Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][C:12]1[N:13]=[CH:14][C:15]2[CH:21]=[C:20]([C:22]3[C:27]([Cl:28])=[C:26]([O:29][CH3:30])[CH:25]=[C:24]([O:31][CH3:32])[C:23]=3[Cl:33])[C:19](=[O:34])[N:18]([CH3:35])[C:16]=2[N:17]=1)([O-])=O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>CCOC(C)=O.O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][C:12]1[N:13]=[CH:14][C:15]2[CH:21]=[C:20]([C:22]3[C:23]([Cl:33])=[C:24]([O:31][CH3:32])[CH:25]=[C:26]([O:29][CH3:30])[C:27]=3[Cl:28])[C:19](=[O:34])[N:18]([CH3:35])[C:16]=2[N:17]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3cnc(Nc4c(C)cccc4[N+](=O)[O-])nc3n(C)c2=O)c1Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(Cl)c(-c2cc3cnc(Nc4c(C)cccc4N)nc3n(C)c2=O)c1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A mixture of 2-(2-nitro-6-methylphenylamino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (10) (810 mg, 1.57 mmol) and tin(II) chloride hydrate (1.77 g, 7.86 mmol) in EtOAc (50 mL) was stirred at 60° C. for 2 hours. The reaction was monitored by LCMS. The reaction mixture was basified with saturated aqueous sodium bicarbonate to pH=8˜9, diluted with H2O (100 mL), and then extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered, and concentrated. The residue was recrystallized with dichloromethane/ethyl acetate/petroleum ether (DCM/EtOAc/PE)=1/1/2 to give 2-(2-amino-6-methylphenylamino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (11) (640 mg, 83% yield) as a grey solid. (MS (ES+) C23H21Cl2N5O3 requires: 485, 487. Found: 486, 488 [M+H]+; 1H-NMR (500 MHz, CDCl3) δ ppm 8.54 (s, 1H), 7.45 (s, 1H), 7.08 (t, J=7.5 Hz, 1H), 6.71 (dd, J=3.5, 7.5 Hz, 2H), 6.65 (br s, 1H), 6.62 (s, 1H), 3.94 (s, 6H), 3.88 (br s, 2H), 3.62 (br s, 3H), 2.24 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[CH:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)([CH3:21])[CH3:20]
Reactant: CC(C)Br
Reactant: COC(=O)c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)cn1
Temperature: 60 °C
Yield: 72.5 %

Procedure:
To methyl 5-hydroxypyridine-2-carboxylate (0.6 g, 3.92 mmol) in DMF (3.6 mL) was added potassium carbonate (2.2 g, 15.7 mmol) followed by 2-bromopropane (736 μL, 7.8 mmol) The reaction mixture was heated at 60° C. for 1.5 hours. The reaction mixture was cooled and filtered using EtOAc and the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with water (3×10 mL) and brine solution (10 mL). The organics were separated and dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using 0-50% EtOAc: hexanes as eluent to give methyl 5-isopropoxypyridine-2-carboxylate (555 mg, 73%) as a colorless oil. ESI-MS m/z calc. 195.1. Found 196.3 (M+1)+; Retention time: 1.09 minutes (3 min run). Lithium hydroxide (5.7 mL of 2 M, 11.37 mmol) was added to a solution of methyl 5-isopropoxypyridine-2-carboxylate (555 mg, 2.84 mmol) in dioxane (4 mL) and stirred at 55° C. for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water and layers were separated. The aqueous layer was acidified with 1N HCl solution and extracted with ethyl acetate. The organics were separated and dried over sodium sulfate, filtered and concentrated in vacuo to give 5-isopropoxypyridine-2-carboxylic acid (150 mg, 29%). ESI-MS m/z calc. 182.1. Found 182.3 (M+1)+; Retention time: 0.33 minutes (3 min run).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1[CH2:12][OH:13].[Cl:14][C:15]([C:25]([F:28])([F:27])[F:26])=[CH:16][C@@H:17]1[C@H:19]([C:20](Cl)=[O:21])[C:18]1([CH3:24])[CH3:23].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:14][C:15]([C:25]([F:26])([F:27])[F:28])=[CH:16][C@@H:17]1[C@H:19]([C:20]([O:13][CH2:12][C:3]2[C:4]([CH3:11])=[CH:5][CH:6]=[C:7]([CH:8]([CH3:10])[CH3:9])[C:2]=2[CH3:1])=[O:21])[C:18]1([CH3:24])[CH3:23]
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: Cc1ccc(C(C)C)c(C)c1CO
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C(C)C)c(C)c1COC(=O)[C@H]1[C@@H](C=C(Cl)C(F)(F)F)C1(C)C

Procedure:
[2,6-Dimethyl-3-(1-methylethyl)phenyl]methanol (0.7 g, 0.004 mole), cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylic acid chloride (0.97 g, 0.004 mole), pyridine (2 ml) and dry toluene (150 ml) were combined to give [2,6-dimethyl-3-(1-methylethyl)phenyl]methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[O:17][N:16]=[C:15]([CH:18]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=2)[CH3:19])[CH:14]=1)=[S:11])(=O)C1C=CC=CC=1.CO.C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[CH2:26]([C:23]1[CH:22]=[CH:21][C:20]([CH:18]([C:15]2[CH:14]=[C:13]([NH:12][C:10]([NH2:9])=[S:11])[O:17][N:16]=2)[CH3:19])=[CH:25][CH:24]=1)[CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)Cc1ccc(C(C)c2cc(NC(=S)NC(=O)c3ccccc3)on2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Cc1ccc(C(C)c2cc(NC(N)=S)on2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 448.3 %

Procedure:
This thiourea (4.65 g) was dissolved in tetrahydrofuran (50 ml) and then methanol (50 ml) and potassium carbonate (3.15 g) were added, after which the mixture was stirred at 50° C. for 5 hours. To the reaction mixture was added a small amount of water, and the resulting mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over sodium sulfate and thereafter concentrated under reduced pressure, to obtain 3-[1-(4-isobutyl-phenyl)-ethyl]-isoxazol-5-yl-thiourea (15.52 g).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][CH:15]=2)[CH2:10]1)=O)(C)(C)C>C(OCC)C>[CH3:20][O:19][C:13]1[CH:12]=[C:11]2[C:16]([CH2:17][CH2:18][NH:9][CH2:10]2)=[CH:15][CH:14]=1
Reactant: COc1ccc2c(c1)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOCC
Product: COc1ccc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 5° C., 50 mL of a saturated solution of hydrogen chloride in diethyl ether were added dropwise to a mixture of 2.3 g of 7-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester in 50 mL of diethyl ether and the reaction mixture stirred for 2 hours at room temperature. The precipitated product (hydrochloride) was separated by filtration, washed with diethyl ether and dried in vacuo. Yield: 1.5 g (7.5 mmol); m.p. 215-218° C., EI-MS: 163 (M+).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][C@H:28]1[NH:33][C@@H:32]([CH3:34])[CH2:31][N:30]([C:35]2[O:36][C:37]3[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=3[N:39]=2)[CH2:29]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:33]2[C@H:32]([CH3:34])[CH2:31][N:30]([C:35]3[O:36][C:37]4[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=4[N:39]=3)[CH2:29][C@@H:28]2[CH3:27])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: C[C@@H]1CN(c2nc3ccccc3o2)C[C@H](C)N1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: C[C@@H]1CN(c2nc3ccccc3o2)C[C@H](C)N1CCCCC1(C(=O)NCC(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-benzoxazole.
Reaction SMILES: I[C:2]1[N:3]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>>[OH:33][CH2:29][CH2:30][C:31]#[C:32][C:2]1[N:3]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: C#CCCO
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(I)n(Cc3cccc4ccccc34)cc21
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C#CCCO)n(Cc3cccc4ccccc34)cc21

Procedure:
The title compound was prepared from 5-iodo-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione and 3-butyn-1-ol in a manner analogous to the method of Example 13 above.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:9][CH2:10][NH:11][CH:12]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13]([O:15]CC)=O.[O-:34][C:35]#[N:36].[K+].Cl>C(O)C.O>[CH2:27]([O:26][C:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:12]1[N:11]([CH2:10][CH2:9][CH:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:35](=[O:34])[NH:36][C:13]1=[O:15])=[O:25])[CH3:28]
Reactant: CCCCCC(CCNC(CCCCCCC(=O)OCC)C(=O)OCC)OC1CCCCO1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCCCC(CCN1C(=O)NC(=O)C1CCCCCCC(=O)OCC)OC1CCCCO1
Yield: 94.2 %

Procedure:
To a solution of diethyl 2-(3-(tetrahydropyran-2-yloxy)octylamino)nonanedioate (7.8 g) in ethanol (32 ml) was added a solution of potassium cyanate (3.0 g) in water (6 ml). The resulting suspension was stirred and cooled during the gradual addition of 2N-hydrochloric acid (16.7 ml). The solution was allowed to stand at room temperature for 22 hours, most of the ethanol was evaporated, water was added, and the insoluble oil was extracted with ether. The ether solution was washed with water, dried over magnesium sulphate, and evaporated. The yellow oil so obtained (8.0 g) was dissolved in light petroleum (b.p. 60°-80° C.) and the solution was refluxed for 4 hours, evaporated to dryness, and the residual oil was heated on the steambath for 2 hours to give 5-(6-ethoxycarbonylhexyl)-1-(3-(tetrahydropyran-2-yloxy)octyl)hydantoin as a yellow oil (7.3 g), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=O)[CH3:18])[C:3]=1[O:20][CH2:21][CH3:22].[CH3:23][CH2:24][O:25][C:26]([CH:28](P(OCC)(OCC)=O)[F:29])=[O:27].C([Li])CCC>C1COCC1>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:18])=[C:28](/[F:29])\[C:26]([O:25][CH2:24][CH3:23])=[O:27])[C:3]=1[O:20][CH2:21][CH3:22]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCOc1c(C(C)=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(c(Br)c1OCC)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure F-1, 1-(4-bromo-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-109, 1.08 g, 2.96 mmol) and triethyl 2-fluoro-2-phosphonoacetate (2.86 g, 11.84 mmol) were reacted with n-butyllithium (1.6 M in hexanes, 7.4 mL, 11.84 mmol) in THF to produce the title compound after purification by flash column chromatography (silica gel, 2% ethyl acetate in hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C(N(CC)C(C)C)(C)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[NH:45]1[C:49]([NH2:50])=[CH:48][CH:47]=[N:46]1.C(=O)([O-])O.[Na+]>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:37]([NH:50][C:49]2[NH:45][N:46]=[CH:47][CH:48]=2)=[O:43])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: Nc1ccn[nH]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccn[nH]4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.8 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (20 mg) was dissolved in chlorobenzene (2 ml) and N,N-diisopropylethylamine (0.2 ml) to prepare a solution. A solution of triphosgene (18 mg) in chlorobenzene (0.5 ml) was then added to the solution, and the mixture was stirred at room temperature for 30 min. Next, 1H-5-pyrazolamine (10 mg) was added thereto, and the mixture was further stirred at 110° C. overnight. The reaction solution was developed through diatomaceous earth impregnated with a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with chloroform. The solvent in the extract was removed by distillation. The residue was purified by HPLC using chloroform/methanol for development to give the title compound (1 mg, yield 4%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.[O:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.[H][H]>C(O)C.O.[Pd]>[CH3:5][CH:4]([CH3:6])[CH2:3][C@H:2]([NH:1][CH:14]1[CH2:15][CH2:16][O:11][CH2:12][CH2:13]1)[C:7]([OH:9])=[O:8]
Reactant: O=C1CCOCC1
Reactant: [H][H]
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)C[C@H](NC1CCOCC1)C(=O)O
Temperature: 0 °C
Yield: 53.5 %

Procedure:
A mixture of L-leucine (20.0 g, 152 mmol), concentrated aqueous HCl solution (13.1 mL, 36.5%), and tetrahydro-4H-pyran-4-one (30.0 g, 300 mmol, Aldrich, Milwaukee, Wis.) was agitated in an atmosphere of hydrogen (pressure, 43-51 psi) at room temperature in a mixture of ethanol and water (1:1, v/v, 400 mL) in the presence of Pd/C (20%, 4 g) until the absorption of hydrogen almost ceased, filtered. The filtrate was treated with concentrated aqueous ammonium hydroxide (29.8%) to adjust the pH to 5.5. White solid precipitated out which was isolated via filtration. The white solid was mixed with 150 mL of water and heated to boiling. After cooling down to 0° C., the white solid was filtered and dried under vacuum affording 17.5 g (53.4%) of the pure titled compound as a white solid; mp >300° C. APCI-MS m/z 216.2 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][NH:20][CH2:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:17]=[CH:18][C:4]1=2)[CH3:2].[CH3:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH2:39][C:40](O)=[O:41])=[CH:31]1.ON1C2C=CC=CC=2N=N1.[ClH:53].CN(C)CCCN=C=NCC.Cl>C(#N)C.C(O)C.CC(O)C>[ClH:53].[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][N:20]([CH2:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:40](=[O:41])[CH2:39][C:32]3[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]([CH3:29])[CH:31]=3)[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: Cn1cc(CC(=O)O)c2ccccc21
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCCc3cccnc3)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: CC#N
Solvent: CC(C)O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCc3cccnc3)C(=O)Cc3cn(C)c4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.6 %

Procedure:
To a solution of 1-ethyl-3,3,5-trimethyl-7-[(2-pyridine 3-ylethylamino)methyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.5 g), 1-methyl-3-indoleacetic acid(0.27 g), and 1-hydroxybenzotriazole (HOBT) (0.24 g) in acetonitrile (10 ml), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (WSC) (0.30 g) was added and stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure. Ethyl acetate and water were added to the residue and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=1:3→0:1). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride in ethanol solution (1.1 ml) was added to a 2-propanol solution (5 ml) of the residue, and the liquid was stirred at room temperature, and concentrated under reduced pressure. Ethanol and ether were added to the residue. The precipitated insoluble matter was separated, washed with ether, and dried to give the title compound(0.26 g) as a pale orange white amorphous.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([I:22])C(=O)C1>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][CH2:13][CH2:12]3)=[N:9][C:10]=2[I:22])[CH:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1nccn2c(C3CCC3)ncc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1nccn2c(C3CCC3)nc(I)c12

Procedure:
8-Chloro-3-cyclobutylimidazo[1,5-a]pyrazine (1058 mg, 5.1 mmol) and NIS (1146 mg, 5.1 mmol) in anh DMF (10 mL) were stirred at 60° C. under Ar for 6 h. The reaction was diluted with DCM (˜400 mL), washed (H2O, brine), dried (Na2SO4) and concentrated under reduced pressure. Purification of the crude material by flash chromatography on silica gel (50 g cartridge, 10:1-8:1-7:1-6:1 hexanes:EtOAc) afforded the title compound as a pale yellow solid; 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J=4.8 Hz, 1H), 7.26 (d, J=4.8 Hz, 1H), 3.75 (quintetd, J=1.2 Hz, 8.4 Hz, 1H), 2.62-2.42 (m, 4H), 2.32-1.98 (m, 2H); MS (ES+): m/z 334.0 (100) [MH+]; HPLC: tR=3.38 min (OpenLynx, polar—5 min).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH2:19]([N:26]1[CH:31]=[C:30]([C:32]#[N:33])[C:29](=[O:34])[N:28]([CH2:35][CH2:36][CH2:37][Cl:38])[C:27]1=[O:39])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[ClH:38].[CH2:19]([N:26]1[CH:31]=[C:30]([C:32]#[N:33])[C:29](=[O:34])[N:28]([CH2:35][CH2:36][CH2:37][N:14]2[CH2:15][CH2:16][N:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3][C:2]([F:1])([F:17])[F:18])[CH2:12][CH2:13]2)[C:27]1=[O:39])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N#Cc1cn(Cc2ccccc2)c(=O)n(CCCCl)c1=O
Reactant: FC(F)(F)COc1ccccc1N1CCNCC1
Product: Cl
Product: N#Cc1cn(Cc2ccccc2)c(=O)n(CCCN2CCN(c3ccccc3OCC(F)(F)F)CC2)c1=O

Procedure:
substituting 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 1-benzyl-3-(3-chloropropyl)-5-cyano-2,4(1H,3H)-pyrimidinedione gave 1-benzyl-3-(3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-5-cyano-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 142°-143° C.; Anal.: Calcd. for C27H28F3N5O3.(HCl)1.2.(H2O)0.5 : C, 57.50; H, 5.18; N, 12.42%; Found: C, 55.93; H, 5.22; N, 11.94%;
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([OH:14])[CH:10]=[C:11](O)[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O.C[O:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[NH2:36]>C(O)CCCCC>[OH:14][C:9]1[C:10]2[C:29](=[O:28])[C:30]3[CH:35]=[CH:34][CH:33]=[N:32][C:31]=3[NH:36][C:11]=2[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH:8]=1
Reactant: COC(=O)c1cccnc1N
Reactant: Oc1cc(O)cc(N2CCOCC2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCO
Solvent: O
Product: O=c1c2cccnc2[nH]c2cc(N3CCOCC3)cc(O)c12
Yield: 2.1 %

Procedure:
5-Morpholin-4-yl-benzene-1,3-diol (345 mg 1.77 mmol), TsOH.H2O (30 mg, 0.20 mmol), and 2-aminonicotinic acid methyl ester (269 mg, 1.77 mmol) were heated at 160° C. in hexanol (5 mL) for 12 hours. Upon cooling, the mixture was purified via flash chromatography CH2Cl2/MeOH (95:5), followed by a second flash column eluting with Et2OAc/hexanes (7:3) to provide 11 mg (2%) of the product. 1H NMR (CDCl3, 400 MHz) δ: 13.5 (s, 1H), 8.80 (br s, 1H), 8.62 (d, 1H), 7.25 (dd, 1H), 6.22 (d, 1H), 6.04 (s, 1H), 5:97 (s, 1H), 3.86-3.83 (m, 4H), 3.40-3.35 (m, 4H). LRMS (APCI, positive): Da/e 296.4 (m−1).
Reaction SMILES: C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.[NH2:27][C:28]1[CH:33]=[C:32]([CH3:34])[C:31]([OH:35])=[C:30]([Cl:36])[CH:29]=1.[Cl:37][C:38]1[N:43]=[C:42](Cl)[C:41]([F:45])=[CH:40][N:39]=1>>[Cl:37][C:38]1[N:43]=[C:42]([NH:27][C:28]2[CH:33]=[C:32]([CH3:34])[C:31]([OH:35])=[C:30]([Cl:36])[CH:29]=2)[C:41]([F:45])=[CH:40][N:39]=1
Reactant: Cc1cc(N)cc(Cl)c1O
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: Cc1cc(Nc2nc(Cl)ncc2F)cc(Cl)c1O

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 4-amino-2-chloro-6-methylphenol and 2,4-dichloro-5-fluoropyrimidine resulted 2-chloro-N4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-4-pyrimidineamine. The reaction of 2-chloro-N4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-4-pyrimidineamine and 3-methoxycarbonylmethyleneoxyaniline (1.95 g, 11 mmol) gave N4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (850 mg, 55%). 1H NMR (CD3OD): δ 2.22 (s, 3H), 3.76 (s, 3H), 4.52 (s, 2H), 6.50 (dt, J=2.7 and 6.3 Hz, 1H), 7.09-7.14 (m, 2H), 7.24 (t, J=1.8 Hz, 1H), 7.30 (t, J=1.2 Hz, 1H), 7.49 (d, J=2.4 Hz, 1H), 7.88 (d, J=3.9 Hz, 1H); 19F NMR (282 MHz, CD3OD): δ−168.70; LCMS: ret. time: 20.63 min.; purity: 98.56%; MS (m/e): 432.96 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC([O:24][CH:25]([CH3:27])C)=O.[C:34]([S:38][C@@H:39]([CH3:42])[CH2:40]O)([CH3:37])([CH3:36])[CH3:35].[S:43]1C=CC=C1CC(O)=O>C1COCC1>[C:25]([S:43][CH2:40][C@@H:39]([S:38][C:34]([CH3:37])([CH3:36])[CH3:35])[CH3:42])(=[O:24])[CH3:27]
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: C[C@@H](CO)SC(C)(C)C
Reactant: O=C(O)Cc1cccs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC[C@H](C)SC(C)(C)C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a stirred solution of 3.54 g of triphenylphosphine in 50 mL of THF at 0° C. was added 2.66 mL of diisopropyl azodicarboxylate. The mixture was stirred for an additional 30 min. To the resulting white precipitate was added 1.00 g of (2S)-2-(t-butylthio)-1-propanol in 5 mL of THF. The reaction mixture was stirred for 10 min, then 0.966 mL of thiolacetic acid was added and stirring was continued at 0° C. for 1 h and at room temperature for 1 h. The solvent was evaporated under vacuum and the residue was purified by flash chromatography (5% CH2Cl2 in hexane) to give 1.16 g of (2S)-1-(acetylthio)-2-(t-butylthio)propane as an oil at 83% yield. Characteristic analytical data are as follows: 1H NMR (300 MHz, CDCl3) δ3.32 (m, 1H), 2.8-2.94 (m, 2H), 2.35 (s, 3 H), 1.38 (s, 9H), 1.33 (d, J=7 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=2)[N:16]=1.COC(OC)[N:27]([CH3:29])C.[NH2:32]N>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=3)[N:16]=2)=[CH:29][NH:27][N:32]=1
Reactant: NN
Reactant: CC(C)c1nnc2ccc(CC(=O)c3ccc(F)cc3F)nn12
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CC(C)c1nnc2ccc(-c3c[nH]nc3-c3ccc(F)cc3F)nn12
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
The 1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.20 g, 0.63 mmol, Preparation #K.1), N,N-dimethylformamide dimethyl acetal (0.14 g, 1.14 mmol) and toluene (2 mL) were heated in an about 110° C. oil bath. After about 30 min, the mixture was cooled and the solvent was concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (2 mL) and hydrazine (0.0360 mL, 1.14 mmol) was added. The mixture was heated to about 95° C. in an oil bath for about 30 min, cooled to ambient temperature, and then concentrated under reduced pressure. The material was purified by RP-HPLC (Table 1, Method d). Concentration of the desired fractions under reduced pressure resulted in precipitation of a tan solid that was collected by filtration and then dried to give the title compound (0.054 g, 25%): LC/MS (Table 1, Method a) Rt=1.69 min; MS m/z: 341.2 (M+H)+.