Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]2[NH:13][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34].O>CN(C=O)C>[CH3:36][O:35][C:33](=[O:34])[CH2:32][NH:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:14])[NH:13]2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc(CC2CCCCC(=O)N2)cc1OCc1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CNc1ccc(CC2CCCCC(=O)N2)cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a mixture of 7-(4-Amino-3-benzyloxybenzyl)-azepan-2-one (600 mg, 1.7 mmol) and potassium carbonate (345 mg, 2.5 mmol) in DMF (10 mL) is added methyl bromoacetate (383 mg, 2.5 mmol). The mixture is stirred at 60° C. for 4 h then is allowed to cool to RT. It is poured into water and extracted with EtOAc and the organic phase is washed with water (3×), brine (1×), and dried over Na2SO4. The solvent is removed under reduced pressure to afford the title compound which is used directly in the next step.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:10]=2)[N:5]=[C:4]([CH3:16])[CH:3]=1.P(Cl)(Cl)([Cl:19])=O.N>>[Cl:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:10]=2)[N:5]=[C:4]([CH3:16])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Nc1ccc2nc(C)cc(O)c2c1
Agent: N
Product: CC(=O)Nc1ccc2nc(C)cc(Cl)c2c1
Temperature: 25 °C
Yield: 145.9 %

Procedure:
N-(4-Hydroxy-2-methyl-6-quinolyl)acetamide (4.32 g, 20 mmol) and phosphorus oxychloride (9.32 ml, 100 mmol) were heated at 100° C. for 15 min. The reaction mixture was cooled to room temperature and poured into ice water. Thereto was added 28% aqueous ammonia to make the solution alkaline. The resulting insoluble matter was collected by filtration, washed with ether and water, dried under reduced pressure at 80° C. to give N-(4-chloro-2-methyl-6-quinolyl)acetamide (6.85 g, crude, yellow solid).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6])[CH3:2].[C:17]([O-:20])([O-])=[O:18].[Cs+].[Cs+]>>[CH2:1]([O:3][C:4](=[O:16])[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:11][CH2:10][NH:9][C:17]([O:20][C:7]([CH3:15])([CH3:8])[CH3:5])=[O:18])[CH:8]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)C(=O)c1cn(CCNC(=O)OC(C)(C)C)c2ccccc12
Yield: 135.9 %

Procedure:
The general procedure 1 was then followed using the above product (6.68 mmol, 1.54 g), ethyl-2-(1H-indol-3-yl)-2-oxoacetate (6.68 mmol, 1.45 g) and Cs2CO3 (9.82 mmol, 3.20 g). The purification was achieved by column chromatography (petro-lether:ethylacetate:diethylamine 5:4:1) to yield ethyl-2-(1-{2-[(tert.-butoxycarbonyl)-amino]ethyl}-1H-indol-3-yl)-2-oxoacetate (4.54 mmol, 68%) as white crystals. Mp=114-115° C. IR {tilde over (ν)} [cm−1]=3357; 2977; 1727; 1686; 1638; 1518. EI-MS (m/z)=360 (7.59%; M+•.). 1H NMR (300 MHz, CDCl3) 8.44 (m; 1H; indole-H); 8.34 (s; 1H; indole-H); 7.42 (m; 1H; indole-H); 7.35 (m; 1H; indole-H); 4.63 (bs; 1H; NH); 4.37 (m; 4H; OCH2CH3; indole-CH2); 3.54 (q; 3J=6.2 Hz; 2H; CH2—N); 1.43 (t; 3H; 3J=7.1 Hz; OCH2CH3); 1.43 (s; 9H; C(CH3)3).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]#[C:11][CH2:12][N:13]1[C:21]2[C:20](Cl)=[N:19][CH:18]=[N:17][C:16]=2[CH:15]=[CH:14]1)(C(C)(C)C)(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)[NH2:27].O>C(O)(C)C>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:20]2[C:21]3[N:13]([CH2:12][C:11]#[C:10][CH2:9][OH:8])[CH:14]=[CH:15][C:16]=3[N:17]=[CH:18][N:19]=2)[CH:28]=[CH:29][C:30]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:40])([F:41])[F:39])[CH:33]=1
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OCC#CCn1ccc2ncnc(Cl)c21
Solvent: CC(C)O
Solvent: O
Product: OCC#CCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 80 °C
Reaction time: 6 h
Yield: 73.9 %

Procedure:
5-(4-{[Tert-butyl(dimethyl)silyl]oxy}but-2-yn-1-yl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (408.3 mg) was dissolved in isopropyl alcohol (7 mL), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (421.0 mg) was added, and the mixture was stirred at 80° C. for 6 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oil was dissolved in tetrahydrofuran (6 mL), a 1.0 M solution (2 mL) of tetrabutylammonium fluoride in tetrahydrofuran was added, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=67:33→20:80) and crystallized from hexane/ethyl acetate to give the title compound (425 mg) as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:28](B(O)O)=[CH:27][CH:26]=[N:25]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:28]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=5)[C:6]=4[CH:16]=3)=[CH:27][CH:26]=[N:25]2)=[CH:22][CH:23]=1
Reactant: OB(O)c1ccnn1-c1ccc(F)cc1
Reactant: Brc1ccc2ncn(-c3ccccc3)c2c1
Product: Fc1ccc(-n2nccc2-c2ccc3ncn(-c4ccccc4)c3c2)cc1

Procedure:
The title compound, off-white solid (39 mg, 30%), MS (ISP) m/z=355.2 [(M+H)+], mp 201° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-phenyl-1H-benzo[d]imidazole (intermediate E) (100 mg, 366 μmol) and 1-(4-fluoro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate A) (98.0 mg, 476 μmol).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[N:30]1([CH2:36][CH2:37][C:38](O)=[O:39])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.ON1C2C=CC=CC=2N=N1.N=C=N.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][N:27]([C:38](=[O:39])[CH2:37][CH2:36][N:30]6[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]6)[CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: Cn1ncc2cc(Nc3ncnc4[nH]c(C5=CCNCC5)cc34)ccc21
Reactant: O=C(O)CCN1CCCCC1
Agent: Cl
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1ncc2cc(Nc3ncnc4[nH]c(C5=CCN(C(=O)CCN6CCCCC6)CC5)cc34)ccc21
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a suspension of (1-methyl-1H-indazol-5-yl)-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine tris-hydrochloride (155.3 mg, 0.3381 mmol, 1 eq), 1-piperidinepropanoic acid (150.1 mg, 0.9548 mmol, 2.8 eq), 1-hydroxybenzotriazole (HOBt) (46.7 mg, 0.346 mmol, 1 eq), and PS-carbodiimide (1.37 mmol/g loading; 1008.7 mg, 1.38 mmol, 4 eq) in anhydrous DMF (10 mL), DiPEA (290 μL, 1.7 mmol, 5 eq) was added and was shaken at rt for 13 h. The resin was filtered off and rinsed several times with DMF. The filtrate was concentrated in vacuo at medium temp (bath temp: max 42° C.), redissolved in MeOH and DCM, and concentrated again under reduced pressure. The crude material was adsorbed onto Hydromatrix, dry loaded, and purified by chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with MeOH:DCM 5%→10% →7N NH3(MeOH):DCM 3%→5%]. Fractions containing product were combined and concentrated in vacuo, affording the title compound as an off-white solid. 1H NMR (400 MHz, DMSOd6): δ=1.30-1.40 (mc, 2H), 1.45-1.53 (mc, 4H), 2.30-2.41 (s, br, 4H), 2.41-2.63 (m, 6H), 3.69 (t, J=5.6 Hz, 2H), 4.03 (s, 3H), 4.23 & 4.13 (s, br, rotamers, 2H), 6.41 (s, br, 1H), 6.75 & 6.77 (s, br, rotamers, 1H), 7.60 (d, J=9.2 Hz, 1H), 7.69 (dd, J=8.8, 2.0 Hz, 1H), 8.01 (s, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.38 & 8.39 (s, br, rotamers, 1H), 9.34 (s, —NH), 11.90 & 11.93 (s, rotamers, 1H). MS (ES+): m/z 485.11 (45) [MH+]. HPLC: tR=1.72 min (ZQ2000, polar—5 min).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[OH:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.O>CN1CCCC1=O>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([N:18]2[CH2:19][CH2:20][CH:15]([CH2:14][CH2:13][OH:12])[CH2:16][CH2:17]2)=[CH:3][CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc(F)cc1
Reactant: OCCC1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(N2CCC(CCO)CC2)cc1
Reaction time: 72 h
Yield: 70.7 %

Procedure:
A solution of 9.84 grams of methyl 4-fluorobenzoate (63.9 mmol) and 12.40 grams of 4-(2-hydroxyethyl)piperdine (96 mmol) in 50 mL N-methylpyrrolidin-2-one was heated to 110°-120° C. and stirred for 72 hours. The dark solution was cooled and poured into 400 mL water. The tan precipitate was filtered off and washed well with water to yield 11.89 grams of crude product as a tan powder (71%). The crude material was recrystallized once from 100 mL ethanol which gave 4.75 grams (40% recovery) of a tan powder. Melting point 110°-115° C. 2H NMR δ (acetone-d6): 1.27 (2H, quad of doub, J=3.8 hz & 12.2 hz); 1.47 (2H, quad, J=6.6 hz); 1.71 (1H, mult); 1.80 (2H, br doub); 2.83 (2H, trip of doub, J=2.5 hz & 12.6 hz); 3.62 (2H, trip, J=6.6 hz); 3.78 (3H, s); 3.92 (2H, br doub); 6.93 (2H, doub); 7.81 (2H, doub). 13C NMR δ (acetone-d6): 32.59, 33.36, 40.30, 48.61, 51.55, 59.81, 114.30, 119.26, 132.0, 155.29, 167.18.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[CH:8]=2)[S:4][N:3]=1.[CH2:18]([C:20]1[C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=[CH:22][C:21]=1[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.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>[Cl:17][C:9]1[CH:8]=[C:7]([C:5]2[S:4][N:3]=[C:2]([C:25]3[C:20]([CH2:18][CH3:19])=[C:21]([CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH:22]=[CH:23][CH:24]=3)[N:6]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1Cl
Reactant: CCc1c(B2OC(C)(C)C(C)(C)O2)cccc1C1CCNCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(-c2nsc(-c3ccc(OC(C)C)c(Cl)c3)n2)cccc1C1CCNCC1
Reaction time: 0.33 h
Yield: 23.3 %

Procedure:
To a solution of 3-bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazole (D43) (548 mg, 1.643 mmol), 4-[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (D119) (544 mg, 1.725 mmol) and Pd(Ph3P)4 (190 mg, 0.164 mmol) in N,N-Dimethylformamide (DMF) (5 mL) and Water (1.000 mL) was added tripotassium phosphate (1395 mg, 6.57 mmol), The solution was sealed and irritated in Biotage MW at 120° C. for 20 min. The mixture was directly dried with silica gel and purified by column chromatography to afford 4-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]piperidine (D122) (169 mg). MS (ES): C24H28ClN3OS requires 441.2. found 442.2 (M+H+).
Reaction SMILES: [C:1]([CH:6]([CH2:10]C#C)[C:7](=O)[CH3:8])([O:3][CH2:4][CH3:5])=O.C(=O)(O)O.[NH2:17][C:18]([NH2:20])=[NH:19].CC(C)=O>CS(C)=O>[CH3:8][C:7]1[C:6]2[CH:10]=[C:4]([CH3:5])[O:3][C:1]=2[N:17]=[C:18]([NH2:20])[N:19]=1
Reactant: C#CCC(C(C)=O)C(=O)OCC
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CC(C)=O
Solvent: CS(C)=O
Product: Cc1cc2c(C)nc(N)nc2o1
Yield: 8.3 %

Procedure:
A mixture of 4.0 g 3-carbethoxy-5-hexyn-2-one and 2.4 g guanidine carbonate was heated in 6 ml dimethylsulfoxide under a nitrogen atmosphere at 110°-120° for 2 hours. The solution was then cooled, acetone added and the solid collected then rinsed with water to afford 0.27 g of 4,6-dimethylfuro[2,3-d]pyrimidin-2-amine: m.p. 263°-265°. The above filtrates were diluted further with water and the deposited solid was collected and dried to give 0.44 g of 2-amino-6-methyl-5-(2-propynyl)-4(3H)pyrimidinone, m.p. 245°-249°. Absorptions at 2.1 (triplet), 2.55 (singlet), and 3.45 (doublet) ppm in the nuclear magnetic resonance spectrum (60 MHz) indicated the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]=[O:10])=[C:4]([NH2:11])[N:3]=1.[CH:12]([O-])=[O:13].[NH4+].C(O)=O>O.[Pd]>[OH2:10].[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH:9][CH:12]=[O:13])=[C:4]([NH2:11])[N:3]=1
Reactant: O=C[O-]
Reactant: Nc1nc(N)c(N=O)c(N)n1
Agent: [Pd]
Agent: [NH4+]
Solvent: O
Solvent: O=CO
Product: Nc1nc(N)c(NC=O)c(N)n1

Procedure:
A suspension of 7.9 g (0.05 mol) of 2,4,6-triamino-5-nitrosopyrimidine in 50 ml of water was mixed with 3.25 g (0.05 mol) of ammonium formate, 13.9 g (0.3 mol) of formic acid and 0.5 g of the palladium catalyst according to Example 1. This mixture was heated for 4 hours to 100° C. After cooling, the catalyst was filtered off, the filtrate concentrated to about 25 ml and neutralised with about 10 ml of 25% aqueous sodium hydroxide solution to pH 7.5. A crystal slurry thereby resulted which was filtered off with suction. In this way, there were obtained 8.1 g (87% of theory) of pale beige crystals of 2,4,6-triamino-5-formylaminopyrimidine hydrate.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][C:5](=[O:14])[NH:4]1.CCN(CC)CC.[CH3:22][C:23]([Si:26](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:25])[CH3:24]>CN(C1C=CN=CC=1)C.CN(C=O)C>[Si:26]([O:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][C:5](=[O:14])[NH:4]1)([C:23]([CH3:25])([CH3:24])[CH3:22])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1N[C@@H](CO)[C@H](c2ccccc2)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@@H]1NC(=O)O[C@H]1c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
To a solution of (4S,5S)-4-hydroxymethyl-5-phenyl-oxazolidin-2-one (3.50 g, 17.2 mmol), NEt3 (4.80 mL, 34.4 mmol), and DMAP (105 mg, 861 μmol) in DMF (20 mL) was added dropwise TBDPSCl (4.86 mL, 18.9 mmol) at room temperature. The reaction was stirred for 3 hours at room temperature. The reaction mixture was then concentrated and diluted with TBME, the organic layers were separated, washed with aqueous NaHCO3 and brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography (120 g SiO2) using EtOAc in heptane from 0% to 60% in order to give the title compound as a white solid (4.28 g, 57%). LC-MS: [M+H] 432.2; Rt 1.36 min; (LCMS method 2).
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:30])[CH:22]=[CH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH:11]=[CH:10]2>[Pd].C(O)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:30])[CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH:11]=[CH:10]2
Reactant: COc1ccc2cc(CCCCC(=O)C=Cc3cccnc3)ccc2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc2cc(CCCCC(=O)CCc3cccnc3)ccc2c1
Yield: 42.6 %

Procedure:
A mixture of ammonium formate (2.0 g), palladium on charcoal (10%; 0.5 g) and 5-(6-methoxy-2-naphthyl)ethyl-1-(3-pyridyl)-1-penten-3-one (0.7 g) in ethanol (50 ml) was heated at reflux for 5 minutes. The reaction mixture was then filtered through Celite and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethyl acetate:dichloromethane (1:5) to give 5-(6methoxy-2-naphthyl)ethyl-1-(3-pyridyl)-3-pentanone (0.3 g). The latter (0.2 g) was dissolved in ethanol (20 ml) and solid sodium borohydride (0.1 g) was added over 10 minutes. The solution was concentrated under reduced pressure and the residue was purified by column chromatography over silica eluting with ethyl acetate to give the title compound as a solid (0.1 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17](=O)[NH2:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17](=[S:37])[NH2:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(N)=S
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.9 %

Procedure:
To a solution of tert-butyl (S)-[2-(4-benzyloxyphenyl)-1-carbamoylethyl]carbamate (1.53 g, 4.12 mmol) in tetrahydrofuran (15 ml) was added Lawesson reagent (1.70 g, 4.12 mmol), and the mixture was stirred at room temperature for 5 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:ethyl acetate=8:1-5:1). Diisopropy ether was added to the obtained residue. The precipitated solid was collected by filtration and washed with diisopropy ether. The obtained solid was dried in vacuo to give tert-butyl (S)-[2-(4-benzyloxyphenyl)-1-thiocarbamoylethyl]carbamate (540 mg, yield 34%).
Reaction SMILES: O/[CH:2]=[C:3](\[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[N:13][CH:14]=1)/[C:4]([O:6]C)=O.OS(C(F)(F)F)(=O)=O.[C:23](=[NH:46])([O:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=2)=[CH:30][CH:29]=1)[NH2:24].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([O:34][C:31]2[CH:32]=[CH:33][C:28]([CH2:27][CH2:26][O:25][C:23]3[NH:46][CH:2]=[C:3]([CH2:8][C:9]4[CH:10]=[N:11][CH:12]=[N:13][CH:14]=4)[C:4](=[O:6])[N:24]=3)=[CH:29][CH:30]=2)=[CH:36][C:37]=1[C:42]([F:43])([F:44])[F:45]
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: COC(=O)/C(=C/O)Cc1cncnc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Temperature: 160 °C
Yield: 24.9 %

Procedure:
To the suspension of methyl (2E)-3-hydroxy-2-(5-pyrimidinylmethyl)-2-propenoate (302 mg, 1.557 mmol) and 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl imidocarbamate triflate (527 mg, 1.038 mmol) in NMP (12 mL) was added K2CO3 (430 mg, 3.11 mmol). The mixture was heated with a microwave reactor at 160° C. for 1 h. Purification via MDAP then afforded the title compound (130 mg, 24.91% yield). LCMS: rt=3.43 min, [M+H+]=503
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[F:10][C:11]1[CH:24]=[CH:23][C:22]2[S:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:25])[CH:19]=3)[C:14](=[O:26])[C:13]=2[CH:12]=1.[Cl-].[NH4+]>O1CCCC1>[F:10][C:11]1[CH:24]=[CH:23][C:22]2[S:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:25])[CH:19]=3)[C:14]([CH:2]3[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]3)([OH:26])[C:13]=2[CH:12]=1
Reactant: O=c1c2ccc(F)cc2sc2ccc(F)cc12
Reactant: CN1CCC(Cl)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCC(C2(O)c3ccc(F)cc3Sc3ccc(F)cc32)CC1

Procedure:
The Grignard reagent prepared from 2.7 g. (0.02 mol) of 4-chloro-N-methylpiperidine and 0.5 g. (0.02 mol) of magnesium turnings in tetrahydrofuran is treated with 2.5 g. (0.01 mol) of 2,6-difluorothioxanthone at a rate to maintain slow reflux. The mixture is refluxed for six hours, hydrolyzed with saturated ammonium chloride solution and extracted with ether to yield 2,6-difluoro-9-(1-methyl-4-piperidyl)-thioxanthene-9-ol, m.p. 207°-209° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6]Br)[CH3:2].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6][N:19]1[CH2:18][CH2:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:21][CH2:20]1)[CH3:2]
Reactant: CCOC(=O)CCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 56 h

Procedure:
Ethyl-3-bromoproprionate (1.67 ml) was added to a suspension of tert-butyl-1-piperazine carboxylate (2.43 g) and potassium carbonate (2.16 g) in acetonitrile (30 ml). The reaction mixture was stirred for 56 hrs at room temperature, after which time the solvent was removed under reduced pressure and the residue partitioned between dichloromethane and water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure to afford tert-butyl 4-(3-ethoxy-3-oxopropyl)-1-piperazinecarboxylate (2.44 g) as an oil.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]([OH:8])([CH3:7])[CH3:6].[C:9]([NH:22][C@H:23]([C:29](O)=[O:30])[CH2:24][CH2:25][C:26](=[O:28])[NH2:27])(=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O>[CH:5]([O:8][C:29](=[O:30])[C@H:23]([CH2:24][CH2:25][C:26](=[O:28])[NH2:27])[NH:22][C:9](=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([CH3:7])[CH3:6]
Reactant: CCCCCCCCCCCC(=O)N[C@@H](CCC(N)=O)C(=O)O
Reactant: CC(C)O
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCC(=O)N[C@@H](CCC(N)=O)C(=O)OC(C)C
Yield: 52.4 %

Procedure:
108 g of L-glutamine was dissolved in 343 g of water and 102 g of aqueous 27% sodium hydroxide solution, and cooled to 10° C. 138 g of acetone was added to it, and 152 g of lauroyl chloride and 108 g of aqueous 27% sodium hydroxide solution were dropwise added thereto. The acylation liquid was diluted with 300 g of water, then neutralized with 35 g of 75% sulfuric acid and filtered to obtain a white powdery substance, N-lauroyl-L-glutamine. 72.4 g of thionyl chloride was dropwise added to 424 g of isopropyl alcohol, then 100 g of N-lauroyl-L-glutamine was added thereto and reacted at room temperature for 8.5 hours. The reaction liquid was added to 2.0 L of water to precipitate the intended product, and this was taken out by filtration to obtain a crude product. This was recrystallized repeatedly three times with acetone to obtain 59.1 g of N-lauroyl-L-glutamine isopropyl ester.