Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:7]([O:8][C@@H:9]2[O:17][C@H:16]([CH2:18][OH:19])[C@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(Cl)Cl>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:24]([O:11][C@@H:10]1[C@@H:12]([O:13][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:14]([O:15][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:16]([CH2:18][O:19][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:17][C@H:9]1[O:8][C@@H:7]1[C@@H:20]([CH2:22][O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:21][CH:2]([O:1][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:3]([O:4][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:5]1[O:6][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)C(OC(=O)c3ccccc3)O[C@@H]2COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lactose (1.0 g, 2.92 mmol) was dissolved in dry pyridine (20 mL) at 0° C. DMAP (cat.) was added. Benzoyl chloride (2.5 equiv., 58 mmol, 6.8 mL) was added dropwise and the solution stirred at room temperature overnight. The solution was poured onto a mixture of ice-water and DCM. The organic layer was washed with NaHCO3(sat.) (×7), brine, H2SO4 (5%) (×2), followed by brine. The solution was dried (Na2SO4) and the solvent evaporated. The product was passed through a short silica plug to remove the remaining benzoyl chloride and the solvent was evaporated to yield 3.67 g (quantitative) of the white solid product which was reacted on without further purification or characterisation.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([NH:26]C=O)[CH:6]=[C:7]([CH2:15][P:16]([O:22]C(C)C)([O:18]C(C)C)=[O:17])[CH2:8][CH2:9][N:10]([C:12](=[O:14])[CH3:13])[CH3:11])[CH3:2].C[Si](C)(C)Br.C(O)C>ClCCl>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([NH2:26])[CH:6]=[C:7]([CH2:15][P:16]([OH:22])([OH:18])=[O:17])[CH2:8][CH2:9][N:10]([C:12](=[O:14])[CH3:13])[CH3:11])[CH3:2]
Reactant: CCOC(=O)C(C=C(CCN(C)C(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(N)C=C(CCN(C)C(C)=O)CP(=O)(O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
8.2 g (18.9 mmol) of 6-(N-acetyl-N-methylamino)-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester are dissolved in 40 ml of dichloromethane, and 9.8 ml (75.6 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 24 hours, 40 ml of ethanol are added dropwise, the mixture is left to stand for a further 24 hours and is concentrated by evaporation, the residue is dissolved in 40 ml of ethanol, and a mixture of 40 ml of propylene oxide and 40 ml of ethanol is added dropwise. A PG,35 suspension forms, which is stirred for a further one hour at room temperature and for one hour at 0° and is then filtered with suction. Drying yields 6-(N-acetyl-N-methylamino)-2-amino-4-phosphonomethyl-hex-3-enoic acid ethyl ester having a melting point of 222°-223° C. (decomp.).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[S:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[S:40](Cl)(=[O:42])=[O:41]>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([S:40]([C:36]4[S:35][CH:39]=[CH:38][CH:37]=4)(=[O:42])=[O:41])[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCN(S(=O)(=O)c4cccs4)CC3)c2[N+](=O)[O-])cc1

Procedure:
Compound A30 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (20 μl), thiophene-2-sulfonyl chloride (9 mg, 0.049 mmol), DMF (0.6 mL), 1H NMR (CDCl3, 400 MHz) δ 2.07 (m, 4H), 3.08 (s, 3H), 3.14 (m, 2H), 3.41 (m, 2H), 5.53 (m, 1H), 7.31 (m, 1H), 7.50 (m, 1H), 7.55 (m, 1H), 7.83 (m, 2H), 7.95 (m, 2H), 8.37 (s, 1H), 10.14 (s, 1H). Exact mass calculated for C20H21N5O7S3 539.06, found 540.2 (MH+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7].[CH3:15][CH:16]([CH3:34])[CH2:17][CH2:18][NH:19][C:20]([C:22]1[N:23]=[N:24][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:26][CH:27]=1)=[O:21]>>[CH3:15][CH:16]([CH3:34])[CH2:17][CH2:18][NH:19][C:20]([C:22]1[N:23]=[N:24][C:25]([N:28]2[CH2:33][CH2:32][N:31]([C:6](=[O:7])[C:5]3[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=3[O:3][C:2]([F:14])([F:13])[F:1])[CH2:30][CH2:29]2)=[CH:26][CH:27]=1)=[O:21]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3OC(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2-trifluoromethoxybenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white solid (83% yield). 1H NMR (400 MHz, CDCl3) δ 8.06, 7.85, 7.53-7.32, 7.01, 4.12-3.36, 1.75-1.66, 1.54-1.48, 0.98. MS (ES+) m/z 466.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:31])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[O:32]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33]1>N1C=CC=CC=1>[Cl:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:22])[CH3:21])=[N:9][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:37]([C:34]3[CH:35]=[CH:36][O:32][CH:33]=3)(=[O:39])=[O:38])[C:3]=2[F:31])[CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)c1ccoc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccoc3)c2F)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
To a solution of 1,1-dimethylethyl {1-[4-(3-amino-2-fluorophenyl)-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-2-yl]-1-methylethyl}carbamate (400 mg, 0.862 mmol) in pyridine (50 mL) was added 3-furansulfonyl chloride (144 mg, 0.862 mmol) (in 5 cc DCM). After 4 h, 3-furansulfonyl chloride (0.20 g) was to the reaction mixture and stirred at rt overnight. The reaction mixture was concentrated in vacuo. The residue was purified via Biotage (3:1-Hex/EtOAc; 25M silica gel column) to obtain the title compound (460 mg 90% yield). MS (ESI): 594.2 [M+H]+
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20])=[C:11]2[C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CC(O)(C)C.CCCCCCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH:21]1([C:19]([C:12]2[C:13]([CH3:18])=[N:14][C:15]3[C:10]([C:11]=2[C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=2)=[CH:9][C:8]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:17][CH:16]=3)=[O:20])[CH2:22][CH2:23]1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C1CC1
Reactant: C1COCCN1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CC(C)(C)O
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C1CC1
Temperature: 110 °C
Yield: 52.5 %

Procedure:
A tube placed under argon was charged with tris(dibenzylideneacetone)dipalladium chloroform complex (5 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (5 mg) and cesium carbonate (110 mg, 0.33 mmol). [6-Bromo-4-(4-methanesulfonyl-phenyl)-2-methyl-quinolin-3-yl]-cyclopropyl-methanone [example 50] (100 mg, 0.22 mmol) in t-BuOH (5 ml) was added, followed by morpholine (24 mg, 0.27 mmol). The tube was sealed and heated at 110° C. for 6 hrs. The reaction mixture was cooled to 20° C., diluted with heptane, and filtered through Celite and purified directly by flash chromatography on silica gel in heptane/AcOEt 80:20 to give a yellow solid (52 mg, 51%). MS: m/z=451 (M+H).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][O:6][C:5]([CH3:17])([C:8]([CH3:16])=[CH:9][C:10]2[S:11][CH:12]=[CH:13][C:14]=2[CH3:15])[O:4]1.[CH3:18][CH:19]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1>>[CH3:17][C:5]1([C:8]([CH3:16])=[CH:9][C:10]2[S:11][CH:12]=[CH:13][C:14]=2[CH3:15])[O:4][CH:3]([CH2:2][N:21]2[CH2:22][CH2:23][CH2:24][CH:19]([CH3:18])[CH2:20]2)[CH2:7][O:6]1
Reactant: CC1CCCNC1
Reactant: CC(=Cc1sccc1C)C1(C)OCC(CCl)O1
Product: CC(=Cc1sccc1C)C1(C)OCC(CN2CCCC(C)C2)O1
Temperature: 120 °C
Yield: 80.9 %

Procedure:
A mixture of 19 g (0.07 mol) of 4-chloromethyl-2-methyl-2-[1-(3-methylthien-2-yl)-propen-2-yl]-dioxolane and 18 g (0.18 mol) of 3-methylpiperidine is heated at 120° C. for 16 hours, with stirring. For working up, the cooled reaction mixture is partitioned between water, and diethyl ether and the organic phase is separated off, dried over magnesium sulphate and evaporated in vacuo. 19 g (81% of theory) of 2-methyl-4-(3-methylpiperidin-1-yl-methyl)-2-[1-(3-methylthien-2-yl]-propen-2-yl]-dioxolane of refractive index nD20 1.5402 are obtained.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH2:20]([NH2:25])[CH2:21][CH2:22][CH2:23][CH3:24].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:25][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Reactant: CCCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCNCc1ccc(Oc2cnc(C(N)=O)cn2)c(F)c1
Reaction time: 8 h
Yield: 65.7 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Part E) (0.400 g, 1.53 mmol), amylamine (0.147 g, 1.68 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (7.7 mL), cap and stir overnight. Add NaBH4 (0.058 g, 1.53 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column 0% to 15% (2.0 M NH3 in methanol) in 80% (ethyl acetate in hexanes) to give the title compound (0.334 g, 66%): TOF MS ES+ 333.2 (M+H)+, HRMS calcd for C17H22N4O2F 333.1727 (M+H)+, found 333.1722, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=10.3 min, 96.8% purity.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([CH2:11][CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]2[CH3:21])[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Li]CCCC.CCCCCC.Cl[Si:34]([CH3:37])([CH3:36])[CH3:35]>CCOCC>[CH3:21][C:13]1[CH:12]([CH2:11][CH:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([Si:34]([CH3:37])([CH3:36])[CH3:35])=[C:2]2[CH3:1])[C:20]2[C:15]([C:14]=1[Si:34]([CH3:37])([CH3:36])[CH3:35])=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: C[Si](C)(C)Cl
Reactant: CC1=Cc2ccccc2C1CC1C(C)=Cc2ccccc21
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1=C([Si](C)(C)C)c2ccccc2C1CC1C(C)=C([Si](C)(C)C)c2ccccc21
Temperature: -50 °C
Yield: 96.8 %

Procedure:
6.32 g of bis(2-methyl-1-indenyl)methane (23.2 mmol) were dissolved in 70 ml Et2O in a 250 ml Schlenk tube, and the white suspension was cooled to −50° C. 19.5 ml of 2.5 M BuLi in hexane (48.8 mmol) were added dropwise over 20 minutes under stirring. The suspension was allowed to warm to room temperature and stirred for 3 hours. The final suspension was light yellow. 6.2 ml of chlorotrimethylsilane (48.8 mmol) were dissolved in 50 ml Et2O. The two mixtures were both cooled to −50° C. and the Li salt suspension in Et2O was added to the chlorotrimethylsilane solution in Et2O. The cooling bath was removed and the reaction mixture was stirred overnight at room temperature. Then the reaction mixture, colored in yellow, was quenched with a few ml of MeOH, filtered and concentrated, thus giving 9.36 g of an brown and viscous liquid (96.8% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:35]#[N:36])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]([CH:16]([CH3:33])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:35]#[N:36])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]([CH:16]([CH3:33])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C#N)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(C#N)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
93 mg (0.19 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-cyano-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate (racemate) (Example 16.1E) were hydrolysed with TFA according to General Method 2. Yield: 91 mg (quant.)
Reaction SMILES: I.C[O:3][C:4]([C@H:6]1[NH:11][C:10](=O)[N:9]2[CH2:13][N:14](C)[CH:15]=[C:8]2[CH2:7]1)=[O:5]>Cl>[CH3:10][NH:11][C@H:6]([C:4]([OH:5])=[O:3])[CH2:7][C:8]1[N:9]=[CH:13][NH:14][CH:15]=1
Reactant: COC(=O)[C@@H]1CC2=CN(C)CN2C(=O)N1
Agent: Cl
Agent: I
Product: CN[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
3.37 g (10 mmol) of (+)-(7S)-5,6,7,8-tetra-hydro-7-(methoxycarbonyl)-2-methyl-5-oxoimidazo[1,5-c]pyrimidine hydroiodide is heated under reflux in 40 ml of 6N HCl until no starting compound can be detected any longer by thin-layer chromatography (6-8 hours). Then, the hydrochloric acid is withdrawn under vacuum, the oily residue is taken up in ethanol and crystallized by addition of ether.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.[NH4+].[Cl-]>CCOCC.C1COCC1>[I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[B:18]([OH:23])[OH:19]
Reactant: COc1cc(I)c(I)cc1OC
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(I)c(B(O)O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
To a solution of 1,2-diiodo-4,5-dimethoxybenzene (Example 6(b), 2.0 g, 5.13 mmol) in 120 mL of a mixture of THF and Et2O (1:1) was added dropwise at −78° C. isopropylmagnesium chloride (2 M in THF, 2.67 mL, 5.39 mmol). After the mixture was stirred for 2 h at that temperature, B(OiPr)3 (10.89 ml, 15.39 mmol) was added. The solution was warmed to room temperature overnight; then a saturated solution of NH4Cl was added, and the resulting mixture was stirred for 30 min at room temperature. The aqueous layer was extracted with Et2O (50 mL, 3 times), dried over Na2SO4 and concentrated. To the concentrated sample, hexane was added and the resulting precipitate was isolated to give 1.05 g of the pure product (67%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][CH2:10]2)=[C:5]([F:12])[C:3]=1[NH2:4].[Br:13]N1C(=O)CCC1=O>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[C:7]([Br:13])[C:6]([CH:9]2[CH2:10][CH2:11]2)=[C:5]([F:12])[C:3]=1[NH2:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1c(Cl)ccc(C2CC2)c1F
Solvent: CN(C)C=O
Product: Nc1c(Cl)cc(Br)c(C2CC2)c1F
Reaction time: 8 h

Procedure:
2-Chloro-5-cyclopropyl-6-fluoroaniline (9.4 g, 50.6 mmol) and N-bromosuccinimide (9.4 g, 52.8 mmol) are dissolved with stirring in 100 mL of anhydrous DMF. The reaction mixture is stirred overnight and then most of the DMF is removed by rotary evaporator under high vacuum. The residue is partitioned between 1:1 Et2O/hexane (500 mL) and water (500 mL). The organic layer is washed with brine (3×250 mL), dried (MgSO4) and concentrated by rotary evaporator. The crude material is purified using flash chromatography (7% CH2Cl2/hexanes) to give 2-chloro-4-bromo-5-cyclopropyl-6-fluoroaniline as a light orange oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N+:3]=1[O-:12].[N-:13]=[N+:14]=[N-:15].[Na+]>CC(C)=O.O>[N:13]([C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N+:3]=1[O-:12])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: [O-][n+]1c(Cl)cnc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=Nc1cnc2ccccc2[n+]1[O-]
Temperature: 25 °C
Reaction time: 60 h

Procedure:
In this example 0.500 grams (0.0028 mol) of 2-chloroquinoxaline 1-oxide and 0.500 grams (0.0080 mol) of sodium azide were added to and dissolved in 35 ml of acetone and 35 ml of water. The solution was stirred at 25° C for 60 hours. The acetone was evaporated in vacuo and the resulting aqueous solution was extracted with methylene chloride. The organic phase was introduced onto a basic alumina column. Elution with chloroform gave 2 azidoquinoxaline-oxide in a yield of 0.080 grams or 16% of theory which was immediately decomposed in boiling benzene for 1 hour. Evaporation of the solvent gave 2-cyanobenzimidazole N-oxide which is tautomeric with N-hydroxy-2-cyanobenzimidazole in a yield of 0.020 grams or 30% of theory having a melting point of 236° C to 238° C with decomposition.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:22]=[CH:21][C:13]3[O:14][C:15]([CH3:20])([CH3:19])[C:16]([CH3:18])=[CH:17][C:12]=3[CH:11]=2)[CH:6]=[CH:7][CH:8]=1.[I-].[Li+]>N1C(C)=CC(C)=CC=1C.ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:22]=[CH:21][C:13]3[O:14][C:15]([CH3:19])([CH3:20])[C:16]([CH3:18])=[CH:17][C:12]=3[CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(Sc2ccc3c(c2)C=C(C)C(C)(C)O3)c1
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CC1=Cc2cc(Sc3cccc(O)c3)ccc2OC1(C)C
Yield: 67.3 %

Procedure:
6-(3-Methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (3.5 g) (see Preparation 6) was dissolved in dry 2,4,6-collidine (15 ml), anhydrous lithium iodide (3 g) was added and the mixture was heated under reflux under a nitrogen atmosphere for 24 hours. After cooling, the mixture was taken up in dichloromethane and washed with 2N aqueous hydrochloric acid solution (×3). The organic layer was dried (anhydrous sodium sulphate), the solvent removed under reduced pressure and the residue chromatographed on silica eluting with a solvent gradient of 1:1 hexane: dichloromethane changing to dichloromethane to yield 6-(3-hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (2.25 g) as an oil.
Reaction SMILES: C1COCC1.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].C[O:14][C:15]1[CH2:19][CH2:18][C:17](=O)[CH:16]=1>C(OCC)(=O)C>[CH2:7]([C:17]1[CH2:18][CH2:19][C:15](=[O:14])[CH:16]=1)[CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12]
Reactant: C=CCCCCBr
Reactant: COC1=CC(=O)CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCCCCC1=CC(=O)CC1
Temperature: 60 °C
Yield: 81.3 %

Procedure:
Mg turnings (972 mg, 40 mmol) were placed into a dry Schlenk flask, then THF (20 mL) was added. 6-Bromo-1-hexene (5.3 mL, 40 mmol) was placed into a separate dry flask, dissolved in THF (20 mL), then added via syringe to the Mg solution. The resulting mixture was heated at 60° C. for 12 h, then cooled to room temperature. The solution of the Grignard reagent was then separated from remaining Mg solid by transferring the solution via syringe to another Schlenk flask. The general procedure for the preparation of substrates using 3-methoxycyclopentenone (2.24 g, 20 mmol) and the solution of the Grignard reagent described above gave, after 24 h and and flash chromatography (4:1 hexanes:ethyl acetate), the title compound as a colorless liquid (2.67 g, 81%). 1H NMR (300 MHz, CDCl3): δ 5.95-5.92 (m, 1H), 5.79 (dddd, J=17.1, 10.2, 6.6, 6.6 Hz, 1H), 5.06-4.92 (m, 2H), 2.66-2.54 (m, 2H), 2.48-2.37 (m, 4H), 2.15-2.04 (m, 2H), 1.69-1.54 (m, 2H), 1.53-1.39 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 209.9, 182.9, 138.3, 129.4, 114.8, 35.4, 33.5, 33.4, 31.6, 28.6, 26.6. IR (neat): 2929, 2860, 1706, 1615, 1437, 1183, 994, 909, 839 cm−1.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][C@H:8]1[CH2:20][CH2:21]OS(C)(=O)=O)=[O:6])[CH:2]=[CH2:3].[Cl-].[NH4+].[N-:29]=[N+:30]=[N-:31].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][C@H:8]1[CH2:20][CH2:21][N:29]=[N+:30]=[N-:31])=[O:6])[CH:2]=[CH2:3]
Reactant: [N-]=[N+]=[N-]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCOS(C)(=O)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCN=[N+]=[N-]
Temperature: 70 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-(t-butyldimethylsilyloxy)-2-(2-methanesulfonyloxyethyl) pyrrolidine (37.6 g) and ammonium chloride (5.84 g) in dimethylformamide (185 ml) was added portionwise sodium azide (7.1 g) at ambient temperature. The mixture was stirred at 70° C. for 3 hours, and poured into a mixture of ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed twice with water and once with brine, dried over magnesium sulfate and evaporated under reduced pressure to give (2R,4R)-1-allyloxycarbonyl-2-(2-azidoethyl)-4-(t-butyl-dimethylsilyloxy) pyrrolidine (29.7 g).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2C(=C[CH:6]=[C:7]([CH:23]3[CH2:27][CH2:26][CH2:25][CH:24]3C(O)=O)[CH:8]=2)N=1.[CH2:31]([NH2:33])[CH3:32]>>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:31](=[CH:32][CH:6]=[C:7]([C:23]3([C:12]([NH:14][CH2:15][CH3:16])=[O:13])[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:8]=2)[N:33]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(C3CCCC3C(=O)O)ccc2n1
Reactant: CCN
Product: CCNC(=O)C1(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)CCCC1

Procedure:
(Preparation by reaction of 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclopentanecarboxylic acid [“A68”] with ethylamine);
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCBr)c1ccc(F)cc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(F)cc2)CC1
Yield: 50.4 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) as starting compound, potassium carbonate (2.5 g) and 6-bromo-1-(4-fluorophenyl)-1-hexanone (1.3 g) were reacted and treated in the same manner as in Example 172 to give 1.0 g of 4-amino-5-chloro-N-((1-(6-(4-fluorophenyl)-6-oxohexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.