Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][CH3:13])[C:10](=[O:14])[C:9]([F:16])([F:15])[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:29])=[CH:26][C:25]=1[O:40][CH3:41].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:17]1([N:7]2[CH2:8][C:9]([F:16])([F:15])[C:10](=[O:14])[N:11]([CH2:12][CH3:13])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]5[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]5)=[O:29])=[CH:26][C:25]=4[O:40][CH3:41])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)ncc21
Yield: 47.8 %

Procedure:
A mixture of 0.05 g (0.15 mmole) of 2-chloro-9-cyclopentyl-5-ethyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-138), 0.05 g (0.18 mmole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.04 g (0.23 mmole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 160 degrees for 2 hours in a microwave reactor. The cooled reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phases were extracted with dichloromethane. The combined organic layers were washed with brine, dried, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient, 0:100-25:75) to give 0.040 g of 4-(9-cyclopentyl-5-ethyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-159).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9](O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[ClH:12]>O>[Cl:12][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:10]
Reactant: COc1cccc(C(C)O)c1
Reactant: Cl
Solvent: O
Product: COc1cccc(C(C)Cl)c1

Procedure:
Into a solution of 152.1 g (1 mol) of 1-(3'-methoxyphenyl)-ethan-1-ol in 750 ml petroleum ether, one introduces hydrogen chloride during ice cooling until water separation is completed. The organic phase is then washed with ice-cold water, dried and the petroleum ether is removed in vacuo. The thermo-labile residue is used without any further purification.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([C@:25]1([CH3:31])[CH2:29][O:28][C:27](=[O:30])[NH:26]1)[CH:19]=[CH:18]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[C:1]1([C@H:7]2[CH2:8][CH2:9][C@H:10]([O:13][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[CH:21]=[C:20]([C@:25]3([CH3:31])[CH2:29][O:28][C:27](=[O:30])[NH:26]3)[CH:19]=[CH:18]4)[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: O[C@H]1CC[C@H](c2ccccc2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@]1(c2ccc3cc(O[C@H]4CC[C@H](c5ccccc5)CC4)ccc3c2)COC(=O)N1

Procedure:
The mixture of trans-4-phenyl-cyclohexanol (86.9 mg, 0.000493 mol), (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (Example 4, 100.0 mg, 0.0004111 mol) and triphenylphosphine (129 mg, 0.000493 mol) in tetrahydrofuran (4 mL, 0.05 mol) was heated to reflux, and diisopropyl azodicarboxylate (0.0971 mL, 0.000493 mol) was added dropwise and was stirred and refluxed for 3 hours. TLC monitoring showed the reaction to be complete. The mixture was taken up into DCM and subjected to chromatographic purification with EtOAc/hexane (10:90 to 80:20) to give (R)-4-(6-(trans-4-phenyl-cyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (160 mg, 97% yield). LCMS 402.28 ([M+1]+, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2].[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][C:7]=12)#[N:2]
Reactant: N#Cc1cc(C(=O)c2ccc(F)cc2)n2c1ccc1ccccc12
Reactant: C1CNCCN1
Product: N#Cc1cc(C(=O)c2ccc(N3CCNCC3)cc2)n2c1ccc1ccccc12

Procedure:
The title compound was prepared as described for Example 21, using 3-cyano-(4-fluoro-benzoyl)-pyrrolo[1,2-a]quinoline ( 58 mg, 0.185 mmol) and piperazine (102 mg, 1.18 mmol), and yielded 57.2 mg (81%). 1H NMR (CDCl3): 8.01 (m, 3H), 7.80 (dd, J=7.8, 1.8 Hz, 1H), 7.64 (s, 2H), 7.52 (m, 2H), 7.34 (d, J=0.6 Hz, 1H), 6.60 (d, J=9.0 Hz, 2H), 3.41 (t, J=5.1 Hz, 4H 3.06 (t, J=4.5 Hz, 4H).
Reaction SMILES: [CH3:1][C:2]1([C:18]([OH:20])=O)[N:6]([C:7](=[O:17])[NH:8][C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=2)[CH2:5][CH2:4][S:3]1.C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[CH3:1][C:2]12[C:18](=[O:20])[N:8]([C:9]3[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=3)[C:7](=[O:17])[N:6]1[CH2:5][CH2:4][S:3]2
Reactant: CC1(C(=O)O)SCCN1C(=O)Nc1cc(Cl)cc(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC12SCCN1C(=O)N(c1cc(Cl)cc(Cl)c1)C2=O
Temperature: 90 °C

Procedure:
5.0 g of the thus obtained 2-methyl-3-(3,5-dichlorophenylcarbamoyl)thiazolidine-2-carboxylic acid and 5 mg of sodium acetate were added to 30 ml of acetic anhydride and heated at 90° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, to which was added water. The resultant crystals were recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 3.92 g of 7a-methyl-6-(3,5-dichlorophenyl)perhydroimidazo[5,1-b]thiazole-5,7-dion (Compound No. 3). The results of the elementary analysis and the melting point were as given in table 1.
Reaction SMILES: C([O:5][P:6]([C:13]([F:52])([F:51])[C:14]1[CH:50]=[CH:49][C:17]([CH2:18][C:19]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([P:37]([O:44]C(C)(C)C)([O:39]C(C)(C)C)=[O:38])([F:36])[F:35])=[CH:30][CH:29]=2)([C:23]([O:25][CH3:26])=[O:24])[C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1)([O:8]C(C)(C)C)=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O.O>[F:52][C:13]([F:51])([P:6]([OH:8])([OH:7])=[O:5])[C:14]1[CH:50]=[CH:49][C:17]([CH2:18][C:19]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[P:37]([OH:44])([OH:39])=[O:38])=[CH:32][CH:33]=2)([C:23]([O:25][CH3:26])=[O:24])[C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1
Reactant: COC(=O)C(Cc1ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)(Cc1ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)C(Cc1ccc(C(F)(F)P(=O)(O)O)cc1)(Cc1ccc(C(F)(F)P(=O)(O)O)cc1)C(=O)O
Yield: 35 %

Procedure:
A solution of 2,2-di{4-[(di-tert-butoxyphosphoryl) (difluoro)methyl]benzyl}-3-methoxy-3-oxopropanoic acid(80 mg) in 5 mL of 10:1 TFA/water was stirred for 1 h and then concentrated. The residue was dissolved in 4 mL of water and washed with 2×5 mL of ether and the aqueous solution was lyopholized to give 20 mg of the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([N+:15]([O-])=O)=[CH:7][C:6]=1[OH:18])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:15][C:8]1[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[C:6]([OH:18])[CH:7]=1
Reactant: CC(C)(C)c1cc(C(C)(C)C)c([N+](=O)[O-])cc1O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)c1cc(C(C)(C)C)c(O)cc1N
Temperature: 25 °C

Procedure:
To a refluxing solution of 2,4-di-tert-butyl-5-nitro-phenol (1.86 g, 7.4 mmol) and ammonium formate (1.86 g) in ethanol (75 mL) was added Pd-5% wt. on activated carbon (900 mg). The reaction mixture was stirred at reflux for 2 h, cooled to room temperature and filtered through Celite. The Celite was washed with methanol and the combined filtrates were concentrated to yield 5-amino-2,4-di-tert-butyl-phenol as a grey solid (1.66 g, quant.). 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H, OH), 6.84 (s, 1H), 6.08 (s, 1H), 4.39 (s, 2H, NH2), 1.27 (m, 18H); HPLC ret. time 2.72 min, 10-99% CH3CN, 5 min run; ESI-MS 222.4 m/z (MH+).
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[NH:10][C:9]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]I>CN(C=O)C>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[N:10]([CH3:24])[C:9]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccc2[nH]c(-c3ccccc3)c(Cc3ccccc3)c2c1
Reactant: CI
Solvent: CN(C)C=O
Product: Cn1c(-c2ccccc2)c(Cc2ccccc2)c2cc(Br)ccc21

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 3-benzyl-5-bromo-2-phenyl-1H-indole (1.811 g, 5 mmol) was reacted with k-t-butoxide (0.589 g, 5.25 mmol) and methyl iodide (0.745 g, 5.25 mmol) in DMF (20 ml) to give the product (1.537 g, 4.085 mmol, 82%) as a white solid, mp 141-145° C. 1H DMSO-d6) δ 3.56 (s, 3H), 3.93 (s, 2H), 7.02 (d, J=6.8 Hz, 2H), 7.07 (t, J=7.3 Hz, 1H), 7.15 (t, J=7.2 Hz, 2H), 7.23 (dd, J=2.0, 8.7 Hz, 1H), 7.40-7.52 (m, 7H); [ESI(+)], m/z 377/379 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([S:44]([CH3:47])(=[O:46])=[O:45])[CH2:14][C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31](=[O:43])[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[CH:26]=[CH:25]4)[N:18]=[CH:17][N:16]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:42][C:39]([F:40])([F:41])[C:35]1[CH:34]=[C:33]([NH:32][C:31]([N:27]2[C:28]3[C:24](=[CH:23][C:22]([O:21][C:19]4[CH:20]=[C:15]([CH2:14][N:13]([S:44]([CH3:47])(=[O:46])=[O:45])[CH:10]5[CH2:11][CH2:12][NH:8][CH2:9]5)[N:16]=[CH:17][N:18]=4)=[CH:30][CH:29]=3)[CH:25]=[CH:26]2)=[O:43])[CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)ncn2)S(C)(=O)=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N(Cc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1)C1CCNC1

Procedure:
(±)-3-(Methanesulfonyl-{6-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (12 mg, 0.018 mmol) is stirred in a solution of DCM (2 mL) and TFA (0.5 mL) overnight. After removal of solvents, the residue is quenched with saturated aqueous sodium bicarbonate. The mixture is extracted with EtOAc (3×). The combined organic layers are washed with water and brine and the organic layer is dried with Na2SO4, filtered, and condensed. The residue is then separated by FCC (0-10%, 2 M NH3 in MeOH/DCM) to provide the title compound. MS (ESI) m/z 574.8 (M−1).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)CCC>O1CCCC1.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>[CH3:16][C:13]1[O:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]3[O:4][CH:3]=[C:2]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:6]=3[CH:7]=2)=[N:15][N:14]=1
Reactant: Cc1nnc(-c2ccc3occ(Br)c3c2)o1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nnc(-c2ccc3occ(-c4ccccn4)c3c2)o1
Yield: 40.8 %

Procedure:
A solution of 2-(3-bromo-1-benzofuran-5-yl)-5-methyl-1,3,4-oxadiazole (279 mg, 1.00 mmol), 2-(tri-n-butylstannyl)pyridine (0.384 mL, 1.20 mmol) and tetrakis(triphenylphosphine)palladium(0) (34.7 mg, 0.0300 mmol) in tetrahydrofuran (5 mL) was heated under reflux under an argon atmosphere for 85 hr. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (hexane/tetrahydrofuran=1/1) and recrystallized from hexane/tetrahydrofuran to give the title compound (113 mg, yield 41%) as colorless crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:7][O:8][C:9]=1[CH3:10])=[O:4].CO.[OH-].[Na+].Cl>O>[C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:7][O:8][C:9]=1[CH3:10])([OH:4])=[O:2]
Reactant: COC(=O)c1c(-c2ccccc2F)noc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1onc(-c2ccccc2F)c1C(=O)O
Temperature: 25 °C
Yield: 96.2 %

Procedure:
A solution of 4-methoxycarbonyl-5-methyl-3-(2-fluorophenyl)isoxazole (2.20 g, 8.84 mmol), MeOH (25 ml), and 2N NaOH (8.8 ml) was heated at 50° C. overnight (19 h). The reaction was cooled to room temperature, diluted with H2O, and acidified (2N HCl) to less than pH 3. The mixture was extracted with EtOAc (twice) and the combined extracts were washed (brine), dried (MgSO4), filtered, and concentrated to give the title compound (1.88 g, 96%). This material was used without further purification.
Reaction SMILES: [C:1]([CH2:3][C:4](OCC)=[O:5])#[N:2].[CH2:9]([O:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH2:17])=[NH:16])[CH2:10][CH3:11]>C(O)C.O>[NH2:2][C:1]1[N:17]=[C:15]([C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12][CH2:9][CH2:10][CH3:11])[NH:16][C:4](=[O:5])[CH:3]=1
Reactant: CCCOc1ccccc1C(=N)N
Reactant: CCOC(=O)CC#N
Solvent: CCO
Solvent: O
Product: CCCOc1ccccc1-c1nc(N)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl cyanoacetate (4.52 g) was added to a stirred solution of 2-propoxybenzamidine in ethanol (prepared from sodium, 1.84 g., in ethanol, 100 ml, and 2-propoxybenzamidine methanesulphonate, 11.61 g). The reaction mixture was stirred at ambient temperature for 18 hours and then evaporated under reduced pressure to leave a residue which was dissolved in water. The aqueous solution was extracted with diethyl ether (2×25 ml) and the combined ether extracts were washed with water. The combined aqueous phase was treated with glacial acetic acid to pH 5 to precipitate a crude product. Further crude product was obtained by extracting the ether extracts with 1 normal sodium hydroxide (2×30 ml) and acidifying the combined alkaline extracts with glacial acetic acid to pH 5. The combined crude product was recrystallised from isopropanol to yield the title compound, 2.34 g, m.p. 183.5°-184.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([N:14]([CH3:16])[NH2:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>O1CCOCC1>[CH3:16][N:14]([C:11]1[N:12]=[N:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)[NH:15][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CN(N)c1ccc(-c2ccc(Cl)cc2)nn1
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)NN(C)c1ccc(-c2ccc(Cl)cc2)nn1
Reaction time: 1 h

Procedure:
A 2.0 g. portion of 6-(p-chlorophenyl)-3-(1-methylhydrazino)pyridazine and 1.30 g. of diisopropylethylamine in 50 ml. of dioxane is warmed slightly in a flask. A 1.0 g. portion of ethyl chloroformate is added and the reaction mixture is stirred for one hour. The dioxane is removed on a rotary evaporator, ethanol and water are added to the residue and a precipitate results. The solid is recrystallized from ethanol to give a pure white solid, m.p. 170°-172° C.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][NH:13]1>O>[CH3:9][O:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(F)n1
Reactant: COCC1CCCN1
Solvent: O
Product: COCC1CCCN1c1cccc(N)n1
Temperature: 205 °C
Yield: 73.6 %

Procedure:
A mixture of 6-fluoropyridin-2-amine (0.5 g, 4.46 mmol) and 2-(methoxymethyl)pyrrolidine (0.617 g, 5.35 mmol) in water (0.2 mL) was heated to 205° C. for 0.5 h in a sealed tube in a microwave oven then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, ethyl acetate:petroleum ether=1:15) to afford 6-(2-(methoxymethyl)pyrrolidin-1-yl)pyridin-2-amine (0.68 g, 74%) as a yellow oil. LC-MS: [M+1]+=208, tR=1.052 min.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6](=[S:28])[NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[CH:4][CH:3]=1
Reactant: COc1ccccc1NC(=O)c1ccc(C)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccccc1NC(=S)c1ccc(C)cc1
Temperature: 50 °C
Yield: 108.8 %

Procedure:
The 4-methyl-2'-methoxybenzanilide (50.0 g) obtained in (1) was dissolved in 200 ml of toluene, and 46.1 g of Lawesson's reagent was added. The mixture was refluxed for 1 hour. After the reaction, the reaction mixture was cooled to about 50° C., and 200 ml of water was added. The mixture was further refluxed for 2 hours. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was evapoated under reduced pressure. The residue was recrystallized from methanol and then cyclohexane to give 31.9 g of 4-methyl-2'-methoxybenzothioanilide. mp 91.0°-93.0° C.
Reaction SMILES: [CH2:1]([C@@H:7]1[C:10](=[O:11])[O:9][C@H:8]1[CH2:12][CH:13]([O:18][C:19](=[O:28])[C@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH:21][CH:22]=[O:23])[CH2:14][CH2:15][CH:16]=[CH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H][H]>C1COCC1.[Pd]>[CH2:1]([C@@H:7]1[C:10](=[O:11])[O:9][C@H:8]1[CH2:12][CH:13]([O:18][C:19](=[O:28])[C@H:20]([CH2:24][CH:25]([CH3:26])[CH3:27])[NH:21][CH:22]=[O:23])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [H][H]
Reactant: C=CCCC(C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)[C@H](CC(C)C)NC=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCC[C@@H]1C(=O)O[C@H]1CC(CCCC)OC(=O)[C@H](CC(C)C)NC=O

Procedure:
A solution of 10 mg of N-formyl-L-leucine 1-[(trans-3-hexyl-4-oxo-2-oxetanyl)methyl]-4-pentenyl ester in 0.5 ml of THF was treated with 2.5 mg of 5% Pd/C and hydrogenated. After the hydrogen uptake was finished the catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was chromatographed over silica gel with toluene/ethyl acetate (8:2) and there was obtained amorphous N-formyl-L-leucine 1-[(trans-3-hexyl-4-oxo-2-oxetanyl]-methyl]pentyl ester as a mixture of 2 diastereomers.
Reaction SMILES: [C:1]1([NH:11][C:12]([NH2:14])=[S:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:15][CH2:16][C:17]([CH2:19]Cl)=O>CC(C)=O>[Cl:15][CH2:16][C:17]1[N:14]=[C:12]([NH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[S:13][CH:19]=1
Reactant: NC(=S)Nc1cccc2ccccc12
Reactant: O=C(CCl)CCl
Solvent: CC(C)=O
Product: ClCc1csc(Nc2cccc3ccccc23)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of naphthalen-1-yl-thiourea (iii) (2.02 g, 10 mmol) in acetone (50 mL) at room temperature was added 1,3-dichloroacetone (1.03 g, 10.5 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and washed with methanol. The filtrate was treated with hexane to afford a white precipitate. The precipitate was filtered and washed with hexane.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]3[CH:13]=[C:14]([CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH2:30][CH3:31])/[CH:15]=[CH:16]/[C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[N:6][C:5]=2[N:4]([CH2:32][CH2:33][CH3:34])[N:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]3[CH:13]=[C:14]([CH2:15][CH2:16][C:17]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[O:18])[CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH2:30][CH3:31])=[N:6][C:5]=2[N:4]([CH2:32][CH2:33][CH3:34])[N:3]=1
Reactant: CCCOc1ccc(/C=C/C(=O)N2CCOCC2)cc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1
Agent: [Pd]
Solvent: CCO
Product: CCCOc1ccc(CCC(=O)N2CCOCC2)cc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1
Reaction time: 14 h
Yield: 71.9 %

Procedure:
A solution of N-[(E)-3-(3-methyl-4-oxo-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-n-propoxycinnamoyl]morpholine (0.5 g, 0.0011 mol) in ethanol (30 ml) was stirred with 10% palladium on charcoal catalyst (0.05 g) under a hydrogen pressure of 50 p.s.i. (3.45 bar) at room temperature for 14 hours. The reaction mixture was filtered and solvent removed by evaporation under vacuum. Trituration of the residue with diethyl ether, followed by crystallisation from ethyl acetate-hexane, afforded the title compound as white crystals (0.37 g, 74%), m.p. 132-133° C. Found: C, 64.39; H, 7.26; N, 14.80. C25H33N5O4 requires C, 64.22; H, 7.11; N, 14.98%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.Cl.[CH3:11][C@@H:12]1[CH2:17][O:16][CH2:15][CH2:14][NH:13]1.C(N(CC)CC)C>CO>[Cl:8][C:6]1[CH:7]=[C:2]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][C@H:12]2[CH3:11])[N:3]=[C:4]([NH2:9])[N:5]=1
Reactant: C[C@@H]1COCCN1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@@H]1COCCN1c1cc(Cl)nc(N)n1
Temperature: 120 °C
Yield: 75.1 %

Procedure:
To 4,6-dichloro-2-pyrimidinamine (500 mg, 3.05 mmol) in CH3OH (10 mL) were added (3R)-3-methylmorpholine hydrochloride (441 mg, 3.2 mmol) and triethylamine (1.28 mL, 9.2 mmol), and the reaction mixture was heated in a microwave at 120° C. for 35 minutes. Side-product started to form. An additional 0.5 eq of (3R)-3-methylmorpholine hydrochloride and 0.2 mL of triethylamine were added, and the mixture was heated in an oil bath at 50° C. for 3 days and in a microwave at 100° C. for 3 hours. The mixture was cooled down, evaporated under vacuum, and the resulting residue was partitioned between EtOAc and water, and extracted with EtOAc (2×) and CH2Cl2 (2×). The combined organics were washed with water and brine, dried (MgSO4), filtered, and evaporated. The resulting material was triturated with Et2O and dried in vacuo to afford the title compound (524 mg). LC-MS (ES) m/z=229, 231 [M+H]+.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:1]([CH:2]=[CH:3][C:4]([OH:6])=[O:5])=[O:7])=[CH:11][CH:10]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Clc1ccccc1
Product: O=C(O)C=CC(=O)c1ccc(Cl)cc1

Procedure:
3-(4-chlorobenzoyl)acrylic acid (1A) was prepared, as a yellow crystalline solid, m.p.: 157°-158° C, by the Friedel-Crafts acylation of chlorobenzene with maleic anhydride by the method of Papa et al., J. Am. Chem. Soc., 70, 3356 (1948).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[CH3:15][N:16]1[CH2:21][CH:20]=[C:19]([C:22]2[CH:27]=[CH:26][NH:25][C:24](=O)[CH:23]=2)[CH2:18][CH2:17]1>>[CH3:15][N:16]1[CH2:17][CH:18]=[C:19]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])[CH:23]=2)[CH2:20][CH2:21]1
Reactant: CN1CC=C(c2cc[nH]c(=O)c2)CC1
Reactant: Cc1onc(-c2ccccc2)c1CO
Product: Cc1onc(-c2ccccc2)c1COc1cc(C2=CCN(C)CC2)ccn1
Yield: 17 %

Procedure:
As described for example 4, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (135 mg, 0.72 mmol) was converted using 1′-methyl-1′,2′,3′,6′-tetrahydro-1H-[4,4′]bipyridinyl-2-one instead of 2-hydroxy-5-trifluoromethylpyridine to the title compound (SiO2, heptane:ethyl acetate:methanol=95:5:0 to 0:80:20, 45 mg, 17%) which was obtained as a yellow oil. MS: m/e=362.3 [M+H]+.