Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][CH2:5][CH2:6][C:7]1[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][NH:10][CH:11]=1.[Li+].[OH-].Cl>O1CCOCC1.O.CCOC(C)=O>[CH3:15][O:14][C:12]([C:8]1[C:7]([CH2:6][CH2:5][CH2:4][C:3]([OH:16])=[O:2])=[CH:11][NH:10][CH:9]=1)=[O:13]
Reactant: COC(=O)CCCc1c[nH]cc1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1c[nH]cc1CCCC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
Methyl 4-(4-methoxy-4-oxobutyl)-1H-pyrrole-3-carboxylate (50 mg, 0.220 mmol) was suspended in anhydrous dioxane (2 mL) and H2O (0.5 mL) and LiOH (5.3 mg, 0.220 mmol) was added. The reaction mixture was stirred at room temperature for 4 h. Reaction solution was acidified with 1N HCl and AcOEt (50 mL) and H2O (20 mL) were added. Acqueous layer was extracted with AcOEt and the combined organic layers anidrified on Na2SO4, filtered and concentrated to give 46 mg (quantitative yield) of the title compound as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][CH:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=2[S:28]([CH3:31])(=[O:30])=[O:29])[C:4]=1[C:32](OCC)=[O:33].[CH2:37]([NH2:39])[CH3:38]>C(#N)C>[CH2:37]([N:39]1[C:32](=[O:33])[C:4]2[CH:5]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=3[S:28]([CH3:31])(=[O:29])=[O:30])[NH:6][C:7](=[O:19])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=3)[C:3]=2[CH2:2]1)[CH3:38]
Reactant: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(C)(=O)=O
Reactant: CCN
Solvent: CC#N
Product: CCN1CC2=C(C1=O)C(c1ccc(C#N)cc1S(C)(=O)=O)NC(=O)N2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(rac)-Ethyl 6-(bromomethyl)-4-[4-cyano-2-(methylsulfonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (200 mg, 0.34 mmol; Example 13A) was dissolved in acetonitrile (5 ml), ethylamine (46.1 mg, 1.02 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was then purified directly by preparative HPLC (column: Kromasil C18, 125 mm×20 mm, 5 μm, 100 Å; mobile phase A: water with 0.01% formic acid, mobile phase B: acetonitrile; gradient: 0 min 10% B→2 min 10% B→9 min 90% B→12 min 90% B→12.1 min 10% B→15 min 10% B; flow rate: 0.35 ml/min; UV detection: 254 nm). This gave 120 mg (70% of theory) of the title compound.
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][SH:4].C(=O)([O-])[O-].[K+].[K+].F[C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[C:20]([N:29]([CH3:31])[CH3:30])([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:21])=[CH:15][CH:14]=1>CC(N(C)C)=O>[SH:4][CH2:3][CH2:2][CH2:1][S:5][C:18]1[CH:17]=[C:16]([C:19](=[O:32])[C:20]([N:29]([CH3:30])[CH3:31])([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH3:21])[CH:15]=[CH:14][CH:13]=1
Reactant: SCCCS
Reactant: CN(C)C(C)(Cc1ccccc1)C(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CN(C)C(C)(Cc1ccccc1)C(=O)c1cccc(SCCCS)c1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
22.8 g (0.21 mol) of 1,3-propanedithiol is dissolved in 50 ml of dry dimethylacetamide, 4.8 g of potassium carbonate are added and the mixture is heated to about 50° C. 10.0 g of 1-(4-fluorophenyl) 2-dimethylamino-2-benzyl-propan-1-one in 50 ml of dry dimethylacetamide are added dropwise. The suspension is stirred at 50° C. for 12 h, the solid is filtered off. The excess 1,3-propandithiol and dimethylacetamide are distilled off. To the residue toulene is added and the resulting precipitate is filtered off. After the toluene is distilled off, the residue is purified by column chromatography on silica gel with ethyl acetate-hexane (1:9) as eluent. The structure is confirmed by the 1H-NMR-spectrum, measured in CDCl3. The signals (δ in ppm) are 1.16 (s,3H), 1.40 (t, 1H), 2.02 (m,2H), 2.34 (s,6H), 2.71 (q,2H), 2.96 (d, 1H), 3.14 (t,2H), 3.68 (d,1H), 6.88 (m,2H), 7.12 (m,3H), 7.29 (d,2H), 8.44 (d,2H).
Reaction SMILES: [SH:1][C:2]1[NH:6][CH:5]=[N:4][N:3]=1.Cl[C:8]1[CH:9]=[CH:10][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:18][C:19]3[S:23][N:22]=[C:21]([CH3:24])[N:20]=3)[C:16]=2[N:17]=1.C(O[K])(C)(C)C.O>CN(C)C(=O)C>[N:4]1[N:3]=[C:2]([S:1][C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:18][C:19]4[S:23][N:22]=[C:21]([CH3:24])[N:20]=4)[C:16]=3[N:17]=2)[NH:6][CH:5]=1
Reactant: Sc1nnc[nH]1
Reactant: Cc1nsc(Nc2ncnc3ccc(Cl)nc23)n1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nsc(Nc2ncnc3ccc(Sc4nnc[nH]4)nc23)n1
Temperature: 130 °C
Reaction time: 16 h
Yield: 2.4 %

Procedure:
3-Mercapto-4H-[1,2,4]triazole (54 mg; 0.54 mmol) and 100 mg (0.36 mmol) of (6-chloro-pyrido[3,2-d]pyrimidin-4-yl)-3-methyl-[1,2,4]thiadiazol-5-yl-amine were added to a solution of 80 mg (0.72 mmol) of tert-butoxy potassium in 3 ml of N,N-dimethylacetamide and the mixture was stirred at 130° C. for 16 hours. Water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was dried and concentrated and the resulting residue was purified by a reversed phase preparative HPLC (0.1% TFA-containing water:acetonitrile=90:10→10:90) to give 3 mg (yield: 2%) of the title compound as a yellow solid.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]([CH3:24])=[C:22]3[C:17]([C:18](=O)[NH:19][N:20]=[C:21]3[CH3:25])=[C:16]2[CH3:27])=[CH:11][CH:10]=1)[CH3:7]>>[Cl:3][C:18]1[C:17]2=[C:16]([CH3:27])[N:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:6][CH3:7])=[CH:10][CH:11]=3)[C:23]([CH3:24])=[C:22]2[C:21]([CH3:25])=[N:20][N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1ccc(-n2c(C)c3c(C)n[nH]c(=O)c3c2C)cc1
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(Cl)c3c2C)cc1
Temperature: 25 °C

Procedure:
A solution of POCl3 (15 mL) and 6-(4-ethoxyphenyl)4,5,7-trimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (1.5 g) were combined and heated at reflux for 48 h. The reaction mixture was allowed to cool to rt, and was quenched by the careful addition of water (50 mL) followed by a saturated aqueous solution NaHCO3 (50 mL). The reaction mixture was extracted with CH2Cl2 (5×50 mL), and the combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to yield 1-chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine as a yellow/green solid. MS (ESI) 316 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:10]2[N:11]=[C:12]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:15]=3)=[C:9]2[CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[H][H]>C(O)C.[Pd]>[CH2:21]([NH:20][C:16]1[N:15]=[C:14]([C:13]2[C:12]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)=[N:11][N:10]3[C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[CH:6][CH:7]=[CH:8][C:9]=23)[CH:19]=[CH:18][N:17]=1)[CH2:22][CH2:23][CH3:24]
Reactant: C=CCNc1cccc2c(-c3ccnc(NCCCC)n3)c(-c3ccc(F)cc3)nn12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(NCCC)cccc23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a solution of N-allyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-7-amine (80 mg, 0.19 mmol) in ethanol (5 mL) was added palladium on carbon (10%, 8 mg). The mixture was stirred overnight at room temperature under a balloon filled with hydrogen. The reaction was filtered through a pad of Celite and concentrated to give 3-[2-(butylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-propylpyrazolo[1,5-α]pyridin-7-amine (79 mg, 99%) as a gold foam. 1H NMR (CDCl3): δ 8.03 (d, 1H), 7.74 (d, 1H), 7.69 (m, 2H), 7.33 (t, 1H), 7.15 (t, 2H), 6.30 (d, 1H), 6.08–6.01 (m, 2H), 5.08 (broad, 1H), 3.47 (q, 2H), 3.37 (q, 2H), 1.87–1.41 (m, 6H), 1.08 (t, 3H), 0.99 (t, 3H); 19F NMR (CDCl3) δ −113.44; MS m/z 419 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][CH:4]=1)#[N:2].[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[NH:20]1[C:1]([C:3]2[CH:19]=[CH:18][C:6]([O:7][C:8]3[CH:9]=[CH:10][C:11]4[B:15]([OH:16])[O:14][CH2:13][C:12]=4[CH:17]=3)=[CH:5][CH:4]=2)=[N:2][N:22]=[N:21]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OB1OCc2cc(Oc3ccc(-c4nnn[nH]4)cc3)ccc21
Temperature: 80 °C
Reaction time: 48 h
Yield: 23.5 %

Procedure:
A mixture of 5-(4-cyanophenoxy)-1-hydroxy-2,1-benzoxaborole (200 mg, 0.797 mmol), sodium azide (103 mg, 1.59 mmol), and ammonium chloride (85 mg, 1.6 mmol) in N,N-dimethylformamide (5 mL) was stirred at 80° C. for two days. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) followed by trituration with ethyl acetate to give the target compound (55 mg, 23%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(OCC)(=O)C>[O:26]=[C:24]([NH:1][C:2]1[N:10]=[C:9]2[C:5]([C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1)[CH3:25]
Reactant: Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Temperature: 23 °C

Procedure:
6-Amino-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (17) (50 mg, 0.164 mmol) and acetic anhydride (0.5 mL) were warmed to 60° C. for 1 h. After cooling to 23° C., the reaction was diluted with ethyl acetate (50 mL), washed with NaOH (1 N, 50 mL), and dried (Na2SO4). Concentration in vacuo afforded 6-(1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (57): Mass Spectrum (CI) 347 (MH+).
Reaction SMILES: [N:1]([C@@:4]12[C@H:21]3[C@@H:12]([C@:13]4([CH3:34])[C@H:18]([CH2:19][CH2:20]3)[CH2:17][C@@H:16]([O:22][C@@H:23]3[O:32][C@@H:31]([CH3:33])[C@H:29]([OH:30])[C@@H:27]([OH:28])[C@H:24]3[O:25][CH3:26])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C@:8]1([CH3:9])[C@@H:7]([C:35]([O:37][CH3:38])=[O:36])[CH2:6][CH2:5]2)=[N+]=[N-].O.NN>>[NH2:1][C@@:4]12[C@H:21]3[C@@H:12]([C@:13]4([CH3:34])[C@H:18]([CH2:19][CH2:20]3)[CH2:17][C@@H:16]([O:22][C@@H:23]3[O:32][C@@H:31]([CH3:33])[C@H:29]([OH:30])[C@@H:27]([OH:28])[C@H:24]3[O:25][CH3:26])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C@:8]1([CH3:9])[C@@H:7]([C:35]([O:37][CH3:38])=[O:36])[CH2:6][CH2:5]2
Reactant: COC(=O)[C@H]1CC[C@]2(N=[N+]=[N-])[C@@H]3CC[C@@H]4C[C@@H](O[C@@H]5O[C@@H](C)[C@H](O)[C@@H](O)[C@H]5OC)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: NN
Solvent: O
Product: COC(=O)[C@H]1CC[C@]2(N)[C@@H]3CC[C@@H]4C[C@@H](O[C@@H]5O[C@@H](C)[C@H](O)[C@@H](O)[C@H]5OC)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
115 mg of the 14β-azido-3β-[(2'-O-methyl)-α-(L)-rhamnopyranosyloxy]-5β-androstane-17β-carboxylic acid, methyl ester obtained as indicated above are treated with hydrazine hydrate in the presence of a catalyst according to the method of Example 15, and 14β-amino-3β-[(2'-O-methyl)-α-(L)-rhamnopyranosyloxy]-5β-androstane-17β-carboxylic acid, methyl ester is obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]([C@@H:5]1[CH2:9][C@H:8]([SH:10])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])=[O:4].C([N-]C1CCCCC1)(C)C.Br[Mg+].C(N(CC)C(C1C=CC=CC=1S([C:50]1[C@H:51]([CH3:74])[C@@H:52]2[C@@H:69]([C@H:70]([OH:72])[CH3:71])[C:68](=[O:73])[N:53]2[C:54]=1[C:55]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][C:62]([N+:65]([O-:67])=[O:66])=[CH:61][CH:60]=1)=[O:56])=O)=O)C.[Cl-].[NH4+]>O.O1CCCC1>[CH3:1][N:2]([CH3:24])[C:3]([C@H:5]1[N:6]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])[CH2:7][C@@H:8]([S:10][C:50]2[C@H:51]([CH3:74])[C@@H:52]3[C@@H:69]([C@H:70]([OH:72])[CH3:71])[C:68](=[O:73])[N:53]3[C:54]=2[C:55]([O:57][CH2:58][C:59]2[CH:60]=[CH:61][C:62]([N+:65]([O-:67])=[O:66])=[CH:63][CH:64]=2)=[O:56])[CH2:9]1)=[O:4]
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Reactant: CN(C)C(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CC(C)[N-]C1CCCCC1
Agent: [Cl-]
Agent: [Mg+]Br
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N(C)C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 0.17 h
Yield: 64.2 %

Procedure:
3 ml of a tetrahydrofuran solution containing 347 mg (0.982 mmol) of (2S,4S)-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-4-mercaptopyrrolidine were cooled in an ice bath, and then 0.97 ml (0.97 mmol) of a tetrahydrofuran solution containing 1M of bromomagnesium isopropylcyclohexylamide were added dropwise to the cooled solution over a period of 4 minutes, after which the mixture was stirred for 10 minutes. 2 ml of a tetrahydrofuran solution containing 464 mg of the crude 4-nitrobenzyl (1R, 5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-hydroxyethyl]-1-carbapen-2-em-3-carboxylate prepared as described in step (a) above was then added to the solution, and the resulting solution was stirred for a further 30 minutes. At the end of this time, a saturated aqueous solution of ammonium chloride was added, followed by water, and then the reaction mixture was extracted with ethyl acetate 3 times. The organic layers were collected, combined and washed with water and then with a saturated aqueous solution of sodium chloride. The solvent was then removed by distillation under reduced pressure, and the resulting oily residue was subjected to column chromatography through 50 g of silica gel. Elution with a 1:9 by volume mixture of methanol and ethyl acetate afforded 365 mg of the title compound as a foam-like solid (a yield of 62% in terms of the compound of Example 37).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][N:11]=1.C(N(CC)CC)C>C1COCC1>[Cl:9][C:10]1[N:15]=[C:14]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][N:11]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc(Cl)nc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under external cooling with ice, 2.22 g (20.0 mmol) 4-fluoroaniline is added dropwise to a solution of 4.46 g (23.0 mmol) 2,4-dichloro-5-nitropyrimidine in 20 ml THF. Then a solution of 2.77 ml (20.0 mmol) triethylamine in 5 ml THF is added slowly under external cooling with ice. The reaction mixture is stirred for 1 hour at room temperature. The precipitate is filtered off and washed with THF. The filtrate is evaporated and crystallized from tert-butyl-methylether giving (2-chloro-5-nitro-pyrimidin-4-yl)-(4-fluoro-phenyl)-amine as yellow crystals; HPLC/MS (B): 2.26 min, [M+H] 269;
Reaction SMILES: S(=O)(=O)(O)[O-].[K+].[C:7]([O:11][C:12]([NH:14][C@@H:15]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:16]([O-:18])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH:26]1([NH2+]C2CCCCC2)CCCCC1.C[Si](C=[N+]=[N-])(C)C.CCCCCC>CCOCC>[CH3:26][O:17][C:16](=[O:18])[C@@H:15]([NH:14][C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1
Reactant: C1CCC([NH2+]C2CCCCC2)CC1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)[O-])c1ccc(Cl)cc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: CCCCCC
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
A 0.5 N potassium bisulfate aqueous solution (4.0 mL) was added to a suspension of dicyclohexylammonium (S)-t-butoxycarbonylamino-(4-chloro-phenyl)acetate (307 mg, 0.657 mmol) in ether (8.0 mL) at room temperature, and the mixture was stirred for 10 minutes. Then, the ether layer was separated, and the aqueous layer was extracted with ether (2×8 mL) and combined with the organic layer. The ether layer was washed with water (12 mL), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was dissolved in benzene (1.8 mL) and methanol (0.9 mL). A solution of trimethylsilyldiazomethane in hexane (2 M, 0.36 mL, 0.72 mmol) was added dropwise under cooling with ice over five minutes, and then the mixture was stirred under cooling with ice for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=5/1) to give the title compound (190 mg, 96%).
Reaction SMILES: [F:1][C:2]([F:24])([C:10]([F:23])([F:22])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4][C:5](OCC)=[O:6].FC(F)(CCC1C=CC=CC=1)CO>>[F:1][C:2]([F:24])([C:10]([F:22])([F:23])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: CCOC(=O)CCC(F)(F)C(F)(F)COCCCc1ccccc1
Agent: OCC(F)(F)CCc1ccccc1
Product: OCCCC(F)(F)C(F)(F)COCCCc1ccccc1
Yield: 77.4 %

Procedure:
Obtained from Intermediate 40 (1.0 g, 2.85 mmol) by the procedure described in Intermediate 2. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (from 10:1 to 5:1) as eluent gave the title compound (0.68 g, 82%) as oil,
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[NH:5][C:6]([CH2:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1)=[O:7].[CH2:25]=C[C@@H]1[C@@H]2C[C@@H]([C@H](O)C3C=CN=C4C=CC=CC=34)N(CC2)C1.CO>C(O)C>[CH3:24][C:22]1[CH:21]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:23]=1)[NH:5][C:6]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH2:18][CH3:25])[C:15]([OH:17])=[O:16])=[CH:19][CH:20]=1)=[O:7]
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Reactant: Cc1cc(C)cc(NC(=O)Cc2ccc(OC(C)C(=O)O)cc2)c1
Solvent: CCO
Solvent: CO
Product: CCC(Oc1ccc(CC(=O)Nc2cc(C)cc(C)c2)cc1)C(=O)O
Temperature: 25 °C

Procedure:
Following the same procedure as described for (−) (18), cinchonidine (8.61 g, 29.3 mmol) in hot ethanol (175 mL) was added to a solution of (±)20 (10.0 g, 29.3 mmol) in hot ethanol. The solution was allowed to cool to room temperature and a portion of the solvent was removed under reduced pressure. Crystals obtained were collected by filtration, 6.6 g, mp 204-205° C. The optical rotation was measured at 21° C.: [α]D−73.3° (c=0.5, methanol). The salt was recrystallized from ethanol to give fluffy white crystals, 3.7 g, mp 206-207° C. The optical rotation was measured at 21° C.: [α]D−74.2° (c=0.5, methanol). The acid was recovered from salt, as described previously for (−)18, to obtain a white solid, 1.7 g. mp 150-15 1° C. The optical rotation was measured at 21° C.: [α]D−28.4° (c=1.2, methanol). Anal:(C20H23NO4); Calculated C 70.36, H 6.79, N 4.10; found C 70.17, H 6.86 and N 4.05
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[NH2:20][C:21]1[N:26]=[C:25](Cl)[C:24]([C:28]#[N:29])=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CC(O)C.CO>[NH2:20][C:21]1[N:26]=[C:25]([NH:12][C@H:10]([C:8]2[N:7]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:6]3[CH:19]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[C:24]([C:28]#[N:29])=[CH:23][N:22]=1
Reactant: N#Cc1cnc(N)nc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC(C)O
Product: C[C@H](Nc1nc(N)ncc1C#N)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Yield: 63 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine.2HCl (85 mg, 0.259 mmol), 2-amino-4-chloropyrimidine-5-carbonitrile (40 mg, 0.26 mmol) and DIPEA (222 μL, 1.29 mmol) in IPA (0.75 mL) was heated at 90° C. in a sealed vial for 21 h. After cooling to RT, the crude mixture was diluted with MeOH and loaded into an Isolute®SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in DCM) followed by trituration from EtOAc/Et2O/cyclohexane to afford 362 as a white solid (61 mg, 63%). LCMS (Method K): RT 3.47 min [M+H]+ 374.02. 1H NMR (DMSO-d6, 400 MHz): δ 8.08 (1H, s), 7.74 (1H, dd, J=8.80, 4.85 Hz), 7.68 (1H, d, J=7.49 Hz), 7.58-7.52 (5H, m), 7.16-6.70 (4H, m), 5.51 (1H, m), 1.47 (3H, d, J=6.80 Hz)
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:15])[CH3:14]>C(Cl)Cl>[CH:13]([N:16]1[CH2:21][CH2:20][N:19]([C:10]([C@@H:8]2[CH2:9][C@H:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:11])[CH2:18][CH2:17]1)([CH3:15])[CH3:14]
Reactant: CC(C)N1CCNCC1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)[C@@H]2C[C@H]2c2ccccc2)CC1
Reaction time: 15 h
Yield: 81.9 %

Procedure:
To a stirring anhydrous DCM (3.5 mL) solution of trans-2-phenyl-1-cyclopropanecarbonyl chloride (0.096 ml, 0.56 mmol), which is commercially available from, for example, Sigma-Aldrich Corporation (P.O. Box 14508, St. Louis, Mo. 63178), under an argon (g) atmosphere was added the 1-isopropylpiperazine (0.167 ml, 1.17 mmol), which is commercially available from, for example, Sigma-Aldrich, in one portion at ambient temperature, wherein the reaction was allowed to stir for ca. 15 h before being washed with dilute aq. K2CO3 (1×2 mL), H2O (2×2 mL), dried over MgSO4, filtered and concentrated in vacuo. The resulting gum was subjected to flash chromatography (basic alumina-24 g; gradient elution: 30-10% EtOAc/Hexane over 14 min at 30 mL/min) to give 125 mg title compound as a colorless tacky solid (82% yield). m/z (ES+) M+1=273.2; HPLC tR=1.44 min. 1H NMR (500 MHz, CDCl3) δ 7.29-7.24 (m, 2H), 7.20-7.16 (m, 1H), 7.10 (d, J=7.0 Hz, 2H), 3.68-3.55 (m, 4H), 2.70 (ddd, J=12.9, 6.7, 6.6 Hz, 1H), 2.54-2.43 (m, 5H), 1.96 (ddd, J=8.4, 5.3, 4.3 Hz, 1H), 1.65 (ddd, J=9.2, 5.3, 4.3 Hz, 1H), 1.25 (ddd, J=8.4, 6.3, 4.3 Hz, 1H), 1.03 (d, J=6.7 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([NH2:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C[CH2:14][N:15]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN>CN(C=O)C.C(OCC)(=O)C>[NH2:12][C:8]1[C:9]([F:11])=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([NH:15][CH3:14])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1cc(C(=O)O)c(F)cc1F
Agent: CN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(N)c(F)cc1F
Reaction time: 2 h
Yield: 40.8 %

Procedure:
To a solution of 2,4-difluoro-5-aminobenzoic acid (1.73 g, 10.0 mmol) in DMF (40 mL) were successively added EDCI (1.62 g, 12.0 mmol), HOBt (2.30 g, 12.0 mmol) and methylamine (6.0 mL, 12.0 mmol, 2 M in MeOH) in that order at RT. After stirring for 2 h, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with NaHCO3 (3×50 mL) followed by 10% LiCl (50 mL). The organic layer was dried, filtered and concentrated to afford 5-amino-2,4-difluoro-N-methylbenzamide (0.76 g, 41%) as a light brownish solid. MS (M+H)+=187. It was used without further purification (>92% pure by HPLC).