Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:19])[NH:6]2.CN1CCCC1=O.O.Cl.[NH2:29][C@H:30]([CH2:32][OH:33])[CH3:31]>>[OH:33][CH2:32][C@H:30]([NH:29][C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:19])[NH:6]2)[CH3:31]
Reactant: O=c1[nH]c2nc(SCc3ccccc3)nc(Cl)c2[nH]1
Reactant: C[C@H](N)CO
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: C[C@H](CO)Nc1nc(SCc2ccccc2)nc2[nH]c(=O)[nH]c12
Temperature: 100 °C
Reaction time: 48 h
Yield: 19.4 %

Procedure:
A solution of the product from example 2, step (f) (0.1 g) in a mixture of alaninol (0.128 g), disopropylethylamine (0.35 ml) and N-methylpyrrolidinone (3 ml) was stirred at 100° C. for 48 h before pouring into H2O (75 ml). 2M HCl solution was then added to pH=2 and the light brown solid formed filtered and recrystallised from EtOH to afford the subtitle compound (22 mg, 19%)
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[CH2:20][S:21][CH2:22][CH2:23][OH:24])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26](OC(=O)C)(=[O:28])[CH3:27].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[CH2:20][S:21][CH2:22][CH2:23][O:24][C:26](=[O:28])[CH3:27])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(CSCCO)NCCCOc1cc(CN2CCCCC2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)OCCSCC(=O)NCCCOc1cc(CN2CCCCC2)ccn1
Temperature: 60 °C
Yield: 75 %

Procedure:
0.49 g of N-[3-(4-piperidinomethyl-2-pyridyloxy)propyl]-2-(2-hydroxyethylthio)acetamide [prepared as described in step (b) above] was added to a mixture of 0.48 ml of acetic anhydride and 0.43 ml of pyridine, and the resulting mixture was warmed at 60° C. for 2 hours. At the end of this time, the reaction mixture was poured into ice-water and a saturated aqueous solution of sodium hydrogencarbonate was added to it. The resulting aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and ethyl acetate as the eluent, to give 0.41 g (yield 75%) of the title compound as an oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]1=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.[C:32](OC(=O)C)(=[O:34])[CH3:33].C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[N:6]([CH2:5][CH2:4][CH2:3][NH:2][C:32](=[O:34])[CH3:33])[C:7](=[N:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:8][CH:9]=2)=[CH:12][CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCCn1c(-c2ccc(Br)cc2)csc1=Nc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NCCCn1c(-c2ccc(Br)cc2)csc1=Nc1ccccc1
Reaction time: 2 h

Procedure:
N-[3-(3-Aminopropyl)-4-(4-bromophenyl)-thiazol-2(3H)-ylidene]-aniline hydrochloride (730 mg) obtained in Example 132 and triethyl-amine (0.77 ml) were dissolved in N,N-dimethylformamide (5 ml), and thereto were added dropwise acetic anhydride in an ice bath under nitrogen atmosphere. The mixture was stirred at the same temperature for 2 hours, and thereto was added a saturated aqueous sodium hydrogen carbonate solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from isopropyl alcohol to give the title compound (580 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3[C:16]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][C:17]=4[S:23][C:14]=3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:25][N:26]([CH3:33])[CH2:27]/[CH:28]=[CH:29]/[C:30](O)=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3[C:16]4[CH2:22][CH2:21][N:20]([C:30](=[O:31])/[CH:29]=[CH:28]/[CH2:27][N:26]([CH3:33])[CH3:25])[CH2:19][CH2:18][C:17]=4[S:23][C:14]=3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: Fc1ccc(Nc2ncnc3sc4c(c23)CCNCC4)cc1Cl
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1CCc2sc3ncnc(Nc4ccc(F)c(Cl)c4)c3c2CC1

Procedure:
The title compound was prepared in analogy to Example 89 from N-(3-chloro-4-fluorophenyl)-6,7,8,9-tetrahydro-5H-pyrimido[5′,4′:4,5]thieno[2,3-d]azepin-4-amine from Example 85A (100 mg, 0.29 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (66 mg, 0.40 mmol) to yield 89 mg (67%).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH:4]([O:14][CH3:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1.[OH-].[Na+]>O.CO>[CH3:15][O:14][CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)[C:3]([OH:16])=[O:2]
Reactant: COC(=O)C(OC)c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(C(=O)O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 96.9 %

Procedure:
A mixture of (RS)-methoxy-(3-nitro-phenyl)-acetic acid methyl ester (1.039 g) and NaOH (0.239 g) in water (0.75 ml) and methanol (10 ml) was stirred at 0° C. for 4.5 h. The reaction mixture was then concentrated (rotavapor, high vac.) and the residue (light yellow solid) was taken in water (25 ml). The resulting solution was acidified to pH˜1 by dropwise addition of 3.0 N HCl. This was extracted with EtOAc (50 ml+25 ml). The combined organics were dried (MgSO4), filtered and concentrated (rotavapor) to leave the crude (RS)-methoxy-(3-nitro-phenyl)-acetic acid (0.944 g) as a light yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][C@H:7]([CH3:9])[N:6]2[C:10]3[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][NH:16][C:15](=[O:23])[C:11]=3[C:12]([O:13][CH3:14])=[C:5]2[C:4]1=[O:24])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[Cl:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:44]Br>CN(C=O)C>[Cl:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:44][N:16]1[CH:17]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:10]2[N:6]3[C@@H:7]([CH3:9])[CH2:8][N:3]([CH2:1][CH3:2])[C:4](=[O:24])[C:5]3=[C:12]([O:13][CH3:14])[C:11]=2[C:15]1=[O:23]
Reactant: CCN1C[C@H](C)n2c(c(OC)c3c(=O)[nH]cc(C(=O)OC)c32)C1=O
Reactant: Fc1ccc(CBr)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCN1C[C@H](C)n2c(c(OC)c3c(=O)n(Cc4ccc(F)c(Cl)c4)cc(C(=O)OC)c32)C1=O
Temperature: -25 °C
Reaction time: 0.42 h

Procedure:
To a cold (−25° C.) solution of methyl (6S)-8-ethyl-10-(methoxy)-6-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrido-[3′,4′:4,5]pyrrolo[1,2-a]-pyrazine-4-carboxylate (0.29 g, 0.87 mmol) in anhydrous DMF (15 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (1 M, 0.96 mmol) was added. The reaction mixture was stirred at −25° C. for 25 minutes and treated with 3-chloro-4-fluorobenzyl bromide (0.27 g, 1.2 mmol; passed through activated basic alumina). The reaction mixture was stirred at 0° C. for 40 minutes and concentrated under vacuum. The residue was partitioned between ethyl acetate and dilute aqueous HCl. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with ethyl acetate-hexane gradient. Collection and concentration of appropriate fractions provided the titled product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]2[N:20]([CH2:21][CH2:22][C:23](O)=[O:24])[C:19](=[O:26])[CH2:18][S:17]2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1>[C:12]([C:9]1[CH:8]=[C:7]([CH:16]2[N:20]([CH2:21][CH2:22][CH2:23][OH:24])[C:19](=[O:26])[CH2:18][S:17]2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(C2SCC(=O)N2CCC(=O)O)cc(C(C)(C)C)c1O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(C2SCC(=O)N2CCCO)cc(C(C)(C)C)c1O
Temperature: -7.5 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a solution of the resulting 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(2-carboxyethyl)-1,3-thiazolidin-4-one (100 mg) in tetrahydrofuran (3 ml) were added dropwise triethylamine (27 mg) and ethyl chloroformate (28 mg) at -10° C. under a nitrogen atmosphere, followed by stirring at -10 to -5° C. for 1 hour. To the mixture was added sodium borohydride (100 mg), the mixture was stirred at room temperature for 3 hours, then poured into ice-water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform-methanol, 98:2) to afford 70 mg (73%) of the product which was identical with that of Reference Example 15.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.[NH:33]1[CH:37]=[N:36][CH:35]=[N:34]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: OCCCCc1ccc(OCc2ccccc2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(COc2ccc(CCCCn3cncn3)cc2)cc1
Yield: 81 %

Procedure:
To a solution of 4-(4-benzyloxyphenyl)butanol (3.55 g), tributyl phosphine (6.84 g) and 1,2,4-triazole (1.86 g) in tetrahydrofuran (75 ml) was added dropwise, at room temperature, diethyl azodicarboxylate (40% toluene solution, 11.8 g). The mixture was heated for two hours under reflux. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1:2, v/v), 1-[4-(4-benzyloxyphenyl)butyl]-1,2,4-triazole (3.45 g, 83%) was obtained. Recrystallization from isopropyl ether gave colorless prisms, mp 68-69° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:5]=[C:6]([Cl:12])[C:7]=1[O:8][CH2:9][CH2:10][NH2:11].[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:5]=[C:6]([Cl:12])[C:7]=1[O:8][CH2:9][CH2:10][NH:11][C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:23][CH:24]=1)=[O:30]
Reactant: NCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: O=C(NCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)Nc1ccc(OC(F)(F)F)cc1
Reaction time: 12 h
Yield: 46.5 %

Procedure:
A solution of 0.20 g of 3,5-dichloro-4-(2-aminoethoxy)-1-(3,3-dichloro-2-propenyloxy)benzene and 0.14 g of 4-trifluoromethoxyphenyl isocyanate dissolved in 10 ml of toluene was heated under reflux, while stirring, for 12 hours, and the reaction mixture was then concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.15 g of 3,5-dichloro-4-(2-(N′-(4-trifluoromethoxyphenyl)ureido)ethoxy)-1-(3,3-dichloro-2-propenyloxy)benzene (46% yield), m.p., 1 25.4° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[F:21])[C:15](O)=O.N>>[F:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc(F)c(F)c1
Agent: N
Product: Fc1ccc(-c2nc(-c3cccnc3)no2)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3,4-difluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.52-7.67 (m, 2 H), 8.12 (ddd, J=8.7, 4.3, 1.5 Hz, 1 H), 8.19 (ddd, J=10.8, 7.5, 2.0 Hz, 1 H), 8.55 (dt, J=8.1, 1.9 Hz, 1 H), 8.74 (dd, J=5.1, 1.7 Hz, 1 H), 9.29 (dd, J=2.0, 0.7 Hz, 1 H) ppm; MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[CH:4]1.C(O)(=O)C>C1COCC1>[CH3:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:3]
Reactant: c1ccc2ocnc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNc1ccccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of sodium borohydride (4.77 g, 126.0 mmol) and benzoxazole (5.00 g, 42.0 mmol) in THF (150 mL) was added ˜1 mL of acetic acid. The reaction mixture was stirred overnight at room temperature and concentrated to dryness under reduced pressure. The excess sodium borohydride was decomposed with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was collected, washed with water, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 104A in near quantitative yield. HPLC retention time=0.34 min. (Condition B). 1H-NMR (500 MHz, d6-DMSO) δ 2.69 (s, 3H), 4.70 (brs, 1H), 6.40-6.42 (m, 2H), 6.63-6.66 (m, 2H), and 9.12 (brs, 1H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17].[OH-].[K+]>CO>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:17][N:16]=[C:10]([OH:12])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCOC(=O)C#Cc1ccc(I)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1cc(-c2ccc(I)cc2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a solution of ethyl 3-(4-iodophenyl)propiolate (420 mg, 1.39 mmol) in MeOH (10 mL), were added hydroxylamine hydrochloride (391 mg, 5.20 mmol) and KOH (5 M in methanol, 1.7 mL, 8.5 mmol). The mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was redissolved in water (15 mL) and acidified with 2 M aqueous HCl to pH 2˜3. The precipitate was collected by filtration to afford the title compound (228 mg, 57%). 1H NMR (DMSO-d6, 400 MHz): δ 11.51 (brs, 1H), 7.94 (d, 2H), 7.65 (d, 2H), 6.67 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]3[CH:26]=[CH:25][C:20]4[NH:21][C:22](=[O:24])[O:23][C:19]=4[CH:18]=3)[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[BH-](OC(C)=O)(OC(C)=O)O[C:30](C)=O.[Na+].[OH-].[Na+]>CO>[CH3:30][N:10]([CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]2[CH:26]=[CH:25][C:20]3[NH:21][C:22](=[O:24])[O:23][C:19]=3[CH:18]=2)[CH2:15][CH2:16]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccccc4)CC3)cc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(CCCc1ccccc1)[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Reaction time: 3 h

Procedure:
To a stirred solution of 6-[trans-4-(3-phenylpropylamino)cyclohexyl]-3H-benzoxazol-2-one (263 mg, 0.750 mmol) in MeOH (10 mL) was added H2O (0.5 mL) and p-formaldehyde (113 mg, 3.75 mmol). After stirring the reaction mixture for 3 hours, NaBH(OAc)3 was added, and stirring was continued for 12 hours. Solid NaOH was added to give a clear solution, which was then concentrated under reduced pressure. Purification by flash chromatography (silica, 95:4:1 CH2Cl2:MeOH:NH4OH) gave 6-{trans-4-[methyl(3-phenylpropyl)-amino]cyclohexyl}-3H-benzoxazol-2-one (160 mg, 59%), as a white solid: mp 58-62° C.; IR (KBr): 2929, 1774 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 8.97 (br s, 1H), 7.26-7.12 (m, 6H), 6.99-6.98 (m, 2H), 2.63 (m, 2H), 2.57 (t, J=7 Hz, 2H), 2.56 (m, 1H), 2.38 (m, 2H), 2.18 (s, 3H), 1.78 (m, 2H), 1.68 (m, 2H), 1.37 (m, 2H), 1.27 (m, 2H); CI-MS (methane) (m/z): 365 [M+H]+; HRMS-API (m/z): [M+H]+ calcd for C23H28N2O2, 365.2229; found, 365.2231; HPLC: method A, 5.95 minutes (95.3%); method B, 10.12 minutes (97.6%); Anal. Calcd for C23H28N2O2.0.25H2O: C, 74.87; H, 7.79; N, 7.59. Found: C, 74.77; H, 7.71; N, 7.81.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][CH:24]=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C([O-])(=O)C.[Na+].[I:30]Cl>C(O)(=O)C.O>[I:30][C:24]1[CH:23]=[N:22][N:15]2[C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:12]([C:4]3[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([CH3:1])[CH:3]=3)=[N:13][C:14]=12
Reactant: ClI
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3nccc3n2)ccc1C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
To a stirred solution of 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (2.12 g, 6.14 mmol) in acetic acid (15 ml) was added at room temperature sodium acetate (0.57 g, 6.95 mmol) and drop wise a solution of iodine monochloride (1.13 g, 6.96 mmol) in acetic acid (3.5 ml). The reaction mixture was stirred at room temperature for 16 h, diluted slowly with water (up to 100 ml), stirred at room temperature for 30 min, the precipitate was filtered off, washed with water and dried to give 3-iodo-5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (2.44 g, 84%) as a yellow solid. MS (EI) 471.0 [(M)+]; mp 160° C.
Reaction SMILES: C(Cl)Cl.[C:4]([CH:7]1[CH2:11][CH2:10][CH2:9][O:8]1)(=[O:6])[CH3:5].OS(C(F)(F)F)(=O)=O.C[SiH](C)C.[Br:24]N1C(=O)CCC1=O>C(N(CC)CC)C>[Br:24][CH2:5][C:4]([CH:7]1[CH2:11][CH2:10][CH2:9][O:8]1)=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)C1CCCO1
Agent: C[SiH](C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)C1CCCO1
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
To a 20-liter glass vessel was added methylene chloride (10.0 liters) followed by acetyltetrahydrofuran (838.0 g, 7.34 moles). The solution was then cooled back to −10° C. and triethylamine was added (854.0 g, 8.44 moles). The vessel was purged with nitrogen and trimethylsilane triflate (1713.0 g, 7.71 moles) was added dropwise at a maximum temperature of −8° C. Addition was typically complete in 45 minutes. After 15 minutes stirring, a sample was removed for TLC and GC analysis, which showed that the reaction was completed. N-bromosuccinimide (1340 g. 7.53 moles) was added to the solution at a maximum temperature of −5° C. over a period of approximately 45 minutes in six portions. After a 30 minute stirring, the solution was sampled for GC and TLC analysis, which showed that the reaction was completed. The solution was then transferred to a 50-liter separating vessel, and 5% sodium bicarbonate (5 liters) was added with caution. The solution was stirred and separated. The upper aqueous phase was discarded, and the methylene chloride phase was washed with water, dried over sodium sulphate, filtered and stored in a freezer before use in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:12])[CH:3]=1.CN(C(ON1N=[N:28][C:23]2[CH:24]=[CH:25][CH:26]=[N:27][C:22]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.CN1CC[C@@H](N)C1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:28][C@@H:23]2[CH2:24][CH2:25][N:27]([CH3:26])[CH2:22]2)=[O:8])=[C:4]([F:12])[CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1cc(F)c(C(=O)O)cc1Cl
Agent: CN1CC[C@@H](N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC[C@@H](NC(=O)c2cc(Cl)c(N)cc2F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
4-amino-5-chloro-2-fluorobenzoic acid (Intermediate 176; 300 mg, 1.58 mmol), HATU (903 mg, 2.37 mmol) and (3R)-1-methylpyrrolidin-3-amine di Hydrochloride (Intermediate 184; 325 mg, 2.37 mmol) were stirred in DMF (5 mL) and diisopropylethylamine (1.2 mL, 7.12 mmol) added. The mixture was stirred for 2 hours at room temperature and then absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (5% ammonia in methanol/DCM) to yield the title compound as a pale orange solid (333 mg, 77%).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([F:9])=[CH:7][CH:8]=1.[NH3:21].CO>C(Cl)Cl>[NH2:21][CH2:2][C:3]1[C:4]([Cl:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([F:9])=[CH:7][CH:8]=1
Reactant: N
Reactant: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CBr)c2Cl)c1
Solvent: ClCCl
Solvent: CO
Product: N#Cc1cc(Cl)cc(Oc2c(F)ccc(CN)c2Cl)c1
Yield: 100 %

Procedure:
The title compound was prepared as described herein using 3-{[3-(bromomethyl)-2-chloro-6-fluorophenyl]oxy}-5-chlorobenzonitrile (728 mg, 1.941 mmol) and NH3 in MeOH (27.7 ml, 194 mmol, 7.0 N) in CH2Cl2 (20 ml) to give the title compound as a white solid (602 mg, 100%) which was used for the next step without purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.37-7.43 (1H, m) 7.34 (1H, s) 7.12-7.21 (2H, m) 6.99 (1H, br. s.) 3.98 (2H, br. s.) 1.65-1.89 (2H, m). LCMS: m/z 311 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:24]3[C:19](=[CH:20][N:21]=[C:22]([N:25](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[CH:23]=3)[CH:18]([CH3:44])[O:17][C:15]=2[CH:16]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:7][C@@H:8]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:24]3[C:19](=[CH:20][N:21]=[C:22]([NH2:25])[CH:23]=3)[CH:18]([CH3:44])[O:17][C:15]=2[CH:16]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc3c(cn2)C(C)Oc2cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc2-3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](N)COc1ccc2c(c1)OC(C)c1cnc(N)cc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a stirred solution of tert-butyl((2S)-1-((2-(bis(4-methoxybenzyl)amino)-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (110 mg, 0.165 mmol) in dichloromethane (10 mL) was added TFA (0.254 mL, 3.29 mmol) and the reaction was stirred at room temperature overnight. The volatiles were evaporated and the crude material was purified by preparative HPLC (0.1% TFA in MeOH) to afford 8-(((S)-2-amino-4-methylpentyl)oxy)-5-methyl-5H-chromeno[3,4-c]pyridin-2-amine (25 mg, 0.069 mmol, 42% yield) as a yellow solid. 1H NMR (400 MHz, MeOD) δ 7.74 (m, 2 H), 6.84 (s, 1 H), 6.75 (dd, J=2.4 Hz, J=8.4 Hz, 1 H), 6.63 (d, J=2.4 Hz, 1 H), 5.18 (m, 1 H), 4.32 (m, 1 H), 4.15 (m, 1 H), 3.65 (m, 1 H), 1.83 (m, 1 H), 1.65 (m, 5 H), 1.04 (m, 6 H); LCMS (ESI) m/e 328.2 [(M+H)+, calcd for C19H26N3O2 328.2]; LC/MS retention time (Method D): tR=1.24 min; HPLC retention time (method A): tR=8.42 min.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9](=[O:14])[O:10][CH2:11]2)=[CH:7][C:6]=1[O:15][C:16](=[O:18])[CH3:17])(=O)C.N1CCOCC1>CN(C)C=O>[OH:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9](=[O:14])[O:10][CH2:11]2)=[CH:7][C:6]=1[O:15][C:16](=[O:18])[CH3:17]
Reactant: CC(=O)Oc1cc2c(cc1OC(C)=O)C(=O)OC2
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2c(cc1O)COC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic acid 6-acetoxy-3-oxo-1,3-dihydro-isobenzofuran-5-yl ester (5.0 g) was dissolved in N,N-dimethylformamide (100 ml) followed by addition of morpholine (1.78 ml). The solution was stirred at room temperature overnight followed by concentration in reduced pressure. Ethyl acetate (200 ml) was added to the remainder. The organic phase was washed two times with a mixture of aqueous HCl (50 ml, 2M) and brine (50 ml). The organic solvent was dried over anhydrous Na2SO4, filtered and evaporated to dryness.