Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([CH3:18])([CH3:17])[C:14]([O-:16])=O)=[CH:8][CH:7]=1.[Na+].[F:21][C:22]([F:35])([F:34])[C:23]1[CH:30]=[C:29]([N:31]=[C:32]=[S:33])[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>>[CH3:19][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:13]([CH3:18])([CH3:17])[C:14](=[O:16])[N:31]([C:29]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:22]([F:35])([F:21])[F:34])[CH:30]=3)[C:32]2=[S:33])=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Reactant: CN(C)CCOc1ccc(NC(C)(C)C(=O)[O-])cc1
Agent: [Na+]
Product: CN(C)CCOc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 17 %

Procedure:
Compound 8 was prepared according to General Method 3. A mixture of sodium 2-(4-(2-(dimethylamino)ethoxy)phenylamino)-2-methylpropanoate (107 mg, 0.37 mmol) and 2-(trifluoromethyl)-4-isothiocyanatobenzonitrile (107 mg, 0.44 mmol) was heated at 100° C. for 1 h then 82° C. for 12 h. The crude product was purified by silica gel chromatography using 100-200 Mesh silica gel (10% methanol in DCM) to obtain 30 mg of 4-(3-(4-(2-(dimethylamino)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. The product was converted its HCl salt by treating with ethanolic HCl, HPLC, Column: HYPERSIL GOLD C18, 4.6×250 mm, 5 μm, Mobile Phase A: 0.05% TFA, Mobile Phase B: ACN, Gradient: 10% to 90% B in 10 min, hold for 10 min. 90% to 10% B in 1 min, Flow Rate: 1 mL/min, Retention time: 9.568 min, M+1, 477.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH2:6]O.[CH:12]#[N:13]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][C:12]#[N:13])[CH:8]=[CH:9][C:10]=1[OH:11]
Reactant: C#N
Reactant: COc1cc(CO)ccc1O
Solvent: CS(C)=O
Product: COc1cc(CC#N)ccc1O
Reaction time: 2 h

Procedure:
185g of 3-methoxy-4-hydroxybenzyl alcohol are dissolved in 1,250 ml of DMSO and 35g of anhydrous hydrocyanic acid are passed in over the course of 1 hour at 125°C. The mixture is then stirred for a further 2 hours, and worked up as indicated above. The yield was 160.5g (82% of theory).
Reaction SMILES: [C:1]1([CH3:11])[C:2]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[F-:12].[K+].O>CC#N>[CH3:11][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([F:12])(=[O:9])=[O:8]
Reactant: [F-]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccccc1S(=O)(=O)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
To a solution of 4-benzyl-6-(4-bromo-phenyl)-morpholine (0.55 g; 1.66 mmol) in THF (25 mL) was added drop wise a solution of n-BuLi in hexanes (1.32 ml; 2.50 mol/1; 3.31 mmol), at −78° C. The resulting mixture was stirred at −78° C., for 30 min. and then 2-methyl-benzenesulfonyl fluoride (0.63 g; 3.64 mmol) was added. After complete addition the mixture was allowed to come to room temperature, and treated with EtOAc and a 5% aqueous NaHCO3-solution. The layers were separated and the organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O) to afford 4-benzyl-2-[4-(toluene-2-sulfonyl)-phenyl]-morpholine (0.50 g). The required 2-methyl-benzenesulfonyl fluoride was prepared as follows: To a solution of o-toluenesulfonyl chloride (0.70 mL; 4.85 mmol) in CH3CN (15 mL) was added spray-dried KF (1.13 g; 19.4 mmol). The resulting mixture was stirred at RT for 18 hours, treated with water and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford 2-methyl-benzenesulfonyl fluoride (0.68 g).
Reaction SMILES: [C:1]([CH:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)(=[O:3])[NH2:2].CCN(CC)CC.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26]>C(Cl)Cl>[C:24]([N:9]1[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][CH:4]1[C:1](=[O:3])[NH2:2])(=[O:27])[CH:25]=[CH2:26]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNC(C(N)=O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.9 %

Procedure:
To a solution of tert-butyl 3-carbamoylpiperazine-1-carboxylate (300 mg, 1.31 mmol) and Et3N (396 mg, 3.93 mmol) in DCM (5 mL) at 0° C., acryloyl chloride (130 mg, 1.44 mmol) in DCM (1 mL) was added and the resulting mixture was stirred at room temperature for 1.5 h. The mixture was partitioned between DCM and saturated NaHCO3 aqueous solution. The organic layer was washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=30:1) to afford the desired product (200 mg, 53.9% yield) as an off-white solid.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11](=[O:13])[CH3:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14](Cl)/[CH:15]=[CH:16]/[CH2:17]Cl.[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC.O>S1(CCCC1)(=O)=O>[C:1]1([S:7]([C:10]2([C:11](=[O:13])[CH3:12])[CH2:17][CH:16]2[CH:15]=[CH2:14])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)CS(=O)(=O)c1ccccc1
Reactant: ClC/C=C/CCl
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: C=CC1CC1(C(C)=O)S(=O)(=O)c1ccccc1
Reaction time: 2 h

Procedure:
Utilizing a phase-transfer procedure similar to that described in Example I, phenylsulfonylacetone was reacted with 1,4-dichlorobutene-2 to obtain 1-phenylsulfonyl-1-acetyl-2-vinylcyclopropane. For the reaction, 9.91 grams phenylsulfonylacetone (Parish Chemical Co.) and 6.25 grams 1,4-dichlorobutene-2 were combined in 20 mls sulfolane containing 6.6 grams potassium hydroxide (85%) and 5 mole percent tricaprylylmethylammonium chloride. The reaction mixture was stirred at 35°-40° C. for 31/2 hours. One-hundred mls water was then added to dissolve the white granular precipitate which had formed and the mixture extracted several times with ether. A crude red oil (10.8 grams) was obtained after removal of the ether and further work-up utilizing a Waters Preparatory Liquid Chromatograph 500A equipped with a gel permeation column and operated at a flow rate of 0.1 l/min yielded the cis and trans isomers of 1-phenylsulfonyl-1-acetyl-2-vinylcyclopropane. ##STR18## trans 1-phenylsulfonyl-1-acetyl-2-vinylcyclopropane
Reaction SMILES: Cl.CC(C)(CC1C=CC(CCN)=CC=1)C(OCC)=O.[C:20]([NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:22])[CH3:21].[Cl-].[CH3:33][O:34][C:35](=[O:42])[C:36]([CH3:41])([CH3:40])[C:37](O)=[O:38]>>[CH3:40][C:36]([CH3:41])([C:37](=[O:38])[C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][NH:23][C:20](=[O:22])[CH3:21])=[CH:27][CH:28]=1)[C:35]([O:34][CH3:33])=[O:42]
Reactant: CC(=O)NCCc1ccccc1
Reactant: COC(=O)C(C)(C)C(=O)O
Agent: CCOC(=O)C(C)(C)Cc1ccc(CCN)cc1
Agent: Cl
Agent: [Cl-]
Product: COC(=O)C(C)(C)C(=O)c1ccc(CCNC(C)=O)cc1

Procedure:
The ethyl α,α-dimethyl-β-[4-(2-aminoethyl)-phenyl]-propionate hydrochloride (m.p. 113°-117° C.) used as starting material is prepared in the following manner: N-acetylphenethylamine is reacted with dimethylmalonic acid methyl ester chloride according to Friedel-Crafts method to give methyl α,α-dimethyl-β-oxo-β-[4-(2-acetamidoethyl)-phenyl]-propionate (b.p. 215°-220° C./0.1 mm.Hg.), this then reduced, via methyl α,α-dimethyl-β-hydroxy-β-[4-(2-acetamidoethyl)-phenyl]-propionate (m.p. 120°-123° C.) to give methyl α,α-dimethyl-β-[4-(2-acetamidoethyl)-phenyl]-propionate (b.p. 180°-190° C./0.1 mm Hg.), saponified to give α,α-dimethyl-β-[4-(2-aminoethyl)-phenyl]-propionic acid hydrochloride (m.p. 230°-235° C.) and thereafter esterified to give the desired ethyl ester hydrochloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[O:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:32])=[C:19]([NH:23][S:24]([C:27]3[O:28][CH:29]=[CH:30][CH:31]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:34]>>[NH2:34][C:2]1[N:7]=[C:6]([C:8]2[O:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:32])=[C:19]([NH:23][S:24]([C:27]3[O:28][CH:29]=[CH:30][CH:31]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2F)c(-c2ccnc(Cl)n2)o1
Agent: [OH-]
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2F)c(-c2ccnc(N)n2)o1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluorophenyl}-2-furansulfonamide (72 mg, 0.151 mmol) and ammonium hydroxide (5 mL), the title compound was obtained as a white solid (62 mg, 89%). 1H-NMR (DMSO-d6): δ ppm 10.57 (br s, 1H), 8.26 (d, J=5.6 Hz, 1H), 7.97 (m, 1H), 7.44-7.48 (m, 1H), 7.23-7.32 (m, 2H), 7.08 (m, 1H), 6.63 (m, 1H) 6.57 (d, J=5.2 Hz, 1H), 1.41 (s, 9H); MS: 458 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@@H:18]2[NH:22][C@H:21]([C:23]([O:25]C)=O)[CH2:20][CH2:19]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])#[N:2].[NH3:27].CO>>[C:1]([C:3]1[CH:4]=[C:5]([C@@H:18]2[NH:22][C@H:21]([C:23]([NH2:27])=[O:25])[CH2:20][CH2:19]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])#[N:2]
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3F)c(C#N)c2)N1
Reactant: N
Solvent: CO
Product: N#Cc1cc([C@H]2CC[C@@H](C(N)=O)N2)ccc1OCc1ccccc1F
Yield: 72 %

Procedure:
A solution of methyl (5R)-5-(3-cyano-4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinate (D73, 64 mg, 0.180 mmol) in 7M NH3/MeOH (2 ml) was stirred 10.5 h at 40° C. The solvent was evaporated and the residue purified via flash chromatography using a DCM/MeOH (98:2 to 8:2) to afford (5R)-5-(3-cyano-4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide (44 mg, 72%) as the free base. The title compound (32 mg) was prepared as described for example 4 in procedure 2. MS: (ES/+) m/z: 340 [MH+], C19H18FN3O2 requires 339. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.37 (br. s., 1H), 8.54 (br. s., 1H), 8.04 (br. s., 1H), 7.97 (dd, 1H), 7.85 (dd, 1H), 7.74 (br. s., 1H), 7.63 (td, 1H), 7.50 (d, 1H), 7.43-7.55 (m, 1H), 7.25-7.36 (m, 2H), 5.32-5.44 (m, 2H), 4.56-4.82 (m, 1H), 4.21-4.42 (m, 1H), 2.22-2.43 (m, 2H), 1.94-2.26 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[CH3:17][C:18]([CH3:36])([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][C@@H:24]1[C:29]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:22])[CH3:19]>CC(O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:26]2[CH2:27][CH2:28][N:23]([C:21]([O:20][C:18]([CH3:17])([CH3:19])[CH3:36])=[O:22])[C@@H:24]([C:29]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25]2)[N:3]=1
Reactant: CC(C)(C)NC(=O)[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2nc(N3CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)NC(C)(C)C)C3)nc(N)c2cc1OC

Procedure:
A solution of 4-amino-2-chloro-6,7-dimethoxyquinazoline (94.4 mg, 0.3939 mmol) and (R)-4-[(1,1-dimethylethoxy)carbonyl]-3-(1,1-dimethylethylamino) carbonyl piperazine (see Askin, D. et al., Tetrahedron Letters 1994, 35, 673-676) (112.4 mg, 0.3939 mol) in 2-propanol (1 mL) was heated at 90° C. (24 h). The solvent was removed in vacuo and the residue subjected to PCTLC (SiO2, 2 mm, 0-10% MeOH/CH2Cl2) which afforded ((R)-1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-[(1,1-dimethylethoxy)carbonyl]-3-(1,1-dimethylethylamino)carbonyl piperazine.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>C(Cl)Cl>[C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:20](=[O:23])[CH2:21][CH3:22])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCC(=O)Nc1ccc(Nc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
A stirred mixture of 1.84 g (10.0 mmol, 1 eq.) of commercial N-phenyl-1,4-phenylenediamine (a black solid) and 1.18 g (14.0 mmol, 1.4 eq.) of NaHCO3 in 40 mL of CH2Cl2 was cooled to 0° C. To this suspension was added a solution of 0.96 mL (11.0 mmol, 1.1 eq.) of propionyl chloride in 10 mL of CH2Cl2 dropwise. The ice bath was removed and the mixture stirred for 1 hour and then poured into a seperatory funnel containing 50 mL of each CH2Cl2 and water. The organic phase was separated and extracted with 50 mL of saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (100 g SiO2, 1:1 ethyl acetate-hexanes) to give 1.79 g (75%) of product. 1H NMR (300 MHz, CDCl3) δ7.41 (d, 2H), 7.21-7.43 (m, 2H), 7.14 9 (bs, 1H), 6.96-7.07 (m, 4H) 6.90 (t, 1H), 5.66 (bs, 1H), 2.38 (q, 2H), 1.25 (t, 3H). MS (DCl) m/e 258 (M+NH4)+, 241 (M+H)+.
Reaction SMILES: [CH:1]12[N:8]([C:9]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[O:19][CH3:20])=[O:10])[CH2:7][CH:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.C1(C2C=CC=CC=2)C=CC=CC=1C(N1C2C(CCNC2)C1)=O.Cl[C:44]1[O:45][C:46]2[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=2[N:48]=1.ClC1C=NC2C(=CC=CC=2)N=1>>[O:45]1[C:46]2[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=2[N:48]=[C:44]1[N:3]1[CH2:4][CH2:5][CH:6]2[CH:1]([N:8]([C:9]([C:11]3[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][CH3:18])=[O:10])[CH2:7]2)[CH2:2]1
Reactant: COc1cccc(OC)c1C(=O)N1CC2CCNCC21
Reactant: Clc1nc2ccccc2o1
Agent: Clc1cnc2ccccc2n1
Agent: O=C(c1ccccc1-c1ccccc1)N1CC2CCNCC21
Product: COc1cccc(OC)c1C(=O)N1CC2CCN(c3nc4ccccc4o3)CC21

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting the trifluoro acetic acid salt of (3,8-diaza-bicyclo[4.2.0]oct-8-yl)-(2,6-dimethoxy-phenyl)-methanone (Intermediate 4) for biphenyl-2-yl-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)methanone and 2-chlorobenzoxazole for 2-chloro quinoxaline. MS (ESI) mass calcd. for C22H23N3O3, 393.45; m/z found, 394.0 [M+H]+. 1H NMR (CDCl3): 7.54-7.26 (m, 3H), 7.24-7.10 (m, 2H), 7.08-7.02 (m, 0.6H), 6.80-6.73 (m, 0.4H), 6.33-6.22 (m, 1H), 4.74-4.64 (m, 1H), 4.14-3.56 (m, 5H), 3.50-3.35 (m, 1H), 2.99-2.85 (m, 1H), 2.72-2.56 (m, 1H), 2.36-2.20 (m, 5H), 2.03-1.78 (m, 2H).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:28][CH:5]2[CH:6]([C:18]3[CH:23]=[CH:22][C:21]([O:24]COC)=[CH:20][CH:19]=3)[O:7][C:8]3[CH:9]=[CH:10][C:11]([O:14]COC)=[CH:12][C:13]=3[CH:4]2[CH2:3]1>C1COCC1.Cl.CCOC(C)=O>[F:29][C:2]1([F:1])[CH2:28][C@@H:5]2[C@H:6]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[O:7][C:8]3[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][C:13]=3[C@@H:4]2[CH2:3]1
Reactant: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(F)(F)CC32)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Oc1ccc([C@@H]2Oc3ccc(O)cc3[C@@H]3CC(F)(F)C[C@@H]32)cc1
Reaction time: 8 h
Yield: 100 %

Procedure:
Stir a solution of difluorocyclopentane 29 (196 mg, 0.480 mmol) in 7 mL of THF and 3 mL of 3 M HCl overnight. Add 1 mL of 5 M HCl and let stir overnight. Dilute the solution with EtOAc. Separate the aqueous solution and extract 2× with EtOAc. The combined organic solutions were washed with saturated aqueous sodium bicarbonate, brine, dried over Na2SO4, filtered, and concentrated. Absorb to 2 g of silica gel and purify by silica gel chromatography (10 g silica gel, 10 to 60% EtOAc/Hexanes over 30 min at 35 mL/min) to give 155 mg (0.48 mmol, 100%) of difluorocyclopentane 30. The enantiomers were separated by preparative chiral chromatography (Chiralpak AD, 65/35 heptane/ethanol).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].Br[CH2:7][C:8]([OH:10])=[O:9]>>[CH2:1]([NH:5][CH2:7][C:8]([OH:10])=[O:9])[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(O)CBr
Reactant: CC(C)CN
Product: CC(C)CNCC(=O)O
Reaction time: 8 h

Procedure:
Isobutylamine (50 mL, 0.5 mol) was cooled in an ice bath, and bromoacetic acid (6.1 g, 43.9 mmol) added slowly as a solid, insuring that each piece dissolved. After stirring overnight, the excess amine was removed and MeOH was added to the resulting oil. The resulting mixture was concentrated, and repeated using MeOH/HCl. Finally, a white solid was recrystallized from ethanol/ether to provide N-isobutylglycine.HCl (3.95 g, 53.7%).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:14][Mg]Br>C1COCC1>[OH:9][CH:8]([C:6]1[N:7]=[C:2]([OH:1])[CH:3]=[C:4]([C:10]([F:13])([F:11])[F:12])[CH:5]=1)[CH3:14]
Reactant: O=Cc1cc(C(F)(F)F)cc(O)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cc(C(F)(F)F)cc(O)n1
Temperature: -78 °C
Yield: 69 %

Procedure:
6-hydroxy-4-(trifluoromethyl)picolinaldehyde (2.00 g, 10.5 mmol) was dissolved in dry THF (20 mL) and cooled to −78° C. Methyl magnesium bromide (24 mmol) was added dropwise over 5 minutes. The mixture was allowed to mix for 15 minutes. The reaction was allowed to warm to room temperature and slowly quenched with saturated ammonium chloride (20 mL). The solution was then extracted with ethyl acetate (3×100 mL). The organic extracts were combined and washed with brine (1×) dried over sodium sulfate and concentrated to yield 1.50 g of desired product (70%). 1HNMR (CDCl3 400 MHz) δ6.70 (s, 1H), 6.28 (s, 1H), 4.80 (m, 1H), 3.46 (q, 1H), 1.55 (d, 3H). Mass Spec.: 208.14 (MH)+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]([NH:19][C:20]1[O:21][C:22]([CH3:38])([CH3:37])[CH:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][CH:29]=2)[S:24](=[O:27])(=[O:26])[N:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])(C(C)(C)C)(C)C.[CH3:39][Mg]Br.[Cl-].[NH4+].O>C1COCC1>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C@@H:11]([NH:19][C:20]1[O:21][C:22]([CH3:37])([CH3:38])[CH:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([OH:36])([CH3:39])[CH3:35])=[CH:30][CH:29]=2)[S:24](=[O:27])(=[O:26])[N:25]=1)[CH2:10][CH2:9][OH:8]
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(C2C(C)(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c3ccccc3F)=NS2(=O)=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)c1ccc(C2C(C)(C)OC(N[C@@H](CCO)c3ccccc3F)=NS2(=O)=O)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-{2-[(S)-3-(tert-butyldimethylsilanyloxy)-1-(2-fluorophenyl)propylamino]-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda*6*-[1,4,3]oxathiazin-5-yl}phenyl)ethanone (174 mg) in THF (2.5 ml) was added dropwise, at −78° C., a solution of methylmagnesium bromide (1.4 M, 0.44 ml). After 30 min at −78° C., ammonium chloride solution was added to the mixture. After the addition of water, the mixture was extracted with ethyl acetate, dried over magnesium sulfate and concentrated. The residue was dissolved in methanol (2 ml), and 0.2 ml of conc. HCl was added. The resulting mixture was purified in a purification laboratory by means of preparative HPLC. This gave the product (28 mg) with a molecular weight of 464.6 g/mol (C23H29FN2O5S); MS (ESI): m/e=465 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=[O:10])[C:3]=1[Cl:12].[OH-:13].[K+].O>C(O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]2=[N+:6]([O-:13])[O:10][N:9]=[C:4]2[C:3]=1[Cl:12]
Reactant: Nc1ccc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: [O-][n+]1onc2c(Cl)c(Br)ccc21
Temperature: -2.5 °C
Reaction time: 1.5 h
Yield: 80.2 %

Procedure:
4-Bromo-3-chloro-2-nitroaniline (4.1 g, 16 mmol) was dissolved in 60 mL ethanol, treated with 45% potassium hydroxide solution (2.0 g, 16 mmol), cooled to −5 to 0° C. and treated drop wise with commercial bleach solution (32 mL, 6 wt. %, 31 mmol) over 20 min. The mixture was stirred for 90 min at 0-15° C. and poured into 700 mL water. The precipitated product was collected by filtration, washed well with water and then dried under vacuum at 80° C. to give the title compound (3.2 g, 81%): EIMS m/z 248.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[Cl:21])[C:6]([CH:12]=[O:13])=[N:7]2.[CH2:22]1COCC1.C[Mg]Br.C(OCC)C>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[Cl:21])[C:6]([CH:12]([OH:13])[CH3:22])=[N:7]2
Reactant: O=Cc1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a stirring hetereogeneous mixture of 5-chloro-3-(2-chloro-5-fluorophenyl)-quinoxaline-2-carbaldehyde (0.1650 g, 0.514 mmol) in THF (5.00 mL, 0.514 mmol) was added methylmagnesium bromide 3 M in diethyl ether (0.257 mL, 0.771 mmol) dropwise at 0° C., and the mixture was then allowed to warm to room temperature and stirred at room temperature. After 5.5 h, the reaction was quenched with NH4Cl (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with water (50 mL×1), brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min and then 50% isocratic of EtOAc for 10 min as eluent to give 1-(5-chloro-3-(2-chloro-5-fluorophenyl)quinoxalin-2-yl)ethanol as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.17 (1 H, dd, J=8.4, 1.4 Hz), 8.09 (1 H, dd, J=7.8, 1.2 Hz), 7.88-7.96 (1 H, m), 7.72 (1 H, dd, J=9.0, 5.1 Hz), 7.61 (1 H, br. s.), 7.44-7.53 (1 H, m), 5.36 (1 H, d, J=6.3 Hz), 4.83 (1 H, br. s.), 1.49 (3 H, br. s.); LC-MS (ESI) m/z 337.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([N:16]=[C:17]=[S:18])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C:19]([NH:22][NH2:23])(=[O:21])[CH3:20].CO>O1CCCC1>[C:19]([NH:22][NH:23][C:17]([NH:16][C:12]1[CH:13]=[CH:14][C:15]2[N:3]([CH2:1][CH3:2])[C:4]3[C:9]([C:10]=2[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[S:18])(=[O:21])[CH3:20]
Reactant: CCn1c2ccccc2c2cc(N=C=S)ccc21
Reactant: CC(=O)NN
Solvent: CO
Solvent: C1CCOC1
Product: CCn1c2ccccc2c2cc(NC(=S)NNC(C)=O)ccc21

Procedure:
3.8 g of 9-ethyl-3-isothiocyanatocarbazole was reacted with 1.1 g of acetylhydrazine in 30 ml of tetrahydrofuran at 60° C. for 2 hours. Then, 10 ml of methanol was added thereto and crystallization was conducted while cooling with ice. Crystals thus precipitated were collected by filtration, and recrystallized from CHCl3 /CH3OH (70 ml/200 ml) to obtain 2.4 g of the desired end compound. m.p. 197°-199° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C>[N+:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)([O-:12])=[O:11]
Reactant: c1ccc2c(c1)CCO2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)CCO2
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
2,3-Dihydrobenzofuran (36 g, 0.3 mol) was added to glacial acetic acid (100 mL), heated to 65° C., then concentrated nitric acid (25 mL, 0.36 mol) was added dropwise into the reaction solution, the temperature of the reaction solution was controlled at 65-75° C. After the end of dropwise addition, the agitation was kept for 0.5 h. It was then cooled to room temperature, filtered, washed with water, and dried to obtain a product (22 g, 44.4%).
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH3:11][Sn:12](Cl)([CH3:14])[CH3:13].C(=O)(O)[O-].[Na+]>CCCCCC.CCOCC>[CH3:11][Sn:12]([CH3:14])([CH3:13])[C:7]1[S:6][CH:10]=[CH:9][N:8]=1
Reactant: C[Sn](C)(C)Cl
Reactant: c1cscn1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: C[Sn](C)(C)c1nccs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To 99.99 ml of n-butyl lithium in hexane, dissolved in 200 ml of ether is added dropwise with stirring over 1 hour, at -78° C., a solution of 16 g of thiazole in 100 ml of ether over 1 hour. A solution of 49.81 g of trimethyltin chloride in 100 ml of ether is added dropwise over 20 minutes followed by additional stirring for 1 hour. The reaction mixture is poured into saturated sodium bicarbonate and the organic layer separated, dried and evaporated to a residue. The residue is vacuum distilled to give 33.4 g of the desired product as a colorless liquid, B.P. 60°-65° C./0.7 mm.