Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=O)[C:5]=2[C:4]2([C:25]3[C:16](=[CH:17][C:18]4[O:23][CH2:22][CH2:21][O:20][C:19]=4[CH:24]=3)[O:15][CH2:14]2)[C:3]1=[O:26].O[C:28]1[C:36]2N=N[NH:33][C:32]=2[CH:31]=[CH:30][CH:29]=1.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.C(N(CC)C(C)C)(C)C.C(N)CCCCC>CN(C)C=O>[CH2:32]([NH:33][C:11]([C:6]1[C:5]2[C:4]3([C:25]4[C:16](=[CH:17][C:18]5[O:23][CH2:22][CH2:21][O:20][C:19]=5[CH:24]=4)[O:15][CH2:14]3)[C:3](=[O:26])[N:2]([CH3:1])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:13])[CH2:31][CH2:30][CH2:29][CH2:28][CH3:36]
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C(=O)O)cccc21
Reactant: Oc1cccc2[nH]nnc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCCCCCN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCNC(=O)c1cccc2c1C1(COc3cc4c(cc31)OCCO4)C(=O)N2C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.9 %

Procedure:
To a stirred solution of 1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylic acid (0.200 g, 0.566 mmol) in N,N-dimethylformamide (12 mL) were added hydroxybenzotriazole (0.151 g, 1.13 mmol), 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.364 g, 1.13 mmol) and N,N-diisopropylethylamine (0.81 mL, 4.5 mmol). The reaction mixture was stirred at ambient temperature for 15 min and N-hexylamine (0.15 mL, 1.1 mmol) was added. The reaction mixture stirred for 72 h at ambient temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and was washed with water (3×150 mL), 1 M aqueous sodium hydroxide (2×100 mL) and brine (2×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was recrystallized from hexanes/ethyl acetate to afford N-hexyl-1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxamide (0.180 g, 73%) as a colorless solid: mp 172-173° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.42-7.36 (m 1H), 7.26-7.22 (m, 1H), 6.99-6.96 (m, 1H), 6.49 (s, 1H), 6.20 (s, 1H), 5.30-5.26 (m, 1H), 4.92 (ABq, 2H), 4.25-4.07 (m, 4H), 3.27-2.97 (m, 5H), 1.30-1.18 (m, 8H), 0.87 (t, J=6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 177.6, 167.0, 155.8, 145.0, 144.1, 137.9, 134.4, 129.5, 127.8, 122.9, 120.6, 110.7, 109.9, 99.8, 78.8, 64.5, 64.0, 58.1, 40.0, 31.4, 28.9, 26.9, 26.5, 22.5, 14.0; MS (ES+) m/z 437.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:4]([C:5]([NH2:7])=[O:6])[C:3]=1[NH2:12].Br[C:14]1[S:15][CH:16]=[CH:17]N=1.N>O>[CH3:11][C:9]1[CH:8]=[C:4]2[C:3](=[C:2]([CH3:1])[CH:10]=1)[N:12]=[C:14]1[S:15][CH:16]=[CH:17][N:7]1[C:5]2=[O:6]
Reactant: Cc1cc(C)c(N)c(C(N)=O)c1
Reactant: Brc1nccs1
Agent: N
Solvent: O
Product: Cc1cc(C)c2nc3sccn3c(=O)c2c1
Temperature: 155 °C
Reaction time: 12 h
Yield: 57.2 %

Procedure:
A mixture of 13.1 g of 3,5-dimethylanthranilamide and 13.1 g of 2-bromothiazole was heated for 30 minutes at 155° C. and stirred for 12 hours. After the mixture had cooled to 25° C., the pH was adjusted to 9 by adding water and 25% strength ammonia solution, while stirring, and the resulting solution was stirred for 10 minutes. The solution was then suction filtered and the filtrate was washed with methanol and dried, 10.5 g of the above compound was obtained; m.p. 190°-192° C. The methanol filtrate was concentrated, taken up in ethyl acetate and chromatographed over aluminum oxide. After concentration a further 4.4 g of the above compound were obtained; total yield: 81%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:21](=[O:24])(=[O:23])[NH2:22])[C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[C:7]([OH:9])=[O:8])([O-])=O.N(C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:21](=[O:24])(=[O:23])[NH2:22])[C:12]=1[NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(Nc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Product: Cc1ccc(Nc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
By substituting 3-nitro-5-sulphamyl-4-(p-toluidino)-benzoic acid for the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the above compound was obtained with a melting point of 249°-252°C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[C:7]=1[N:13]=[C:14]=[S:15]>>[NH2:3][CH2:2][CH2:1][NH:4][C:14]([NH:13][C:7]1[C:8]([Br:12])=[CH:9][CH:10]=[CH:11][C:6]=1[Br:5])=[S:15]
Reactant: NCCN
Reactant: S=C=Nc1c(Br)cccc1Br
Product: NCCNC(=S)Nc1c(Br)cccc1Br

Procedure:
In a similar manner to that described in Example 1, ethylenediamine was reacted with 2,6-dibromophenylisothiocyanate to yield 1-(2-aminoethyl)-3-(2,6-dibromophenyl)thiourea, melting point 155°-157°.
Reaction SMILES: [F:1][C:2]1[C:9]([CH2:10][CH2:11][OH:12])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.FC(F)(F)C(O)=O.[CH:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([N:30]2[CH2:35][C:34]3([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[O:33][CH2:32][CH2:31]2)=[O:29])[N:27]=1)([CH3:22])[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1CCCC1=O.C(#N)C>[F:1][C:2]1[C:9]([CH2:10][CH2:11][OH:12])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:38]1[CH2:39][CH2:40][C:34]2([O:33][CH2:32][CH2:31][N:30]([C:28]([C:26]3[N:27]=[C:23]([CH:20]([CH3:21])[CH3:22])[S:24][CH:25]=3)=[O:29])[CH2:35]2)[CH2:36][CH2:37]1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: O=Cc1cccc(CCO)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)cs1
Reaction time: 1 h

Procedure:
2-Fluoro-3-(2-hydroxyethyl)benzaldehyde (example 48, step a) (0.19 g) was added to a solution of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.32 g) and acetic acid (0.043 mL) in N-methyl-2-pyrrolidinone (5 mL). The resulting mixture was stirred for 1 h then sodium triacetoxyborohydride (0.24 g) was added portionwise over 5 min. The resulting mixture was stirred overnight, diluted with acetonitrile (20 mL) and applied to a SCX cartridge (10 g Varian, pre-wetted with acetonitrile (50 mL)). The cartridge was washed with acetonitrile (50 mL) and eluted with 10% ‘880’ aqueous ammonia in acetonitrile solution (50 mL). The eluent was evaporated, azeotroped with toluene and purified by silica gel chromatography eluting with 77.5:17.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a yellow gum. Yield 0.33 g.
Reaction SMILES: [OH-].[NH4+].[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[N:18]=[C:17]([CH3:19])[C:16]([N:20](C(=O)CC(C)(C)C)[C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:15]([CH3:35])[N:14]=1>CO>[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[N:18]=[C:17]([CH3:19])[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[C:15]([CH3:35])[N:14]=1
Reactant: Cc1nc(N2CCc3ccccc3C2)nc(C)c1N(C(=O)CC(C)(C)C)C(=O)CC(C)(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(N2CCc3ccccc3C2)nc(C)c1NC(=O)CC(C)(C)C
Reaction time: 20 h
Yield: 77.1 %

Procedure:
An aqueous solution of ammonium hydroxide (30%, 1 ml) was added to a solution of 6f (0.031 g, 0.07 mmol) in methanol (1 ml) and stirred for 20 hours. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and chromatographed to yield the title compound (0.019 g, 0.054 mmol, 77%). 1H NMR (CDCl3, 400 MHz) δ 1.11 (s, 9H), 2.23 (s, 2H), 2.30 (s, 6H), 2.91 (t, J=6.0 Hz, 2H), 4.04 (t, J=6.0 Hz, 2H), 4.89 (s, 2H), 6.68 (s, 1H), 7.17 (dd, J=7.8, 3.4 Hz, 4H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[CH:6][N:7](C(OCC)C)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=1)[CH3:3].CN(C)CCN(C)C.C([Li])CCC.[F:35][C:36]([F:44])([F:43])[C:37]([C:39]([F:42])([F:41])[F:40])=[O:38].C(=O)(O)[O-].[Na+]>O1CCCC1.CCCCCC>[CH3:3][CH:2]([C:4]1[N:5]=[C:6]([C:37]([C:39]([F:42])([F:41])[F:40])([C:36]([F:44])([F:43])[F:35])[OH:38])[NH:7][C:8]=1[C:9]1[CH:10]=[CH:11][C:12]([S:15][CH3:16])=[CH:13][CH:14]=1)[CH3:1]
Reactant: CCOC(C)n1cnc(C(C)C)c1-c1ccc(SC)cc1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: CN(C)CCN(C)C
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1ccc(-c2[nH]c(C(O)(C(F)(F)F)C(F)(F)F)nc2C(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a stirred solution of 4-(1-methyethyl)-5-(4-methylthiophenyl)-1-(α-ethoxyethyl)imidazole (9.8 g, 32.2 mmol) in 110 ml of dry tetrahydrofuran was added 4.31 g (37.1 mmoles) of tetramethylethylenediamine. The reaction mixture was cooled to -78° C. and 32.24 ml of 1.65M n-butyl lithium in hexane was added dropwise via an addition funnel. After stirring the mixture an additional 20 minutes, hexafluoroacetone (9.0 ml) was condensed and added dropwise. The mixture was stirred at -78° C. for 1 hour and then 150 ml of saturated aqueous sodium bicarbonate solution was added dropwise. The reaction mixture was warmed to room temperature and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and concentrated to dryness in vacuo. The residue was stirred overnight in 215 ml of ethanol and 215 ml of 2N aqueous hydrochloric acid. The ethanol was removed in vacuo and the reaction mixture was basified to a pH of 8 with saturated aqueous potassium carbonate. The reaction mixture was extracted with ether, washed with 10% aqueous sodium bicarbonate and dried over anhydrous potassium carbonate. The residue was purified via flash chromatography on silica gel (92:8 hexane/ethyl acetate) to afford 7.55 g (59%) of a yellow oil which was triturated with hexane to give 7.55 g (59%) of the product as a white crystalline solid, m.p. 115°-117° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:16])[CH2:12][C:13]([OH:15])=O)[CH2:7][CH2:6]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:43]1[CH:47]=[N:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=2)=[N:44]1>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11](=[O:16])[CH2:12][C:13]([NH:54][C:51]2[CH:50]=[CH:49][C:48]([C:45]3[N:46]=[CH:47][O:43][N:44]=3)=[CH:53][CH:52]=2)=[O:15])[CH2:9][CH2:10]1
Reactant: O=C(O)CC(=O)N1CCC(Oc2ccccc2Cl)CC1
Reactant: Nc1ccc(-c2ncon2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC(=O)N1CCC(Oc2ccccc2Cl)CC1)Nc1ccc(-c2ncon2)cc1
Reaction time: 8 h
Yield: 60 %

Procedure:
To a stirred solution of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid (0.1 g, 0.00034 mole) in DMF (2 mL) was added DMAP (0.063 g, 0.00051 mole), HOBt (0.055 g, 0.00041 mole) and EDCI.HCl (0.079 g, 0.00041 mole). After 2 minutes 4-[1, 2, 4]-oxadiazol-3-yl-phenylamine (0.06 g, 0.00037 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure to afford 0.09 g (61%) of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-N-(4-[1,2,4]oxadiazol-3-yl-phenyl)-3-oxo-propionamide. LC-MS purity: 441 (M+1)+, 94.4%, 1H NMR (CDCl3): δ 10.5 (s, 1H), 8.8 (s, 1H), 8.1 (d, 2H), 7.74 (d, 2H), 7.4 (d, 1H), 7.2 (d, 1H), 6.96 (t, 2H), 4.7 (q, 1H), 4.1 (m, 1H), 3.8 (m, 1H), 3.6 (m, 2H), 3.55 (s, 2H), 2.0 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[N:8]2)=[CH:4][CH:3]=1.N#N.[Li]CCCC.[F:25][CH:26]([P:28](=[O:48])([O-:47])[O:29][C:30]1[CH:35]=[C:34](C(C)(C)C)[C:33]([CH2:40]Br)=[C:32](C(C)(C)C)[C:31]=1[Br:46])[F:27]>C1COCC1>[N:7]1([CH:6]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=2)[CH2:40][C:33]2[CH:34]=[CH:35][C:30]([O:29][P:28]([CH:26]([F:27])[F:25])(=[O:47])[OH:48])=[C:31]([Br:46])[CH:32]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[N:8]1
Reactant: Fc1ccc(Cn2nnc3ccccc32)cc1
Reactant: CC(C)(C)c1cc(OP(=O)([O-])C(F)F)c(Br)c(C(C)(C)C)c1CBr
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=P(O)(Oc1ccc(CC(c2ccc(F)cc2)n2nnc3ccccc32)cc1Br)C(F)F
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 50.5 %

Procedure:
A solution of 1-(4-fluorobenzyl)-1H-benzotriazole (91 mg) in THF (5 mL) at −78° C. was pumped under high vacuum for 5 min., then N2 was introduced in the reaction vessel. A solution of 0.98M n-BuLi in hexanes (0.41 mL) was then added, and the solution turned deep blue immediately. After stirring for 5 min at −78° C., a solution of (2-bromo-4-bromomethylphenyl)difluoromethylphosphonic acid di-tert-butyl ester (Example 1, Step 6)(157 mg) in THF (1.5 mL) was added. The deep blue color disappeared. The mixture was then stirred at −78° C. for 15 min then quenched with H2O and extracted with EtOAc. The EtOAc extract was washed with brine, dried (MgSO4) and concentrated. Chromatography over silica gel and elution with hexane:EtOAc (65:35, 0.2% Et3N), provided 85 mg of the intermediate.
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[CH:4]1([Zr+3:9])[CH:8]=[CH:7][CH:6]=[CH:5]1.[CH3:10][Si:11]1([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)[CH2:14][CH2:13][CH2:12]1.[Li]>ClCCl>[Cl-:1].[Cl-:1].[CH3:10][Si:11]1([C:15]2[CH:23]([Zr+2:9][CH:4]3[CH:8]=[CH:7][CH:6]=[CH:5]3)[C:18]3[C:17]([CH:16]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:13][CH2:14]1
Reactant: [Zr+3]C1C=CC=C1
Reactant: C[Si]1(C2C=Cc3ccccc32)CCC1
Agent: [Cl-]
Agent: [Li]
Solvent: ClCCl
Product: C[Si]1(C2=Cc3ccccc3C2[Zr+2]C2C=CC=C2)CCC1
Reaction time: 8 h
Yield: 144.1 %

Procedure:
5 g (19.03 mmol) of cyclopentadienylzirconium trichloride (CpZrCl3) was placed into a flask with 20 mL of dichloromethane to form suspension. 3.92 g (19.03 mmol) of lithium 1-(1-methyl-1-silacyclobutyl)indene was also placed into another flask with 20 mL of dichloromethane to form suspension. The suspension of CpZrCl3 in the first flask was slowly added into the suspension of lithium 1-(1-methyl-1-silacyclobutyl)indene in the second flask, and then the remained reactant in the first flask was washed with 10 mL of dichloromethane and added into the second flask. After repeating the washing and addition process for three times, the reaction mixture was stirred overnight. After the completion of reaction, LiCl was filtered and removed from the formed yellowish solution with 11G4 filter. The solvent was then evaporated from the filtrate under vacuum and the remaining volatile material was also removed under vacuum at 50° C. overnight. The concentrate was then sublimated at 130° C. in the presence of 50μ Hg to obtain 5.85 g (72% of yield) of pure ((1-methyl-1-silacyclobutyl)-indenyl)(cyclopentadienyl)zirconium dichloride having the following 1H NMR (CDCl3, ppm) data: δ7.95 (d, 1H), 7.92 (d, 1H), 7.42-7.28 (m, 2H), 7.14 (d, 1H), 6.84 (d, 1H), 6.10 (s, 5H, C5H5), 2.38-2.15 (m, 2H), 1.57-1.27 (m, 4H), 0.74 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2[C:10](=[N:11][NH:12][C:13]=2[NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][CH:18]([C:22](=O)[CH3:23])[C:19](=O)[CH3:20]>CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2=[C:13]3[N:12]([N:11]=[C:10]2[CH2:9]1)[C:22]([CH3:23])=[C:18]([F:17])[C:19]([CH3:20])=[N:16]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)C(F)C(C)=O
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Solvent: CC(=O)O
Product: Cc1nc2c3c(nn2c(C)c1F)CN(C(=O)OC(C)(C)C)C3
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of 3-amino-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (4.3 g; 19.2 mmol; 1 eq.) and 3-fluoropentane-2,4-dione (2.49 g; 21.1 mmol; 1.1 eq.) in AcOH (40 mL) was stirred at room temperature for 18 hours. 3-fluoropentane-2,4-dione (0.45 g; 3.83 mmol; 0.2 eq.) was added and the reaction mixture was stirred for one hour then concentrated in vacuo. The residue was partitioned between EA and 1M NaOH and the aqueous layer extracted with EA. The combined organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (10 to 40% EA in cyclohexane) afforded the title compound (3 g, 58%) as a white solid. HPLC (max plot) 99.4%; Rt 3.83 min. UPLC/MS: (MS+) 307.2 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.O=[C:28]([CH3:42])[CH2:29][CH2:30][N:31]1C(=O)C2C(=CC=CC=2)C1=O>>[F:1][C:2]1[C:10]2[O:9][C:8]([CH:21]3[CH2:22][CH2:23][N:24]([CH:28]([CH3:42])[CH2:29][CH2:30][NH2:31])[CH2:25][CH2:26]3)([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:15][CH:16]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc2c1OC(c1ccc(C(F)(F)F)cc1)(C1CCNCC1)O2
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Product: CC(CCN)N1CCC(C2(c3ccc(C(F)(F)F)cc3)Oc3cccc(F)c3O2)CC1

Procedure:
Using general procedure B with the above amine (18 mg, 0.049 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (21 mg, 0.098 mmol) and then using general procedure D afforded 3-{4-[4-fluoro-2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a white solid (11 mg, 52% over 2 steps).
Reaction SMILES: C([Si]([O:8]/[C:9](/[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)=[CH:10]\[CH3:11])(C)C)(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:43]C)C=C4)N(CC2)C1.CS(N)(=O)=O>C(O)(C)(C)C.O>[OH:43][C@H:10]([CH3:11])[C:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)=[O:8]
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1ccc2ccccc2c1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: CS(N)(=O)=O
Solvent: O
Solvent: CC(C)(C)O
Product: C[C@@H](O)C(=O)c1ccc2ccccc2c1
Yield: 78 %

Procedure:
Compound 10i was synthesized by a procedure similar to that described for (R)-10a using (Z)-tert-butyl(1-(naphthalen-2-yl)prop-1-enyloxy)dimethylsilane, (9i, 4.7 g, 0.016 mol), AD-mix-β (22.0 g), and CH3SO2NH2 (1.55 g, 0.016 mol) in tert-butyl alcohol-water (60 mL:60 mL). The reaction was quenched with sodium sulfite (15.7 g). After purification by column chromatography on silica gel, 2.5 g (80%) of the desired product was isolated: [α]20D +115° (c 0.7, CHCl3); 1H NMR (CDCl3) δ 8.44 (s, 1H), 8.01-7.86-8.00 (m, 4H), 7.69-7.54 (m, 2H), 5.37-5.27 (m, 1H), 3.86 (d, 1H, J=6.5 Hz), 1.52 (d, 3H, J=7.0 Hz); 13C NMR (CDCl3) δ 202.3, 136.0, 132.4, 130.7, 130.5, 129.7, 129.0, 128.8, 127.9, 127.1, 124.0, 69.4, 22.5. C13H12O2.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([O:11][CH3:12])[C:3]=1C=O.ClC1C=CC=C(C(OO)=[O:21])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[OH:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(F)c(F)c1C=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(F)c(F)c1O
Reaction time: 0.33 h
Yield: 70.8 %

Procedure:
To a solution of 2,3-difluoro-6-methoxybenzaldehyde (2.58 g) in methylene chloride (45 mL) was added 3-chloroperbenzoic acid (5.97 g) under ice-cooling, and the mixture was heated for reflux overnight. The reaction mixture was cooled in ice. To the mixture was added 10% aqueous sodium sulfite solution, and the resulting mixture was stirred for 20 minutes. The organic layer was separated and washed with water twice, a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL)-methanol (7.5 mL). To the solution was added sodium methoxide (28% methanol solution, 3.75 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=2/3) and column chromatography on aminopropylated silica gel (eluent: ethyl acetate/methanol=9/1−3/2) successively to give the title compound (1.7 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1cccc(Cl)c1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1c(Cl)cccc1CO
Reaction time: 2 h
Yield: 74.8 %

Procedure:
A solution of methyl 2-amino-3-chlorobenzoate(1.7 g, 9.16 mmol) in THF (40 mL) was dropwise added to a suspension of the LAH(521 mg, 13.7 mmol) in THF(15 mL) at room temperature over 10 min under N2, and stirred for 2 hrs. The reaction was carefully quenched with saturated Na2SO4 (10 mL) at 0° C., extracted with Et2O (2×50 mL). The combined organic layers were washes with brine(30 mL), dried on MgSO4, and concentrated on rotary vacuum to afford the expected product as a yellow solid(1.08 g, 75%), which was pure enough to be used in the next step without further purification; 1H NMR (400 MHz, CDCl3) δppm 1.65 (s, 1H), 4.59-4.70 (m, 4H), 6.60-6.65 (m, 1H), 6.96 (dd, J=7.55, 1.26 Hz, 1H), 7.19-7.25 (m, 1H); Mass spec. 158.02 (MH+), Calc. for C7H8ClNO2 157.03.
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:6]([C:16]#[N:17])=[C:5]([Cl:18])[N+:4]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[C:25]1([SH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.O>C(O)C>[Cl-:18].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:6]([C:16]#[N:17])=[C:5]([S:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N+:4]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Sc1ccccc1
Reactant: CCCCCCNc1cc(N)[n+](CCCCCC)c(Cl)c1C#N
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CCCCCCNc1cc(N)[n+](CCCCCC)c(Sc2ccccc2)c1C#N
Reaction time: 16 h
Yield: 51.9 %

Procedure:
3.7 gms (.01 ml) of 2-amino-6-chloro-5-cyano-1-n-hexyl-4-n-hexylamino pyridinium chloride (compound 11 - Table 1) was dissolved in ethanol and 1.1 gm (.01 mole) thiophenol and 1.0 gm (0.01 mole) of triethylamine added. The solution was left 16 hours at room temperature poured into iced water and 2.3 gms (50% yield) of 2-amino-5-cyano-1-n-hexyl-4-n-hexylamino-6-phenylmercapto pyridinium chloride (compound 78 - Table 5) filtered off (MPt 227° -228°C).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([C:34]([CH3:38])([CH3:37])[C:35]#[N:36])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([C:34]([CH3:38])([CH3:37])[C:35]#[N:36])(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: CC(C)(C#N)S(=O)(=O)c1ccccc1Br
Product: CC(C)(C#N)S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 2-((2-bromophenyl)sulfonyl)-2-methylpropanenitrile. MS (ESI): mass calcd. for C20H17FN4O2S, 396.11; m/z found, 397.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 2H), 8.19 (d, J=7.9, 1H), 7.94 (m, 1H), 7.84 (m, 1H), 7.59 (m, 1H), 7.52 (d, J=7.5, 1H), 7.40 (dd, J=11.8, 1.1, 1H), 7.31 (dd, J=7.9, 1.4, 1H), 1.51 (s, 6H).