Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][NH:16][CH3:17].C1COCC1>>[CH3:15][N:16]([CH3:17])[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)c1nc(C(F)(F)F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
A mixture of 2-chloro-6-(trifluoromethyl)nicotinic acid (APOLLO, 2.5 g, 11.1 mmol) and 2M N-methylmethanamine in THF solvent (50 ml, 25 mmol) was stirred for 24 hours at room temperature according to J. Med. Chem., 2005, 48, 71. Then the reaction mixture was evaporated in vacuo to give the title compound (2.5 g, 96%).
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].C([O-])([O-])=O.[Cs+].[Cs+].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>CN(C=O)C>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:8][C:5]1[C:6](=[O:7])[CH:1]=[C:2]([CH2:9][OH:10])[O:3][CH:4]=1
Reactant: BrCCCCCBr
Reactant: O=c1cc(CO)occ1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1cc(CO)occ1OCCCCCBr
Temperature: 110 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
Kojic acid (2 g, 14.1 mmol), Cs2CO3 (4.6 g, 14.1 mmol) and DMF (12 mL) were charged in a 100 ml round-bottomed flask equipped with a magnetic stirrer. 1,5-Dibromopentane (8.1 g, 35.2 mmol) was added and the reaction mixture was stirred for 2 h at 110° C. After evaporation of DMF, the reaction mixture was poured in 50 mL of H2O, extracted with CH2Cl2 (2×100 mL). The organic layer was washed with brine (2×20 mL), dried over MgSO4, filtered and evaporated to dryness. The crude compound was purified by column chromatography (SiO2; CH2Cl2:MeOH 99:1 to 95:5) to give after evaporation 5-(5-bromopentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 10 (1.9 g, 46% yield) as a brown oil.
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[CH:19][C:18]([C:21]([NH:23][C@H:24]3[C@@H:28]([OH:29])[CH2:27][NH:26][CH2:25]3)=[O:22])=[CH:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1.Cl[C:31]1[CH:36]=[C:35]([C:37]([C:39]2[S:40][CH:41]=[CH:42][N:43]=2)=[O:38])[CH:34]=[CH:33][N:32]=1>C(O)CCC>[F:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[CH:19][C:18]([C:21]([NH:23][C@H:24]3[C@@H:28]([OH:29])[CH2:27][N:26]([C:31]4[CH:36]=[C:35]([C:37]([C:39]5[S:40][CH:41]=[CH:42][N:43]=5)=[O:38])[CH:34]=[CH:33][N:32]=4)[CH2:25]3)=[O:22])=[CH:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(c1ccnc(Cl)c1)c1nccs1
Reactant: O=C(N[C@@H]1CNC[C@@H]1O)c1cnc(-c2cccc(F)c2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: O=C(N[C@@H]1CN(c2cc(C(=O)c3nccs3)ccn2)C[C@@H]1O)c1cnc(-c2cccc(F)c2)nc1
Temperature: 85 °C
Yield: 34 %

Procedure:
To a vial was added cis-2-(3-fluorophenyl)-N-(4-hydroxypyrrolidin-3-yl)pyrimidine-5-carboxamide-TFA salt (50 mg, 0.12 mmol), n-butanol (0.2 mL), TEA (0.016 mL, 0.12 mmol) and (2-chloropyridin-4-yl)(thiazol-2-yl)methanone (40.5 mg, 0.18 mmol. The reaction mixture was heated to 85° C. for 4 hrs and then cooled to rt. The residue mixture was purified by RP-HPLC to give the desired product, cis-2-(3-fluorophenyl)-N-(4-hydroxy-1-(4-(thiazole-2-carbonyl)pyridin-2-yl)pyrrolidin-3-yl)pyrimidine-5-carboxamide (20 mg, 34%). HRMS (M+H) expected=491.1302, observed=491.1357.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1C=C2OCOC2=C[C:20]=1[C:28](=O)C)=[O:17])(=[O:10])=[O:9].[NH2:32][C:33]1[CH:38]=[CH:37]C(C)=CN=1>>[Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1[N:32]=[CH:33][C:38]([CH3:37])=[CH:28][CH:20]=1)=[O:17])(=[O:9])=[O:10]
Reactant: CC(=O)c1cc2c(cc1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl)OCO2
Reactant: Cc1ccc(N)nc1
Product: Cc1ccc(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)nc1

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3-methyl-6-pyridyl)aminocarbonyl]thiophene-3-sulfonamide was prepared by the method set forth for N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide (EXAMPLE 148), except that 2-amino-5-picoline was used instead of 2'-amino-4',5'-(methylenedioxy)acetophenone, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3-methyl-6pyridyl)aminocarbonyl]thiophene-3-sulfonamide was obtained, via HPLC purification of the crude reaction mixture, as a bright yellow powder (17% yield, m.p. 158°-160° C.).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[NH:10][C@@H:11]([CH3:29])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]3C[O:27]3)[C:20]=2C=O)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C([C:38](OO)=[O:39])C=1.CC(C)=O.ClCCl>ClCCl>[CH2:1]([O:8][C:9](=[O:30])[NH:10][C@@H:11]([CH3:29])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][CH2:25][C@@H:26]([CH2:38][OH:39])[O:27][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@@H](Cn1ncc2ccc(OC[C@@H]3CO3)c(C=O)c21)NC(=O)OCc1ccccc1
Solvent: CC(C)=O
Solvent: ClCCl
Product: C[C@@H](Cn1ncc2ccc3c(c21)O[C@H](CO)CO3)NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 59.9 %

Procedure:
To a stirred solution of the epoxide from Step A (0.86 g, 2.10 mmol) in dichloromethane (100 mL) was added m-chloroperbenzoic acid (70%, 0.62 g, 2.52 mmol) in portions under nitrogen atmosphere. After the addition completed the reaction mixture was stirred overnight. The reaction was quenched by a saturated aqueous solution of sodium thiosulfate (20 mL) and dichloromethane was evaporated. To the aqueous residue was added potassium carbonate (1.0 g) and methanol (200 mL), the resulting mixture was stirred for ½ h and organic solvent was evaporated. The residue was extracted with ethyl acetate (50 mL×3), dried and evaporated to dryness to afford an oil. Chromatography on silica eluting with a gradient of 0% to 10% acetone/dichloromethane gave an oil (0.50 g, 60%). LCMS (+APCI) m/z 397 (M+H), 1H NMR (600 MHz, CDCl3) δ 7.82 (s, 1H), 7.33-7.13 (m, 5H), 7.14 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 5.04-4.97 (m, 3H), 4.65 (ddd, J=6.6, 13.4, 51.6 Hz, 2H), 4.32 (m, 3H), 4.08 (m, 2H), 3.91 (m, 2H), 1.18(d, J=7.2 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13]C(N)=O>C(C1C=CC2C(=CC=CC=2)C=1C(C)C)(C)C.P(O)(O)O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC(N)=O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)c1ccc2ccccc2c1C(C)C
Agent: OP(O)O
Product: NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
83.5 g (0.5 mol) of 4-nitrobenzoic acid, 33.0 g (0.55 mol) of urea and 0.5 g of phosphorous acid are heated in 250 ml of diisopropylnaphthalene with stirring at from 150° to 158° C. for 8 h. After cooling the batch to 25° C. the solid is filtered off with suction and washed with 50 ml of diisopropylnaphthalene. The filter cake is introduced into 250 ml of water, and the mixture is adjusted to a pH of 12 using aqueous sodium hydroxide solution and is stirred at 25° C. for 30 min. Subsequently the solid is filtered off with suction and dried at 100° C. 81.4 g of 4-nitrobenzamide are obtained having a melting point of from 191° to 194° C. This corresponds to a yield of 98% of theory.
Reaction SMILES: CS(O[CH:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:25])[CH2:11][CH2:10]1)(=O)=O.CN(C)C=O.[Cl-:36].[Li+]>O>[Cl:36][CH:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:25])[CH2:11][CH2:10]1
Reactant: [Cl-]
Reactant: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)OS(C)(=O)=O
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCC(Cl)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC

Procedure:
A solution of 1.35 g. of ethyl 15-methanesulfonyloxy 9-oxo-prostanoate (Example 90) in 40 ml. of N,N-dimethylformamide containing 650 mg. of lithium chloride is heated on the steam bath for 18 hours. The cooled solution is diluted with water and the resulting mixture is extracted with ether. The ether extract is washed with saline, dried with saline, dried with anhydrous magnesium sulfate and evaporated to dryness to give an oil. Chromatography on silica gel affords an oil; λ max. 5.78 μ (carbonyl groups).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=NOC)[CH2:15][CH2:14]3)[N:10]=1)=[O:5])[CH3:2].[ClH:29].CC(C)=[O:32]>O1CCOCC1>[ClH:29].[ClH:29].[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:32])[CH2:15][CH2:14]3)[N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)CCC3=NOC)c(-c2ccncc2)[nH]1
Reactant: CC(C)=O
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccc3c(c2)CCC3=O)c(-c2ccncc2)[nH]1
Temperature: 100 °C
Yield: 88 %

Procedure:
A mixture of the product of Step 5 (1.0 g, 2.7 mmol) and 5M HCl (15 ml) in dioxane (30 ml)/acetone (30 ml) was heated to 100° C. for 3 hour. The mixture was cooled to room temperature and the solvent evaporated in vacuo. The residue was co-evaporated with acetone (2×20 ml) and ethanol/acetone (1:1, 20 ml) to give the title compound (1.0 g, 88%); MS(ES−) m/e 346 [M−H]−.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[CH:7]([Si:9]([CH3:12])([CH3:11])Cl)=[CH2:8].C(N(CC)CC)C>O1CCCC1>[CH:4]([N:3]1[CH:7]([SiH:9]([CH3:12])[CH3:11])[CH2:8][O:6][C:2]1=[O:1])=[CH2:5]
Reactant: C=C[Si](C)(C)Cl
Reactant: O=C1NCCO1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CN1C(=O)OCC1[SiH](C)C

Procedure:
A 3-vinyldimethylsilyl-2-oxazolidinone was prepared in accordance with the following procedure. A mixture of 34.8 grams of 2-oxazolidinone and 48.17 grams of vinyldimethylchlorosilane was prepared in 750 ml of tetrahydrofuran solvent. 40.26 grams of triethylamine was added dropwise. The mixture was then heated in a distillation apparatus with continuous reflux for a period of 30 minutes.
Reaction SMILES: F[C:2]1[N:26]=[CH:25][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)=[C:13]([CH3:24])[CH:12]=3)[C:4]=2[CH:3]=1.C(OC(=O)[NH:33][CH:34]1[CH:39]2[CH:35]1[CH2:36][NH:37][CH2:38]2)(C)(C)C>C(O)C.C(Cl)(Cl)Cl>[NH2:33][CH:34]1[CH:39]2[CH:35]1[CH2:36][N:37]([C:2]1[N:26]=[CH:25][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([O:17][C:18]5[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=5)=[C:13]([CH3:24])[CH:12]=4)[C:4]=3[CH:3]=1)[CH2:38]2
Reactant: CC(C)(C)OC(=O)NC1C2CNCC21
Reactant: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1Oc1cccnc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Cc1cc(Nc2ncnc3cnc(N4CC5C(N)C5C4)cc23)ccc1Oc1cccnc1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
A solution of 2.71 g (7.83 mmol) of (6-fluoro-pyrido[3,4-d]pyrimidin-4-yl)-[3-methyl-4-(pyridin-3-yloxy)-phenyl]-amine and 31.0 g (156.5 mmol) of (3-aza-bicyclo[3.1.0]hex-6-yl)-carbamic acid tert-butyl ester in 20 mL of ethanol in a sealed tube was heated at 105° C. for 24 hours. The mixture was cooled to room temperature and diluted with chloroform. The organics were washed sequentially with 3×150 mL saturated sodium bicarbonate and 1×50 mL of saturated sodium chloride, dried over sodium sulfate and evaporated. Chromatography over silica gel, eluting with 5% methanol/chloroform afforded 1.79 g (43%) of the title compound. 1H NMR (CDCl3): δ 8.93 (s, 1), 8.53 (s, 1), 8.33 (m, 2), 7.60 (m, 3), 7.21 (m, 2), 6.96 (d, 1), 6.24 (m, 1), 4.83 (m, 1), 3.81 (m, 2), 3.51 (m, 2), 3.47 (m, 1), 2.36 (m, 1), 2.26 (s, 3), 1.88 (m, 1).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:17][CH3:18])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([C:19](O)=[O:20])[C:7]2=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:28]=[CH:27][NH:26][N:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[NH:26]1[CH:27]=[CH:28][C:24]([NH:23][C:19]([C:8]2[C:7](=[O:22])[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[C:11]3[N:12]=[C:13]([NH:17][CH3:18])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=2)=[O:20])=[N:25]1
Reactant: CNc1nc(C)c2cc(C(=O)O)c(=O)n(C3CCCC3)c2n1
Reactant: Nc1cc[nH]n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNc1nc(C)c2cc(C(=O)Nc3cc[nH]n3)c(=O)n(C3CCCC3)c2n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To 110 μL of 0.1 M solution of example 89 in DMF in a test tube (10×95 mm) was added 100 μL of 0.1 M solution of 3-aminopyrazole in DMF followed by 110 μL each of 0.1 M solution of HATU and triethylamine, respectively. The reaction mixture was stirred at 80° C. for 8 h. After the removal of the solvent in vacuo, the residue was reconstituted in 1.2 mL of DMSO and subjected to HPLC purification to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[C:6]2=[N:5][CH:4]=1)#[CH:2].I[C:24]1[CH:25]=[C:26]([CH:40]=[CH:41][C:42]=1[CH3:43])[C:27]([NH:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=1)=[O:28].C(N(C(C)C)CC)(C)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:43][C:42]1[CH:24]=[CH:25][C:26]([C:27]([NH:29][C:30]2[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[CH:32][N:31]=2)=[O:28])=[CH:40][C:41]=1[C:2]#[C:1][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[C:6]2=[N:5][CH:4]=1
Reactant: C#Cc1cnc2c(Nc3ccc(S(C)(=O)=O)cc3)cccn12
Reactant: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccn2)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccn2)cc1C#Cc1cnc2c(Nc3ccc(S(C)(=O)=O)cc3)cccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
A mixture of 3-ethynyl-N-(4-(methylsulfonyl) phenyl)imidazo[1,2-a]pyridin-8-amine 5 (0.048 g, 0.154 mmol), 0.069 g (0.170 mmol) of 3-iodo-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide, 0.009 g (0.008 mmol) of Pd(PPh3)4, 0.002 g (0.012 mmol) of Cul, and 0.04 mL (0.23 mmol) of diisopropylethylamine in 0.8 mL of DMF was stirred at ambient temperature overnight under an atmosphere of N2. The reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (triethylamine-treated silica gel; eluted with 10% EtOAc/hexanes to 100% EtOAc) to provide 0.047 g of product as a solid: 590 m/z (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([OH:28])=O)[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1.C(Cl)CCl.[NH2:33][O:34]C1CCCCO1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:33][OH:34])=[O:28])[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccn3)CC1)O2
Reactant: NOC1CCCCO1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccn3)CC1)O2)NO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(E)-3-{1′-(pyridin-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (133 mg, crude compound from STEP B) was dissolved in DCM (4 ml) and TEA (0.098 ml, 0.704 mmol). EDC (101 mg, 0.53 mmol) HOBT (71 mg, 0.53 mmol) and NH2OTHP (49 mg, 0.42 mmol) were added, the mixture was stirred at RT overnight and then partitioned between water and DCM. The organic phase was dried over Na2SO4 and evaporated. The crude residue was purified by column chromatography (eluent: DCM/MeOH/NH4OH 96:4:0.2) and the resulting (E)-3-{1′-(pyridin-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide was dissolved in DCM and treated with HCl/Et2O for 4 h. The precipitate was filtered and washed with DCM to give (E)-3-{1′-(pyridin-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide as its di-hydrochloride (66 mg, white powder).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[CH3:15]S(O)(=O)=O.C(=O)(O)[O-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(Br)ccc2n1
Reactant: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc2cc(Br)ccc2n1
Temperature: 20 °C
Reaction time: 8 h
Yield: 325 %

Procedure:
A mixture of 6-bromo-2-quinolinecarboxylic acid (331 g, from multiple batches, 1.31 mol) and methanesulfonic acid (22 mL, 33 g, 0.34 mol) in methanol (2 L) was refluxed for 6 hr. The mixture was treated with a solution of sodium bicarbonate (29 g, 0.34 mol) in water (350 mL) and the resulting suspension was slowly cooled to 20° C. and stirred overnight. The suspension was filtered and the cake was washed with water (1 L). The solid was dried in a vacuum oven at 50° C. for 3 days to yield methyl 6-bromo-2-quinolinecarboxylate (294 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J=9 Hz, 1H), 8.40 (d, J=2 Hz, 1H), 8.14 (d, J=9 Hz, 1H), 8.08 (d, J=9 Hz, 1H), 7.97 (m, 1H), 3.93 (s, 3H). ES-LCMS m/z 267 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[O:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[O:19][C@H:20]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1>C(Cl)Cl>[NH:22]1[CH2:23][CH2:24][C@H:20]([O:19][N:10]2[C:11](=[O:18])[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]2=[O:8])[CH2:21]1.[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](ON2C(=O)c3ccccc3C2=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2ccccc2C(=O)N1O[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Trifluoroacetic acid (3.42 g, 30 mmol) was added at 0° C. to a solution of (S)-tert-butyl 3-(1,3-dioxoisoin dolin-2-yloxy)pyrrolidin-1-carboxylate (3.32 g, 10 mmol) in CH2Cl2 (25 ml), and the whole was stirred at room temperature for 17 hours. The reaction was concentrated in vacuo and the residue was triturated with diethyl ether (100 ml) to give (S)-2-(pyrrolidin-3-yloxy)isoindoline-1,3-dione) trifluoroacetic acid salt (2.77 g, 80%) as a white solid.
Reaction SMILES: [SH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].O=[C:8]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].B(F)(F)F.CCOCC>C(Cl)Cl>[OH:5][CH2:4][CH:3]1[O:6][C:8]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:1][CH2:2]1
Reactant: CCOC(=O)CCC(=O)CCC(=O)OCC
Reactant: OCC(O)CS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CCC1(CCC(=O)OCC)OC(CO)CS1

Procedure:
The title compound was prepared according to the procedure of Example 1 using 3-mercapto-1,2-propanediol (10.8 g, 0.1 mol), diethyl 4-oxopimelate (23 g, 0.1 mol) and boron trifluoride etherate (2.5 ml) in methylene chloride (300 ml). The crude product was chromatographed on silica gel using 40% ethyl acetate/hexane as eluent to give 14.5 g (45%) of product.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:10](=[O:11])[O:9][CH2:8]2)(=O)C.[H-].[Na+].[OH:17][C:18]([C:40]([F:43])([F:42])[F:41])([CH2:31][CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:33])[CH2:19]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[OH:17][C:18]([C:40]([F:41])([F:42])[F:43])([CH2:31][CH:32]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH3:33])[CH2:19][NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:10](=[O:11])[O:9][CH2:8]2
Reactant: CC(=O)Nc1ccc2c(c1)COC2=O
Reactant: Cc1ccc(S(=O)(=O)OCC(O)(CC(C)c2ccccc2)C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(CC(O)(CNc1ccc2c(c1)COC2=O)C(F)(F)F)c1ccccc1
Reaction time: 0.33 h
Yield: 35.3 %

Procedure:
760 mg of 5-acetamido-phthalide in 20 ml of dimethylformamide is mixed at 0° C. with 144 mg of sodium hydride (80% in mineral oil), and, after 20 minutes, with 800 mg of 4-toluenesulfonic acid-(2-hydroxy-4-phenyl-2-trifluoromethyl-pentyl)-ester. After 16 hours at 60° C., the solvent is concentrated by evaporation in a vacuum, the residue is dissolved in ethyl acetate, washed with water, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel with cyclohexane/ethyl acetate (2:1), 266 mg of 5-(2-hydroxy-4-phenyl-2-trifluoromethyl-pentylamino)-phthalide, melting point 110° C., is obtained.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:14]([CH2:16][C:17](=[O:19])[OH:18])[OH:15])[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH2:26]([O:19][C:17](=[O:18])[CH2:16][C@H:14]([OH:15])[C@H:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CC(=O)OCc1ccccc1

Procedure:
Boc-Statine, 8.83 g., was dissolved in dry dimethylformamide and treated at 25° C. for 4.5 hours with 4.43 g. potassium carbonate and 3.81 ml. benzyl bromide. The mixture was concentrated in vacuo, 500 ml. ethyl acetate was added and the suspension was washed with saturated aqueous lithium chloride (2×50 ml.), water (5×50 ml.), dried magnesium sulfate, filtered and concentrated to give 11.8 g. of a yellow syrup which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[Cl:17].[H-].[Na+].CS(C)=O>O>[NH2:1][C:2]1[CH:7]=[C:6]([O:16][C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[C:11]([Cl:17])[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(O)cc1Cl
Reactant: Nc1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1cc(Oc2ccc(N)c(Cl)c2)ccn1
Yield: 55.6 %

Procedure:
The publicly known compound 2-amino-4-chloropyridine (5.0 g), 4-amino-3-chlorophenol (11 g), sodium hydride (60% in oil) (3.1 g) and dimethylsulfoxide (80 ml) were stirred at 160° C. for 9.5 hours. Water was added, extraction was performed with ethyl acetate, and the extract solution was washed 5 times with water. The extract solution was then passed through a glass filter coated with silica gel. The silica gel was washed with ethyl acetate, the ethyl acetate layers were combined, and the solvent was distilled off under reduced pressure to obtain 5.1 g of a dark violet solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:24]=[C:23]([NH:25][C:26]([NH:28][C:29](=[O:37])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[S:27])[CH:22]=[CH:21][C:4]=1[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([C:16]([OH:18])=O)[CH:14]=2)[N:9]=[CH:8][CH:7]=1.[CH3:38][NH2:39]>O1CCCC1>[F:2][C:3]1[CH:24]=[C:23]([NH:25][C:26]([NH:28][C:29](=[O:37])[CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[S:27])[CH:22]=[CH:21][C:4]=1[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([C:16]([NH:39][CH3:38])=[O:18])[CH:14]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2cc1C(=O)O
Reactant: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)c1cc2c(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ccnc2cc1OC
Temperature: 30 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Similar to the synthesis of Example 1, compound 1e (20 mg), 40% aqueous solution of methylamine (5 μL), and DMTMM•n-hydrate (22 mg) were dissolved in tetrahydrofuran (1 mL), followed by stirring at 30° C. for 1 hour, to thereby yield the titled compound 6 (18.4 mg, yield: 96%).