Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:12])[CH:3]=1.Cl.Cl.[CH3:15][N:16]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[CH2:17]1.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(C=O)C>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH:21][C@@H:18]2[CH2:19][CH2:20][N:16]([CH3:15])[CH2:17]2)=[O:8])=[C:4]([F:12])[CH:3]=1
Reactant: CN1CC[C@@H](N)C1
Reactant: Nc1cc(F)c(C(=O)O)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
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(F)c(N)cc2F)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-amino-2,5-difluoro-benzoic acid (Rare Chemicals GmbH; 450 mg, 2.6 mmol), (3R)-1-methylpyrrolidin-3-amine di Hydrochloride (Intermediate 184; 473 mg, 2.73 mmol), HATU (1.08 g 2.86 mmol) and DIPEA (2.25 mL, 13 mmol) were combined in DMF (10 mL) and stirred at room temperature for 4 hours. The solvent was evaporated and the residue dissolved in MeOH and added to an SCX-2 column (20 g), pre-wet with MeOH (2 column volumes). The column was flushed with MeOH (2 column volumes) and eluted with 2M ammonia in MeOH. Product containing fractions were combined and evaporated and the resultant material dissolved in DCM and purified on a silica column eluting with 5% 2M ammonia in MeOH/DCM. Fractions containing product were combined and evaporated to a yellow gum. Diethylether was added and re-evaporated and dried under high vacuum to yield the title compound as a yellow gum, which slowly crystallised to a cream solid (550 mg, 83%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)=O)([O-])=O.[H][H].N>[Pd].CCOCCO>[CH:19]1[CH:20]=[C:4]([NH2:1])[CH:5]=[C:6]([CH2:7][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:18]=1
Reactant: [H][H]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: N
Solvent: CCOCCO
Product: Nc1ccc(Cc2cccc(N)c2)cc1

Procedure:
15.3 g (0.05 mol) of 3,4'-dinitro-4-chlorobenzophenone, 0.75 g of 5% Pd/C and 50 ml of ethyl cellosolve were charged in a closed glass vessel equipped with a thermometer and a stirrer. While stirring the mixture at a temperature of 75° to 80° C., hydrogen was introduced thereinto and 10.3 l (0.46 mol) of hydrogen was absorbed in 13 hours. Since no more absorption of hydrogen was observed, the reaction was terminated at this point. The reaction solution was neutralized with 3.6 g (0.06 mol) of 28% aqueous ammonia. The catalyst was removed by filtration. The filtrate was concentrated to obtain 3,4'-diaminodiphenylmethane as a brown oil. A high performance liquid chromatography revealed that the purity was 88.2%.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:11][NH2:12]>>[CH3:11][NH:12][CH2:2][CH:3]=[CH:4][C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)C#CC=CCBr
Reactant: CN
Product: CNCC=CC#CC(C)(C)C

Procedure:
Reacting 1-bromo-6,6-dimethylhept-2-en-4-yne with excess methylamine to form N-methyl-N-(6,6-dimethylhept-2-en-4-ynyl)amine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=O.ClCCCl.C(#[N:35])C.ClS(N=C=O)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5]#[N:35]
Reactant: CC#N
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzoic acid (0.222 g, 0.569 mmol) in 1,2-dichloroethane (1.5 mL, 19 mmol) and acetonitrile (1.5 mL, 29 mmol) under argon were added chlorosulfonyl isocyanate (0.074 mL, 0.853 mmol) and triethylamine (0.12 mL, 0.853 mmol). The reaction mixture was stirred at 90° C. for 18 h. The cooled reaction mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 solution and brine; dried (MgSO4). ISCO purification (with 10% to 50% EtOAc/hexanes) afforded 3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)benzonitrile as an off-white solid. MS (ESI) m/z: Calculated: 371.1; Observed: 372.0 (M++1).
Reaction SMILES: [O:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([CH3:31])([OH:30])[CH3:29])=[C:22]([CH3:32])[CH:21]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:33])[Si](C(C)(C)C)(C)C.C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CCOC(C)=O>[CH2:16]([C:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:1])=[C:10]([CH3:33])[CH:11]=1)([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])([CH3:29])[CH3:31])=[C:22]([CH3:32])[CH:21]=1)[CH2:18][CH3:19])[CH3:17]
Reactant: CCC(CC)(c1ccc(CCC(C)(C)O)c(C)c1)c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(CCC(C)(C)O)c(C)c1
Yield: 79 %

Procedure:
To a solution of 4-(4-{1-[4-(tert-butyl-dimethylsiloxy)-3-methylphenyl]-1-ethylpropyl}-2-methylphenyl)-2-methylbutan-2-ol (0.25 g, 0.50 mmol) in anhyd THF (1.5 mL) was added a 1.0M solution of TBAF in THF (0.70 mL, 0.70 mmol). After 1.5 h the reaction mixture was diluted with EtOAc (30 mL), washed with satd NH4Cl (20 mL) and brine, then dried (Na2SO4) and concentrated under reduced pressure. The crude material was chromatographed (silica, EtOAc/Hex, 0:100 to 40:60) to yield the title compound (0.14 g, 74%) as a white tacky solid: 1H-NMR (C6D6) δ 7.23-7.28 (2H, m), 7.16-7.22 (2H, m), 7.11 (1H, dd, J=2.3, 8.3), 6.64 (1H, d, J=8.3), 5.39 (1H, br s), 2.66 (2H, m), 2.25 (6H, s), 2.21 (4H, q, J=7.3), 1.62 (2H, m), 1.14 (6H, t, J=7.3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[C:15]([O:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27])=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl-].[NH4+]>O1CCCC1.O>[C:15]([O:19][C:20](=[O:21])[NH:22][CH2:26][CH2:25][CH2:24][C:23]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH3:9])[CH:3]=1)=[O:27])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: CSc1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1cccc(C(=O)CCCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
Cool a solution of 3-bromothioanisole (10.68 g, 52.6 mmol) in tetrahydrofuran (250 mL) to −78° C., and add n-butyllithium (2.5 M in hexanes, 25.9 mL, 64.8 mmol) over 25 min. Stir the reaction at −78° C. for 1.25 h, then slowly add a solution of 1-(tert-butoxycarbonyl)-2-pyrrolidinone (7.50 g, 40.5 mmol) in tetrahydrofuran (100 mL). Stir the reaction for 2 h at −78° C., then add saturated aqueous ammonium chloride (100 mL). Upon warming to room temperature, add water (200 mL), and extract the reaction with dichloromethane (3×300 mL). Combine the organic extracts and dry over magnesium sulfate, filter, and evaporate under reduced pressure to afford a crude mixture (14.91 g). Purify the crude mixture by flash chromatography (330 g RediSep silica gel column, gradient from 0:100 to 30:70 ethyl acetate:hexanes) to provide slightly impure product (10.34 g, 83%), which is used without further purification. MS (APCI+): 210 [C16H23NO3S—C5H8O2+H]+; 1H NMR (300 MHz, CDCl3): δ 7.81-7.82 (m, 1H), 7.67-7.71 (m, 1H), 7.41-7.45 (m, 1H), 7.34-7.39 (m, 1H), 4.64 (br s, 1H), 3.17-3.26 (m, 2H), 3.00 (t, J=7.1 Hz, 2H), 2.52 (s, 3H), 1.93 (quintet, J=7.0 Hz, 2H), 1.42 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.Cl[C:17]([O:19][CH2:20][CH:21]([O:23][CH3:24])[CH3:22])=[O:18]>O1CCCC1>[CH3:24][O:23][CH:21]([CH3:22])[CH2:20][O:19][C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:18]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: COC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: COC(C)COC(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Temperature: 60 °C
Yield: 72.6 %

Procedure:
5.0 g (24.6 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone are dissolved in 150 ml of absolute tetrahydrofuran by heating to 60° C., with stirring. The solution is allowed to cool to room temperature, 5.6 g (36.7 millimoles) of 2-methoxypropyl chloroformate are added and the mixture is then stirred for 14 hours under reflux. It is concentrated, water is added and the product is filtered off and recrystallized from dimethylformamide/water, giving 5.7 g (73% of theory) of 4,5-dihydro-6-[p-(2-methoxypropoxycarbonylamino)-phenyl]-5-methyl-3(2H)-pyridazinone as colorless crystals of melting point 173°-175° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH:33]([CH3:35])[CH3:34])[CH2:24][NH:25]C(=O)OC(C)(C)C)=[CH:19][CH:18]=1.[ClH:36]>CCOCC>[ClH:36].[NH2:25][CH2:24][CH:23]([C:20]1[CH:19]=[CH:18][C:17]([C:4]2[C:5]3[C:6]4[CH:16]=[CH:15][S:14][C:7]=4[C:8](=[O:13])[NH:9][C:10]=3[CH:11]=[CH:12][C:3]=2[O:2][CH3:1])=[CH:22][CH:21]=1)[CH:33]([CH3:34])[CH3:35]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(CNC(=O)OC(C)(C)C)C(C)C)cc1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(CN)C(C)C)cc1
Yield: 97 %

Procedure:
Following General Procedure D1, tert-butyl 2-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)-3-methylbutylcarbamate (30 mg, 0.060 mmol) was reacted with HCl in ether (3 mL) to afford the desired product (22 mg, 97%) as an off-white solid; 1H NMR (500 MHz, DMSO-d) δ 7.93 (s, 3H), 7.62 (d, J=5.4 Hz, 1H), 7.53 (d, J=9.1 Hz, 1H), 7.41 (d, J=9.0 Hz, 2H), 7.38-7.33 (m, 1H), 7.24 (d, J=8.2 Hz, 2H), 5.72 (d, J=5.4 Hz, 1H), 3.70 (s, 3H), 3.38-3.26 (m, 2H), 2.87 (dt, J=12.9, 6.3 Hz, 1H), 2.01 (dq, J=13.3, 6.6 Hz, 1H), 0.97 (t, J=7.8 Hz, 3H), 0.82 (t, J=9.9 Hz, 3H); ESI MS m/z 393 [C23H24N2O2S+H]+. HPLC 98.4% (AUC), tR=11.65 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
0.072 mol (12.6 g) of 4-chloro-2-nitrophenol, 40 ml of acetone and 9.72 g of potassium carbonate are introduced into a 250 ml three-necked flask equipped with a stirring system, a thermometer and a condenser. The mixture is brought to 40° C. and 9.72 g of dimethyl sulphate are then added drop by drop; the mixture is heated under reflux for 5 hours; the potassium sulphate is separated; the acetone solution is concentrated under reduced pressure and the 4-chloro-2-nitroanisole is precipitated. It is separated and then crystallized in a water/acetone mixture.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27](O)(=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CCCCC(=O)O
Agent: Cl
Product: CCCCC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (77 mg, 75%), MS (ISP) m/z=411.5 [(M+H)+], mp 167° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and pentanoic acid.
Reaction SMILES: [CH:1]([S:4]([NH2:7])(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH2:8]([O:10][C:11]([C:13]1[O:14][C:15]2[CH:22]=[CH:21][CH:20]=[C:19](OS(C(F)(F)F)(=O)=O)[C:16]=2[C:17]=1[CH3:18])=[O:12])[CH3:9]>>[CH2:8]([O:10][C:11]([C:13]1[O:14][C:15]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:7][S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[C:16]=2[C:17]=1[CH3:18])=[O:12])[CH3:9]
Reactant: CCOC(=O)c1oc2cccc(OS(=O)(=O)C(F)(F)F)c2c1C
Reactant: CC(C)S(N)(=O)=O
Product: CCOC(=O)c1oc2cccc(NS(=O)(=O)C(C)C)c2c1C
Yield: 23 %

Procedure:
Coupling of isopropylsulfonamide with 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester was carried out according to Example 36, Step 1 to give 3-methyl-4-(propane-2-sulfonylamino)-benzofuran-2-carboxylic acid ethyl ester in 23% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.4 (t, J=6.4 Hz, 9 H) 2.9 (t, 3 H) 3.5 (m, 1 H) 4.5 (q, J=7.1 Hz, 2 H) 6.6 (s, 1 H) 7.4 (m, 3 H).
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[S:21]1[CH2:25][C:24](=[O:26])[NH:23][C:22]1=[O:27].N1CCCCC1>CCO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:2](=[O:1])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][CH:25]2[S:21][C:22](=[O:27])[NH:23][C:24]2=[O:26])=[CH:7][CH:6]=1
Reactant: COc1ccccc1C(O)COc1ccc(C=O)cc1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccccc1C(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 80.2 %

Procedure:
To a stirring solution of 4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy]benzaldehyde (1.71 g, 6.28 mmol) in absolute EtOH (50 ml) was added 2,4-thiazolidinedione (0.81 g, 6.91 mmol) and piperidine (0.68 mL, 6.9 mmol), and the resulting solution was heated to reflux. The reaction was refluxed overnight and then evaporated in vacuo. The residue was dissolved in EtOAc and this solution was washed with aqueous HOAc (pH 5-6), brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was adsorbed onto silica gel and chromatographed on silica gel eluting with 20-40% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 1.87 g (80%) of the title compound as a light yellow solid. MS (ESI−) for C19H17NO5S m/z 370.1 (M−H)−.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH3:8][NH:9][CH2:10][CH2:11][NH:12][CH3:13]>C1(C)C=CC=CC=1>[CH3:8][N:9]1[CH2:10][CH2:11][N:12]([CH3:13])[CH:6]1[C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: O=Cc1ccsc1
Reactant: CNCCNC
Solvent: Cc1ccccc1
Product: CN1CCN(C)C1c1ccsc1
Reaction time: 16 h

Procedure:
3-Thiophenecarbaldehyde (22.43 g) was dissolved in toluene (200 ml) and N,N'-dimethylethylenediamine (22.3 ml) was added. The mixture was stirred for 16 hours with removing azeotropic water under reflux by Dean-stark trap. The reaction mixture was concentrated under reduced pressure and the residue was distilled under reduced pressure to give 1,3-dimethyl-2-(3-thienyl)imidazolidine (5.88 g).
Reaction SMILES: C[Al](C)C.[NH2:5][CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[C:24]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[N:25][O:26][C:27]=2[CH2:28][OH:29])=[N:17][CH:16]=1.C1(C)C=CC=CC=1>O1CCOCC1>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:24]2[C:23]([CH2:22][O:21][C:18]3[CH:19]=[CH:20][C:15]([C:14]([NH:5][CH:6]4[CH2:11][CH2:10][O:9][CH2:8][CH2:7]4)=[O:13])=[CH:16][N:17]=3)=[C:27]([CH2:28][OH:29])[O:26][N:25]=2)=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Reactant: NC1CCOCC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=C(NC1CCOCC1)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
A trimethylaluminium solution (2 M in toluene, 418 μL, 0.84 mmol) was added to a solution of 4-aminotetrahydropyran (87.2 mg, 0.84 mmol) in dioxane (3.75 mL). 6-[3-(4-Fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (75.0 mg, 0.21 mmol) in dioxane (3.75 mL) was added after 1 h at 50° C. The reaction mixture was stirred at 85° C. overnight. Again trimethylaluminium solution in toluene (2 M in toluene, 418 μL, 0.84 mmol) and 4-aminotetrahydropyran (87.2 mg, 0.84 mmol) were added and stirring was continued for 3 h at 85° C. The solvent was removed by distillation. The residue was purified by chromatography (Isolute® SPE flash NH2 column, ethyl acetate:heptane=1:1 to 9:1) to afford the title compound (24 mg, 27%) as white solid. MS: m/e=428.2 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][N:13]1[CH:23]=[N:22][C:15]([CH2:16][C@@H:17]([C:19]([OH:21])=[O:20])[NH2:18])=[CH:14]1>C1COCC1.C([O-])(O)=O.[Na+]>[NH:18]([C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])[C@H:17]([C:19]([OH:21])=[O:20])[CH2:16][C:15]1[N:22]=[CH:23][N:13]([CH3:12])[CH:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cn1cnc(C[C@H](N)C(=O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cnc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.5 %

Procedure:
Benzyl chloroformate (0.24 mL, 1.7 mmol) was added dropwise to a slurry of 1-methyl-L-histidine (0.25 g, 1.5 mmol) in THF (5 mL) and saturated aqueous NaHCO3, (5 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated and diluted with H2O, washed with ether, and the pH adjusted to 6-7 with iN HCl. The mixture was concentrated, then diluted with CHCl3 (150 mL) and MeOH (15 mL), and stirred for 1 hour. The mixture was dried (MgSO4) and concentrated to provide 0.48 g of the title compound which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=Cc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cccc(-c2ccc(C=O)nc2)c1
Temperature: 77.5 °C
Yield: 64.8 %

Procedure:
To a solution of 5-bromopicolinaldehyde (1.0 g, 5.43 mmol) in toluene (10 mL) and ethanol (8 mL) was added (3-methoxyphenyl)boronic acid (1.2 g, 8.1 mmol), 2M sodium carbonate (3.4 g, 32.6 mmol, 8 mL water), Pd(PPh3)4 (0.228 g, 0.25 mmol) under argon. The resulting mixture was heated at 75-80° C., for 4 h. The contents were cooled to room temperature, diluted with ethyl acetate (150 mL) and washed with bicarbonate solution (2×100 mL) and brine solution (2×100 mL). The organic layer was dried over sodium sulphate, which was distilled off to obtain the crude product. The crude product was purified by flash chromatography (100-200 microns; 15% ethyl acetate in hexane) to afford 5-(3-methoxyphenyl)picolinaldehyde (0.75 g, 65% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.02 (s, 1H), 9.14 (s, 1H), 8.33 (d, 1H), 7.98 (d, 1H), 7.45 (t, 1H), 7.38 (d, 2H), 7.03 (d, 1H), 3.84 (s, 3H); LC-MS m/z calculated for [M+H]+ 214.08 found, 214.3.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)C1C=CC=CC=1>[Pd].CCO>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][CH:15]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:9]=1[OH:8])[CH3:16]
Reactant: COc1ccccc1NC(C)c1cccc(-c2ccccc2)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccccc1NC(C)c1cccc(-c2ccccc2)c1O
Reaction time: 2 h
Yield: 61.3 %

Procedure:
A mixture of 19 (1.9 g, 4.6 mmol), 20% Pd—C (˜55% H2O) and EtOH (50 mL) was hydrogenated at 20 psi H2 for 2 hr at which time LCMS show no 19 remained. The mixture was filtered through Celite, washing the Celite pad with EtOH (100 mL). The filtrate was concentrated under reduced pressure to give a yellow-green oil. The crude product was purified on an Analogic MPLC, eluting with a gradient of 0%-20% EtOAc/hexanes to give 0.9 g (60%) of D1 as a faintly yellow viscous oil. On lengthy standing (>2 months) D1 slowly crystallized as a white solid (mp 116.0-116.8° C.).
Reaction SMILES: COP([CH2:7][C:8]([O:10][CH3:11])=[O:9])(OC)=O.[H-].[Na+].[CH:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20])=O>C1COCC1.CCCCCCC>[C:19]([C:18]1[CH:17]=[C:16](/[CH:14]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])[CH:23]=[CH:22][CH:21]=1)#[N:20]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: N#Cc1cccc(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
Methyl 2-(dimethoxyphosphoryl)acetate (20.83 g, 114.39 mmol) was dissolved in THF (500 mL). Sodium hydride (4.58 g, 114.39 mmol) was added in small portions. 3-formylbenzonitrile (10 g, 76.26 mmol) was added dissolved in 50 mL of THF and the reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with heptane, washed with H2O, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was triturated in heptane, filtered, washed with heptane and dried under vacuum, giving 13.26 g title compound (93%) as a white powder. 1H NMR (400 MHz, CDCl3) δ ppm 3.83 (s, 3H) 6.50 (d, J=16.02 Hz, 1H) 7.52 (t, J=7.81 Hz, 1H) 7.61-7.84 (m, 4H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([NH:9][NH2:10])=[N:7][CH:6]=[CH:5][N:4]=1.[C:11]([N:16]=[C:17]=[S:18])(=[O:15])[O:12][CH2:13][CH3:14].CO>C(Cl)(Cl)Cl>[Cl:2][C:3]1[C:8]([NH:9][NH:10][C:17]([NH:16][C:11](=[O:15])[O:12][CH2:13][CH3:14])=[S:18])=[N:7][CH:6]=[CH:5][N:4]=1
Reactant: NNc1nccnc1Cl
Reactant: CCOC(=O)N=C=S
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NC(=S)NNc1nccnc1Cl
Yield: 120.9 %

Procedure:
A solution of 2-chloro-3-hydrazinylpyrazine hydrochloride (3.32 g, 18.34 mmol) in anhydrous chloroform was treated with O-ethyl carbonisothiocyanatidate (1.9 mL, 16.11 mmol) at room temperature. Anhydrous methanol (10 mL) was added to the reaction mixture which was then concentrated under reduced pressure to yield ethyl 2-(3-chloropyrazin-2-yl)hydrazinecarbonothioylcarbamate (5.37 g) as an orange solid.