 191 μl (1.74 mmol) of NMM in 5.6 ml of DMF are added to 122 mg (0.696 mmol) of N-methoxycarbonyl-(L)-valine and 173 mg (0.58 mmol) of TPTU in 2.9 ml of DMF and the mixture is stirred at room temperature for 16 hours. The reaction mixture is poured into ice-water, stirred for 30 min and filtered. Column chromatography of the residue (SiO2 ; methylene chloride/THF 4:1) and stirring in ether yield the title compound: m.p: 134°-135° C.; HPLC20-100 : tRet =14.0; FAB MS (M+H)+ =697.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:12])[CH:6]=[C:7]1[CH2:11][CH2:10][CH2:9][NH:8]1.[C:13]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br)#[N:14].Cl>C1(C)C=CC=CC=1>[CH3:3][O:4][C:5](=[O:12])[C:6](=[C:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)[CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([C:13]#[N:14])[CH:16]=1
Reactant: COC(=O)C=C1CCCN1
Reactant: N#Cc1cccc(CBr)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1cccc(C#N)c1)=C1CCCN1
Temperature: 0 °C
Yield: 55.1 %

Procedure:
To a flask containing a 60% dispersion of NaH (0.91 g, 22.7 mmol), and toluene (60 mL), under nitrogen, is added Pyrrolidin-2-ylidene-acetic acid methyl ester (3.2 g, 22.7 mmol) and the mixture is refluxed for 1 h. The reaction mixture was cooled to 0° C. and a solution of m-cyanobenzylbromide (4.45 g, 22.7 mmol) in toluene (60 mL) is added dropwise. The reaction is allowed to warm to RT and then heated at 60° C. overnight. The mixture is cooled to RT and with vigorous stirring 1 N HCl is added to obtain a pH of 6. The toluene was decanted and dried over Na2SO4 and concentrated. Purification by flash chromatography (9:9:1 of CH2Cl2:hexanes:EtOAc) gave the title compound as a wet solid (3.2 g, 12.5 mmol). 1H NMR (CDCl3, 300 MHz) 8.32(br. s, 1H), 7.48-7.25(m, 4H), 3.63(s, 3H), 3.62-3.55(m, 2H), 3.53(s, 2H), 2.66-2.48(m, 2H), 2.10-1.90(m, 2H).
Reaction SMILES: [Li]CCCC.CCCCCC.[C:12]([C:14]1([F:22])[CH:19]2[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]2)[CH2:15]1)#[CH:13].[CH:23]1([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C1COCC1>[CH:31]1([C:29]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([OH:30])[C:13]#[C:12][C:14]2([F:22])[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: C#CC1(F)CN2CCC1CC2
Reactant: O=C(c1ccccc1)C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(C#CC1(F)CN2CCC1CC2)(c1ccccc1)C1CCCCC1
Reaction time: 0.5 h

Procedure:
A 1.6 N solution of BuLi in hexane (730 μA, 1.16 mmol) was added dropwise to a solution of 3-ethynyl-3-fluoroquinuclidine 57 (162 mg, 1.06 mmol) in THF (5 ml) at 0° C. After stirring for 30 minutes, cyclohexyl(phenyl)methanone (207 mg, 1.16 mmol) in THF (1 ml) was added slowly. After 30 minutes, the reaction was quenched by the addition of saturated aqueous NH4Cl solution and diluted with AcOEt. The organic phase was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by chromatography over silica gel (CH2Cl2/MeOH 97.5/2.5) and 1-cyclohexyl-3-(3-fluoro-1-azabicyclo[2.2.2]oct-3-yl)-1-phenylprop-2-yn-1-ol 111 was obtained as colorless foam (mixture of diastereomers, 30 mg, 8%).
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([CH2:18]C(O)=O)([C:15]([OH:17])=[O:16])=[O:14].[OH-].[K+].Cl>O>[C:1]1([CH2:7][C:8]([OH:12])([C:9]([OH:11])=[O:10])[CH2:18][C:13](=[O:14])[C:15]([OH:17])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C(=O)Cc1ccccc1
Reactant: O=C(O)CC(=O)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(=O)CC(O)(Cc1ccccc1)C(=O)O

Procedure:
5.0 g (30.5 mmol) of phenylpyruvic acid and 12.1 g (91.4 mmol) of oxaloacetic acid were added to 25 ml of water preliminarily dissolving 13.8 g of potassium hydroxide (purity of 85%) therein, for reaction at ambient temperature for 72 hours. Using the conc. hydrochloric acid, the reaction solution was adjusted to pH 2.2, for extraction into ethyl acetate. The organic layer was rinsed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated to obtain the residue. The residue was recrystallized in ethyl acetate and toluene to obtain PHOG of 2.8 g (11.3 mmol.) in crystal.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[H-].[K+].C([Li])(C)(C)C.C(O[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1)(C)C>C1COCC1>[CH3:11][C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1)=[CH:10][CH:9]=2
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc2cc(Br)ccc2[nH]1
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 63.2 %

Procedure:
A solution of 5-bromo-2-methyl-1H-indole (5.04 g, 24 mmol) in THF (25 mL) was added dropwise to a suspension of potassium hydride (3.2 g, 24 mmol) in THF at 0° C. After fifteen minutes at 0° C., the solution was cooled to −78° C. and a t-butyl lithium solution (1.7 M in pentane, 28.2 mL, 48 mmol) was added dropwise via syringe while maintaining the temperature below −55° C. After an additional 15 minutes, the solution was cooled to −78° C. and treated with a 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (9.8 mL, 48 mmol) dropwise via syringe. The solution was stirred at −78° C. for 1.5 hours, allowed to warm to room temperature and quenched with saturated aqueous ammonium chloride. The solution was diluted with ethyl acetate and filtered to remove inorganic material. The filtrate was extracted with ethyl acetate. The combined organics were washed with brine, dried (MgSO4) and concentrated. The concentrate was purified by flash chromatography on silica gel using 10% ethyl acetate/hexanes to give 3.9 g (63% yield) of the desired product. MS (ESI(+)) m/e 258 (M+H)+.
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].[CH2:5]([C:7]([CH2:35][CH3:36])([CH:9](O)[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:6].C(N(S(F)(F)[F:43])CC)C>ClCCl>[PH:1](=[O:2])([OH:4])[OH:3].[CH2:5]([C:7]([CH2:35][CH3:36])([CH:9]([F:43])[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:6]
Reactant: CCC(C)(CC)C(O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CCN(CC)S(F)(F)F
Agent: O=[PH](O)O
Solvent: ClCCl
Product: CCC(C)(CC)C(F)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -70 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
A solution of diethyl 3-hydroxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.0 g, prepared as described in Example 24) in dichloromethane (3 ml) was added dropwise with stirring at -70° C., to a solution of diethylaminosulphur trifluoride (0.37 g) in dichloromethane (7 ml). The mixture was stirred at -70° C. for two hours, allowed to warm to room temperature and, after a further one hour, diluted with dichloromethane, washed with water and sodium bicarbonate solution, dried over magnesium sulphate, and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (19:1) as eluant, to give diethyl 3-fluoro-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.50 g, m.p. 97-98° C.). NMR (CDCl3): δ 1.3(6H,t), 1.7-2.0(2H,m), 2.1-2.5(2H,m), 4.1(4H,m), 5.5-5.7(1H,m), 7.1-7.3(15H,m), 7.95(1H,s). M/S: M+ 507.
Reaction SMILES: C(O[K])(C)(C)C.[C:7]([O:11][C:12](=[O:18])[N:13]([CH2:15][CH2:16][OH:17])[CH3:14])([CH3:10])([CH3:9])[CH3:8].F[C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[O:23]>O1CCOCC1>[C:7]([O:11][C:12](=[O:18])[N:13]([CH2:15][CH2:16][O:17][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[O:23])[CH3:14])([CH3:10])([CH3:8])[CH3:9]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: O=Cc1ccccc1F
Agent: CC(C)(C)O[K]
Solvent: C1COCCO1
Product: CN(CCOc1ccccc1C=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28.6 %

Procedure:
tBuOK (2.69 g; 24 mmol; 1.2 eq.) was added portionwise to a solution of (2-hydroxy-ethyl)-methyl-carbamic acid tert-butyl ester (3.5 g; 20 mmol; 1 eq.) and 2-fluoro-benzaldehyde (2.97 g; 24 mmol; 1.2 eq.) in 1,4-dioxane (30 mL) and the reaction mixture was stirred at room temperature for 20 minutes. After dilution with EA, the solution was washed with water (2×) then brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (15% to 50% EA in cyclohexane) afforded the title compound (1.6 g, 29%) as a colourless oil. HPLC (max plot) 89.3%; Rt 4.21 min.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].CN1CCCC1=O.[NH2:19][CH:20]([CH2:23][OH:24])[CH2:21][OH:22]>C(N(CC)CC)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:19][CH:20]([CH2:23][OH:24])[CH2:21][OH:22])=[C:3]([CH3:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: NC(CO)CO
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])ccc1NC(CO)CO
Temperature: 60 °C
Yield: 11 %

Procedure:
2 g of 2-fluoro-5-nitrotoluene were added to a solution of 20 ml of N-methylpyrrolidinone, 1.4 g of 2-amino-1,3-propanediol, and 1.57 g of triethylamine. The reaction medium was heated at 60° C. for 10 hours and, after cooling to room temperature, was poured into a water/ice mixture. The resulting medium was extracted with ethyl acetate and the organic phase was then concentrated under vacuum. 0.32 g of 2-(4-nitro-2-methylphenylamino)propane-1,3-diol (13) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[CH3:11][O:12][C:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1Br)=[O:14].CCOC(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.[Zn].Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][O:12][C:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)=[O:14]
Reactant: COC(=O)c1ccncc1Br
Reactant: N#Cc1ccc(CBr)cc1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccncc1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-cyanobenzyl bromide (625 mg, 3.27 mmol) in dry THF (4mL) was added slowly over ~3 min. to a suspension of activated Zn (dust; 250 mg) in dry THF (2 mL) at 0° under an argon atmosphere. The ice-bath was removed and the slurry was stirred at room temperature for a further 30 min. Then 3-bromopyridin-4-carboxylic acid methyl ester (540 mg. 2.5 mmol) followed by dichlorobis(triphenylphosphine)nickel (II) (50 mg). The resultant reddish-brown mixture was stirred for 3 h at ~40°-45° C. The mixture was cooled and distributed between EtOAc (100 ml) and 5% aqueous citric acid (50 mL). The organic layer was washed with H2O (2×50 mL), dried with Na2SO4. After evaporation of the solvent the residue was purified on silica gel, eluting with 35% EtOAc in hexane to give 420 mg as a clear gum. FAB ms (M+1) 253.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[I:17]Cl>C(Cl)Cl>[I:17][C:11]1[S:10][C:9]([NH2:12])=[N:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: ClI
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1nc(-c2ccccc2)c(I)s1
Reaction time: 0.5 h

Procedure:
4-Phenyl-thiazol-2-ylamine (0.881 g, 5.00 mmol) was dissolved in 10 mL of CH2Cl2 and 2 mL of acetic acid and treated at 0° C. with iodine monochloride (5.25 mL of 1M in CH2Cl2, 1.05 eq.) and kept at this temperature for 0.5 h. Pouring onto crashed ice/Na2CO3, twofold extraction with ethyl acetate, washing with water and brine, drying over sodium sulfate, and evaporation to dryness produced 1.60 g of the title compound as dark brown gum, sufficiently pure to be used for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][SH:8])=[CH:5][CH:4]=1.[H-].[Na+].CS(O[CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)(=O)=O.[Cl-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][S:8][CH:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[CH:5][CH:4]=1
Reactant: CN1CCC(OS(C)(=O)=O)CC1
Reactant: COc1ccc(CS)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CSC2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10.9 ml of 4-methoxybenzyl mercaptan were dissolved in 55 ml of dry dimethylformamide, and 3.4 g of sodium hydride (as a 55% w/w suspension in mineral oil) were added to the solution, whilst ice-cooling. The mixture was then stirred at room temperature for 30 minutes. At the end of this time, a solution of 12.6 g of 4-methanesulfonyloxy-1-methylpiperidine in 63 ml of dry dimethylformamide was added to the mixture, which was then allowed to stand overnight at room temperature. The reaction mixture was then poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract as washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel (eluted with a 1:4 by volume mixture of ethyl acetate and methanol) to afford 9.01 g of the title compound as an oil.
Reaction SMILES: [O:1]=C1C2C(C=CN=2)=NC1=O.C1C=CC2SC3C=CC=CC=3NC=2C=1.[CH3:25][C:26]12[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[C:30](=[O:36])[O:29][C:27]2=[O:28].C(OCCO)(=O)C(C)=C>C1C(Cl)=CC=C(Cl)C=1>[CH3:25][C:26]1([CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[C:30]([OH:29])=[O:36])[C:27]([OH:1])=[O:28]
Reactant: O=c1nc2ccnc-2c1=O
Reactant: CC12CCCCC1C(=O)OC2=O
Agent: C=C(C)C(=O)OCCO
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: Clc1ccc(Cl)cc1
Product: CC1(C(=O)O)CCCCC1C(=O)O

Procedure:
2.35 g (0.005 mol) of the diketopyrrolopyrrole of the formula XIX (Example 6) and 30 ml of dichlorobenzene are placed under nitrogen in a sulfonating flask, 5.0 mg (0.05 mmol) of thiodiphenylamine are added, and the mixture is heated with stirring at 110°-115° C. 3.17 g (0.010 mol) of the methyl-hexahydrophthalic acid derivative (isomer mixture) of the formula ##STR43## (obtained by generally known methods from methylhexahydrophthalic anhydride and hydroxyethyl methacrylate) are added dropwise with vigorous stirring over the course of 15 minutes to the clear orange-red solution, stirring is continued for about 2 hours at 110°-115° C., and then the mixture is cooled to room temperature. The clear dark red solution is washed in a separating funnel 3 times with 20 ml of 5% sodium hydroxide solution and 2 times with 30 ml of deionized water, and the organic phase is dried over MgSO4 ·H2O, filtered and concentrated to dryness under a high vacuum. The resulting product is recrystallized from 30 ml of ethanol, to give 3.05 g (81.3% of theory) of a crystalline product of the formula ##STR44## with a melting point of 69.6° C.