Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][S:29]([CH2:32][C:33](O)=[O:34])(=[O:31])=[O:30]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[CH2:32][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CS(=O)(=O)CC(=O)O
Agent: Cl
Product: CS(=O)(=O)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (100 mg, 74%), MS (ISP) m/z=451.3 [(M+H)+], mp 187° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (132 mg, 0.3 mmol) and 2-methanesulfonyl-acetic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([CH:17]=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)#[N:16].N12CCCN=C1CCCCC2>C(#N)C>[C:15]([CH2:17][C:18]1([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]1)#[N:16]
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.3 g, 0.022 mol) in acetonitrile (50 mL) was added tert-butyl 4-(cyanomethylene)piperidine-1-carboxylate (4.9 g, 0.022 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (3.3 mL, 0.022 mol). The resulting mixture was stirred at room temperature overnight. After being evaporated to dryness, the residue was purified on silica gel, eluting with 0-100% EtOAc in hexanes, to give the desired product (5.62 g, 61%). LCMS (M+H) 417.1.
Reaction SMILES: Br[C:2]1[N:3]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH:13]1[CH2:16][CH2:15][CH2:14]1)[N:5]=2.C[O-].[Na+].[C:26](OCC)(=[O:28])C.O>CO>[CH:13]1([O:12][C:6]2[N:5]=[C:4]3[C:9]([N:10]=[C:2]([O:28][CH3:26])[N:3]3[CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[C:8]([NH2:11])[N:7]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(C)=O
Reactant: Nc1nc(OC2CCC2)nc2c1nc(Br)n2C1CCCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc2c(N)nc(OC3CCC3)nc2n1C1CCCCO1
Temperature: 67 °C

Procedure:
8-Bromo-2-(cyclobutyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.79 g, 4.86 mmol) was dissolved in anhydrous methanol (25 ml) and 25% sodium methoxide in methanol (2.274 ml, 9.72 mmol) was added under nitrogen. The mixture was heated at 67° C. for 24 hours and then cooled to room temperature. Ethyl acetate and water were added and the layers separated. The aqueous layer was extracted twice more with ethyl acetate, and the organic extracts were combined, washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give the title compound as a cream foam (1.27 g).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:24])[C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16]C=CC=3)N=2)=[CH:7][CH:6]=1.C(OC1C=CC(C(O)=O)=C([F:42])C=1)C1C=CC=CC=1>>[CH2:12]([O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([N:3]([O:2][CH3:1])[CH3:24])=[O:23])=[C:10]([F:42])[CH:9]=1)[C:13]1[CH:22]=[CH:21][CH:20]=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1F
Reactant: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Product: CON(C)C(=O)c1ccc(OCc2ccccc2)cc1F

Procedure:
Following the procedure for the preparation of N-Methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide but substituting 4-Benzyloxy-2-fluoro-benzoic acid provided the title compound. MS: (M+H m/z=290.2).
Reaction SMILES: [CH:1]([CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)=O.[CH3:15][NH2:16]>CO.C(Cl)Cl>[CH3:15][NH:16][CH2:1][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)C1
Solvent: ClCCl
Solvent: CO
Product: CNCC1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 12 h
Yield: 95.2 %

Procedure:
To a solution of 1,1-dimethylethyl 3-formyl-1-pyrrolidinecarboxylate (500 mg, 2.51 mmol) in MeOH/DCM (6 mL, 1:1) were added NaHCO (1.05 g, 12.6 mmol) followed by methylamine (2.51 mL, 5.02 mmol, 2.0 M in MeOH). After 12 h at 25° C., NaBH (1.05 g, 12.6 mmol) was added. After 1 h, the reaction was concentrated and the residue was partitioned between DCM and H O. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over MgSO4, concentrated and purified via column chromatography (silica, 4% MeOH in DCM (1% NH OH)) yielding the title compound (512 mg, 95%) as a brown oil: LC/MS (ES) m/e 215 (M+H).
Reaction SMILES: [Cl-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([NH:10][CH2:11][CH:12]2[O:16][CH2:15][CH2:14][O:13]2)[C:7]([N+:17]([O-])=O)=[CH:6][CH:5]=1>C(O)C.O.[Fe]>[NH2:17][C:7]1[C:8]([NH:10][CH2:11][CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[N:9][C:4]([Cl:3])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NCC1OCCO1
Agent: [Fe]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Cl)nc1NCC1OCCO1
Reaction time: 0.33 h
Yield: 73.5 %

Procedure:
To a suspension of 13 g of iron powder in 650 mL of ethanol and 350 mL of water, 14 g of sodium chloride was added, and the mixture was heated under reflux while stirring for 20 minutes. Thereto was added 10 g of 6-chloro-N-(1,3-dioxolan-2-ylmethyl)-3-nitropyridin-2-amine at 65° C., and the mixture was heated under reflux while stirring for 30 minutes. The insoluble substance was filtered off, the solvent was distilled off to be 300 mL under reduced pressure, ethyl acetate was added thereto, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of ethyl acetate to obtain 6.5 g of 3-amino-6-chloro-2-(1,3-dioxolan-2-ylmethyl)aminopyridine as a light purple solid.
Reaction SMILES: O[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH3:28])[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:14][CH:13]=1)[C:3]1[N:4]([CH2:8][CH2:9][O:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:11][O:10][CH2:9][CH2:8][N:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[CH2:2][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH3:28])[S:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:20])=[O:21])=[CH:14][CH:13]=1
Reactant: COCCn1cccc1C(O)c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COCCn1cccc1Cc1ccc(N(C)S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 16 mg (0.04 mmol) of N-(4-{1-hydroxy-1-[1-(2-methoxyethyl)-1H-pyrrol-2-yl]-methyl}-phenyl)-N-methyl-benzenesulfonamide (Example 93) in 1.5 mL CH2Cl2 at 0° C. were added 620 μL (3.88 mmol) of triethylsilane followed by 100 μL (0.79 mmol) of boron trifluoride diethyl etherate dropwise. The mixture was warmed to room temperature and stirred for 2.5 h. After this time, the reaction mixture was cooled to 0° C., quenched by the addition of a saturated aqueous solution of sodium bicarbonate, allowed to warm to room temperature, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc, 3:1) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17].[I:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]=[C:26]=[O:27].CCN(CC)CC.Cl>C1COCC1>[I:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:27])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: O=C=Nc1ccccc1I
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1I
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methoxyphenylacetate (1.94 g, 8.16 mmol) in THF (20 ml) was added 2-iodophenylisocyanate (2.0 g, 8.16 mmol) and Et3N (114 ul, 0.816 mmol). After stirring overnight, the mixture was poured into 1 N HCl (200 ml). The resulting precipitate was collected by filtration and dissolved in CHCl3 (200 ml). The solution was dried over MgSO4 and evaporated to give tert-butyl 4-[N′-(2-iodophenyl)ureido]-3-methoxyphenylacetate (3.93 g, quant) as a pale yellow amorphous solid 1H-NMR (CDCl3) δ1.44 (s, 9 H), 3.49 (s, 2 H), 3.85 (s, 3 H), 6.78-6.88 (m, 4 H), 7.07 (s, 1 H), 7.31-7.35 (m, 1 H), 7.76 (dd, J=7.8, 1.5 Hz, 1 H), 7.95 (d, J=8.3 Hz, 1 H), 7.99 (dd, J=8.3, 1.5 Hz, 1 H). MS (ESI), m/z 483 (M++1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][C:23]1[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=1[O:25][CH2:26][CH:27]1[CH2:29][O:28]1>>[OH:28][CH:27]([CH2:26][O:25][C:24]1[CH:30]=[CH:31][CH:32]=[CH:33][C:23]=1[CH3:22])[CH2:29][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Cc1ccccc1OCC1CO1
Product: Cc1ccccc1OCC(O)CN1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 173 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-[(2-methylphenoxy)methyl]oxirane and conditions outlined in procedure X. LCMS: 466 [M+H]; Rt=1.05 min.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:3]=1[CH2:4][N:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](=[O:14])[NH:7][C:6]1=[O:15].[C:21]([O:25][C:26](=[O:37])[NH:27][C@H:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:29]O)([CH3:24])([CH3:23])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:21]([O:25][C:26](=[O:37])[NH:27][C@H:28]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:29][N:7]1[C:8](=[O:14])[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]([CH2:4][C:3]2[C:2]([F:1])=[CH:19][CH:18]=[CH:17][C:16]=2[F:20])[C:6]1=[O:15])([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1ccccc1
Reactant: O=c1[nH]c(=O)n(Cc2c(F)cccc2F)cc1[N+](=O)[O-]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c([N+](=O)[O-])cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
1-(2,6-difluoro-benzyl)-5-nitro-1H-pyrimidine-2,4-dione (82 mg, 0.29 mmol), ((R)-2-hydroxy-1-phenyl-ethyl)-carbamic acid tert-butyl ester (69 mg, 0.29 mmol), and triphenylphosphine (114 mg, 0.44 mmol) were dissolved in anhydrous tetrahydrofuran (2 mL). To this solution was added diethyl azodicarboxylate (200 μl, 0.44 mmol), followed by stirring at room temperature for 4 hrs. The solution was concentrated, after which the residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate/dichloromethane, 3/1/1) and dried in a vacuum to afford 67 mg of the compound as a colorless oil (yield 67%). 1H NMR (300 MHz, CDCl3) δ 1.30 (9H, s), 3.40 (1H, d), 4.50 (1H, m), 5.08-5.27 (4H, m), 7.02 (2H, t), 7.26-7.47 (6H, m), 8.78 (1H, s)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[OH:9][C@@H:10]1[CH2:14][CH2:13][O:12][CH2:11]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C@@H:10]2[CH2:14][CH2:13][O:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: O[C@@H]1CCOC1
Reactant: Clc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1ccc(O[C@@H]2CCOC2)nc1
Temperature: 90 °C
Yield: 46.4 %

Procedure:
To a solution of 5-bromo-2-chloropyridine (10 g, 52.1 mmol) in 100 mL of DMF was added commercially available (R)-(−)-3-hydroxytetrahydrofuran (6.87 g, 78.1 mmol) and Cs2CO3 (33.85 g, 0.104 mol), the resulting mixture was heated 90° C. for 36 hours. The solvent was concentrated and the residue was extracted with EtOAc (500 ml), washed with water (200 ml). The organic layer was dried over Na2SO4, concentrated and purified by chromatography on silica gel (eluting with Petrol ether:EtOAc=100:1) to afford 5-Bromo-2-[(R)-(tetrahydro-furan-3-yl)oxy]-pyridine (5.9 g, yield: 47%) as a solid. 1HNMR (CDCl3 400 MHz): δ 8.15 (d, J=2.4 Hz, 1H), 7.61-7.64 (m, 1H), 6.64 (d, J=8.8 Hz, 1H), 5.47-5.50 (m, 1H), 3.85-4.02 (m, 4H), 2.07-2.28 (m, 2H). [α]D20=+18.5 (C=0.189, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:19][CH:20]=2)[S:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)(=[O:37])=[O:36])[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3ccccc3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3ccccc3)cc2)S(=O)(=O)c2ccccn2)c1

Procedure:
The title compound of Step B was prepared following the method described in Step B of Example 1 from 3-(3-{[(biphenyl-4-ylmethyl)-amino]-methyl}-phenyl)-propionic acid methyl ester, prepared in Step A of Example 12m and pyridine-2-sulfonyl chloride hydrochloride, of Preparation 47, using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.65 (d, 1H), 7.95 (d, 1H), 7.83 (m, 1H), 7.51 (dd, 2H), 7.45-7.29 (m, 6H), 7.16-7.10 (m, 3H), 7.08-6.90 (m, 3H), 4.50 (s, 2H), 4.48 (s, 2H), 3.64 (s, 3H), 2.79 (t, 2H), 2.49 (t, 2H); MS 501 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:11])=[CH:5][CH:4]=1.[C:32]([O:36][C:37]([NH:39][S:40](N1C=CC(=[N+](C)C)C=C1)(=[O:42])=[O:41])=[O:38])([CH3:35])([CH3:34])[CH3:33].C(N(CC)CC)C>ClCCl>[O:11]=[C:10]([NH:12][CH2:13][C:14]1[C:15]([C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[N:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=1)[CH:9]([C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][S:40]([NH:39][C:37](=[O:38])[O:36][C:32]([CH3:34])([CH3:33])[CH3:35])(=[O:41])=[O:42])=[CH:8][CH:7]=1)[CH3:31]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CN)cc2)c1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CNS(=O)(=O)NC(=O)OC(C)(C)C)cc2)c1
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a stirred solution of 2-(4-(aminomethyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (167 mg, 0.39 mmol) in dichloromethane the intermediate (A) (117 mg, 0.39 mmol) and triethylamine (0.20 mL, 0.56 mmol) was added was stirred for overnight. The reaction mixture was stirred for overnight at room temperature. The mixture was diluted with dichloromethane and washed with water, brine, dried over magnesium sulfate and filtered. The filtrate was evaporated and the residue was purified by column chromatography. Tert-butyl N-(4-(1-oxo-1-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methylamino)propan-2-yl)benzyl)sulfamoylcarbamate (118 mg) was obtained as 50% yield.
Reaction SMILES: N12CCCN=C1CCCCC2.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20].Cl[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[CH:17]=[CH:18]/[C:19]([O:21][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])=[O:20]
Reactant: OCCCCCCCl
Reactant: COc1ccc(/C=C/C(=O)O)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1ccc(/C=C/C(=O)OCCCCCCO)cc1OC
Temperature: 80 °C
Reaction time: 19 h

Procedure:
A solution consisting of 0.72 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene (1.5-5) and 5 ml of dimethylformamide was added dropwise to a solution of 1.0 g of (E)-3,4-dimethoxycinnamic acid in 10 ml of dimethylformamide in the course of 10 minutes at room temperature. The reaction mixture was then heated to 80° C., 0.18 g of tetrabutylammonium iodide and 0.71 ml of 6-chlorohexanol were then added in succession and the reaction was then allowed to continue for 19 hours. Thereafter, the reaction mixture was cooled to room temperature and was partitioned between diethyl ether and 1 N hydrochloric acid and the organic phase was washed several times with saturated sodium chloride solution. The organic phase was then dried over magnesium sulfate, filtered and evaporated down. Chromatography of the residue over 150 g of silica gel using 3:2 toluene/ethyl acetate gave 1.35 g of 6-hydroxyhexyl (E)-3,4-dimethoxycinnamate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][CH:43]([C:45]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:46]=1[O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[OH:44]>>[CH2:53]([O:52][C:46]1[CH:47]=[CH:48][C:49]([Cl:51])=[CH:50][C:45]=1[CH:43]([OH:44])[CH2:42][NH:41][C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: NCC(O)c1cc(Cl)ccc1OCc1ccccc1
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCC(O)c1cc(Cl)ccc1OCc1ccccc1
Yield: 64.2 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (75 mg, 0.13 mmol) and 2-amino-1-[2-(benzyloxy)-5-chlorophenyl]-1-ethanol (45 mg, 0.16 mmol) according to Method C to give the title compound (66 mg) as a diasteromeric mixture. 1H-NMR (400 MHz, CD3OD) d 4.77 (s, 1H), 4.75 (s, 1H), 4.55 (m, 1H), 4.22 (m, 1H), 1.33-1.32 (9H); HRMS m/z 789.2713 (calc. of monoisotopic mass for C41H44ClN3O11 gives 789.2664).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[C:8]1[C:17]([N:19]([CH2:41][CH:42]([CH3:44])[CH3:43])[C@H:20]1[CH2:25][C@@H:24]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1)=[O:18].C(OCC)(=O)C.[ClH:51]>C(OCC)(=O)C>[ClH:51].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[C:8]1[C:17]([N:19]([CH2:41][CH:42]([CH3:44])[CH3:43])[C@H:20]1[CH2:25][C@@H:24]([C:26]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[O:27])[CH2:23][NH:22][CH2:21]1)=[O:18]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)cc2c1C(=O)CCC2
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)cc2c1C(=O)CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-7-oxo-4,5,6,7-tetrahydro-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (100 mg) was dissolved in ethyl acetate (1 ml), 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was dried under reduced pressure to give the object product (52 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH2:25][C:26]([F:29])([F:28])[F:27])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])C.[Li+].[I-]>N1C=CC=CC=1>[Cl:24][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:25][C:26]([F:29])([F:27])[F:28])[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23]
Reactant: CCOC(=O)c1c(CC(F)(F)F)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(O)c1c(CC(F)(F)F)nc2ccc(Cl)cc2c1Cc1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 20 step D from 6-chloro-4-(2-chloro-benzyl)-2-(2,2,2-trifluoro-ethyl)-quinoline-3-carboxylic acid ethyl ester (70 mg, 0.16 mmol) and LiI (212 mg, 1.58 mmol) in pyridine. Off white solid (15 mg, 23%). LC-MS: 412 (M−H)−.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:11]=[C:12]([NH:16]C(=O)OC(C)(C)C)[CH:13]=[CH:14][CH:15]=2)=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[N:1]1[C:2]([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[NH2:16])=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2cn3ncccc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(-c2cn3ncccc3n2)c1
Yield: 75 %

Procedure:
A solution of tert-butyl 3-(imidazo[1,2-b]pyridazin-2-yl)phenylcarbamate (1 mmol) and TFA (4 mmol) in CH2Cl2 (10 ml) was stirred at 35° C. overnight. Then 1 M NaOH (4 ml) was added, and the mixture was extracted with EtOAc. The organic layer was concentrated to give 3-(imidazo[1,2-b]pyridazin-2-yl)aniline with a yield of 75%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1(S([N:16]2[C:20]3=[CH:21][N:22]=[CH:23][CH:24]=[C:19]3[C:18]([C:25]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[N:28][N:27]4[CH2:36][CH2:37][CH2:38][C:26]=34)=[CH:17]2)(=O)=O)C=CC=CC=1>CO>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:29]1[C:25]([C:18]2[C:19]3[C:20](=[CH:21][N:22]=[CH:23][CH:24]=3)[NH:16][CH:17]=2)=[C:26]2[CH2:38][CH2:37][CH2:36][N:27]2[N:28]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2c(-c3ccccn3)nn3c2CCC3)c2ccncc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ccc(-c2nn3c(c2-c2c[nH]c4cnccc24)CCC3)nc1
Yield: 64.5 %

Procedure:
Add potassium carbonate (40 mg, 0.29 mmol) to a solution of 1-benzenesulfonyl-3-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-pyrrolo[2,3-c]pyridine (Example 12, Part A; 16 mg, 0.036 mmol) in methanol (3 mL). Reflux the reaction mixture overnight (15 h). Concentrate the mixture in vacuo and purify by silica gel chromatography, using the appropriate mixture of methylene chloride, chloroform, methanol, and concentrated aqueous ammonium hydroxide, to provide 7 mg (64%) of the title compound as a tan solid. MS (ES) m/z=302 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH3:11].[CH3:12][O-:13].[Na+]>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][OH:13])[NH2:8]
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1ccc(CCO)c(F)c1

Procedure:
2-Fluoro-4-nitrotoluene and p-formaldehyde were allowed to undergo the reaction in DMSO in the presence of sodium methoxide, and then the resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain 3-fluoro-4-(2-hydroxyethyl)aniline. F: 156.