Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([Cl:9])[S:6][C:5]=1[Cl:10])(=[O:3])[CH3:2].CO[CH2:13][Cl:14]>[Ti](Cl)(Cl)(Cl)Cl.ClCCl>[C:1]([C:4]1[C:8]([CH2:13][Cl:14])=[C:7]([Cl:9])[S:6][C:5]=1[Cl:10])(=[O:3])[CH3:2]
Reactant: COCCl
Reactant: CC(=O)c1cc(Cl)sc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)c1c(Cl)sc(Cl)c1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 266.9 %

Procedure:
33 ml of titanium tetrachloride (a 2 moles/liter dichloromethane solution, 66.0 mmoles) was dropwise added, at 10° C. with ice-cooling, to a solution of 5.0 g (32;4 mmoles) of 3-acetyl-2,5-dichlorothiophene dissolved in 26 ml (323.0 mmoles) of chloromethyl methyl ether. The mixture was stirred at room temperature for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction action. After the completion of the reaction, the reaction mixture was poured into ice water, followed by extraction with chloroform. The resulting organic layer was washed with sodium bicarbonate, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=9/1) to obtain 2.6 g (yield: 39.7%) of 3-acetyl-4-chloromethyl-2,5-dichlorothiophene as yellow crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[NH:17][C:18]1[N:19]=[CH:20][C:21]2[CH2:27][N:26]([C:28](=[O:45])[CH2:29][CH2:30][CH2:31][CH2:32][C:33]3[N:37](C(OC(C)(C)C)=O)[CH:36]=[N:35][CH:34]=3)[CH2:25][CH2:24][C:22]=2[N:23]=1>ClCCl>[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[NH:17][C:18]1[N:19]=[CH:20][C:21]2[CH2:27][N:26]([C:28](=[O:45])[CH2:29][CH2:30][CH2:31][CH2:32][C:33]3[N:37]=[CH:36][NH:35][CH:34]=3)[CH2:25][CH2:24][C:22]=2[N:23]=1
Reactant: CC(C)(C)OC(=O)n1cncc1CCCCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCCc1c[nH]cn1)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Yield: 82.8 %

Procedure:
Add trifluoroacetic acid (1.5 mL) to a solution of tert-butyl 5-[5-[2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-5-oxo-pentyl]imidazole-1-carboxylate (0.030 g; 0.058 mmoles) in dichloromethane (8 mL). Stir the reaction at room temperature for 2 hr. Concentrate the mixture and add saturated sodium bicarbonate (10 mL) and water (20 mL), then extract with dichloromethane (3×20 mL). Wash the combined organic extracts with brine, dry over sodium sulfate, filter, and concentrate. Purify the crude product by column chromatography (0 to 10% methanol in dichloromethane) to afford 1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-5-(1H-imidazol-4-yl)pentan-1-one (0.020 g; 83%) as a white solid: MS (m/z): 417 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([O:24][CH3:25])([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH:13]=1)[CH:4]([NH:6]C(OCC)=O)[CH3:5].[OH-].[K+].O>CO>[CH3:1][O:2][C:3]([O:24][CH3:25])([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH:13]=1)[CH:4]([NH2:6])[CH3:5]
Reactant: CCOC(=O)NC(C)C(OC)(OC)c1ccc2cc(OC)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2cc(C(OC)(OC)C(C)N)ccc2c1
Yield: 60.5 %

Procedure:
653 mg (1.8 mmols) of (-)-1-(6-methoxy-2-naphthyl)-2-(ethoxycarbonyl)amino-1-propanone dimethyl acetal and 5 ml of a 30% aqueous potassium hydroxide solution were heated at reflux in 50 ml of methanol for 5 days. After adding 20 ml of water, the mixture was extracted with ethyl acetate (20 ml×3), and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (Florisil, ethyl acetate) to obtain 300 mg of (+)-1-(6-methoxy-2-naphthyl)-2-amino-1-propanone dimethyl acetal as colorless crystals having a melting point of 84°-86° C. Yield, 58%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:21](=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])=[C:6]([NH:8][C:9](=[O:20])[NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16][C:17](O)=[O:18])[N:15]=2)[CH:7]=1.[CH3:31][NH2:32].C1COCC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:21](=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])=[C:6]([NH:8][C:9](=[O:20])[NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:32][CH3:31])=[O:18])[N:15]=2)[CH:7]=1
Reactant: CN
Reactant: COc1ccccc1C(=O)c1ccc(F)cc1NC(=O)Nc1nc(CC(=O)O)cs1
Solvent: C1CCOC1
Product: CNC(=O)Cc1csc(NC(=O)Nc2cc(F)ccc2C(=O)c2ccccc2OC)n1
Yield: 65 %

Procedure:
2-(2-{3-[5-Fluoro-2-(2-methoxy-benzoyl)-phenyl]-ureido}-thiazol-4-yl)-N-methyl-acetamide (144 mg, 65%) was prepared from (2-{3-[5-fluoro-2-(2-methoxy-benzoyl)-phenyl]-ureido}-thiazol-4-yl)-acetic acid (215 mg, 0.5 mmol) and 1N solution of methyl amine in THF (0.5 mL, 0.5 mmol) following the general procedure K.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[C:30]([F:36])=[CH:31][CH:32]=[CH:33][C:34]=3[F:35])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCNCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-piperazinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.50 g, 0.734 mmol) in DCM (10 mL) was treated with methanesulfonyl chloride (0.074 mL, 0.954 mmol) and stirred at rt for 3 h. Silica was added and concentrated. The residue was column chromatographed with EtOAc/DCM to give title compound of Step C (0.38 g, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.93 (s, 1H), 8.32 (d, J=5.5 Hz, 1H), 7.64-7.74 (m, 1H), 7.42-7.50 (m, 1H), 7.39 (t, J=6.1 Hz, 1H), 7.29-7.35 (m, 1H), 7.25 (t, J=9.1 Hz, 2H), 6.49 (d, J=5.4 Hz, 1H), 3.63-3.76 (m, 4H), 3.27 (t, J=4.7 Hz, 4H), 2.93 (s, 3H). m/z (ES+): 646 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:12])[CH:7]=[C:8]([CH3:11])[C:9]=1[Br:10].S(O[CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])(C1C=CC(C)=CC=1)(=O)=O.O>CN(C=O)C>[CH3:3][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([CH3:11])[C:9]=1[Br:10])[O:12][CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CCOP(=O)(COS(=O)(=O)c1ccc(C)cc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(COc1cc(C)c(Br)c(C)c1)OCC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred suspension of NaH (0.5 g, 22.0 mmol) in anhydrous DMF (20 mL) at 0° C. was added 3,5-dimethyl-4-bromophenol (2.2 g, 11.0 mmol) in DMF (5 mL) followed by diethyl tosyloxymethylphosphonate (3.9 g, 24.2 mmol) in DMF (5.0 mL) 30 min later. The reaction mixture was stirred for 14 h at room temperature and poured into water (30 mL). The aqueous solution was extracted with ethyl acetate (2×100 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (2:3) to afford diethyl (3,5-dimethyl-4-bromophenoxy)methylphosphonate as a syrup. (1.85 g, 48%): 1H NMR (300 MHz, CDCl3): δ 6.88 (s, 2H), 4.15-4.25 (m, 6H), 2.41 (s, 2H), 1.40 (t, J=6.0 Hz, 6H); LC-MS m/z=351[α]3H20BrO4P+H]+; TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (2:3); Rf=0.3.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][S:4]([OH:7])(=[O:6])=[O:5].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>>[CH2:10]([O:9][CH2:8][C@H:2]([NH:1][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:3][S:4]([OH:7])(=[O:6])=[O:5])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](COCc1ccccc1)CS(=O)(=O)O
Product: O=C(N[C@@H](COCc1ccccc1)CS(=O)(=O)O)OCc1ccccc1

Procedure:
(S)-3-Benzyloxy-2-benzyloxycarbonylamino-propane-1-sulfonic acid was prepared by an analogous procedure as described in example 26 iv) starting from 1.76 g (7.19 mmol) (S)-2-amino-3-benzyloxy-propane-1-sulfonic acid and 1.16 ml (1.1 equiv.) benzyl chloroformate. Final purification by preparative RP-HPLC CH3CN/H2O gradient+0.1% TFA) gave pure (S)-3-benzyloxy-2-benzyloxycarbonylamino-propane-1-sulfonic acid as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(N(CC)CC)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1cccc(Br)c1
Reactant: C#CCCCCCCCCCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC#Cc1cccc(C=O)c1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
To a solution of 3-bromobenzaldehyde (26.5 g) and (25.0 g) 1-dodecyne in triethylamine (105 ml) was added bis(triphenylphosphine)palladium(II)chloride (1.73 g) followed by copper(1) iodide (0.24 g). The resultant mixture was stirred in the dark at 55° C. for 7 hrs, under nitrogen. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to yield 37.7 g 3-(1-dodecynyl)benzaldehyde. The filtrate was an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@@H:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:23](N2C=NC=C2)=[O:24])C=1>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:17])[C@@H:7]([N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:23]1=[O:24])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@H](Nc1ccccc1N)C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](C(=O)OC(C)(C)C)n1c(=O)[nH]c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of (S)-2-(2-Amino-phenylamino)-propionic acid tert-butyl ester (1.5 g, 6.3 mmol) in THF (10 mL) was added CDI (1.03 g, 6.3 mmol). The reaction mixture was stirred at room temperature for 1 h. When the reaction was completed, the reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over Na2SO4 and concentrated to afford 1.6 g of the desired product as an oily residue. The LCMS indicated only 40% purity; however, this product was used for the next reaction without further purification. LCMS (ESMS): m/z 263.38 (M+H+).
Reaction SMILES: [NH2:1]/[C:2](/[N:5]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)[CH2:6][CH2:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]([CH3:22])([CH3:21])[C:14]([O:16]C(C)(C)C)=[O:15])=[CH:10][CH:9]=1)=[N:3]\[OH:4].[CH:36]1([C:42](Cl)=O)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:36]1([C:42]2[O:4][N:3]=[C:2]([N:5]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:35])[F:34])=[CH:28][CH:27]=3)[CH2:6][CH2:7][C:8]3[CH:24]=[CH:23][C:11]([O:12][C:13]([CH3:21])([CH3:22])[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=3)[N:1]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)/C(N)=N/O)cc1
Reactant: O=C(Cl)C1CCCCC1
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2noc(C3CCCCC3)n2)cc1)C(=O)O

Procedure:
Similarly prepared from tert-butyl 2-[4-(2-{[(E)-amino(hydroxyimino)methyl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and cyclohexanecarbonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:32]([O:36][C:37]([NH:39][CH2:40][C:41](O)=[O:42])=[O:38])([CH3:35])([CH3:34])[CH3:33]>CC(N(C)C)=O>[C:32]([O:36][C:37](=[O:38])[NH:39][CH2:40][C:41](=[O:42])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([CH:20]4[CH2:21][CH2:22]4)=[O:19])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: Nc1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Temperature: 150 °C

Procedure:
Cyclopropanecarboxylic acid [5-(4-amino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (0.05 g, 0.17 mmol) was dissolved in dimethylacetamide (1 mL), diisopropylethylamine (0.036 mL, 0.204 mmol) and N-(tert-butoxycarbonyl)glycine (0.036 g, 0.204 mmol) were added followed by 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate (0.078 g, 0.204 mmol) and the mixture was heated to 150° C. for 10 min in a microwave. The reaction mixture was transferred to a vial and purified by prep LCMS. LCMS method: 1, RT: 4.08 min, MI: 451 [M+1].
Reaction SMILES: C(S([C:11]1[C:12]2[CH:19]=[CH:18][N:17]([C@H:20]3[CH2:36][C@@H:23]4[O:24][CH:25]([C:28]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=5)[O:26][CH2:27][C@@H:22]4[CH2:21]3)[C:13]=2[N:14]=[CH:15][N:16]=1)(=O)=O)C1C=CC=CC=1.[NH2:37][C@H:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39]1.CCN(C(C)C)C(C)C>C(O)C>[C@H:38]1([NH:37][C:11]2[C:12]3[CH:19]=[CH:18][N:17]([C@H:20]4[CH2:36][C@@H:23]5[O:24][CH:25]([C:28]6[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=6)[O:26][CH2:27][C@@H:22]5[CH2:21]4)[C:13]=3[N:14]=[CH:15][N:16]=2)[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39]1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(S(=O)(=O)Cc6ccccc6)ncnc54)C[C@@H]3O2)cc1
Reactant: N[C@@H]1CCc2ccccc21
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(N[C@@H]6CCc7ccccc76)ncnc54)C[C@@H]3O2)cc1
Temperature: 110 °C
Yield: 73.3 %

Procedure:
In a 0.5-2 mL microwave vial, 4-(benzylsulfonyl)-7-[(4aS,6R,7aS)-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-6-yl]-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.198 mmol), (R)-(−)-1-aminoindan (0.127 mL, 0.989 mmol), and DIPEA (0.172 mL, 0.989 mol) were dissolved in ethanol (1.22 mL). The vial was sealed and heated to 110° C. overnight. The solution was then concentrated in vacuo and the resulting material was purified via silica gel chromatography eluting with a gradient of 20 to 50% EtOAc in hexanes to afford the product as an orange oil (70.0 mg, 73%). LC/MS: Rt=1.42 min, ES+ 483 (FA standard).
Reaction SMILES: [F:1][C:2]1([F:40])[CH2:5][C:4]([NH:32]C(=O)OC(C)(C)C)([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:20][C:19]4[C:18]5=[N:28][N:29]=[C:30]([OH:31])[N:17]5[CH:16]=[CH:15][C:14]=4[N:13]=3)=[CH:8][CH:7]=2)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[NH2:32][C:4]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:20][C:19]4[C:18]5=[N:28][N:29]=[C:30]([OH:31])[N:17]5[CH:16]=[CH:15][C:14]=4[N:13]=3)=[CH:10][CH:11]=2)[CH2:5][C:2]([F:1])([F:40])[CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccn5c(O)nnc5c4cc3-c3ccccc3)cc2)CC(F)(F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: NC1(c2ccc(-c3nc4ccn5c(O)nnc5c4cc3-c3ccccc3)cc2)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl {3,3-difluoro-1-[4-(3-hydroxy-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (5-20) (11 mg, 0.021 mmol) in CHCl3 (0.5 mL) was added TFA (0.5 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography (Sunfire C18) eluting with 5 to 95% acetonitrile/(0.1% TFA/water) gradient. The appropriate fractions were free based by suspending in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 8-[4-(1-amino-3,3-difluorocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-3-ol (5-21) as a yellow oil. HRMS (M+H)+: observed=444.1636, calculated=444.1653.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].C1(C)C(C)=CC=CC=1>>[Cl:10][C:9]1[C:4]([F:1])=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: [F-]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: [K+]
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1cccc(Cl)c1F
Temperature: 150 °C
Reaction time: 6 h

Procedure:
In a 1-liter flange flask fitted with a distillation bridge and stirrer, 139 g (2.4 mol) of potassium fluoride were introduced at 120° C. into the melt of 576 g (3.0 mol) of 2,3-dichloronitrobenzene. Subsequently, 20 g (0.19 mol) of xylene were added and the reaction suspension was azeotropically dried by application of a vacuum of 60 mbar and heating to 150° C. After the xylene had been distilled off, the distillation bridge was replaced by a reflux condenser, the reaction suspension was heated to 190° C. and stirred for 6 hours at this temperature. Amount of 3-chloro-2-fluoronitrobenzene formed: 0.5 GC area-% after 6 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:23]([C:24]([O:26]C)=[O:25])=[C:16]3[CH2:17][CH:18]([O:20][CH2:21][CH3:22])[O:19][C:15]3=[CH:14][CH:13]=2)[N:4]=1.[OH-].[Na+].O>CS(C)=O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:23]([C:24]([OH:26])=[O:25])=[C:16]3[CH2:17][CH:18]([O:20][CH2:21][CH3:22])[O:19][C:15]3=[CH:14][CH:13]=2)[N:6]=1
Reactant: CCOC1Cc2c(ccc(Oc3nc(OC)cc(OC)n3)c2C(=O)OC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOC1Cc2c(ccc(Oc3nc(OC)cc(OC)n3)c2C(=O)O)O1
Reaction time: 0.17 h
Yield: 86.6 %

Procedure:
While stirring 1.2 g of methyl 5-(4,6-dimethoxypyrimidin-2-yl)oxy-2-ethoxy-2,3-dihydrobenzofuran-4-carboxylate in 20 ml of dimethylsulfoxide at room temperature, 2 ml of a 2N sodium hydroxide aqueous solution was dropwise added thereto over a period of 10 minutes and then the mixture was further stirred for 15 hours. The mixture was poured into water and extracted with diethyl ether. Then, the aqueous layer was acidified with 10% hydrochloric acid, and precipitated crystals were extracted with ethyl acetate, and the organic layer was washed with water and then dried over anhydrous sodium sulfate. It was concentrated under reduced pressure, and the oily substance thereby obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to obtain 1.0 g (yield: 87%) of the desired compound.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][S:7][C:6]1=[CH:11][N+:12]([O-:14])=[O:13])(=[O:4])=[O:3].[Cl:15]N1C(=O)CCC1=O>ClC(Cl)C>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][S:7][C:6]1=[C:11]([Cl:15])[N+:12]([O-:14])=[O:13])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N1CCCSC1=C[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(Cl)Cl
Product: CS(=O)(=O)N1CCCSC1=C(Cl)[N+](=O)[O-]

Procedure:
A stirred solution of 0.238 g of (1A), 0.15 g of N-chlorosuccinimide and about 1 mg of azoisobutyronitrile in 10 ml of dichloroethane was refluxed overnight. The resulting mixture was cooled, washed with water, dried (MgSO4) and stripped of solvent, giving a yellow oil. The oil was flash-chromatographed over silica gel, using methylene chloride as eluent, to give (2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[N:27][CH:28]=[C:29]([CH:33]=2)[C:30](O)=[O:31])[N:21]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:30](=[O:31])[C:29]3[CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=[N:27][CH:28]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1csc(-c2ccc(F)cc2)n1
Product: CC(C)(CNC(=O)c1cncc(-c2noc(C(F)(F)F)n2)c1)c1csc(-c2ccc(F)cc2)n1
Yield: 26 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropan-1-amine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (50 mg, yield 26%). 1H NMR (400 MHz, MeOD) δ 9.36 (d, J=2.0 Hz, 1H), 9.11 (d, J=2.3 Hz, 1H), 8.77-8.76 (t, J=2.1 Hz, 1H), 8.00-7.96 (m, 2H), 7.30 (s, 1H), 7.18-7.14 (t, J=8.8 Hz, 2H), 3.75 (s, 2H), 1.50 (s, 6H). MS (ESI) m/z: Calculated for C22H17F4N5O2S: 491.10. found: 492.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH:20]=O)[CH:14]=1)[CH2:8][CH:9]([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2].[CH:23]1([NH2:26])[CH2:25][CH2:24]1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH2:20][NH:26][CH:23]2[CH2:25][CH2:24]2)[CH:14]=1)[CH2:8][CH:9]([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(C=O)c1)CC(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)c(CNC2CC2)c1)CC(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
A mixture of (4-chloro-3-formyl-benzyl)-(2,2-difluoro-ethyl)-carbamic acid tert-butyl ester (563 mg, 1.69 mmol) and cyclopropylamine (0.180 mL, 2.52 mmol) in MeOH (18 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt. NaBH4 (96 mg, 2.53 mmol) was added by portions, and the reaction was stirred for 1 h. The solvents were removed under reduced pressure, and the resulting oil was diluted with EtOAc. The mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 95:5) yielded the title compound (558 mg, 88%). LC-MS: tR=0.76 min; ES+: 375.17.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][C@@H:11]([CH3:15])[C:12]([OH:14])=[O:13])=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:15][C@@H:11]([C:12]([OH:14])=[O:13])[CH2:10][C@@H:9]([C:16]([OH:18])=[O:17])[NH2:8]
Reactant: C[C@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)O)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](C[C@H](N)C(=O)O)C(=O)O
Reaction time: 48 h

Procedure:
The Boc-protected diacid, (2S, 4R)-N-t-butoxycarbonyl- 4-methyl glutamic acid, was subjected to a mixture of trifluoroacetic acid:methylene chloride (40:60, 100 mL) for 3 hr at room temperature. The volatiles were removed in vacuo and the residue was azeotroped with toluene (50 mL). Water (150 mL) was added and the aqueous phase extracted with a 5% solution of trioctylamine in chloroform (3 x 200 mL). The combined organic phases were washed with water (50 mL) and the combined aqueous phases evaporated by being placed on a lyophilizer for 48 hr to give the product (4.6 g, 66% in two steps) as a white foam which was recrystallized in acetone and water. mp=169°-170° C., 1H NMR (200 MHz, D2O): δ 3.80 (dd, J=7.3, 7.3 Hz, 1H), 2.55 (m, 1H), 2.15 (ddd, J=14.7, 8.7, 6.6 Hz, 1H), 1.75 (ddd, J=14.6, 7.4, 5.4 Hz, 1H), 1.05 (d, J=7.0 Hz, 3H). Anal. Calculated for C6H11NO4 : C, 44.71; H, 6.88; N, 8.69. Found: C, 44.59; H, 6.85; N, 8.61.