Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C@H:6]([NH2:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]=[C:33]=[O:34]>CO>[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[NH:32][C:33](=[O:34])[NH:11][C@@H:6]([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[CH2:7][C:8]([O-:10])=[O:9]
Reactant: C[N+](C)(C)C[C@H](N)CC(=O)[O-]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)Nc1ccc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
To a solution of (R)-aminocarnitine (35 mg, 0.22 mmol) and diisopropylethylamine (0.11 mL, 0.65 mmol) in MeOH (2 mL) was added 2-chloro-1-isocyanato-4-(trifluoromethyl)benzene (67 uL, 0.44 mmol) and the reaction stirred at room temperature overnight. The MeOH was removed in vacuo and the residue titurated several times with 1:1 ether/EtOAc, the resulting solid was filtered and dried to give the title compound as a white powder (15 mg, 18%). NMR (300 MHz, CD3OD) δ 8.37 (m, 1H), 7.68 (m, 1H), 7.53 (m, 1H), 4.29 (m, 1H), 3.78-3.48 (m, 2H), 3.25 (s, 9H), 2.70-2.49 (m, 2H); MS ESI 382.1 [M+H]+, calcd for [C15H19ClF3N3O3+H]+ 382.78.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Br:10])=[N:8][CH:9]=1)(=[O:3])[CH3:2].[CH2:11](O)[CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:10][C:7]1[CH:6]=[CH:5][C:4]([C:1]2([CH3:2])[O:13][CH2:12][CH2:11][O:3]2)=[CH:9][N:8]=1
Reactant: CC(=O)c1ccc(Br)nc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(c2ccc(Br)nc2)OCCO1
Temperature: 140 °C
Reaction time: 5 h
Yield: 78.5 %

Procedure:
A mixture of 5-acetyl-2-bromopyridine (0.6 g, 3.00 mmol), ethylene glycol (0.535 ml, 9.60 mmol), p-toluenesulfonic acid monohydrate (0.171 g, 0.900 mmol), and toluene (12.00 ml) was stirred at 140° C. for 5 hours. The reaction mixture was washed with saturated sodium bicarbonate and brine. The aqueous layer was back extracted with ethyl acetate and the combined organics dried with magnesium sulfate and concentrated to give crude 2-bromo-5-(2-methyl-1,3-dioxolan-2-yl)pyridine (0.575 g, 2.356 mmol, 79% yield) as an orange oil. It was used without further purification.
Reaction SMILES: CS[C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[N:4]=1.[CH3:21][O:22][CH2:23][C:24]([NH:26][NH2:27])=O>CN(C)P(=O)(N(C)C)N(C)C>[CH3:21][O:22][CH2:23][C:24]1[N:4]2[C:5]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:6]=3[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:8][CH2:9][C:3]2=[N:27][N:26]=1
Reactant: COCC(=O)NN
Reactant: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
A solution of 10.0 g of 2-(methylthio)-5-phenyl-7-chloro-3H-1,4-benzodiazepine and 4.85 g of 2-methoxyacetic acid hydrazide (cp. E. J. Browne and J. B. Polya, J.Chem.Soc. 1962, 5149-5152) in 70 ml of abs. hexamethylphosphoric acid triamide is heaated for 11 hours at 140°. The solvent is then distilled off in vacuo. The residue is taken up in methylene chloride; the solution is washed with water and then with saturated sodium chloride solution, dried over sodium sulphate, and concentrated by evaporation. Crystallisation of the concentration residue from ethyl acetate/petroleum ether yields 1-(methoxymethyl)-6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine, M.P. 185°-191°. After chromatography of the mother liquor on 100 g of silica gel "Merck", a further amount of final product of the same melting point can be isolated.
Reaction SMILES: Cl.C(N=C=N[CH2:7][CH2:8][CH2:9]N(C)C)C.[CH3:13][C:14]1[CH2:19][CH2:18][CH2:17][C:16]([CH3:21])([CH3:20])[C:15]=1/[CH:22]=[CH:23]/[C:24](/[CH3:33])=[CH:25]/[CH:26]=[CH:27]/[C:28](/[CH3:32])=[CH:29]/[CH2:30][OH:31]>C(Cl)Cl>[C:30]([O:31][CH2:30]/[CH:29]=[C:28](\[CH3:32])/[CH:27]=[CH:26]/[CH:25]=[C:24](\[CH3:33])/[CH:23]=[CH:22]/[C:15]1[C:16]([CH3:20])([CH3:21])[CH2:17][CH2:18][CH2:19][C:14]=1[CH3:13])(=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]/[CH:22]=[CH:15]\[CH:14]=[CH:19]\[CH2:18][CH2:17][CH2:16][CH2:9][CH2:8][CH3:7]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC/C=C/C=C\CCCCCCCC(=O)OC/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride [EDCI] (0.71 g, 3.67 mmol) and anhydrous methylene chloride 15 ml were added to nitrogen filled, three mouth- round bottom flask and melted. The reaction mixture was cooled down into 0° C. Conjugated linoleic acid was added, and stirred for approximately 30 minutes. Retinol (0.87 g, 3.05 mmol) and N,N′-dimethylaminopyridine (DMAP) solubilized in anhydrous methylene chloride 7 ml were added into the reaction mixture, and stirred for 4 hours at room temperature. Organic phase were washed with water (20 ml×2) and brine (20 ml×2) and dried with anhydrous MgSO4, concentrated under low pressure and separated with column chromatography (solvent:ethylacetate/hexane=1/8).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:15][CH2:14][CH2:13][CH:12]([CH:16]=[O:17])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:18][Mg]Br.CO>C1COCC1>[CH2:2]([N:9]1[CH2:15][CH2:14][CH2:13][CH:12]([CH:16]([OH:17])[CH3:18])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[Mg]Br
Reactant: O=CC1CCCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)C1CCCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
To an ice-cooled suspension of 1-benzylazepane-4-carbaldehyde hydrochloride (1.0 g, 3.95 mmol) in THF (15 mL) was added methylmagnesium bromide (3M in diethyl ether, 4 mL) dropwise. The mixture was slowly warmed to RT and then stirred for 18 h at RT. MeOH was then added and volatiles were removed in vacuo. The resulting residue was dissolved in DMF and filtered thought a pad of silica eluting with 10% 2M NH3/MeOH in DCM. The residue was further purified by column chromatography (Si-PCC, gradient 0-10% 2M NH3/MeOH in DCM) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording 1-(1-Benzylazepan-4-yl)ethanol (600 mg, 65%). 1H NMR (CDCl3, 400 MHz): δ 7.38-7.19 (5H, m), 3.99-3.47 (5H, m), 2.92-2.38 (4H, m), 2.01-1.51 (6H, m), 1.19 (3H, m)
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7]([NH2:9])=[O:8])=[CH:3][CH:2]=1.N1C=CC=CC=1.[S:17](Cl)(Cl)=[O:18]>CCOCC>[S:17](=[N:9][C:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)=[O:8])=[O:18]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(N)=O)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(C(=O)N=S=O)cc1
Reaction time: 0.08 h

Procedure:
10 g of p-toluamide were suspended in 100 ml of ether and 12.5 ml of pyridine under argon. The 5.8 ml of thionyl chloride dissolved in 10 ml of ether were added dropwise at 5° C. and the mixture was stirred for a further 5 minutes. Subsequently, the cooling was removed and the mixture was stirred at room temperature for a further 16 hours. Under argon, the solid pyridinium hydrochloride was then filtered off, and then the solution was concentrated. The residue was used without further workup.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[CH2:11](Cl)[CH:12]=[CH2:13]>[OH-].[Na+].C(O)(C)C>[CH2:13]([O:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:10])[CH:12]=[CH2:11]
Reactant: C=CCCl
Reactant: Cc1cc(Br)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: C=CCOc1c(C)cc(Br)cc1C
Temperature: 60 °C
Reaction time: 15 h
Yield: 97.9 %

Procedure:
A mixture of 4-bromo-2,6-dimethyl-phenol (20.1 g, 100 mmol) and allylchloride (32.7 g, 428 mmol) in 3 N aq. NaOH (100 mL) and isopropanol (250 mL) is stirred at 60° C. for 15 h before it is diluted with 1 N aq. NaOH (100 mL). The mixture is extracted with diethyl ether (300 mL, 150 mL) and the combined org. extracts are washed with 1 N aq. NaOH (2×100 mL), 1 M aq. NaH2PO4 (50 mL), dried over Na2SO4, filtered and concentrated to give 2-allyloxy-5-bromo-1,3-dimethyl-benzene (23.6 g) as a yellow oil, LC-MS: tR=1.08 min, [M+1]+=241.20.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[CH2:8]C1(C)CCCCC1=O)([CH3:4])([CH3:3])[CH3:2].[C:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:27])[CH3:26]>>[C:21]([C:18]1[CH:17]=[C:7]([CH2:8][CH2:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:27])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:19]=1[OH:20])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(=O)c1ccccc1
Reactant: CC1(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CCCCC1=O
Product: CC(C)(C)c1cc(CCC(=O)c2ccccc2)cc(C(C)(C)C)c1O
Yield: 53 %

Procedure:
If, in this example, the 2-methylcyclohexanone is replaced by an equivalent quantity of acetophenone, an otherwise identical procedure gives phenyl (3,5-ditert.butyl-4-hydroxyphenylethyl) ketone in a yield of 53%.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Br:13])=[O:22]
Reactant: O=C=Nc1ccccc1Br
Reactant: Nc1ccc(C(F)(F)F)cc1O
Product: O=C(Nc1ccc(C(F)(F)F)cc1O)Nc1ccccc1Br

Procedure:
The urea was prepared from 2-hydroxy 4-trifluoromethyl aniline(example 7a, 0.171 g, 1 mmol) and 2-bromo phenyl isocyanate (1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compounds (0.25 g, 54%). EI-MS m/z 375 (M+H)+
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]2[N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH2:30][N:31]=2)[CH2:10]1)(C(C)(C)C)(C)C.Cl.C(=O)(O)[O-].[Na+]>CO>[OH:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([C:27]2[N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH2:30][N:31]=2)[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](C2=NCCN2C(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCN=C1[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.6 %

Procedure:
To a solution of (2S, 4R)-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)-2-[1-(4-nitrobenzyloxycarbonyl) -2-imidazolin-2-yl]pyrrolidine (1.4 g) in methanol was added conc. hydrochloric acid (0.4 ml). After stirring at ambient temperature for 20 hours, saturated aqueous sodium bicarbonate (3 ml) was added thereto. The mixture was evaporated, extracted with ethyl acetate, and washed with water and brine successively. The dried organic layer was evaporated, the obtained oil was subjected to a column chromatography on silica gel and eluted with a mixture of dichloromethane and methanol (20:1, V/V) to give (2S,4R)-4- hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-[1-(4-nitrobenzyloxycarbonyl) -2-imidazolin-2-yl]pyrrolidine (660 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)[CH:8]=[C:9]2[C:12]#[N:13])=[CH:4][CH:3]=1.Cl.[NH+]1C=CC=CC=1>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:8]=[C:9]2[C:12]#[N:13])=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cc(C#N)c3cc(O)ccc3c2)cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: N#Cc1cc(-c2ccc(O)cc2)cc2ccc(O)cc12

Procedure:
The title compound was prepared by reacting 7-hydroxy-3-(4-methoxyphenyl)-1-naphthonitrile (0.14 g, 0.51 mmol) with pyridinium HCl (3 g) according to method B to yield 0.10 g (75%) of a white solid: mp 254–257° C.; 1H NMR (DMSO-d6): δ 6.89 (2H, d, J=8.53 Hz), 7.25 (1H, dd, J=2.15 Hz, J=8.88 Hz), 7.36 (1H, d, J=1.86 Hz), 7.67 (2H, d, J=8.55 Hz), 8.00 (1H, d, J=8.94 Hz), 8.31–8.38 (2H, m), 9.70 (1H, bs), 10.44 (1H, bs); MS (ESI) m/z 260 (M−H)−.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([I:17])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5])C.Cl>[OH-].[Na+].O>[I:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[NH:8][CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15]2=[O:16]
Reactant: CCOC(=O)c1c[nH]c2c(I)cccc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1c[nH]c2c(I)cccc2c1=O
Temperature: 25 °C
Yield: 81.7 %

Procedure:
8-Iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (2 g, 5.83 mmol) was suspended in 10% NaOH in water (20 mL). The mixture was stirred under reflux for 1 h. The crude was cooled to room temperature and acidified with concentrated HCl. The solid was filtered off and thoroughly washed with water to afford 8-iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid as a pinkish solid (1.5 g, 81.6%). 1H NMR (DMSO-d6, 400 MHz) δ 7.04 (t, 1H), 8.12-8.16 (m, 2H), 8.71 (s, 1H). Exact mass calculated for C10H6INO3 314.94, found 316 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH:10]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[C:7]([O:8][CH:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Br
Reactant: ClC(c1cccnc1)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ncccc1OC(c1cccnc1)c1cccnc1
Reaction time: 8 h

Procedure:
To the solution of 2-bromo-3-hydroxypyridine (0.90 g, 5.18 mmol) and 3-[chloro(pyridin-3-yl)methyl]pyridine (2-1) (0.82 g, 3.99 mmol) in DMF (10 mL) at 0° C. was added Cs2CO3 (1.95 g, 5.98 mmol). The mixture was stirred overnight, poured into water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layer was dried, filtered, and concentrated to give a solid. The solid was purified by silica gel chromatography (3% MeOH in CH2Cl2) to give 2-bromo-3-(dipyridin-3-ylmethoxy)pyridine (2-2). LRMS m/z (M+H) Calcd: 343.2, found: 343.0.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][C@H:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[NH2:33]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:33][C@@H:29]4[CH2:30][CH2:31][CH2:32][C@@H:28]4[CH2:27][O:26][CH3:25])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: COC[C@H]1CCC[C@H]1N
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: COC[C@H]1CCC[C@H]1NC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (1R,2S)-2-(methoxymethyl)cyclopentanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42-1.60 (m, 2H) 1.60-1.83 (m, 3 H) 1.84-2.01 (m, 1 H) 2.20-2.37 (m, 1 H) 2.44 (s, 3 H) 3.19 (s, 3 H) 3.20-3.27 (m, 1 H) 3.40 (dd, J=9.35, 6.06 Hz, 2 H) 4.43 (t, J=7.45 Hz, 1 H) 7.67 (d, J=7.58 Hz, 1 H) 7.74 (br. s., 1 H) 7.81 (d, J=18.69 Hz, 1 H) 8.24-8.70 (m, 3 H) 8.88 (d, J=1.77 Hz, 1 H) 13.24 (br. s., 1 H). MS m/z [M+H]+ 432.2.
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].O1CCCC1.[CH3:20][C:21]([CH3:25])=[CH:22][Mg]Br>CCCCCC>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[CH:20]=[C:21]([CH3:25])[CH3:22])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Reactant: CC(C)=C[Mg]Br
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)=C[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
In an argon atmosphere, 8.44 g (36.2 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 17 mL of hexane and after adding a (2-methylprop-1-en-1-yl)magnesium bromide tetrahydrofuran solution (0.56 mol/L, 68.0 mL, 38.1 mmol), the resulting solution was stirred at room temperature for 18 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 90° C./3.5×102 Pa) to obtain 1,3-di-tert-butyl-2-(2-methylprop-1-en-1-yl)-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)CHC(CH3)2) as a yellow liquid (yielded amount: 6.30 g, yield: 69%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]S(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH2:24](O)[CH2:25][CH2:26][CH3:27].C1CCN2C(=NCCC2)CC1>COCCOC>[CH2:24]([O:8][C:6]1[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=[C:2]([NH2:1])[N:7]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCO
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CCCCOc1nc(N)nc(-c2ccco2)c1[N+](=O)[O-]

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester, butanol and DBU in DME. EI-MS m/e (%): 278 (M+, 24), 249 ([M—C2H5]+, 28), 193 (70), 177 (100), 150 (48), 108 (86), 94 (62), 70 (48), 69 (46), 43 (68), 41 (62), 29 (45).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].O>CN(C=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: Sc1cccs1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CSc1cccs1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
To a solution of thiophene-2-thiol (1.2 g, 10.3 mmol) in anhydrous DMF (30 mL) was added cesium carbonate (3.9 g, 12 mmol) and the resulting suspension was stirred for 15 min at ambient temperature, then treated with methyl bromoacetate (1.53 g, 10 mmol). The purple suspension was stirred for 1 h, then poured into water (30 mL) and extracted twice with 300 mL EtOAc. The combined organic extracts were washed with brine, dried, filtered, concentrated and the residue was purified via column chromatography eluting with 10% EtOAc/Hexanes to give 1.48 g (79%) of the title compound.
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:7]=2[CH2:6][CH2:5]1)[C:2]#[CH:3].Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:20]([Cl:35])=[CH:19][N:18]=1>>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[N:22][C:17]([NH:15][C:12]2[CH:13]=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:1][C:2]#[CH:3])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:18][CH:19]=1
Reactant: C#CCN1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)Nc1ccccc1Nc1nc(Cl)ncc1Cl
Product: C#CCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4NS(C)(=O)=O)n3)cc2CC1

Procedure:
N-{2-[5-Chloro-2-(3-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide was prepared from 3-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-phenyl]-methanesulfonamide in an analogous manner to Example 322. Product isolated as an orange foam (55 mg, 22%). LCMS (m/e) 497 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.03 (s, 1H), 7.72-7.67 (m, 1H), 7.54-7.48 (m, 2H), 7.38-7.30 (m, 2H), 7.18-7.15 (m, 1H), 7.09-7.04 (m, 1H), 7.03 (s, 1H), 6.6.97-6.91 (m, 1H), 3.45 (s, 2H), 2.93 (s, 3H), 2.91-2.85 (m, 2H,), 2.80-2.65 (m, 6H), 2.24 (s, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([O:28][CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[C:25]([NH2:27])[CH:26]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([O:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[C:25]([NH:27][S:2]([CH3:1])(=[O:4])=[O:3])[CH:26]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an N2 atmosphere 39 μL (0.5 mmol) methanesulphonic acid chloride are added to a solution of 100 mg (0.24 mmol) 5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-phenylamine and 161 μL (2 mmol) pyridine in 10 mL DCM and the reaction mixture is stirred for 2 h at RT. To complete the reaction a further 160 μL pyridine and 39 μL methanesulphonic acid chloride are added and the mixture is stirred overnight. It is combined with 10% Na2CO3 solution, the organic phase is separated off and the solvent is eliminated i.vac. The residue is purified by HPLC.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].COCCN(S(F)(F)[F:31])CCOC>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:31])[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccc(C#N)cc2)C1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C#N)cc2)C1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 64 %

Procedure:
Into a 250-mL 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 3-(4-cyanophenyl)-3-hydroxyazetidine-1-carboxylate (compound 43.2, 5.00 g, 18.2 mmol) in dichloromethane (120 mL). The solution was cooled to −78° C. and Deoxo-Fluor® (bis(2-methoxyethyl)aminosulfur trifluoride) (5.99 g, 27.1 mmol) was added drop-wise. The resulting mixture was stirred for 1.5 h at −78° C., then carefully quenched with sodium bicarbonate (50 mL, 1 M). The organic layer was additionally washed with brine (2×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/50-1/30) as the eluent to yield 3.2 g (64%) of the title compound as colorless oil.