Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10](=[O:15])N(C)OC)=[CH:6][N:5]2[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1>>[NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10](=[O:15])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:6][N:5]2[C:16]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CON(C)C(=O)c1ccc2nc(N)c(-c3ccccc3)n2c1
Reactant: Fc1cccc(Br)c1
Product: Nc1nc2ccc(C(=O)c3cccc(F)c3)cn2c1-c1ccccc1

Procedure:
The 2-amino-3-phenyl-6-(N-methyl-N-methoxycarbamoyl)imidazo[1,2-a]pyridine (148 mg, 0.500 mmol) and 1-bromo-3-fluorobenzene were converted to product in a manner substantially analogous to Example 141 to give 37 mg. (37%). MS(FAB+) m/z 332.2 (M++1, 86.6), NMR (200 MHz, CDCl3) d 4.22 (bs, 2H, NH), 7.21-7.55 (m, 11H, ArH+H7+H8), 8.69 (d, J57=1.1, H5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:7]=[CH:6][C:5]=2[C:4]=1[CH:21]=O.[C:23]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.ClCCl.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3]1[C:4]([CH2:21][N:33]2[CH2:32][CH2:31][N:30]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:35][CH2:34]2)=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH:7]=[CH:6]2
Reactant: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1C=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1CN1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
5-Methoxy-1-(phenylsulfonyl)-1H-indole-4-carbaldehyde (0.10 g, 0.317 mmol, Intermediate 75), boc-piperazine (0.118 g, 0.634 mmol) and acetic acid (0.095 g, 1.58 mmol) were dissolved in THF (5 mL) and sodium triacetoxyborohydride (0.134 g, 0.63 mmol) were added. The mixture was stirred for 2 hours and diluted with dichloromethane and 1N Na2CO3. The mixture was extracted with dichloromethane (2×) and the combined organics were dried (MgSO4) and evaporated. The crude product was ran through a plug of silica gel eluating with 5% MeOH in dichloromethane. Yield 100 mg (65%). White solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:50])[CH2:7][CH2:6][N:5]([CH2:8][C:9]([NH:11][C:12]23[CH2:46][CH2:45][C@@H:44]([CH:47]([CH3:49])[CH3:48])[C@@H:13]2[C@@H:14]2[C@@:27]([CH3:30])([CH2:28][CH2:29]3)[C@@:26]3([CH3:31])[C@@H:17]([C@:18]4([CH3:43])[C@@H:23]([CH2:24][CH2:25]3)[C:22]([CH3:33])([CH3:32])[C@@H:21]([C:34]3[CH:42]=[CH:41][C:37]([C:38]([O-:40])=[O:39])=[CH:36][CH:35]=3)[CH2:20][CH2:19]4)[CH2:16][CH2:15]2)=[O:10])[CH2:4][CH2:3]1.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52].O.[OH-].[Li+]>C1COCC1>[O:50]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][C:9]([NH:11][C@:12]23[CH2:46][CH2:45][C@@H:44]([CH:47]([CH3:48])[CH3:49])[C@@H:13]2[C@@H:14]2[C@@:27]([CH3:30])([CH2:28][CH2:29]3)[C@@:26]3([CH3:31])[C@@H:17]([C@:18]4([CH3:43])[C@@H:23]([CH2:24][CH2:25]3)[C:22]([CH3:33])([CH3:32])[C@@H:21]([C:34]3[CH:35]=[CH:36][C:37]([C:38]([OH:40])=[O:39])=[CH:41][CH:42]=3)[CH2:20][CH2:19]4)[CH2:16][CH2:15]2)=[O:10])[CH2:4][CH2:3]1.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]
Reactant: CC(C)[C@@H]1CCC2(NC(=O)CN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](c6ccc(C(=O)[O-])cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H]1CC[C@]2(NC(=O)CN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Reaction time: 5.5 h

Procedure:
To a solution of 4-[(1S,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-[[2-(1,1-dioxo-1,4-thiazinan-4-yl)acetyl]amino]-1-isopropyl-5a,5b,8,8,11a-pentamethyl-1,2,3,4,5,6,7,7a,9,10,11,11b,12,13,13a,13b-hexadecahydrocyclopenta[a]chrysen-9-yl]benzoate, TFA (24.3 mg, 0.029 mmol) in THF (3 mL) was added a 0.753 molar aqueous solution of lithium hydroxide monohydrate (0.232 mL, 0.116 mmol). The reaction mixture was heated to 75° C. After 5.5 h, the reaction mixture was concentrated to dryness. The crude residue was dissolved in THF (1.2 mL), MeOH (0.3 mL) and 1N HCl (0.2 mL). The resulting solution was filtered and purified using prep HPLC method 3 to give 4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-(((1,1-dioxido-4-thiomorpholinyl)acetyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, TFA (16.5 mg, 0.020 mmol, 69.1% yield) as a white solid. LCMS: m/z 709.6 (M+H+), retention time 2.072 min (method 6). 1H NMR (500 MHz, METHANOL-d4) δ=7.91 (d, J=8.2 Hz, 2H), 7.26 (d, J=8.2 Hz, 2H), 7.11 (s, 1H), 3.25-3.20 (m, 6H), 3.17 (d, J=5.5 Hz, 4H), 2.65-2.59 (m, 1H), 2.44 (dd, J=2.7, 13.1 Hz, 1H), 2.37 (dd, J=7.0, 12.5 Hz, 1H), 2.19-2.04 (m, 1H), 1.98-1.89 (m, 1H), 1.85 (d, J=13.1 Hz, 1H), 1.74 (dd, J=3.7, 7.9 Hz, 2H), 1.71-1.60 (m, 3H), 1.56-1.45 (m, 8H), 1.44-1.37 (m, 4H), 1.36-1.25 (m, 2H), 1.16-1.09 (m, 2H), 1.05 (s, 3H), 1.04 (s, 3H), 1.00 (s, 3H), 0.95 (d, J=2.1 Hz, 1H), 0.91 (d, J=6.7 Hz, 3H), 0.81 (d, J=6.7 Hz, 3H), 0.78 (s, 3H), 0.72 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C1C(=O)N([Br:22])C(=O)C1>C(Cl)Cl.C(OCC)(=O)C>[Br:22][C:10]1[C:11]([NH2:14])=[N:12][CH:13]=[C:8]([C:2]2([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][CH2:7]2)[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(c2ccc(N)nc2)CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(c2cnc(N)c(Br)c2)CCOCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 100 %

Procedure:
To an ice cold solution of 5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-2-amine (50 mg, 0.26 mmol) in DCM (5 mL) was added NBS (50.9 mg, 0.28 mmol) in two portions. The reaction mixture was stirred at ambient temperature for 40 min. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered off, and concentrated to give 3-bromo-5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-2-amine (70 mg, 0.26 mmol, 99% yield) as yellow color residue. LCMS (m/z): 271/273 (MH+), 0.41 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].S(=O)(=O)(O)[OH:14]>FC(F)(F)C(O)=O>[NH2:2][C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1)=[O:14]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cccc(CC(=O)O)c1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cccc(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
A solution of 3-cyanophenylacetic acid (0.2 g, 1.24 mmol) in a mixture of trifluoroacetic acid (1 ml) and concentrated sulfuric acid (0.5 ml) was stirred at room temperature for 16 h. The reaction mixture was then poured into ice-cold water and the resulting solid was filtered, washed with water and dried under vacuum to give 2-[3-(aminocarbonyl)phenyl]acetic acid (0.167 g, 75% yield). MS (EI) for C9H9NO3: 178 (M−H).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[O:6]1[CH2:10][CH2:9][O:8][C:7]21[CH2:15][CH2:14][C:13]1[C:16]3[C:21](=O)[NH:20][CH:19]=[N:18][C:17]=3[S:23][C:12]=1[CH2:11]2>C(N(CC)CC)C>[Cl:3][C:21]1[C:16]2[C:13]3[CH2:14][CH2:15][C:7]4([CH2:11][C:12]=3[S:23][C:17]=2[N:18]=[CH:19][N:20]=1)[O:8][CH2:9][CH2:10][O:6]4
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2sc3c(c12)CCC1(C3)OCCO1
Solvent: CCN(CC)CC
Product: Clc1ncnc2sc3c(c12)CCC1(C3)OCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a stirring 0° C. POCl3 (200 mL) solution of 3,5,6,8-tetrahydro-4H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolan]-4-one (20.0 g, 0.076 mol) was added triethylamine (200 mL) from a dropping funnel over a 15 min. period. The contents were allowed to warm to rt, and then heated to 80° C. After 3 h, the contents were removed from heating, and allowed to cool to rt. The heterogeneous mixture was concentrated under reduced pressure, the residue diluted with ethyl acetate (100 mL), and again concentrated. The residue was diluted with ethyl acetate (100 mL) and the heterogeneous mixture poured onto a stirring mixture of ice-water/sq. NaHCO3 (800 mL). After 5 min. stirring, the now pH=7 contents were filtered and the solid filter cake washed with water. The product was dried in vacuum oven overnight to afford the desired product (20.7 g, 97%) as an off-white solid. 1H-NMR (DMSO-d6) δ 8.82 (s, 1H), 3.97 (s, 4H), 3.10 (t, 2H), 3.07 (s, 2H), 1.95 (t, 2H); LCMS RT=2.45 min; [M+H]+=283.1.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][C:5](=O)[CH3:6].Cl.[CH3:10][O:11][C:12](=[O:15])[CH2:13][NH2:14].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH3:1][C:2]1[N:14]([CH2:13][C:12]([O:11][CH3:10])=[O:15])[C:5]([CH3:6])=[CH:4][CH:3]=1
Reactant: COC(=O)CN
Reactant: CC(=O)CCC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)Cn1c(C)ccc1C

Procedure:
A solution of hexan-2,5-dione (23 g.), glycine methyl ester hydrochloride (25 g.), and sodium acetate (16 g.) in acetic acid (100 cm3) was heated under reflux for 1 hour. The mixture was then poured into water, extracted with ether, and the ethereal phase washed with sodium carbonate solution, dried, and evaporated to yield a brown oil. The product was then distilled under vacuum to give methyl (2,5-dimethyl-1H-pyrrol-1-yl)acetate as a colourless oil which crystallised on standing. (22.1 g.) b.p. 123°-129° C./15 mm, m.p. 44°-46° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][CH:6]([OH:8])[CH:5]([OH:9])[CH:4]2[C:10]([CH3:16])([CH3:15])[CH:11]3[CH2:14][C:3]12[CH2:13][CH2:12]3.CO[C:20](OC)([CH3:22])[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+].CCCCCCCCCCCCCC>C1COCC1>[CH3:1][C:2]1([CH3:17])[CH2:7][CH:6]2[CH:5]([O:9][C:20]([CH3:22])([CH3:21])[O:8]2)[CH:4]2[C:10]([CH3:16])([CH3:15])[CH:11]3[CH2:14][C:3]12[CH2:13][CH2:12]3
Reactant: CC1(C)C2CCC3(C2)C1C(O)C(O)CC3(C)C
Reactant: COC(C)(C)OC
Agent: CCCCCCCCCCCCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CC1(C)OC2CC(C)(C)C34CCC(C3)C(C)(C)C4C2O1
Reaction time: 2 h
Yield: 24 %

Procedure:
A solution of diols from Example 1d (3.0 g, ˜6.5 mmol of the main diastereomeric pair of enantiomers of 5a), 2,2-dimethoxypropane (4.0 g, 0.38 mol) lithium bromide (0.1 g) and p-toluenesulfonic acid (0.1 g) in THF (40 ml) was stirred at r. t. for 2 h, then poured onto saturated aqueous sodium bicarbonate solution (100 ml) and extracted with MTBE (2×100 ml). The combined organic phases were washed with water (2×100 ml), dried (Na2SO4), concentrated in vacuo and the residue (3.0 g) purified by flash chromatography (MTBE/hexane 1:20) to afford a mixture of isomeric diols (0.60 g, colourless oil) in which the main diastereoisomeric pair of enantiomers of 2,2,6,6,10,10-hexamethyl-5,7-dioxatetracyclo[9.2.1.01.9, 04.8]tetradecane (Ia) constituted 73% (24% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Br)(Br)(Br)[Br:13]>ClCCl>[Br:13][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: BrC(Br)(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-nitrobenzyl alcohol (6 g, 39 mmoles) is put into solution in dichloromethane (100 ml) and carbon tetrabromide (14.9 g, 45 mmoles) is added. Triphenylphosphne (11.8 g, 45 mmoles) is added in portions to the medium at 0° C. Then the mixture is agitated for 2 hours at ambient temperature. Th e solvent is evaporated off and the product obtained is purified on silica gel in an ethyl acetate/heptane mixture (1/2). It is obtained in the form of white needle-shaped crystals (7.2 g; 85%). Melting point: 97-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([CH3:20])[CH:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)[OH:12].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([CH3:20])[C:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)=[O:12]
Reactant: COc1ccc(Cl)c(C(C)C(O)c2ccnc(Cl)c2)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COc1ccc(Cl)c(C(C)C(=O)c2ccnc(Cl)c2)c1
Reaction time: 2 h
Yield: 81.2 %

Procedure:
2-(2-Chloro-5-methoxy-phenyl)-1-(2-chloro-pyridin-4-yl)-propan-1-ol (140 mg) was dissolved in CH2Cl2 (20 mL). To this solution was added 3 Å molecular sieves (140 mg) and then tetrapropylammonium perruthenate (15.8 mg) and 4-methyl-morpholine-4-oxide (121 mg). The mixture was allowed to stir for 2 hours. The reaction mixture was applied directly to a silica gel column and the column was eluted with ethyl acetate:heptane 3:7. The appropriate fractions were combined and evaporated to give the title compound as a colorless gum (113 mg). MS (neg. ion, m/e)=308.4 ((M−H)−).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:24][C:25]([NH2:29])([CH2:27][CH3:28])[CH3:26].CCN=C=NCCCN(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:29][C:25]([CH2:27][CH3:28])([CH3:26])[CH3:24])=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(Cl)cc21
Reactant: CCC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
A mixture of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.07 g, 0.3 mmol), 2-methylbutan-2-amine (0.05 g, 0.57 mmol), EDCI (0.057 g, 0.3 mmol), DMAP (0.037 g, 0.3 mmol), HATU (0.114 g, 0.3 mmol) and DIPEA (0.163 g, 1.26 mmol) in 10 mL of DMF were stirred at room temperature overnight. The solvent was removed under reduced pressure at 70° C. The residue was triturated with water and then purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 57% acetonitrile/43% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 80% acetonitrile/20% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-tert-pentyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.019 g, 22%) as a white solid. MS: (M+H)+=397; 1H NMR (300 MHz, DMSO): δ12.86 (s, 1H), 9.10 (s, 1H), 8.47-8.40 (m, 2H), 8.03 (s, 1H), 7.83 (s, 1H), 7.32 (d, 1H, J=8.4 Hz), 4.20 (s, 3H), 2.03-1.91 (m, 2H), 1.48 (s, 6H), 0.89 (t, 3H, J=7.4 Hz).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[CH3:12][C:13]1[S:17][C:16]2[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=2[C:14]=1[C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1.CCN(C(C)C)C(C)C>ClCCl.O1CCCC1.CO.[OH-].[Na+]>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:28][C:25]1[CH:24]=[CH:23][C:22]([C:14]2[C:15]3[CH2:21][CH2:20][CH2:19][CH2:18][C:16]=3[S:17][C:13]=2[CH3:12])=[CH:27][N:26]=1)=[O:5]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cc1sc2c(c1-c1ccc(N)nc1)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc2c(c1-c1ccc(NC(=O)c3c(F)cccc3F)nc1)CCCC2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
Under an atmosphere of argon, 2,6-difluorobenzoyl chloride (9.4 mg, 53 μmol) was added to a stirred solution of 240 (6.5 mg, 26 μmol) and Hünig's base (28 μL, 21 mg, 0.2 mmol) in dichloromethane (0.5 mL) at room temperature. The reaction was stirred for 0.5 h. The solution was diluted with tetrahydrofuran (0.6 mL), methanol (0.4 mL) and 2 M sodium hydroxide solution (0.2 mL). The mixture was stirred and heated to 60° C. for 5 min then cooled to room temperature, diluted with dichloromethane (5 mL), dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-20% ethyl acetate in hexane) provided 236 (5.1 mg, 50%) as a solid: LRESIMS m/z 385.1 [M+H]+, calcd. for C21H19F2N2O1S1 385.1.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])(=O)C.[Na+].[Br:14]Br.[OH-].[Na+]>C(O)(=O)C>[Br:14][C:4]1[N:3]=[C:2]([F:1])[C:7]([NH2:8])=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: Nc1cccnc1F
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1ccc(Br)nc1F
Temperature: 2.5 °C
Yield: 76.4 %

Procedure:
To a stirred solution of 2-fluoro-pyridin-3-ylamine (3.0 g, 26.79 mmol) in acetic acid (24 mL), sodium acetate (2.17 g, 26.46 mmol) was added. The reaction mixture was cooled to 0-5° C. and a solution of bromine (1.37 mL, 26.74 mmol) in acetic acid (8 ml) was added dropwise. After 1 hour the reaction mixture was cooled to 0° C., 10% aqueous sodium hydroxide solution was added to adjust the pH ˜5 and the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 20% ethyl acetate in hexane to afford 6-bromo-2-fluoro-pyridin-3-ylamine (3.9 g) as a brown solid. 1H NMR (400 MHz, CDCl3) δ: 7.15 (d, J=7.8 Hz, 1H), 7.00 (dd, J=10.1, 7.8 Hz, 1H), 3.80 (s, 2H). ESMS: m/z 191.32, 193.34 [M+1]+
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([NH:18][OH:19])=[NH:17])=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[C:42]1([O:48]C(Cl)=O)C=CC=CC=1>ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]2[NH:17][C:42](=[O:48])[O:19][N:18]=2)=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C(=N)NO)c(C(F)(F)F)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2noc(=O)[nH]2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 89.3 mg of 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-N-hydroxy-2-trifluoromethyl-benzamidine in 2 ml of anhydrous dichloromethane were added 92 μl pyridine followed by 21.6 μl phenylchloroformate dropwise. The resulting mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo. To a solution of the resulting residue in 2.5 ml of acetonitrile was added 88 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene. The mixture was stirred under microwave heating at 180° C. for 10 minutes (or stirred at room temperature overnight). The solvent was removed in vacuo and the crude product was purified by column chromatography on silica gel (heptane 1/ethyl acetate 1 then dichloromethane 95/methanol 5 followed by another column with dichloromethane 90/acetone 10) to give 65 mg of 3-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-trifluoromethyl-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH:14]([CH3:16])[CH3:15])[C:8](O)=[O:9])(=[O:4])=[O:3].S(Cl)([Cl:19])=O>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH:14]([CH3:16])[CH3:15])[C:8]([Cl:19])=[O:9])(=[O:4])=[O:3]
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1ccc(C(=O)O)cc1S(C)(=O)=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(C(=O)Cl)cc1S(C)(=O)=O

Procedure:
4.0 g of 3-methylsulfonyl-4-i-propylbenzoic acid, 1.5 ml of thionyl chloride and 3 drops of DMF are heated under reflux for 10 h in 30 ml of toluene. The solvent is subsequently removed in vacuo and the product is taken for further use without purification.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]3[CH:22]=[C:21]4[C:16]([CH2:17][CH2:18][CH2:19][NH:20]4)=[CH:15][C:14]=3[O:23][CH3:24])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C=O.[C:27]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C.C(OCC)(=O)C>[O:4]1[C:5]2([CH2:6][CH2:7][N:8]([CH2:11][CH2:12][C:13]3[CH:22]=[C:21]4[C:16]([CH2:17][CH2:18][CH2:19][N:20]4[CH3:27])=[CH:15][C:14]=3[O:23][CH3:24])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: [BH3-]C#N
Reactant: COc1cc2c(cc1CCN1CCC3(CC1)OCCO3)NCCC2
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1CCN1CCC3(CC1)OCCO3)N(C)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
196 mg of 7-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethyl)-6-methoxy-1,2,3,4tetrahydroquinoline was dissolved in 5 ml of acetonitrile. Thereafter, 1 ml of 37% formalin, 190 mg of sodium cyanoborohydride, and 0.15 ml acetic acid were added to the reaction solution, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, the reaction solution was diluted with ethyl acetate, and then washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate), so as to obtain 100 mg of the subject compound.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:8](=[O:21])[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1B(O)O.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C:2]1[C:11]2[CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:8](=[O:21])[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COc1ccc(CN2Cc3c(Cl)ccnc3NC2=O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3c(-c4ccc(F)cc4F)ccnc3NC2=O)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
1 (65 mg, 0.21 mmol), 2,4-difluorophenylboronic acid (101 mg, 0.64 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), S-Phos (18 mg, 0.04 mmol), and K2CO3 (88 mg; 0.64 mmol) were suspended in dioxane (2 mL), and stirred overnight at 100° C. The crude product was purified directly via HPLC to provide 127 (7% yield). LC-MS (M+H=382, obsd.=382).
Reaction SMILES: I[CH2:2][CH2:3][C@@H:4]([O:11][C:12]1[C:20]2[S:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:23][NH2:24].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>O1CCCC1.CO>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[S:19]1[C:20]2[C:12]([O:11][C@@H:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:3][CH2:2][NH:24][CH3:23])=[CH:13][CH:14]=[CH:15][C:16]=2[CH:17]=[C:18]1[C:21]#[N:22]
Reactant: CN
Reactant: N#Cc1cc2cccc(O[C@H](CCI)c3ccccc3)c2s1
Agent: O=C(O)/C=C/C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CNCC[C@@H](Oc1cccc2cc(C#N)sc12)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
To a solution of 7-{[(1R)-3-iodo-1-phenylpropyl]oxy}-1-benzothiophene-2-carbonitrile (156 mg, 0.37 mmol) in tetrahydrofuran (1.5 mL) was added 40% aqueous methylamine (0.5 mL) and the solution was stirred at room temperature for 16 hours. The solvent removed in vacuo and the residue purified by flash chromatography with a gradient of 0–15% methanol in dichloromethane. To a solution of free base (96 mg, 0.3 mmol) in methanol (1 mL) and added a warm solution of fumaric acid (26 mg, 0.3 mmol) in methanol (1 mL). The solvent removed in vacuo, and the solid residue triturated with ether (5 mL), then dried in a vacuum oven at 40° C. for 1 hour to give the title compound (120 mg, 74%); δH (300 MHz, DMSO) 8.40 (1H, s, 3-ArH), 7.61–7.52 (1H, m, ArH), 7.49–7.23 (6H, m, ArH), 7.05–6.98 (1H, m, ArH), 6.45 (2H, s, CHCO2H), 5.85–5.75 (1H, m, CHO), 3.05–2.90 (2H, m, 1-CH2), 2.52 (3H, s, NHCH3) and 2.46–2.07 (2H, m, 2-CH2).