Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[N:32][O:33][C:34](=[O:48])[C@@H:35]([NH:40]C(OC(C)(C)C)=O)[C@@H:36]([CH3:39])[CH2:37][CH3:38])[C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.Cl.C(O)C>C(O)C>[NH2:1][C:2](=[N:32][O:33][C:34](=[O:48])[C@@H:35]([NH2:40])[C@@H:36]([CH3:39])[CH2:37][CH3:38])[C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH2:27])=[O:26])=[CH:28][CH:29]=3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)ON=C(N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(N)=O)cc3)CC2)cc1
Agent: Cl
Solvent: CCO
Product: CC[C@H](C)[C@H](N)C(=O)ON=C(N)c1ccc(OCCCC2CCN(CCCOc3ccc(C(N)=O)cc3)CC2)cc1
Reaction time: 5 h
Yield: 76.5 %

Procedure:
To an ethanol (5 mL) solution of 0.20 g of 4-(3-{4-[3-(4-{amino[(2S,3S)-2-(tert-butoxycarbonyl)amino-3-methylpentanoyloxyimino]methyl}phenoxy)propyl]-1-piperidinyl}propoxy)benzamide=O-[(2S,3S)-2 (tert-butoxycarbonyl)amino-3-methylpentanoyl]oxime was added 2 mL of 2.9 mol/L hydrogen chloride/ethanol at room temperature, which was then stirred at the same temperature for 5 hours. Thereto was added 2 mL of 2.9 mol/L hydrogen chloride/ethanol, which was then stirred for 26 hours. Thereto was further added 1 mL of 2.9 mol/L hydrogen chloride/ethanol, which was then stirred for 3 days. The solvent was distilled off under reduced pressure, and the resultant solid was suspended in diisopropyl ether, followed by collecting the solid matter by filtration before washing with diisopropyl ether to provide 0.13 g of 4-{3-[4-(3-{4-[amino((2S,3S)-2-amino-3-methylpentanoyloxyimino)methyl]phenoxy}propyl)-1-piperidinyl]propoxy}benzamide=O-((2S,3S)-2-amino-3-methylpentanoyl)oxime hydrochloride as white solid form.
Reaction SMILES: CC1N(C2C=CC=C(C(F)(F)F)C=2)N=C(C2C=NC=NC=2)C=1C(O)=O.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]([CH3:38])=[C:36]([C:39]([OH:41])=O)[C:35]([C:42]3[CH:43]=[N:44][CH:45]=[N:46][CH:47]=3)=[N:34]2)=[CH:29][C:28]=1[C:48]([F:51])([F:50])[F:49].Cl.Cl.[NH:54]1[CH2:59][CH2:58][CH:57]([N:60]2[CH2:64][CH2:63][CH2:62][C@H:61]2[CH2:65][OH:66])[CH2:56][CH2:55]1>>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]([CH3:38])=[C:36]([C:39]([N:54]3[CH2:55][CH2:56][CH:57]([N:60]4[CH2:64][CH2:63][CH2:62][C@H:61]4[CH2:65][OH:66])[CH2:58][CH2:59]3)=[O:41])[C:35]([C:42]3[CH:47]=[N:46][CH:45]=[N:44][CH:43]=3)=[N:34]2)=[CH:29][C:28]=1[C:48]([F:51])([F:50])[F:49]
Reactant: OC[C@@H]1CCCN1C1CCNCC1
Reactant: Cc1c(C(=O)O)c(-c2cncnc2)nn1-c1ccc(Br)c(C(F)(F)F)c1
Agent: Cc1c(C(=O)O)c(-c2cncnc2)nn1-c1cccc(C(F)(F)F)c1
Agent: Cl
Product: Cc1c(C(=O)N2CCC(N3CCC[C@H]3CO)CC2)c(-c2cncnc2)nn1-c1ccc(Br)c(C(F)(F)F)c1

Procedure:
In analogy to the procedure described in Example 160E], a mixture of 5-methyl-3-pyrimidin-5-yl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid and 1-(4-bromo-3-trifluoromethyl-phenyl)-5-methyl-3-pyrimidin-5-yl-1H-pyrazole-4-carboxylic acid (example 173D]) and ((S)-1-piperidin-4-yl-pyrrolidin-2-yl)-methanoldihydrochloride (Example 161A]) gave a mixture of the title compound and example 175. Purification by reversed phase HPLC (MeCN:H2O) afforded [4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-[5-methyl-3-pyrimidin-5-yl-1-(3-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-methanone (Example 175) and [1-(4-bromo-3-trifluoromethyl-phenyl)-5-methyl-3-pyrimidin-5-yl-1H-pyrazol-4-yl]-[4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-methanone) as a white solid (31%). MS: 593.4 (1 Br, MH+).
Reaction SMILES: [Br:1][C:2]1[C:27]([CH3:28])=[CH:26][C:5]([O:6][C@H:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[C:8]2=[O:25])=[C:4]([F:29])[CH:3]=1.[ClH:30]>C(Cl)Cl.CO.O1CCOCC1>[ClH:30].[Br:1][C:2]1[C:27]([CH3:28])=[CH:26][C:5]([O:6][C@H:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:8]2=[O:25])=[C:4]([F:29])[CH:3]=1
Reactant: Cc1cc(O[C@H]2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)c(F)cc1Br
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(O[C@H]2CCN(C3CCNCC3)C2=O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
(S)-tert-butyl 4-(3-(4-bromo-2-fluoro-5-methylphenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (2.3 g, 4.9 mmol) was dissolved in CH2Cl2:MeOH (9:1, 50 mL). 4N HCl in dioxane (10 mL) was added and the reaction stirred at ambient temperature overnight. The reaction was concentrated to afford crude (S)-3-(4-bromo-2-fluoro-5-methylphenoxy)-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (2.0 g, 4.9 mmol, 101% yield) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH3:12])=[O:10].[CH3:13][O:14][CH2:15]COC.[H-].[Na+].COCCl>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:13][O:14][CH3:15])[C:9]([NH:11][CH3:12])=[O:10]
Reactant: CNC(=O)Nc1ccccc1F
Reactant: COCCOC
Agent: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CNC(=O)N(COC)c1ccccc1F
Reaction time: 0.25 h

Procedure:
To a stirred solution of 8.4 g. (0.05 mol) of N-(2-fluorophenyl)-N'-methyl urea dissolved in 200 ml. of 1,2-dimethoxyethane there was added 2.4 g. of a 50% dispersion of sodium hydride (0.05 mol) in mineral oil. The resulting mixture was stirred for 15 minutes more. Then 4.2 g. (0.05 mol) of chloromethyl methyl ether was added dropwise. After all ether was added, the mixture was stirred for 16 hours. At the end of this time it was filtered through a layer of magnesium sulfate. The filtrate was evaporated to give an oily residue which crystallized upon standing. These crystals were washed with hexane and then dried to give 6.2 g. of product, melting point 57°-59°C. Analysis: Calculated for C10H13FN2O2 : F, 8.96%; Found: F, 8.97%. The infrared spectrum showed strong adsorptions at 6.1, 6.6, 6.7, 6.9, 7.8, 9.1 and 13.5μ. The NMR spectra was consistent with the assigned structure.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)=[N:10][N:9]2[CH:34]=1)=[O:4].[CH3:35][NH2:36].CO>C(#N)C>[CH3:35][NH:36][CH2:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)=[N:10][N:9]2[CH:34]=1)=[O:4]
Reactant: O=C(CCl)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: CN
Solvent: CC#N
Solvent: CO
Product: CNCC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 25 %

Procedure:
Using N-[3-({2-[(chloroacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide (92 mg, 0.187 mmol), methylamine/methanol (2 mL) solution and acetonitrile (1 mL) as starting materials and in the same manner as in Example 398, the title compound (22 mg, 25%) was obtained as a white powder.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].O.[CH2:14]([NH2:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(O)(C)C>[CH2:14]([NH:32][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCCCNC1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
60 g of D-galactose were suspended in 330 ml of isopropanol and 170 ml of water and heated to 50°. After addition of 90 g of stearylamine, the mixture was stirred until all the amine had gone into solution. On cooling, the glycosylamine crystallised out. The solid material was filtered off with suction, washed consecutively with ethanol and with ether and dried in vacuo.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[S:9][C:4]=2[CH:5]=[N+:6]([O-])[CH:7]=1.P(Br)(Br)([Br:22])=O.C([O-])(O)=O.[Na+]>ClCCCl>[Br:22][C:5]1[C:4]2[S:9][C:10]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])=[N:11][C:3]=2[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: [O-][n+]1cc(Br)c2nc(-c3c(F)cccc3Cl)sc2c1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Fc1cccc(Cl)c1-c1nc2c(Br)cnc(Br)c2s1
Temperature: 70 °C
Yield: 71 %

Procedure:
To a suspension of 7-bromo-2-(2-chloro-6-fluoro-phenyl)-5-oxido-thiazolo[5,4-c]pyridin-5-ium (2.0 mmol, 720 mg) in 1,2-dichloroethane (30 mL) was added POBr3 (8.0 mmol, 2.3 g). The mixture was heated at 70° C. for 3 hours. The mixture was cooled to room temperature, and sat. NaHCO3 solution was added. The aqueous layer was extracted with DCM. The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel chromatography (0-15% EtOAc/hexane) to give the title compound as a white solid (600 mg, 71% yield). 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.49 (dd, J=14.2, 8.0 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 7.19 (t, J=8.7 Hz, 1H). LCMS (ESI) m/z 422.9 [M+H+].
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][C:11]([C:17]#[N:18])([N:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C(OCC)C>[NH2:18][CH2:17][C:11]1([N:14]([CH3:15])[CH3:16])[CH2:10][CH2:9][CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1
Reactant: CN(C)C1(C#N)CCC(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CN(C)C1(CN)CCC(Cc2ccccc2)CC1
Reaction time: 4 h

Procedure:
A solution of 9.5 mmole of 4-benzyl-1-cyano-1-(dimethylamino)cyclohexane in 25 ml of diethyl ether was added to a suspension of 0.40 g of LAH in 10 ml of diethyl ether cooled in an ice-methanol bath. Following 4 hours' stirring at 20° to 25° C., the mixture was treated in turn with 0.4 ml of water, 0.4 ml of 15% sodium hydroxide and 1.2 ml of water. The inorganic gel was collected on a filter, and the filtrate was concentrated in vacuo to give (1-aminomethyl-4-benzyl-1-cyclohexyl)dimethylamine was a viscous gum.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.ClC(Cl)(Cl)S(O[CH2:17][C:18]([F:21])([F:20])[F:19])(=O)=O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH:6][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:4][C:3]=2[O:2]1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: Nc1ccc2c(c1)OCO2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: FC(F)(F)CNc1ccc2c(c1)OCO2

Procedure:
A mixture of 7 g. (0.051 mole) of 3,4-methylenedioxyaniline, 14.5 g. (0.051 mole) of 2,2,2-trifluoroethyl trichloromethanesulfonate, and 5.2 g (0.052 mole) of triethylamine in 60 ml. of toluene was heated under reflux for 3 1/2 hours. The cooled mixture was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily residue is distilled (b.p. 1.9 mm. 103°-5°) to give pure 3,4-methylenedioxy-N-(2,2,2-trifluoroethyl)-aniline.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]#[C:15][Si](C(C)C)(C(C)C)C(C)C)=[CH:11][CH:12]=2)[C@H:7]([NH:26][C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]#[CH:15])=[CH:11][CH:12]=2)[C@H:7]([NH:26][C:27]2[N:28]=[CH:29][CH:30]=[CH:31][N:32]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C#C[Si](C(C)C)(C(C)C)C(C)C)cc2[C@H](Nc2ncccn2)C[C@@H]1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc2c(c1)[C@H](Nc1ncccn1)C[C@H](C)N2C(C)=O
Reaction time: 0.5 h

Procedure:
A solution of (2S,4R)-1-acetyl-2-methyl-N-2-pyrimidinyl-6-{[tris(1-methylethyl)silyl]ethynyl}-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 113) (220 mg, 0.475 mmol) in tetrahydrofuran (THF) (5 mL) at room temperature was treated with TBAF (1N in THF, 0.571 mL, 0.571 mmol) and the resulting mixture was stirred at this temperature for 30 min then most of the solvent was removed in vacuo. The residue was partitioned between AcOEt and water and the layers were separated. The organic phase was washed with water then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 10 G column (gradient:5 to 25% (20% MeOH in DCM) in DCM) gave (2S,4R)-1-acetyl-6-ethynyl-2-methyl-N-2-pyrimidinyl-1,2,3,4-tetrahydro-4-quinolinamine as an orange foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[N:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.Cl.[F:24][C:25]([F:34])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[F:34][C:25]([F:24])([F:33])[C:26]1[N:30]=[C:29]([CH2:31][NH:32][C:20]([C:10]2[N:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=2)=[O:21])[O:28][N:27]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Reactant: NCc1nc(C(F)(F)F)no1
Agent: Cl
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1

Procedure:
The title compound was synthesized in analogy to Example 41, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid (example M) and C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride (CAS registry No. 944905-93-5; example AK) as starting materials; LC-MS (UV peak area/ESI) 100.0%, 482.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Reactant: NC1CCOCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc2c(c(NC3CCOCC3)n1)SCC2
Temperature: 130 °C

Procedure:
0.68 g (II) are placed in 6 ml dioxane, then 1.72 ml diisopropylethylamine and then 0.6 g 4-aminotetrahydropyran are added. The reaction mixture is heated to 130° C. until no further reaction takes place, then cooled and evaporated down. The product is treated with water in the ultrasound bath and the solid is suction filtered and dried. 0.66 g (III-3) are obtained. Analytical HPLC-MS (method A): RT=1.08 min.
Reaction SMILES: [O:1]([Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])S(C(F)(F)F)(=O)=O.[Br:19][CH2:20][C@H:21]([CH3:25])[CH2:22][CH2:23]O.N1C(C)=CC=CC=1C.Cl>C(Cl)Cl>[CH:10]([Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[O:1][CH2:23][CH2:22][C@@H:21]([CH3:25])[CH2:20][Br:19])([CH3:12])[CH3:11]
Reactant: C[C@@H](CBr)CCO
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)[Si](OCC[C@@H](C)CBr)(C(C)C)C(C)C
Temperature: 0 °C

Procedure:
15.4 ml of triisopropylsilyl triflate are added to a solution of 8.7 g of (R)-4-bromo-3-methylbutan-1-ol in 320 ml of methylene chloride at 0° C., and 6.6 ml of 2,6-lutidine are then added in the course of 30 min. The reaction mixture is subsequently poured onto 100 ml of ice-water and the aqueous phase is acidified by addition of 2N hydrochloric acid (pH 3). It is extracted with methylene chloride and the organic phase is washed with a 5% sodium bicarbonate solution and saturated sodium chloride solution and dried over sodium sulfate. After purification of the crude product by FC over 200 g of silica gel (mobile phase J), the title compound is obtained: Rf (J)=0.48.
Reaction SMILES: F[C:2]1C=C(C2C(=C=O)C(OC)C(=O)NN=2)C=CC=1C.[C:20]([C:23]1[C:24](=[O:35])[NH:25][N:26]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:28]=1)([OH:22])=[O:21]>>[CH3:2][O:21][C:20]([C:23]1[C:24](=[O:35])[NH:25][N:26]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:28]=1)=[O:22]
Reactant: COC1C(=O)NN=C(c2ccc(C)c(F)c2)C1=C=O
Reactant: O=C(O)c1cc(-c2ccccc2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccccc2)n[nH]c1=O
Yield: 98.9 %

Procedure:
Following the procedure of Example 1 (5), 4-carboxy-6-phenyl-2H-pyridazin-3-one was reacted to yield the title compound as pale yellow crystals (yield: 98.9%).
Reaction SMILES: [CH2:1]1[S:6](=[O:8])(=[O:7])[O:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[NH:9]([CH2:4][CH2:3][CH2:2][CH2:1][S:6]([OH:5])(=[O:8])=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: O=S1(=O)CCCCO1
Solvent: CCO
Product: O=S(=O)(O)CCCCNc1ccccc1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of butanesultone (27.2 g, 0.2 mol) and aniline (46.5 g, 0.5 mol) in ethanol is heated under reflux for 4 hr. and cooled to room temperature to precipitate a white solid. The precipitates are filtered and recrystallized in ethanol to obtain 4-anilino-1-butanesulfonic acid (42.2 g, 90%) as white crystals. 4-Anilino-1-butanesulfonic acid (10 g) is dissolved in water and neutralized by sodium hydroxide. The neutral solution is concentrated under reduced pressure to give white solids. The solids are crystallized in methanol-chloroform to obtain 4-anilino-1-butanesulfonic acid sodium salt (10.0 g, 92%) as white crystals.
Reaction SMILES: C[O-].[Na+].O1CCCC1.[F:9][C:10]1[CH:15]=[C:14]([I:16])[CH:13]=[CH:12][C:11]=1[N:17]1[C:22]2[N:23]([CH3:40])[C:24](=[O:39])[C:25]([CH3:38])=[C:26]([NH:27][C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][CH:33]=3)[C:21]=2[C:20](=[O:41])[N:19]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[C:18]1=[O:51]>CO>[F:9][C:10]1[CH:15]=[C:14]([I:16])[CH:13]=[CH:12][C:11]=1[NH:17][C:22]1[N:23]([CH3:40])[C:24](=[O:39])[C:25]([CH3:38])=[C:26]2[C:21]=1[C:20](=[O:41])[N:19]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)[C:18](=[O:51])[N:27]2[C:28]1[CH:29]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccc(Cn2c(=O)c3c(Nc4cccc(NC(C)=O)c4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c3n(-c3cccc(NC(C)=O)c3)c2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.4 %

Procedure:
To a solution (305 mg) of 28% sodium methoxide in methanol were added tetrahydrofuran (4.00 ml) and N-{3-[1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-ylamino]-phenyl}-acetamide 87 (1.00 g). The wall was washed with tetrahydrofuran (4.00 ml). The mixture was stirred at room temperature for 1.5 hrs., 2N hydrochloric acid (900 μl) was added, and the mixture was concentrated under reduced pressure. To the residue was added isopropyl alcohol, methanol and water, and after refluxing, the mixture was allowed to cool to room temperature with stirring. The precipitated crystals were collected by filtration, washed with methanol, and dried to give N-{3-[5-(2-fluoro-4-iodophenylamino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide 88 (974 mg, yield 97.2%) as colorless crystals.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>C(O)(C)C.C(O)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:20][N:22]4[CH2:23][CH2:24][C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:21]4)[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CC(C)O
Product: OC(CN1CCC(c2noc3cc(F)ccc23)CC1)CN1CCc2ccccc2C1

Procedure:
A mixture of N-[3-(2,3-epoxy)propyl]-4-(6-fluoro-1,2-benzisoxaz-3-yl)piperidine (3.56 g, 12.9 mmol) and 1,2,3,4-tetrahydroisoquinoline (2.06 g, 15.4 mmol) in isopropyl alcohol (150 ml) was heated at reflux for 4 hours. At the end of the reaction, the solvent was removed. The residual oil was purified by flash chromatography over a silica gel column (SiO2, 45 g, eluted with 1% CH2OH: 99% methylene chloride). The product thus purified as a light oil, weighed 4.15 g. The oil was treated with a solution of fumaric acid (1.98 gin, 17 mmol) in ethanol. The white crystals so obtained were recrystallized in a large volume of hot ethanol (~150 ml). The recrystallized crystals weighed 2.75 g, m.p. 179°-181 ° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+]>C1COCC1.CCOC(C)=O>[O:9]=[C:8]1[NH:4][CH2:3][CH2:2][CH2:7][N:1]1[C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N2CCCNC2=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 168.7 %

Procedure:
(R)-tert-Butyl 3-aminopiperidine-1-carboxylate (1.28 g, 6.4 mmol) was dissolved in 15 mL dry THF. To it was added 3-chloropropyl isocyante (660 μL, 6.4 mmol), and the mixture was stirred at RT for 3 hours. To it was added NaH (60% in mineral oil, 310 mg, 7.68 mmol) and the mixture was stirred for overnight. Another batch of NaH (310 mg, 7.68 mmol) was then added to drive the cyclization to completion, The mixture was diluted with 200 mL EtOAc, washed with water, dried, concentrated and subjected to silica flash column using 0 to 5% MeOh in DCM to isolate (R)-tert-butyl 3-(2-oxotetrahydropyrimidin-1(2H)-yl)piperidine-1-carboxylate (408) (1.53 g, 84%) as a white solid. It was dissolved in 50 mL dry THF. To the solution was added NaH (440 mg, 10.80 mmol), and the mixture was stirred for 15 min at RT. Then iodomethane (680 μL, 10.80 mmol) was added, and it was stirred at RT for overnight. It was diluted with 200 mL EtOAc and 30 mL water. The organic phase was separated, washed with water, dried, concentrated and subjected to silica flash column with 0 to 4% MeOH in DCM to isolate (R)-tert-butyl 3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidine-1-carboxylate (409) (1.52 g, 95%) as a white solid. It was treated with 20 mL commercial 4N HCl in dioxane at RT for 30 min to yield (R)-1-methyl-3-(piperidin-3-yl)tetrahydropyrimidin-2(1H)-one hydrochloride (410) (1.27 g) as a white solid after evaporation in vacuo to dryness.
Reaction SMILES: [C:1]([C:4]1[N:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[F:22])=[CH:11][C:10]([C:23]1[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH:24]=1)=[C:9]([O:36][CH3:37])[CH:8]=2)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>C(Cl)Cl>[F:22][C:16]1[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=1[NH:14][C:13]1[C:12]2[C:7](=[CH:8][C:9]([O:36][CH3:37])=[C:10]([C:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH:24]=3)[CH:11]=2)[N:6]=[N:5][C:4]=1[C:1]([NH2:2])=[O:3]
Reactant: COc1cc2nnc(C(N)=O)c(Nc3ccc(C)cc3F)c2cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2nnc(C(N)=O)c(Nc3ccc(C)cc3F)c2cc1C1=CCNCC1
Yield: 79.6 %

Procedure:
A solution of tert-butyl 4-(3-carbamoyl-4-(2-fluoro-4-methylphenylamino)-7-methoxycinnolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Example 53, 1.5 g, 2.96 mmol) in CH2Cl2 (11.84 mL) and trifluoroacetic acid (11.84 mL, 153.68 mmol) was stirred for 16 hours, concentrated under reduced pressure, and the residue purified with silica chromatography CH2Cl2/5% MeOH (1% NH4OH) to give 960 mg (80%) product. m/z 408.