Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:12]([C:13]3[CH:25]=[CH:24][C:23]4[C:22]5[C:17](=[CH:18][C:19](I)=[CH:20][CH:21]=5)[C:16]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:15]=4[CH:14]=3)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1>C1(C)C=CC=CC=1.O.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>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:12]([C:13]3[CH:25]=[CH:24][C:23]4[C:22]5[C:17](=[CH:18][C:19]([C:18]6[C:17]7[C:16]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:15]8[C:23](=[CH:24][CH:25]=[CH:13][CH:14]=8)[C:22]=7[CH:21]=[CH:20][CH:19]=6)=[CH:20][CH:21]=5)[C:16]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:15]=4[CH:14]=3)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: CCCCCCCCC1(CCCCCCCC)c2cc(I)ccc2-c2ccc(-c3ccccc3-c3ccncc3)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCC1(CCCCCCCC)c2cc(-c3ccccc3-c3ccncc3)ccc2-c2ccc(-c3cccc4c3C(CCCCCC)(CCCCCC)c3ccccc3-4)cc21
Temperature: 110 °C
Reaction time: 48 h

Procedure:
To a solution of 400 mg (0.60 mmol) of 2-(6-p-pyridyl-phenyl)-7-iodo-9,9-dioctylfluorene, 362 mg (0.60 mmol) of 2-(4,4,5,5 tetramethyl-1,3,2-dioxaborolane)-9,9-dihexylfluorene in 10 mL of toluene was added: 4 mg (0.004 mmol) Pd(PPh3)4 and 2.5 ml of an 20% (3.1 mmol) Et4NOH solution in water. This two-phase reaction mixture was stirred for 48 h at 110° C. after which it was extracted using dichloromethane/water. The organic layer was dried on MgSO4 and the solvents were removed under reduced pressure. The crude product was purified using flash chromatography. Yield 450 mg (86%). 1H NMR (400 MHz, CDCl3): δ=8.74 (d, 3J=4.9 Hz, 1H; CH—N), 8.13 (d, 3J=4.6 Hz, 2H; CH—C—C(CH)—N), 7.84-7.77 (mp, 6H, ArH), 7.74 (d, 3J=6.0 Hz, 2H, CH—CH—CH—N), 7.69-7.63 (mp, 6H; ArH), 7.39-7.30 (mp, 3H; ArH), 7.27-7.24 (mp, 1H (obscured by CDCl3 peak; ArH), 2.11-2.02 (mp, 8H, C—CH2), 1.18-1.09 (mp, 32H, CH2), 0.81-0.74 (mp, 20H, CH2—CH3). 13C{1H} NMR (500 MHz, CDCl3): δ=157.1 (CN), 151.8, 151.4, 151.0 (C—C—CH2), 149.8 (CH—N), 142.2, 140.8, 140.6, 140.42; 140.39, 140.3, 139.9, 139.3, 138.1 (ArC), 136.8 (CH—CH—CH—N), 127.5, 127.3, 126.9, 126.8, 126.1, 126.0, 122.1, 122.0, 121.44, 121.38, 120.4, 120.0, 119.8, 119.7 (CH), 55.3, 55.1 (C—CH2), 40.4 (C—CH2), 31.7, 31.5, 30.0, 29.7, 29.18, 29.16 (CH2), 23.8, 23.7 (C—CH2—CH2), 22.6, 22.5 (CH3—CH2), 14.03, 13.99 (CH3). Exact Mass (IE): 875.6367 [M]+(calcd 875.6369) fractions m/z: 762.3 (m; [M-(C8H17)]+, 650.4 (m; [M-(C8H17)2]+. C65H81N: calcd. C, 89.09; H, 9.32; N, 1.60. found: C, 88.60; H, 9.25; N, 1.52.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([C@@H:10]1[CH2:14][N:13]([CH2:15][CH3:16])[C@H:12]([C:17](OCC)=[O:18])[CH2:11]1)=[N+]=[N-].[OH-].[Na+]>O1CCCC1>[NH2:7][C@@H:10]1[CH2:14][N:13]([CH2:15][CH3:16])[C@H:12]([CH2:17][OH:18])[CH2:11]1
Reactant: CCOC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN1C[C@@H](N)C[C@H]1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.41 g of lithium aluminium hydride were suspended in 10 ml of tetrahydrofuran and while cooling, a solution of 1.9 g of (2S,4S)-4-azido-2-ethoxycarbonyl-N-ethyl pyrrolidine in 4 ml of tetrahydrofuran was dropwise added thereto. After stirring at the same temperature for 1 hour, the temperature of reaction mixture was raised to room temperature and the mixture was stirred for 2 hours. To this, a mixture of 1 ml of 1N-NaOH solution and 9 ml of tetrahydrofuran was added to decompose lithium aluminium hydride and undissolved material was filtered. The filtrate was concentrated under reduced pressure to obtain (2S,4S)-4-amino-N-ethyl2-hydroxymethyl pyrrolidine. Yield 1.05 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][C:10]1[N:11]=[N:12][S:13][C:14]=1[C:15](O)=[O:16].Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>C1COCC1.C(OCC)(=O)C.O.C(Cl)CCl>[Br:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:15]([C:14]2[S:13][N:12]=[N:11][C:10]=2[CH3:9])=[O:16])=[N:3][CH:4]=1
Reactant: Nc1cnc(Br)cn1
Reactant: Cc1nnsc1C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: O
Product: Cc1nnsc1C(=O)Nc1cnc(Br)cn1
Reaction time: 24 h
Yield: 22.3 %

Procedure:
To a solution of 2-amino-5-bromopyrazine (1.0 g, 5.74 mmol, 1.2 eq) and 4-methyl-1,2,3-thiadiazole-5-carboxylic acid (690 mg, 4.79 mmol, 1.0 eq) in THF (20 mL) at room temperature was sequentially added EDC. HCl (970 mg, 7.18 mmol, 1.5 eq), HOBT (1.37 g, 7.18 mmol, 1.5 eq) and diisopropylethyl amine (1.23 mL, 9.58 mmol, 2.0 eq). The resulting solution was stirred at the same temperature for 24 h. Water (30 mL) was added to the reaction mixture followed by ethyl acetate (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with 1N hydrochloric acid (20 mL), saturated sodium bicarbonate solution (20 mL), brine (20 mL) dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel) to afford 321 mg of the desired product as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H, D2O exchangeable), 9.20 (s, 1H), 8.72 (s, 1H), 2.83 (s, 3H); ESI-MS (m/z) 300, 302 [(MH)+, Br79,81].
Reaction SMILES: O[C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][C:5]1[C:6]([CH:16]([OH:32])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=2)=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([OH:15])[CH:9]=[CH:8]2>Cl.C(Cl)Cl>[N:26]1([CH2:25][CH2:24][O:23][C:20]2[CH:21]=[CH:22][C:17]([CH:16]3[C:6]4[C:7]5[CH:8]=[CH:9][C:10]([OH:15])=[CH:11][C:12]=5[CH:13]=[CH:14][C:5]=4[CH2:4][C:3]4[CH:2]=[CH:36][CH:35]=[CH:34][C:33]=4[O:32]3)=[CH:18][CH:19]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Oc1ccc2c(C(O)c3ccc(OCCN4CCCCC4)cc3)c(Cc3ccccc3O)ccc2c1
Agent: Cl
Solvent: ClCCl
Product: Oc1ccc2c3c(ccc2c1)Cc1ccccc1OC3c1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
Dissolve 6-(2-hydroxy-benzyl)-5-{hydroxy-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-naphthalen-2-ol (80 mg, 0.17 mmol) in HCl solution (20% 1M aq. HCl in THF). Stir at r.t. for 2 h and warm gently for 10 min. Dilute with CH2Cl2, wash with sat. NaHCO3, water and brine, dry over MgSO4, filter and concentrate. Purify the crude product by flash chromatography (0-5% (2M NH3 in MeOH)/CH2Cl2) to afford 13-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-7,13-dihydro-12-oxa-benzo[4,5]cyclohepta[1,2-a]naphthalen-3-ol (43 mg, 56%).
Reaction SMILES: [C:1](=[S:3])=S.[C:4]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][NH2:14])[CH2:9][CH2:8]1)(=[O:6])[CH3:5]>O1CCCC1>[C:4]([N:7]1[CH2:8][CH2:9][CH:10]([CH2:13][N:14]=[C:1]=[S:3])[CH2:11][CH2:12]1)(=[O:6])[CH3:5]
Reactant: S=C=S
Reactant: CC(=O)N1CCC(CN)CC1
Solvent: C1CCOC1
Product: CC(=O)N1CCC(CN=C=S)CC1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred and cooled (-10° C.) mixture of 41.6 parts of N,N'-methanetetraylbis[cyclohexanamine], 101 parts of carbon disulfide and 450 parts of tetrahydrofuran was added dropwise a solution of 31.2 parts of 1-acetyl-4-piperidinmethanamine in 90 parts of tetrahydrofuran. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was evaporated. 2,2'-Oxybispropane was added to the residue. The precipitate was filtered off and the filtrate was evaporated, yielding 40 parts (100%) of 1-acetyl-4-(isothiocyanatomethyl)piperidine as a residue (intermediate 10).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Br[C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]=[N:34][N:33]=[CH:32]2.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)(=[O:10])=[O:11])=[CH:6][C:5]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[CH:35]=[N:34][N:33]=[CH:32]3)=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3)c2)OC1(C)C
Reactant: Brc1ccc2cnncc2c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(-c2ccc3cnncc3c2)cnc1Cl)c1ccc(F)cc1
Temperature: 100 °C

Procedure:
A suspension of N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (102 mg, 247 μmol), 6-bromophthalazine (43 mg, 206 μmol), dichloro[1,1′bis(diphenylphoshino)ferrocene]palladium(II)dichloromethane adduct (11 mg, 15 μmol), and Na2CO3 (65 mg, 617 μmol) in 1,4-dioxane (2 mL) and water (1 mL) was sparged with nitrogen for 5 minutes, then heated to 100° C. for 2 hours. The reaction was then partitioned between 9:1 CHCl3/IPA (30 mL) and 5% NaHCO3 (10 mL). The separated organic was dried over Na2SO4, concentrated onto dry silica, and then purified on silica eluting with 2→5% of MeOH/DCM. Product was isolated as light yellow solid. MS (ESI pos. ion) m/z calc'd for C19H12ClFN4O2S: 414.0; found 415.0. 1H NMR (400 MHz, DMSO-d6) δ 7.44 (t, J=8.8 Hz, 2 H) 7.80-7.87 (m, 2 H) 8.24 (d, J=2.1 Hz, 1 H) 8.32 (d, J=8.4 Hz, 1 H) 8.38 (dd, J=8.7, 2.0 Hz, 1 H) 8.54 (s, 1 H) 8.79 (d, J=2.1 Hz, 1 H) 9.76 (s, 2 H) 10.60 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH3:12].C1COCC1>[Ni].CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(N)ccc1Cl
Yield: 92.6 %

Procedure:
A mixture of 36 g of 2-chloro-5-nitroanisole and Raney nickel® in 150 ml of MeOH and 200 ml of THF is hydrogenated in Parr apparatus for 4 hours, at 35° C. and under a pressure of 1.3 bar. The catalyst is filtered off over Celite® and the filtrate is concentrated under vacuum. 28 g of the expected product are obtained and are used without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[OH-].[Na+]>O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(=O)CCCCOCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(CCCCCOCc2ccccc2)cc1
Reaction time: 20 h

Procedure:
To a mixture of 16 g of formula (VIII) compound obtained in the preceding example and 21 g of triethylsilane were added 30.1 ml of trifluoroacetic acid and it was left under agitation for 20 hours at room temperature. Then, it was diluted with water, basified by means of concentrated NaOH, extracted with methylene chloride, washed with water, dried on sodium sulfate, the filtrate was evaporated and the residue chromatographed on a silica column [eluent: methylene chloride (99)-methanol (1) mixture]. Thus, 14 g of the expected compound were obtained in the form of an oil (Yield: 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2([CH2:18][OH:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:38]=[CH:37][O:36][N:35]=2)=[CH:30][CH:29]=1.BrC1C=CC(CN(C2(CO)CCCCC2)S(C2C=CC(Cl)=CC=2)(=O)=O)=CC=1>>[O:36]1[CH:37]=[N:38][C:34]([C:31]2[CH:32]=[CH:33][C:28]([CH2:27][N:11]([C:12]3([CH2:18][OH:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])=[CH:29][CH:30]=2)=[N:35]1
Reactant: BrCc1ccc(-c2ncon2)cc1
Reactant: O=S(=O)(NC1(CO)CCCCC1)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(Br)cc1)C1(CO)CCCCC1
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncon2)cc1)C1(CO)CCCCC1
Yield: 9.1 %

Procedure:
The title compound was synthesized from 4-chloro-N-(1-(hydroxymethyl)cyclohexyl)benzenesulfonamide (114 mg, 0.38 mmol), cesium carbonate (244 mg, 0.75 mmol), and 3-(4-(bromomethyl)phenyl)-1,2,4-oxadiazole (99 mg, 0.41 mmol) according to the procedure described for N-(4-bromobenzyl)-4-chloro-N-(1-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 39) to give N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-4-chloro-N-(1-(hydroxymethyl)cyclohexyl)benzenesulfonamide (16 mg, 9%). 1H NMR (400 MHz, CDCl3) δ ppm 8.75 (1H, s), 8.08 (2H, d, J=8.31 Hz), 7.80 (2H, d, J=8.56 Hz), 7.39-7.45 (4H, m), 4.38 (2H, d, J=5.79 Hz), 4.08-4.12 (2H, m), 1.68-1.82 (2H, m), 1.29-1.49 (8H, m). LC/MS R.T.=2.93 min; [M+Na]+=484.20.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][F:20])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1.CO.[CH3:23][NH:24][CH3:25]>>[CH3:23][N:24]([C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][F:20])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1)[CH3:25]
Reactant: FCCOc1ccc2cc(-c3ccnc(Cl)n3)sc2c1
Reactant: CNC
Solvent: CO
Product: CN(C)c1nccc(-c2cc3ccc(OCCF)cc3s2)n1
Yield: 93.3 %

Procedure:
2-[2-(N,N-Dimethylamino)pyrimidine-4-yl]-6-(2-fluoroethoxy)benzothiophene (1-36, 77 mg, 93%) was prepared in the same manner as in Example 35 as a yellow solid using 2-(2-chloropyrimidine-4-yl)-6-(2-fluoroethoxy)benzothiophene (105b, 80 mg, 0.26 mmol) obtained in Preparation Example 20 and a 2.0 M dimethylamine methanol solution (NHMe2 in MeOH, 0.26 mL, 0.52 mmol).
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:13][C:14]1[CH:21]=[C:20]([N:6]2[CH2:7][CH2:8][C@:4]([CH:1]3[CH2:3][CH2:2]3)([OH:12])[C@@H:5]2[CH:9]([CH3:10])[CH3:11])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC(C)[C@@H]1N(c2ccc(C#N)c(Cl)c2)CC[C@@]1(O)C1CC1

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3R)-3-cyclopropyl-2-isopropylpyrrolidin-3-ol 0.5 oxalate (215 mg), 2-chloro-4-fluorobenzonitrile (156 mg) and lithium carbonate (163 mg), the title compound was obtained as a pale-brown solid (yield: 130 mg, yield: 43%).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:11][C:12]1[C:5]2[C:3](=[C:2]([I:1])[CH:8]=[CH:7][CH:6]=2)[N:4]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccccc1I
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(I)cccc2c1O
Temperature: 25 °C

Procedure:
A solution of 2-iodoaniline (8.22 g) and diethyl ethoxymethylenemalonate (8.00 mL) is heated at 130° C. for 1 h. The reaction is cooled to room temperature. Diphenyl ether (100 mL) is added and the reaction is heated at 250° C. for 1.25 h. The reaction is cooled to room temperature and the resulting solid is filtered, washed thoroughly with hexanes, and dried to give ethyl 4-hydroxy-8-iodo-3-quinolinecarboxylate (6.84 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.[N:38]1([C:42](=O)[CH2:43]Cl)[CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:42][CH2:43][O:37][C:36]2[CH:35]=[CH:34][C:4]([CH2:5][CH2:7][NH:8][C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=3[CH:17]3[CH2:26][CH2:25][C:24]4[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=4[CH2:18]3)=[CH:3][C:2]=2[F:1])[CH2:41][CH2:40][CH2:39]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Reactant: O=C(CCl)N1CCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCC3)c(F)c2)c1
Yield: 39.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 1-azetidin-1-yl-2-chloroethanone (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.7 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].I[CH3:21].[H-].[Na+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:21])[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: CI
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccccc1)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-(4-fluoro-3-nitro-phenyl)-benzamide (1.60 g, 6.15 mmol) in anhydrous DMF was added iodomethane (3.49 g, 24.60 mmol, 1.53 ml) under argon. 60% Sodium hydride (0.37 g, 9.23 mmol) was then added portionwise to the cooled solution (0° C.) and the reaction mixture was then stirred at room temperature for 24 h. The solution was poured slowly into water and the aqueous layer was extracted 3× with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography, eluting with hexane/ethyl acetate (4:1) to give N-(4-fluoro-3-nitro-phenyl)-N-methyl-benzamide. (1.47 g, 87%)
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]([CH2:22][C:23]1[C:28]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:27][CH:26]=[CH:25][N:24]=1)[CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=1.[Li+].[BH4-]>CO>[C:33]([O:32][C:30](=[O:31])[NH:29][C:28]1[C:23]([CH2:22][N:13]([CH2:12][C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[CH2:3][OH:2])[CH2:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:24][CH:25]=[CH:26][CH:27]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1C)Cc1ncccc1NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: Cc1cccnc1CN(Cc1ccc(C#N)cc1CO)Cc1ncccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 98.7 %

Procedure:
To a cold (0° C.) solution of 2-{[(3-tert-Butoxycarbonylamino-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-5-cyano-benzoic acid methyl ester (0.388 g, 0.77 mmol) in MeOH (7 mL) was added LiBH4 (107 mg, 4.91 mmol) and the mixture was allowed to warm to room temperature overnight. The mixture was concentrated and the residue was partitioned between CH2Cl2 (50 mL) and 1.0 N NaOH (15 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4) and concentrated and provided 0.36 g of (2-{[(4-Cyano-2-hydroxymethyl-benzyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-carbamic acid tert-butyl ester as a white solid, which was used without further purification.
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:34])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[C:26]([CH2:29][CH2:30][C:31](=[O:33])[CH3:32])[CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1.[CH3:36][Mg]Br>C1COCC1>[F:35][C:2]1([F:1])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:34])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[C:26]([CH2:29][CH2:30][C:31]([OH:33])([CH3:36])[CH3:32])[CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1
Reactant: C[Mg]Br
Reactant: CC(=O)CCc1ccc2ncc(C(=O)Nc3cc(-c4noc(C5CC(F)(F)C5)n4)ccc3C)n2c1
Solvent: C1CCOC1
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(CCC(C)(C)O)cn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxamide (F53) (40 mg, 0.083 mmol) in anhydrous THF (2 mL) at −78° C. under a stream of Argon was added methylmagnesium bromide (83 uL, 0.25 mmol). The reaction was stirred to room temperature for 30 minutes. The reaction was cooled to 0° C. and was quenched with saturated NH4Cl (2 mL). The crude product was extracted with ethylacetate. The organic was washed with water, brine and dried over anhydrous sodium sulfate. The solvent was concentrated and the crude product was purified by reverse phase preparative HPLC to give N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(3-hydroxy-3-methylbutyl)imidazo[1,2-a]pyridine-3-carboxamide (F54). 1H NMR (400 MHz, d6-DMSO) δ 10.18 (s, 1H), 9.36 (s, 1H), 8.68 (s, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.86-7.82 (m, 2H), 7.65-7.62 (m, 1H), 7.51 (d, J=8.4 Hz, 1H), 3.91-3.84 (m, 1H), 3.25-3.04 (m, 4H), 2.78-2.73 (m, 2H), 2.37 (s, 3H), 1.71-1.67 (m, 2H), 1.16 (s, 6H). MS m/z 496.21 (M+1)+.
Reaction SMILES: CC(C)([O-])C.[K+:6].[C:7]([C:9]1([CH2:15][C:16]([OH:18])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)#[N:8]>O1CCCC1>[C:7]([C:9]1([CH2:15][C:16]([O-:18])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)#[N:8].[K+:6]
Reactant: N#CC1(CC(=O)O)CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC1(CC(=O)[O-])CCCCC1
Reaction time: 0.17 h
Yield: 100.7 %

Procedure:
To a 250-mL flask under nitrogen is added 14.8 g (0.13 mol) of potassium tertiary butoxide followed by 74 mL of tetrahydrofuran. The solution is stirred for 10 minutes, suction filtered, and washed using 50 mL of tetrahydrofuran. The filtrates are combined and transferred into an addition funnel on a separate 250-mL flask containing 20 g (0.12 mol) of dried 1-cyanocyclohexaneacetic acid and 100 mL of tetrahydrofuran. The potassium tertiary butoxide solution is added dropwise over 5 minutes to the previous solution. The precipitate is cooled in an ice bath, suction filtered, and washed with 25 mL of cold tetrahydrofuran. The filter cake is dried in a vacuum oven at 50° C. for 16 hours to give 24.8 g of potassium 1-cyanocyclohexaneacetate as a white crystalline solid; mp 196°-199° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Cl:13].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].CCN(CC)CC>C1COCC1>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:23])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Cl:13]
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: O=C=Nc1ccccc1Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Br)c(Cl)c1
Reaction time: 24 h
Yield: 67.3 %

Procedure:
To a mixture of methyl 4-amino-3-chlorophenylacetate (1.00 g, 5.01 mmol) and 2-bromophenyl isocyanate (0.62 ml, 5.01 mmol) in THF (20 ml) was added Et3N (0.14 ml, 1.00 mmol) at room temperature. After 1 day stirring, 2-bromophenyl isocyanate (0.60 ml, 5.01 mmol) was added to the reaction mixture and stirred 24 h. The reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 4-[N′-(2bromophenyl)ureido]-3-chlorophenylacetate (1.34 g, 67%) as a colorless powder. 1H-NMR (CDCl3) δ3.58 (s, 3H), 3.70 (s, 2H), 6.98 (m, 3H), 7.19 (dd, J=8.3, 1.9 Hz, 1H), 7.32 (m, 1H), 7.51 (m, 2H),k 8.05 (m, 1H); MS (ESI) m/z 398 (M++1), 400 (M++3), 402 (M++5).