Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][N:7]([CH3:11])[C:8]([NH2:10])=[NH:9].C[O-].[Na+].C([O:17][C:18](=O)[CH2:19][C:20](OCC)=[O:21])C>CO>[CH3:6][N:7]([CH3:11])[C:8]1[N:10]=[C:18]([OH:17])[CH:19]=[C:20]([OH:21])[N:9]=1
Reactant: CN(C)C(=N)N
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CN(C)c1nc(O)cc(O)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.7 %

Procedure:
136 g (0.5 mol) of N,N-dimethylguanidine sulphate were added to a solution of 162 g (3 mol) of sodium methylate in 1 l of methanol at 0° to 5° C. 160 g (1 mol) of malonic acid diethyl ester were then allowed to run in without cooling and the mixture was stirred for 24 hours at room temperature. The solvent was then distilled off in vacuo and the residue was dissolved in water. The solution was brought to approximately pH 5 by adding glacial acetic acid; it was then cooled to 0°-5° C and the product which had precipitated was filtered off. 75 g (48% of theory) of 2-dimethylamino-4,6-dihydroxypyrimidine were thus obtained in the form of a colorless powder of melting point > 300° C.
Reaction SMILES: [C:1]1([CH2:7][N:8](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:9][CH2:10][CH2:11][N:12]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:13][CH2:14][CH2:15][N:16]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)S(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N.[Na].[Cl-].[NH4+]>>[C:1]1([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][N:12]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:13][CH2:14][CH2:15][NH:16][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCCN(CCCN(Cc2ccccc2)S(=O)(=O)c2ccc(C)cc2)C(=O)OC(C)(C)C)Cc2ccccc2)cc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)N(CCCNCc1ccccc1)CCCNCc1ccccc1

Procedure:
Mix 1,9-bis[(phenyl)methyl]-1,9-bis[(4-methylphenyl)sulfonyl]-5-(t-butyloxycarbonyl)-1,5,9-triazanonane (720 mg, 1 mmol) in dry liquid ammonia (25 mL) at -40° C. Add small pieces of sodium until a permanent blue color remains. Discharge the excess sodium with saturated ammonium chloride. Allow the ammonia to evaporate spontaneously and partition the residue between ethyl acetate and water. Separate the organic phase, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography to give the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[C:11]2[N:15]([CH3:16])/[C:14](=[N:17]\[H])/[N:13]([CH3:19])[C:12]2=[O:20])=[CH:2]1.[CH3:21]I>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[C:11]2[N:15]([CH3:16])/[C:14](=[N:17]\[CH3:21])/[N:13]([CH3:19])[C:12]2=[O:20])=[CH:2]1
Reactant: CI
Reactant: [H]/N=C1/N(C)C(=O)C(=Cc2c[nH]c3ccccc23)N1C
Solvent: CO
Product: C/N=C1/N(C)C(=O)C(=Cc2c[nH]c3ccccc23)N1C
Yield: 20.3 %

Procedure:
500 mg of (E)-5-(indol-3-ylmethylene)-1,3-dimethyl-2-imino-4-imidazolidinone are refluxed in methanol for 24 hours with 425 mg of methyl iodide. The product is chromatographed on silica gel and alumina. There are obtained 107 mg of (E)-5-(indol-3-ylmethylene)-1,3-dimethyl-2-methylimino-4-imidazolidinone.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[NH2:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C(=O)(O)[O-].[Na+].O>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])=[O:15])[C:5]3[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=3[N:7]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(N)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Yield: 44.2 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (80 mg, 0.21 mmol) and (3-aminophenyl)boronic acid (46.9 mg, 0.34 mmol) in DME/water (3 ml:1 ml). PdCl2(dppf)-CH2Cl2 adduct (8.74 mg, 0.01 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (53.9 mg, 0.64 mmol) was added, the vessel was sealed, and the reaction mixture was irradiated (microwave) at 150° C. for 25 min. After cooling, 2 mL of water was added to the black mixture and solids that precipitated were filtered. DCM/MeOH (1:1) was added, the mixture was pre-absorbed on silica gel and purified by silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH). The isolated product was treated with EtOH/EtOAc/hexanes (1:1:1). The solids that precipitated were filtered and dried to afford the title compound (40 mg, 42%) as a light grey solid. LCMS E-S (M+H)=431.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (br. s., 1H), 8.96 (t, J=4.93 Hz, 1H), 8.34 (s, 1H), 8.02 (s, 1H), 7.46 (t, J=1.89 Hz, 1H), 7.36 (d, J=7.58 Hz, 1H), 7.18 (t, J=7.71 Hz, 1H), 6.69 (dd, J=7.83, 1.52 Hz, 1H), 5.90 (s, 1H), 5.25-5.37 (m, 3H), 4.40 (d, J=4.80 Hz, 2H), 2.22 (s, 3H), 2.13 (s, 3H), 1.55 (s, 3H), 1.54 (s, 3H).
Reaction SMILES: [C:1]([NH:8][C:9]([NH:11][C:12](=[O:34])[CH2:13][N:14]1[C:18]([CH:19]2[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20]2)=[CH:17][CH:16]=[C:15]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[NH:10])(OC(C)(C)C)=O.Br[CH2:36][CH2:37][C:38]#[N:39]>CN(C=O)C>[NH2:10]/[C:9](/[NH:8][CH2:1][CH2:36][CH2:37][C:38]#[N:39])=[N:11]\[C:12](=[O:34])[CH2:13][N:14]1[C:18]([C@H:19]2[CH2:20][CH2:21][C@H:22]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:24]2)=[CH:17][CH:16]=[C:15]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCC1CCC(c2ccc(-c3ccccc3)n2CC(=O)NC(=N)NC(=O)OC(C)(C)C)CC1
Reactant: N#CCCBr
Solvent: CN(C)C=O
Product: CCC[C@H]1CC[C@H](c2ccc(-c3ccccc3)n2CC(=O)/N=C(\N)NCCCC#N)CC1
Reaction time: 0.13 h

Procedure:
In a 10 mL glass microwave reaction vessel under nitrogen, 17 mg (0.425 mmol) sodium hydride (obtained as a 60% dispersion in mineral oil) was slurried with a solution of 0.133 g (0.28 mmol) N-Boc-N′-{2-[2-phenyl-5-(4-propyl-cyclohexyl)-pyrrol-1-yl]-acetyl}-guanidine from Step 8 in 4 ml anhydrous DMF, and 41 mg (0.28 mmol) 3-bromopropionitrile. The reaction vessel was capped and microwave at 150° C. for 460 sec in a microwave reactor. (Emrys™ Microwave Synthesizer, Personal Chemistry Inc., Foxboro, Mass.) The reaction was concentrated and redissolved in 2 mL CH2Cl2. 0.66 mL trifluoroacetic acid was added and the reactions were shaken for 1 hr. The reactions were then concentrated, redissolved in DMSO:MeCN (4:1) and purified by Gilson preparative 4HPLC to afford 34.5 mg of the title compound [2LC-MS data; molecular ion and retention time): m/z 434 (M+H); 2.77 min] as an oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[C:14]=1[O:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1.Cl>C(OCC)(=O)C>[CH3:8][NH:9][C:10]([N:27]1[C:28]([CH3:30])=[CH:29][C:25]([O:24][C:14]2[C:15]([Cl:23])=[CH:16][C:17]([C:19]([F:22])([F:20])[F:21])=[CH:18][C:13]=2[Cl:12])=[N:26]1)=[O:11]
Reactant: CN=C=O
Reactant: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.1 %

Procedure:
Triethylamine (0.40 g, 4.0 mmol) and methyl isocyanate (0.25 g, 4.4 mmol) were added to a solution of 3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole (1.24 g, 4.0 mmol) in ethyl acetate (20 ml), and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-methyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.87 g, yield: 59.0%). mp: 113-114° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.60 (d, J=0.7 Hz, 3H), 2.88 (d, J=4.9 Hz, 3H), 5.77 (d, J=0.7 Hz, 1H), 6.50-6.75 (m, 1H), 7.66 (s, 2H).
Reaction SMILES: CS(O[C:6]1([CH3:23])[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>C(O)(C)C>[C:11]1([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:9][C:6]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)([CH3:23])[CH2:7]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: C1CCNC1
Solvent: CC(C)O
Product: CC1(N2CCCC2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 70 °C
Yield: 65.5 %

Procedure:
A mixture of 1-(diphenylmethyl)-3-methyl-3-azetidinyl methanesulfonate (1.55 g, 4.68 mmol) (J. Med. Chem. 1993, 36, 801-810) and pyrrolidine (3.86 ml, 46.68 mmol) in isopropanol (15 ml) was heated to 70° C. overnight. After cooling to room temperature, the mixture was concentrated to dryness in vacuo. Water (100 ml) was added, and the mixture was extracted with dichloromethane (2×100 ml). The combined organic solution was washed with brine (60 ml), dried (Na2SO4) and concentrated. The residue was purified via RP-HPLC to provide 1-[1-(diphenylmethyl)-3-methyl-3-azetidinyl]pyrrolidine (0.94 g, 65%). LCMS: (M+H)+: 307.2.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[S:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.Cl[CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1>O1CCCC1>[S:5]1[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=[C:4]1[S:3][CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1
Reactant: Sc1nc2ccccc2s1
Reactant: ClC1CCCc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1cnc2c(c1)CCCC2Sc1nc2ccccc2s1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
2.0 g (66.67 mmol) of 80% sodium hydride in oil were added to 9.97 g (59.1 mmol) of 2-mercaptobenzothiazole in 250 ml of dry tetrahydrofuran under nitrogen. The suspension was stirred at ambient temperature and, when effervescence had ceased 10 g (59.65 mmol) of 8-chloro-5,6,7,8-tetrahydroquinoline were added via a syringe. The reaction mixture was stirred at ambient temperature for 48 hours and the solvent was removed under reduced pressure. The residue was partitioned between water and dichloromethane and the organic phase was washed with water, dried over MgSO4 and concentrated to dryness under reduced pressure. The resulting oil was purified by flash column chromatography over silica (75 g)with elution with a mixture of dichloromethane and diethyl ether (1:0 gradually changing to 0:1). The pale yellow oil residue was crystallized from a mixture of dichloromethane-40°-60° petroleum ether to obtain 10.9 g (61%) of 8-(2-benzothiazolylthio)-5,6,7,8-tetrahydroquinoline in form of white crystals melting at 72° -3° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.F[C:16]1[C:21]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:20][N:19]=[C:18]2[NH:27][CH:28]=[C:29]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[C:17]=12>C(O)(CC)C>[CH:33]1([C:31]([NH:30][C:29]2[C:17]3[C:18](=[N:19][CH:20]=[C:21]([O:22][CH2:23][CH2:24][O:25][CH3:26])[C:16]=3[N:1]3[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]3)[NH:27][CH:28]=2)=[O:32])[CH2:34][CH2:35]1
Reactant: COCCOc1cnc2[nH]cc(NC(=O)C3CC3)c2c1F
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCC(C)O
Product: COCCOc1cnc2[nH]cc(NC(=O)C3CC3)c2c1N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 150 °C
Reaction time: 24 h
Yield: 46.7 %

Procedure:
(R)-tert-Butyl piperidin-3-ylcarbamate (307 mg, 1.53 mmol) was added to N-(4-fluoro-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (150 mg, 0.511 mmol) in s-BuOH (3 mL), and the reaction was stirred at 150° C. for 24 hours in a sealed tube. After cooling down and concentration, the residue was purified by reverse phase chromatography (SP4, 25M, water/ACN 90/10→0/100, 30 CV) to yield (R)-tert-butyl 1-(3-(cyclopropanecarboxamido)-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (113 mg, 46.7% yield) as a solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=4)[C:11]=3[CH:23]=2)=[N:4][N:3]=1.S(Cl)([Cl:26])=O>ClCCCl>[Cl:26][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[C:11]3[CH:23]=[C:7]([C:5]4[O:6][C:2]([CH3:1])=[N:3][N:4]=4)[CH:8]=[CH:9][C:10]=3[O:14][CH:13]=2)=[CH:16][CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nnc(-c2ccc3occ(-c4ccc(CO)cc4)c3c2)o1
Solvent: ClCCCl
Product: Cc1nnc(-c2ccc3occ(-c4ccc(CCl)cc4)c3c2)o1

Procedure:
To a solution of [4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]phenyl]methanol (204 mg, 0.66 mmol) in 1,2-dichloroethane (5 mL) was added thionyl chloride (0.240 mL, 3.33 mmol), and the resulting mixture was heated under reflux for 1 hr. After cooling, the reaction mixture was concentrated under reduced pressure to give crude 2-[3-[4-(chloromethyl)phenyl]-1-benzofuran-5-yl]-5-methyl-1,3,4-oxadiazole as yellow crystals.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[N:9]2[CH:10]=[C:11]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][C:8]2=[N:7][CH:6]=[C:5]1[C:30]([O:32]CC)=[O:31].O.Cl>O.O1CCCC1>[O:3]=[C:4]1[N:9]2[CH:10]=[C:11]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][C:8]2=[N:7][CH:6]=[C:5]1[C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)c1cnc2cc(OCc3ccccc3)c(OCc3ccccc3)cn2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc2cc(OCc3ccccc3)c(OCc3ccccc3)cn2c1=O
Temperature: 40 °C
Reaction time: 8 h

Procedure:
20.3 ml of 1N sodium hydroxide solution was added to a solution of 4-oxo-7,8-bis(phenylmethoxy)-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid, ethyl ester (6.61 g, 15.36 mmol) in 240 ml of water:tetrahydrofuran 1:1). After stirring overnight at 40° C., 200 ml of water was added, and the pH was adjusted to 2 with 3N hydrochloric acid. The resulting precipitate was filtered off with suction, washed with water and dried in vacuo. Yield: 5.28 g; melting point 207.8° C.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:32]=[CH:31][N:14]3[C:15](=[O:30])[C:16](/[CH:25]=[CH:26]/[C:27](O)=[O:28])=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.O>[OH:28][CH2:27]/[CH:26]=[CH:25]/[C:16]1[C:15](=[O:30])[N:14]2[CH:31]=[CH:32][C:11]([CH2:10][CH2:9][C:6]3[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=3)=[CH:12][C:13]2=[N:18][C:17]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)O)c(N4CCOCC4)nc3c2)n1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/CO)c(N4CCOCC4)nc3c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(E)-3-{8-[2-(4-Isopropyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4-oxo-4H-pyrido-[1,2-a]pyrimidin-3-yl}-2-propenoic acid (222.7 mg, 0.49 mmol) dissolved in tetrahydrofuran (8 ml) was added with triethylamine (342 μl) and ethyl chloroformate (141 μl) at −20° C., then stirred at room temperature for 1 hour, and subsequently added with aqueous sodium borohydride (0.8 M, 4 ml) at room temperature. The aqueous sodium borohydride was occasionally added until the reaction was completed, and the completion of the reaction was confirmed by TLC. Then, the reaction solution was added with water and extracted with chloroform and chloroform:methanol=10:1, and the organic layer collected was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=100:1→60:1→30:1) to recover 81 mg (37%) of the title compound and 82 mg of the starting material.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([CH:10]2[CH:14](N)[CH2:13][O:12][O:11]2)=[CH:8][CH:7]=[CH:6][CH:5]=1.N([O-])=O.[Na+].[I-:21].[K+]>OS(O)(=O)=O.O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([CH:10]2[CH:14]([I:21])[CH2:13][O:12][O:11]2)=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [I-]
Reactant: COC(=O)c1ccccc1C1OOCC1N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: COC(=O)c1ccccc1C1OOCC1I
Reaction time: 1 h

Procedure:
A solution of 5-amino-2,3-dioxolanebenzoic acid methyl ester (0.5 g 2.5 mmol) (Chemische Berichte 1971, 104(8), 2347) in H2SO4 (0.5 ml in 9.5 ml) at 0° C. is treated with a solution of sodium nitrite (0.21 ml, 3.1 mmol) in water (1 ml), stirred for 1 hour, treated with a solution of potassium iodide (1.24 g, 7.5 mmol) in water (2 ml), and stirred at 80° C. for 10 min. The reaction mixture is quenched with water and extracted with dichloromethane (20 ml). Organic layer is separated and washed with water (25 ml), dried with sodium sulphate, and evaporated to give 5-iodo-2,3-dioxolanebenzoic acid methyl ester which is directly used in the next step.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.O>C(Cl)Cl>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][N+:19]([O-:32])=[CH:18][CH:17]=3)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(Nc2nccc(-c3ccncc3)n2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: [O-][n+]1ccc(-c2ccnc(Nc3cccc(C(F)(F)F)c3)n2)cc1
Reaction time: 2 h

Procedure:
10.57 g (33.4 mmol) of N-(3-trifluoromethyl-phenyl)-4-pyridyl-2-pyrimidineamine are suspended in 200 ml of methylene chloride, and 10.49 g (33.42 mmol, 55% strength) of m-chloroperbenzoic acid are added. After 2 hours, 200 ml of water are added. The reaction product is isolated by filtration, washed with sodium carbonate solution and water and, after drying, N-(3-trifluoromethyl-phenyl)-4-(N-oxido-4-pyridyl)-2-pyrimidineamine is obtained. More product is obtained by chromatography (methylene chloride:methanol=9: 1) of the concentrated mother liquor; Rf =0.16 (methylene chloride:methanol=9:1).
Reaction SMILES: O[CH2:2][CH:3]1[CH:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][CH:6]2[CH:5]([N:13]2[CH:21]=[N:20][C:19]3[C:18](=[O:22])[NH:17][C:16]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])=[N:15][C:14]2=3)[O:4]1.[CH2:29]([O:31][P:32]([CH:37]=CC1C(OC(=O)C2C=CC=CC=2)C(OC)C(N2C=NC3C(=O)NC(NC(=O)C(C)C)=NC2=3)O1)([O:34][CH2:35][CH3:36])=[O:33])[CH3:30]>>[CH2:29]([O:31][P:32]([CH:37]=[CH:2][CH:3]1[CH:7]2[CH:6]([O:10][C:9]([CH3:11])([CH3:12])[O:8]2)[CH:5]([N:13]2[CH:21]=[N:20][C:19]3[C:18](=[O:22])[NH:17][C:16]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])=[N:15][C:14]2=3)[O:4]1)(=[O:33])[O:34][CH2:35][CH3:36])[CH3:30]
Reactant: CCOP(=O)(C=CC1OC(n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)C(OC)C1OC(=O)c1ccccc1)OCC
Reactant: CC(C)C(=O)Nc1nc2c(ncn2C2OC(CO)C3OC(C)(C)OC32)c(=O)[nH]1
Product: CCOP(=O)(C=CC1OC(n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)C2OC(C)(C)OC12)OCC
Yield: 64 %

Procedure:
Compound 18.3 (1.7 g, 64% yield) was was synthesized from compound 18.2 (2.0 g, 5.09 mmol) using the procedure described for the preparation of compound 16.7.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](C)[N:4]([C:8](=N)[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])N=1.CS(O)(=O)=O.C([NH2:30])CCC>>[NH2:30][CH2:1][CH2:2][CH2:6][CH2:5][NH:4][CH:8]=[N:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: CCCCN
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Agent: CS(=O)(=O)O
Product: Cc1ccc(S(=O)(=O)N=CNCCCCN)cc1

Procedure:
The compound of Example 11 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of n-butylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 269.36; found mol. wt. (M+H) 270.3; 539.1 (Dimer)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:6][C:7]1[C:8]([N:22]2[C:26]([CH3:27])=[N:25][N:24]=[C:23]2Br)=[C:9]2[C:14](=[CH:15][C:16]=1[Cl:17])[N:13]=[C:12]([O:18][CH3:19])[C:11]([O:20][CH3:21])=[N:10]2>>[Cl:6][C:7]1[C:8]([N:22]2[C:26]([CH3:27])=[N:25][N:24]=[C:23]2[N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[C:9]2[C:14](=[CH:15][C:16]=1[Cl:17])[N:13]=[C:12]([O:18][CH3:19])[C:11]([O:20][CH3:21])=[N:10]2
Reactant: c1c[nH]cn1
Reactant: COc1nc2cc(Cl)c(Cl)c(-n3c(C)nnc3Br)c2nc1OC
Product: COc1nc2cc(Cl)c(Cl)c(-n3c(C)nnc3-n3ccnc3)c2nc1OC
Temperature: 100 °C
Reaction time: 3 h
Yield: 32.1 %

Procedure:
A mixture of imidazole (78 mg, 1.15 mmol) and 6,7-dichloro-2,3-dimethoxy-5-(3-bromo-5-methyl-4H-1,2,4-triazol-4-yl)quinoxaline (48 mg, 0.115 mmol) was heated at 100° C. for 1 hour then at 120° C. for 3 hours. After being cooled the mixture was partitioned between water (15 mL) and dichloromethane (2×15 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using dichloromethane:methanol (98:2 changing to 95:5, by volume) to give the title compound (15 mg, 32%) as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Na+].[I-:11].[OH-].[Na+].[O-]Cl.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([I:11])[C:3]=1[OH:9]
Reactant: [I-]
Reactant: Oc1ccc(F)cc1F
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Product: Oc1c(F)cc(F)cc1I
Temperature: 0 °C
Yield: 41.2 %

Procedure:
To a stirred solution of 10 g of 2,4-difluorophenol in 300 mL of methanol at 0° C., add 22.5 g (150.2 millimoles (mmol) of NaI and 3.08 g (77 mmol) of NaOH. To the resulting mixture add 175 mL of 5% aqueous NaOCl solution (commercial bleach) over a one hour period. Stir the resulting slurry for one more hour at 0° C. Add 100 mL of 10% aqueous Na2S2O3 solution, and acidify the resulting reaction mixture by adding dilute hydrochloric acid. Extract the resulting mixture with methylene chloride, wash the resulting organic layer with brine and dry it over anhydrous magnesium sulfate. Remove solvent and purify the residue by flash chromatography using 50 vol % methylene chloride in hexanes to yield 8.10 g (41.16%) of pure 2,4-difluoro-6-iodophenol (P7) as a white solid.