Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:19]=[C:18](B(O)O)[CH:17]=[CH:16][N:15]=1.[CH3:23][C:24]1[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][N:25]=1>>[Cl:13][C:14]1[CH:19]=[C:18]([C:5]2[C:6]3[S:10][C:9]([CH3:11])=[N:8][C:7]=3[C:2]([NH:30][C:28]3[CH:27]=[CH:26][N:25]=[C:24]([CH3:23])[CH:29]=3)=[N:3][CH:4]=2)[CH:17]=[CH:16][N:15]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: Cc1cc(N)ccn1
Reactant: Cc1nc2c(Cl)ncc(I)c2s1
Product: Cc1cc(Nc2ncc(-c3ccnc(Cl)c3)c3sc(C)nc23)ccn1

Procedure:
The title compound, MS: m/e=368.1 (M+H+), was prepared in accordance with the general method of example 2, step 1 and step 2 from 4-chloro-7-iodo-2-methyl-thiazolo[4,5-c]pyridine (Example B), 2-chloropyridin-4-boronic acid and 2-methyl-4-aminopyridine.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:6]=2[N:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[CH3:1][N:2]([CH3:14])[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([CH2:12][NH2:13])=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)c1nc2cc(C#N)ccc2o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CN(C)c1nc2cc(CN)ccc2o1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2-(Dimethylamino)-1,3-benzoxazole-5-carbonitrile (1.5 g, 8.0 mmol) in 150 mL of dry ether, 640 mg (16.0 mmol) of LiAlH4 were slowly added. The mixture was stirred at room temperature for 1.5 h and the excess of reagent was decomposed by careful addition of the minimum amount of water and filtered. The solids were washed with hot EtOAc (3×100 mL) giving a residue after evaporation. The purification by column chromatography yield 622 mg (41%) of the title compound as a white solid. Rf (CH2Cl2/MeOH 9:1+0.25% NH3) 0.2; 1H NMR (CD3OD) δ 7.23 (s, 1H, H-4), 7.15 (d, 1H, J=8.1 Hz, H-7), 6.89 (d, 1H, J=8.1 Hz, H-6), 3.83 (s, 2H, CH2), 3.14 (s, 6H, CH3×2); 13C NMR (CD3OD) δ 163.7 (C-2), 148.4 (C-7a), 144.2 (C-3a), 139.8 (C-5), 119.6 (C-6), 114.9 (C-4), 108.7 (C-7), 47.1 (CH2), 38.0 (CH3); mass spectrum (ES+): m/e 192.0 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)cc1F
Temperature: 90 °C
Yield: 94 %

Procedure:
A solution of 2-fluoro-4-hydroxybenzoic acid (50.0 g) and concentrated sulfuric acid (10 mL) in methanol (700 mL) was stirred with heating at 90° C. for 16 hr. The reaction solution was concentrated, and the resulting colorless crystals were washed with water, and dried to give the title compound (51 g, yield 94%) as colorless crystals.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:19]([N:21]1[CH2:34][CH2:33][CH2:32][C@H:22]1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=O)C1C=CC=CC=1.Br.C(O)(=O)C>CCOCC>[NH2:11][C@H:12]([C:19]([N:21]1[CH2:34][CH2:33][CH2:32][C@H:22]1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1
Reactant: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 161.4 %

Procedure:
To 1.79 g of compound (95) was added 19 ml of 25% hydrobromic acid--acetic acid cooled in an ice bath followed by stirring one hour at room temperature. The reaction mixture was added to 190 ml of desiccator ether and precipitates thus formed were quickly collected by filtration and dried overnight in a desiccator containing potassium hydroxide to provide 2.05 g of L-histidyl-N-phenyl-L-prolinamide.2-hydrobromide (96).
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:10](=[O:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:8][C:2]([F:9])([CH:10]([OH:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: O=CCCc1ccccc1
Product: CCOC(=O)C(F)(F)C(O)CCc1ccccc1

Procedure:
According to the procedure of Thaisrivongs et. al. (J. Med. Chem., 1986, 29, 2080), ethyl bromodifluoroacetate was condensed with hydrocinnamaldehyde to give the desired compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:14][CH2:15][C:16]([Cl:18])=[O:17]>ClCCl>[ClH:18].[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:16](=[O:17])[CH2:15][Br:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CBr
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Solvent: ClCCl
Product: Cl
Product: O=C(CBr)N[C@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.4 %

Procedure:
(S)-(+)-1-Benzyl-3-aminopyrrolidine (6 g, 34 mmol) was dissolved in dichloromethane (12 ml). To this solution, a solution of bromoacetyl chloride (5.46 g, 34 mmol) in dichloromethane (5 ml) was added at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was filtered, washed with dichloromethane and dried in vacuo to afford 7.3 g (64%) of (3S)-N-(1-benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride as a solid which was used directly in the next step. 4-Hydroxy-2-methoxybenzaldehyde (2.39 g, 16 mmol) was dissolved in DMF (10 ml) and potassium carbonate (7.3 g, 52 mmol) was added followed by a suspension of the above (3S)-N-(1-benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride (3.5 g, 10 mmol) in DMF (20 ml). The resulting mixture was stirred at room temperature for 16 hours. The mixture was then partitioned between water (100 ml) and ethyl acetate (30 ml). The aqueous phase was extracted with ethyl acetate (2×20 ml) and the combined organic extracts were washed with saturated sodium chloride (3×15 ml), dried (MgSO4) and concentrated in vacuo. The residue (4 g) was crystallised from a mixture of diethyl ether and heptane, filtered and dried in vacuo to afford 2.7 g (71%) (S)-N-(1-benzylpyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy)-acetamide as a solid. M.p.: 96-100° C.
Reaction SMILES: CO[C:3]([C:5]1[O:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[Mg]Br.[C:22](=[O:25])(O)[O-].[Na+].Cl>C1COCC1.CCOC(C)=O>[O:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][C:14]=1[O:25][CH3:22])([C:15]1[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][C:16]=1[O:18][CH3:19])[OH:4]
Reactant: COC(=O)c1ccco1
Reactant: O=C([O-])O
Reactant: COc1ccc([Mg]Br)c(OC)c1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(O)(c2ccco2)c2ccc(OC)cc2OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Methyl-2-furoate (1.58 g, 0.0125 mol) was dissolved in 100 mL of dry THF. A dropping funnel containing 50 mL of a 0.5 M solution of 2,4-dimethoxyphenylmagnesium bromide in THF (Aldrich) was attached to the reaction flask and the system was purged with argon. The reaction flask was submerged in an ice bath for 5 minutes, at which time the Grignard solution was added drop-wise over 15 minutes. After addition was complete, the reaction was allowed to warm to room temperature and was stirred overnight. A brown solution resulted after 14 hours of stirring. This solution was added to 150 g crushed ice and the slush was stirred with ˜0.5 g sodium bicarbonate during drop-wise addition of conc. HCl A violet color was observed upon addition of acid, which was continued until effervescence was observed. The resulting neutral suspension was extracted into ˜400 mL EtOAc and the organic layer was dried over MgSO4. Removal of solvent in a rotary evaporator gave a clear/yellow oil. Upon standing in ˜30 mL EtOAc (12 h), the oil had turned deep blue and a white crystalline solid had settled out. The solid was collected and gave 1.7 g desired product. The blue solution was chromatographed in 50% EtOAc/50% hexanes and the second product to elute (deep violet upon acid treatment on TLC plate) was collected. Recrystallization of this product gave an additional 1.3 g pure desired alcohol. 3.0 g/4.6 g=65% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[CH:17][C:10]=12)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:16]=[CH:17][C:10]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccnc2[nH]ccc12
Reactant: CS(=O)(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccnc2c1ccn2S(C)(=O)=O
Reaction time: 0.25 h

Procedure:
To a stirred solution of (1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-carbamic acid tert-butyl ester (400 mg, 1.62 mmol) in DMF (10.0 mL) was added powdered KOH (143 mg, 1.88 mmol). After 15 minutes, methanesulfonyl chloride (137 μL, 1.78 mmol) was added. After 15 hours, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (25 mL), dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-50% ethyl acetate in heptane to afford (1-methanesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:26]=[C:12]2[C:13]([NH:17][C:18]3[CH:23]=[C:22]([NH:24][CH3:25])[N:21]=[CH:20][N:19]=3)=[N:14][CH:15]=[CH:16][C:11]2=[N:10]1.ClC1N=CN=C(NC2C3=CN(C4C(Cl)=CC=CC=4Cl)N=C3C=CN=2)C=1.[F:52][CH:53]1CN[CH2:54]1.CCN(C(C)C)C(C)C>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[CH:26]=[C:12]2[C:13]([NH:17][C:18]3[CH:23]=[C:22]([N:24]4[CH2:54][CH:53]([F:52])[CH2:25]4)[N:21]=[CH:20][N:19]=3)=[N:14][CH:15]=[CH:16][C:11]2=[N:10]1
Reactant: FC1CNC1
Reactant: CNc1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Agent: Clc1cc(Nc2nccc3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Solvent: CCN(C(C)C)C(C)C
Product: FC1CN(c2cc(Nc3nccc4nn(-c5c(Cl)cccc5Cl)cc34)ncn2)C1
Yield: 93 %

Procedure:
Following the procedure described for N-[2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-4-yl]-N′-methylpyrimidine-4,6-diamine, (6-chloropyrimidin-4-yl)-[2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-4-yl]amine and 3-fluoroazetidine with added DIPEA (103 μL, 0.6 mmol) were reacted to afford the title compound as a yellow solid (81 mg, 93% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.28 (br s, 1H), 9.14 (s, 1H), 8.29 (s, 1H), 7.94 (s, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.70 (dd, J=9.1, 7.3 Hz, 2H), 7.16 (br s, 1H), 5.62-5.46 (m, 1H), 4.38 (ddd, J=21.3, 10.5, 5.9 Hz, 2H), 4.14 (d, J=10.5 Hz, 1H), 4.08 (d, J=10.5 Hz, 1H). LCMS (Method B): RT=3.16 min, m/z: 430 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:19])[C:5]2[CH:11]=[C:10](Br)[C:9](=[O:13])[N:8]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][N:31](C(OC(C)(C)C)=O)[CH:32]=2)O1.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](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.CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:19])[C:5]2[CH:11]=[C:10]([C:28]3[CH:29]=[N:30][NH:31][CH:32]=3)[C:9](=[O:13])[N:8]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nc(N)nc2c1cc(Br)c(=O)n2C1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N)nc2c1cc(-c1cn[nH]c1)c(=O)n2C1CCCC1
Temperature: 120 °C
Yield: 65 %

Procedure:
To a solution of 2-amino-6-bromo-8-cyclopentyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.31 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxy late 110 mg, 1.2 equiv), dichlorobis(triphenylphosphine)palladium(II) (6.5 mg, 009 mmol), DMF (2 mL) in a 10 mL microwave vial was added potassium carbonate (3 M, 0.8 mL). The solution was degassed with N2 for 10 min before being capped and heated in the microwave reactor for 10 min at 120° C. Once complete, the reaction was diluted with 1 N NaOH (10 mL) and EtOAc (50 mL). The EtOAc layer was washed with 3N HCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was submitted for chromatography purification. the title compound was obtained in (62.5 mg, 65% yield).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH:6]([C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=1)=[O:7]>S(=O)(=O)(O)O>[CH:6]([C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][C:13]=1[N+:1]([O-:4])=[O:2])=[O:7]
Reactant: CC(=O)Nc1cccc(C=O)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)Nc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 5 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
A solution of potassium nitrate (6.2 g, 61 mmol) in sulfuric acid (30 mL) was added dropwise to stirred solution of N-(3-formylphenyl)acetamide (10.0 g, 61 mmol) in sulfuric acid (120 mL) maintained at 5° C. After 2 hours, the reaction mixture was poured onto ice water (500 mL) and filtered to give N-(3-formyl-4-nitrophenyl)acetamide (6.2 g, 48%) mp 131°-135° C., used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH3:12])[CH:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:19][Si]([N-][Si](C)(C)C)(C)C.[K+].IC>O1CCCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH3:12])[C:5]2([CH3:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CN1C(=O)c2ccc(Br)cc2C1c1ccccc1
Agent: [K+]
Solvent: CO
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)c2ccc(Br)cc2C1(C)c1ccccc1
Temperature: -30 °C
Reaction time: 16 h

Procedure:
To a solution of 5-Bromo-2-methyl-3-phenyl-2,3-dihydro-isoindol-1-one (250 mg; 0.83 mmol) in 2.5 ml of anhydrous tetrahydrofuran at −30° C. is added an 0.5 mol/l potassium bis(trimethylsilyl)amide (2.5 ml; 1.24 mmol) solution. After 30 minutes iodomethane (77 μl; 1.24 mmol) is added and stirred for 16 hours at −30° C. The reaction mixture is diluted with methanol and purified via reversed phase chromatography under basic conditions.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([CH2:8][N:9]=C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7])([CH3:4])[CH3:3].[CH:23]1(Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[C:2]([O:5][C:6](=[O:7])[CH:8]([NH2:9])[CH:23]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)([CH3:4])([CH3:3])[CH3:1]
Reactant: BrC1CCCCCC1
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(N)C1CCCCCC1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a soln. of N-(diphenylmethylene)glycerine tert-butyl ester (6.83 mmol) and (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphthol[7,6,1,2-cde]azepinium bromide (6.84 μmol) in 45 mL toluene were sequentially added cycloheptyl bromide (8.2 mmol) and CsOH H2O (34.2 mmol) at −10° C. The reaction mixture was stirred at −10° C. for 10 min and then at RT for 4 days. Another portion of (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphthol[7,6,1,2-cde]azepinium bromide (6.84 μmol) was added and stirring was continued at RT for another 24 h. The reaction was quenched with water and extracted 3 times with DCM. The comb. org. layers were combined, conc. and the residue was redissolved in 100 mL THF. A soln. of 100 mL aq. 0.5 M citric acid soln. was added and the mixture was stirred at RT for 4 h. The mixture was concentrated to half of its volume and extracted twice with Et2O. The aqueous layer was basified with solid NaHCO3 and extracted 3 times with DCM. The comb. org. layers were dried over MgSO4 and conc. in vacuo to obtain the desired product as yellow oil.
Reaction SMILES: CCN(C1C=CC=CC=1)CC.O[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([CH2:22][CH3:23])[N:16]=[CH:15][N:14]=1.C(OCC)(=O)C.P(Cl)(Cl)[Cl:31]>>[Cl:31][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([CH2:22][CH3:23])[N:16]=[CH:15][N:14]=1
Reactant: CCc1ncnc(O)c1[N+](=O)[O-]
Reactant: ClP(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: CCc1ncnc(Cl)c1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
18.7 g (0.125 mol) of diethylaniline are dissolved in 18 ml of phosphorus chloride, and then 8.46 g (0.05 mol) of 4-hydroxy-5-nitro-6-ethylpyrimidine are stirred in. During the addition, the temperature rises from 22° to 47° C. A solution is formed which is heated at 60° C. for 2 hours. It is then stirred with ice-water and ethyl acetate for 30 minutes for the purpose of hydrolysis. The organic phase is separated off and combined with the extracts obtained by extraction, and the mixture is washed with NaHCO3 solution. Removal of the solvent yields 9.1 g of crude product, which is purified by column chromatography on silica gel (eluant:ethyl acetate/hexane 20:80 parts). 6.76 g (72.1% of the theoretical yield) of pure product are obtained in the form of an oil.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]([CH:16]1[CH:20]([C@H:21]([CH3:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:19][N:18](CC2C=CC=CC=2)[CH2:17]1)=[O:15].O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:12][O:13][C:14]([CH:16]1[CH:20]([C@H:21]([CH3:31])[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH2:19][N:18]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:17]1)=[O:15]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C1CN(Cc2ccccc2)CC1[C@H](C)CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CC1[C@H](C)CO[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
Benzyloxycarbonyl chloride (3.25 mL, 22.8 mmol) was added to a solution of 1-benzyl-4-[(S)-2-(tert-butyldimethylsilyloxy)-1-(methyl)ethyl]pyrrolidine-3-carboxylic acid methyl ester (2.97 g, 7.58 mmol) in dichloromethane (20 mL), and the mixture was stirred for one hour. Saturated sodium bicarbonate water was added to the reaction mixture. The organic layer was separated, dried over magnesium sulfate, and filtered. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 3.1 g (96%) of the diastereomer mixture title compound as a colorless oil. The diastereomers were used for the next step without separation.
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH2:22]OS(C2C=CC(C)=CC=2)(=O)=O)/[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=1.O>CN1CCCC1=O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH2:22][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)/[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)OC/C(=C\c2ccc(Cl)cc2)CC(C)(C)C)cc1
Reactant: c1nc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)C/C(=C/c1ccc(Cl)cc1)Cn1cncn1
Temperature: 50 °C
Reaction time: 12 h
Yield: 70.5 %

Procedure:
9.2 g of sodium hydroxide are added to a solution of 16.8 g of 1,2,4-triazole in 150 ml of N-methylpyrrolidone and the mixture is heated at 50° C. for 30 minutes. After the reaction mixture has been cooled to room temperature, 73.1 g of Z-1-(4-chlorophenyl)-2-(4-methylphenylsulfonyloxymethyl)-4,4-dimethylpent-1-ene, dissolved in 100 ml of N-methylpyrrolidone, are slowly added dropwise to the solution and stirring is carried out for 12 hours at room temperature. Thereafter, 200 ml of water are added and the mixture is extracted several times with methyl tert-butyl ether, and the organic phase is washed twice with water, dried over sodium sulfate and evaporated down. The remaining residue is chromatographed over silica gel using 9:1 n-hexane/ethyl acetate to give 38 g (71%) of Z-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-4,4-dimethylpent-1-ene, which can be crystallized from methyl tert-butyl ether/n-hexane (mp.: 81°-84° C., compound No. A1).
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:18])[CH2:6]1)C.Cl.[C:20]([NH2:25])(=[NH:24])[CH2:21][CH2:22][CH3:23]>>[F:17][C:14]1[CH:15]=[CH:16][C:9]2[NH:8][C:7](=[O:18])[CH2:6][C:5]3[CH:4]=[N:24][C:20]([CH2:21][CH2:22][CH3:23])=[N:25][C:11]=3[C:10]=2[CH:13]=1
Reactant: CCCC(=N)N
Reactant: CN(C)C=C1CC(=O)Nc2ccc(F)cc2C1=O
Agent: Cl
Product: CCCc1ncc2c(n1)-c1cc(F)ccc1NC(=O)C2
Yield: 50 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-7-fluoro-3,4-dihydro-1H-benzazepine-2,5-dione and butyramidine hydrochloride. Yield: 50%.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:11]([NH2:13])[CH3:12]>>[CH2:11]([NH:13][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)[CH3:12]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CCN
Product: CCNc1ccc(C(=O)O)cn1
Temperature: 170 °C
Yield: 84 %

Procedure:
6-Chloronicotinic acid (100 g, 0.63 mol) was treated with ethylamine (70% in water, 500 ml). The reaction was sealed in an autoclave and heated to 170° C. for 6 hours. The reaction mixture was evaporated, partially neutralised with concentrated HCl and the pH adjusted to 5 with glacial acetic acid. The solid product was filtered off and dried in vacuo for 18 hours to give 6-(ethylamino)nicotinic acid (87.8 g, 84%).
Reaction SMILES: F[C:2]1[C:3]([CH3:19])=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[C:5]([O:7][CH3:8])=[O:6].CN(C)C=O.[CH3:25][S-:26].[Na+]>C(OCC)(=O)C>[CH3:19][C:3]1[C:2]([S:26][CH3:25])=[C:11]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(C(F)(F)C(F)(F)F)c(F)c1C
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(F)(F)C(F)(F)F)c(SC)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
2.1 g (7.34 mmol) of methyl 3-fluoro-2-methyl-4-(pentafluoroethyl)benzoate were introduced into 20 ml of N,N-dimethylformamide and then admixed with 758 mg (95% by weight; 10.3 mmol) of sodium thiomethoxide. The mixture was stirred at RT for 2 hours and then freed from the solvent. The residue was taken up in ethyl acetate and water, the aqueous phase was extracted twice with ethyl acetate, and, finally, the combined organic phases were dried and freed from the solvent. The residue was purified by chromatography, giving 1.28 g of clean product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6].Br[CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:1][CH2:2][CH2:3][N:4]([S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6])[CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCN(CCO)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 15 h

Procedure:
To a solution of 8.7 g of N-(2-hydroxy-ethyl)-2-nitro-benzenesulfonamide (Skerlj, R. T.; Nan, S.; Zhou, Y.; Bridger, G. J. Tetrahedron Lett. 2002 (43) 7569-7571) in 87 ml of DMF, under argon, was added 8.8 ml of tert-butyl 3-bromopropionate and 14.6 g of K2CO3. The mixture was stirred for 15 hours at 40° C. and a further 5 ml of tert-butyl 3-bromopropionate were then added. The mixture was heated at 40° C. overnight and then filtered through a sinter of porosity 4. The cake was washed with ethyl acetate and the filtrate was then concentrated under reduced pressure and purified by flash chromatography on silica (Merck EasyVarioPrep 400 g column, Si60 15-40 μm), using a gradient of 0 to 10% EtOAc in DCM. The fractions containing the desired product were combined and concentrated under reduced pressure. 9.54 g of tert-butyl 3-[(2-hydroxy-ethyl)-(2-nitro-benzenesulfonyl)-amino]-propionate were obtained. LC/MS (C): tr=3.39 min; [M+Na]+: m/z 397.