Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=4)=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]2[C@H:26]3[CH2:31][CH2:30][CH2:29][C@H:27]3[N:28]=[C:3]12.[Cl:32]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[Cl:32][C:11]1[N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[N:20]=3)=[CH:15][CH:14]=2)[CH:9]=[C:6]2[C:5]=1[N:4]1[C@H:26]3[CH2:31][CH2:30][CH2:29][C@H:27]3[N:28]=[C:3]1[N:2]([CH3:1])[C:7]2=[O:8]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1C(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)cc2N2C1=N[C@@H]1CCC[C@@H]12
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: CN1C(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)c(Cl)c2N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 0 °C
Yield: 44.7 %

Procedure:
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-2-(4-(6-fluoropyridin-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one (38 mg, 0.082 mmol) is dissolved in a mixture of CCl4 and DMF (8/1, v/v). The solution is cooled to 0° C., and then a solution of N-chlorosuccinimide (10.9 mg, 0.082 mmol) in CCl4 and DMF (8/1, v/v) is added dropwise. The reaction mixture is stirred at room temperature for half an hour. Solvents are removed under vacuum, and the residue is purified by a semi-preparative HPLC to give pure product as off white solids (16.5 mg, yield 45%). MS (ESI) m/z 450.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[S:17][C:10]=12.[C:29]1([CH2:35][C:36]([N:38]=[C:39]=[S:40])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:39]([NH:38][C:36](=[O:37])[CH2:35][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[S:40])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:22][CH:23]=3)[S:17][C:10]=12
Reactant: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
To a solution of 49 (46.7 mg, 0.1 mmol) in dry THF (5 mL), 2-phenylacetyl isothiocyanate (40 mg, 0.2 mmol) was added and the reaction was allowed to stir for 30 minutes. The THF was removed under reduced pressure and the resultant product was purified by column chromatography on silica gel, eluent hexane/EtOAc (1:1), to afford the title compound 50 (35.4 mg, 53% yield). 1HNMR (DMSO) δ (ppm): 12.49 (s, 1H),1 1.85 (s, 1H), 8.57 (d, J=5.5 Hz, 1H), 8.30 (s, 1H), 8.17 (d, J=8.4Hz, 2H), 8.02 (d, J=8.4 Hz, 2H), 7.63-7.52 (m, 5H), 7.34 (d, J=4.1 Hz, 2H), 6.71 (d, J=5.3 Hz, 1H), 3.82 (brs, 2H), 3.27 9s, 3H) MS (m/z) 592.0 (M+).
Reaction SMILES: [CH2:1]([C:3]1[C:12]([OH:13])=[CH:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:13][C:12]1[C:3]([CH2:1][CH3:2])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CCc1nc2ncccc2cc1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: CCc1nc2ncccc2cc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 140 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
2-Ethyl-[1,8]naphthyridin-3-ol (30 mg), 4-chloro-6,7-dimethoxyquinoline (115 mg), and 4-dimethylaminopyridine (63 mg) were suspended in o-dichlorobenzene (2 ml), and the suspension was stirred at 140° C. for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (35 mg, yield 57%).
Reaction SMILES: [OH:1][C@H:2]([CH2:45][O:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][C:35](=[O:38])[N:34]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:33]=3[CH:44]=2)=[CH:7][CH:6]=1.[H-].[Na+].[CH3:55]I>O1CCCC1>[CH3:55][O:1][C@H:2]([CH2:45][O:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][C:35](=[O:38])[N:34]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:33]=3[CH:44]=2)=[CH:7][CH:6]=1
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC[C@H](O)COc4ccccc4)cc3)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC[C@@H](COc4ccccc4)OC)cc3)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The solution of 0.330 g of benzyl 4-[4-(2(R)-hydroxy-3-phenoxypropoxy)phenyl]-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate in 3.0 ml of tetrahydrofuran is cooled to 0° C. and admixed with stirring with 0.018 g of NaH dispersion (60%). The mixture is stirred at room temperature over 1.5 hours and subsequently admixed with 0.056 ml of methyl iodide. The reaction mixture is stirred for a further 2 hours, poured onto water (40 ml) and extracted with ethyl acetate (2×40 ml). The organic phases are washed with brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.33 (1:1 EtOAc-heptane); Rt=5.54.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([C:32]5[CH:37]=[CH:36][C:35]([C:38]6[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=6)=[CH:34][CH:33]=5)[CH2:28][CH2:27]4)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>O1CCCC1.[Pd]>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C@H:26]4[CH2:27][CH2:28][C@H:29]([C:32]5[CH:33]=[CH:34][C:35]([C:38]6[CH:39]=[CH:40][C:41]([C:44]#[N:45])=[CH:42][CH:43]=6)=[CH:36][CH:37]=5)[CH2:30][CH2:31]4)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C=C[C@H]4CC[C@H](c5ccc(-c6ccc(C#N)cc6)cc5)CC4)cc3)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(CC[C@H]4CC[C@H](c5ccc(-c6ccc(C#N)cc6)cc5)CC4)cc3)cc2)CC1

Procedure:
A solution of 0.214 g of 4'-[trans-4-[2-(4'-(trans-4-pentylcyclohexyl)-4-biphenylyl)vinyl]cyclohexyl]-4-biphenylcarbonitrile in 200 ml of tetrahydrofuran was treated with 52.5 mg of palladium/carbon (5%) and hydrogenated at room temperature until the hydrogen uptake came to a stand-still (1.75 hours). The reaction mixture was subsequently gassed with nitrogen and suction filtered (rinsing with hot tetrahydrofuran). After concentrating the filtrate in vacuo and drying at 50° C. under a water-jet vacuum there was obtained 0.310 g of colourless, solid 4'-[trans-4-[2-(4'-(trans-4-pentylcyclohexyl)-4-biphenylyl)ethyl]cyclohexyl]-4-biphenylcarbonitrile which still contained solvent. Recrystallization from tetrahydrofuran gave colourless needles with (S-N) 194.5° C. and cl.p. (N-I) 440° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH2:16]1N2CN3CN(C2)CN1C3.C(OC(=O)C)(=O)C.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:8](=[O:15])[CH:9]([CH2:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:16]2
Reactant: CC(C)(C)CCC(=O)c1ccccc1Cl
Reactant: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(C)(C)CC1Cc2cccc(Cl)c2C1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
101.8 g (453 mmole) 1-(2-Chloro-phenyl)-4,4-dimethyl-pentan-1-one, 133.4 g (2.1 eq.) urotropine and 124.7 g (2.7 eq.) of acetic anhydride were placed in a 1000 ml roundbottom flask and the mixture was stirred at 80° C. for 4 h. Then 200 ml water and 200 ml 2M NaOH were added and the mixture was extracted two times with 250 ml dichloromethane each. The organic layer was washed two times with 150 ml saturated aqueous ammonium chloride and dried over magnesium sulphate. The solvent amount was reduced in vacuo to a total of 250 ml volume and the solution was added dropwise over a period of 2.5 h to 1000 g of hot (70-75° C.) concentrated sulphuric acid. After stirring for an additional 30 min at 75° C. the mixture was allowed to stand overnight at room temperature. The mixture was given to approx. 800 g of ice and extracted three times with 250 ml dichloromethane each. The organic layer was washed twice with 250 ml of a saturated sodium bicarbonate solution and once with 200 ml of a saturated sodium chloride solution. After drying over magnesium sulphate the solvent was removed in vacuo. The product was purified by column chromatography on silica (heptane/dichloromethane 1:1) to yield 79.4 g (74%) of the desired product as a slightly off-white oil, which slowly crystallized. 1H-NMR (400 MHz, CDCl3): δ=7.44 (t, 1H, aromatic), 7.30 (d, 1H, aromatic), 7.27 (d, 1H, aromatic), 3.38 (dd, 1H, COCH), 2.79, 2.60 (2×m, 2H, benzylic), 2.10, 1.21 (2×m, 1H, CH2-t-Bu), 0.90 (s, 9H, t-Bu) ppm.
Reaction SMILES: [CH:1]12[CH2:7][C:4]([NH:8][C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][N:13]=[CH:12]4)([CH2:5][CH2:6]1)[CH2:3][NH:2]2.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:2]2[CH2:3][C:4]3([NH:8][C:9]4[CH:10]=[C:11]5[C:15](=[CH:16][CH:17]=4)[NH:14][N:13]=[CH:12]5)[CH2:7][CH:1]2[CH2:6][CH2:5]3)=[CH:21][CH:20]=1
Reactant: c1cc2[nH]ncc2cc1NC12CCC(C1)NC2
Reactant: Cc1ccc(C=O)cc1
Product: Cc1ccc(CN2CC3(Nc4ccc5[nH]ncc5c4)CCC2C3)cc1

Procedure:
Reaction of Intermediate 25 with 4-methylbenzaldehyde affords the title compound.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=3[F:37])=[O:25])=[CH:19][CH:18]=2)=[C:11]([C:14]([NH2:16])=[O:15])[NH:12][CH:13]=1)=O)(C)(C)C.[ClH:38]>O1CCOCC1.CCCCC>[ClH:38].[NH2:8][C:9]1[C:10]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:30]=[CH:29][C:28]=3[F:37])=[O:25])=[CH:19][CH:18]=2)=[C:11]([C:14]([NH2:16])=[O:15])[NH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1c[nH]c(C(N)=O)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCC
Product: NC(=O)c1[nH]cc(N)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
To 0.15 g (0.288 mmol) of 4-tert-butyloxycarbonylamino-3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrole-2-carboxamide suspended in 1 cm3 of dioxane is added, at a temperature in the region of 20° C., 0.72 cm3 of a 4N solution of hydrogen chloride in dioxane. After stirring for 5 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue, which is purified by flash chromatography [eluent: dichloromethane/methanol/acetonitrile (gradient of from 90/5/5 to 80/10/10 by volume)]. After concentrating the fractions under reduced pressure, 85 mg of a yellow solid are obtained, and are then stirred in 4 cm3 of pentane for 16 hours. After filtering through a No 3 sinter funnel, the solid is washed with twice 1 cm3 of pentane and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. for 4 hours to give 47 mg of 4-amino-3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrole-2-carboxamide hydrochloride in the form of a yellow solid melting at about 174° C.; 1H NMR (400 MHz, DMSO d6, δ in ppm) from 5.30 to 8.00 (very broad m, 2H); 6.34 (d, J=2.5 Hz, 1H); 7.27 (d, J=8.5 Hz, 2H); 7.39 (m, 1H); 7.50 (partially masked m, 1H); 7.53 (d, J=8.5 Hz, 2H); 8.63 (broad d, J=7.0 Hz, 1H); 8.96 (broad s, 1H); 9.29 (s, 1H); 10.7 (broad s, 1H):; ES+: m/z=422: [M+H]+; ES−: m/z=420: [M−H]−.
Reaction SMILES: [Cl:1][C:2]1([C:11]([OH:13])=O)[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[CH:5]=[CH:4][NH:3]1.C(N(CC)CC)C.N1C(F)=NC(F)=NC=1[F:23]>ClCCl>[Cl:1][C:2]1([C:11]([F:23])=[O:13])[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[CH:5]=[CH:4][NH:3]1
Reactant: Fc1nc(F)nc(F)n1
Reactant: CCNC1=NC(Cl)(C(=O)O)NC=C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC1=NC(Cl)(C(=O)F)NC=C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution containing 7.0 g (34.72 mmol) of acid prepared in step 2.4 and 5.32 mL (38.19 mmol) of triethylamine in 98 mL of dichloromethane are added 5.89 mL (69.79 mmol) of cyanuric fluoride. The mixture is stirred for 3 hours and the solution is diluted with 590 mL of CH2Cl2 and 190 mL of ice-cold aqueous NaHCO3. The organic phase is washed twice with 190 mL of ice-cold aqueous NaHCO3 and dried over MgSO4. The solvent is then evaporated off under reduced pressure. 7.0 g of expected product are obtained in the form of a red oil that solidifies slowly, and that is used as obtained in the following step. Quantitative yield.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[C:5]([I:13])=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl[CH2:24][C:25]1[C:26]2[C:31]([CH:32]=[C:33]3[C:38]=1[CH:37]=[CH:36][CH:35]=[CH:34]3)=[CH:30][CH:29]=[CH:28][CH:27]=2.C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.CN(C=O)C>[CH:27]1[C:26]2[C:31](=[CH:32][C:33]3[C:38]([C:25]=2[CH2:24][O:1][C:2]2[C:3]4[O:16][N:15]=[C:14]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[C:4]=4[C:5]([I:13])=[N:6][C:7]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:30]=[CH:29][CH:28]=1
Reactant: ClCc1c2ccccc2cc2ccccc12
Reactant: CCOC(=O)c1nc(I)c2c(-c3ccccc3)noc2c1O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(I)c2c(-c3ccccc3)noc2c1OCc1c2ccccc2cc2ccccc12
Temperature: 55 °C
Reaction time: 3 h
Yield: 45.6 %

Procedure:
Ethyl 7-hydroxy-4-iodo-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (300 mg, 0.73 mmol), 9-chloromethylanthracene (249 mg, 1.10 mmol), 18-crown-6 (29 mg, 0.11 mmol) and K2CO3 (152 mg, 1.10 mmol) were added to DMF, and the mixture was stirred at 55° C. for 3 h. EtOAc (50 mL) was added and the organic layer was washed with brine and dried over MgSO4. Solvent was removed in vacuo and the crude product was purified twice by flash chromatography (0-30% EtOAc/hexanes) to give 200 mg of the title compound. 1H NMR (CDCl3, 200 MHz): δ=8.65-8.80 (m, 2H), 8.18 (s, 1H), 7.70-7.80 (m, 2H), 7.40-7.55 (m, 3H), 7.18-7.30 (m, 6H), 6.30 (s, 2H), 3.95 (q, 2H, J=7.0 Hz), 0.72 (t, 3H, J=7.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:46]=[C:45]4[C:41]([C:42]([CH3:47])=[N:43][NH:44]4)=[CH:40][CH:39]=3)=[CH:34][CH:33]=2)[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][NH:14][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:46]=[C:45]4[C:41]([C:42]([CH3:47])=[N:43][NH:44]4)=[CH:40][CH:39]=3)=[CH:34][CH:33]=2)[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(COc4ccc(-c5ccc6c(C)n[nH]c6c5)cc4)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(COc4ccc(-c5ccc6c(C)n[nH]c6c5)cc4)nc(N)n3)CC2)CN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((4-(3-methyl-1H-indazol-6-yl)phenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (150 mg, 0.19 mmol) in CH2Cl2 (5 mL) was added TFA (3 mL), and the resulting mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo, and the resulting material partitioned between CH2Cl2 and saturated NaHCO3, and extracted. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by prep-TLC (CH2Cl2/MeOH) provided (S)-ethyl 8-(2-amino-6-((4-(3-methyl-1H-indazol-6-yl)phenoxy)methyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a brown solid.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[N:9][C:8]([O:11][CH2:12][C@H:13]2[C@H:18]([OH:19])[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1)[CH2:2][CH2:3][CH3:4].C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([C:5]1[N:10]=[N:9][C:8]([O:11][CH2:12][C@H:13]2[C@H:18]([OH:19])[CH2:17][CH2:16][N:15]([CH3:35])[CH2:14]2)=[CH:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(OC[C@@H]2CNCC[C@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nnc(OC[C@@H]2CN(C)CC[C@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (±)-trans-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-piperidin-4-ol (0.117 mmol, 0.06 g) in DCM (1 mL) was added formaldehyde solution (1 mL) followed by sodium triacetoxyborohydride (0.3 g) and continued stirring the reaction mixture for 3 h at room temperature. The reaction mixture was diluted with DCM (10 mL), washed the organic layer with water, dried the organic layer, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography by eluting with DCM (200 mL) followed 10% methanolic solution of ammonia (2 M solution of NH3 in methanol) in DCM to provide (±)-trans-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-1-methyl-piperidin-4-ol which was treated with 4 N HCl in dioxane. The volatiles were removed under reduced pressure, and the salt was washed with anhydrous ether and dried under high vacuum to provide the title compound (0.058 g). LCMS: m/z 455 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.81 (1H, s), 7.47 (2H, d), 7.13 (2H, d), 4.6-4.76 (2H, m), 4.42-4.48 (1H, m), 3.52-3.85 (3H, m), 3.12-3.22 (4H, m), 2.92 (3H, s), 2.21-2.36 (2H, m), 1.84-2.04 (4H, m), 1.23-1.64 (11H, m), 0.82 (3H, t).
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[C:5]2[N:6]=[C:7]([CH3:31])[C:8]([C@H:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])=[C:9]([C:10]3[C:11]([CH3:21])=[C:12]4[C:17](=[C:18]([F:20])[CH:19]=3)[O:16][CH2:15][CH2:14][CH2:13]4)[N:4]2[N:3]=1.[N:33]([C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)=[C:34]=[O:35].CCN(C(C)C)C(C)C>C1COCC1>[C:27]([O:26][C@@H:22]([C:8]1[C:7]([CH3:31])=[N:6][C:5]2[N:4]([N:3]=[C:2]([NH:1][C:34]([NH:33][C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)=[O:35])[CH:32]=2)[C:9]=1[C:10]1[C:11]([CH3:21])=[C:12]2[C:17](=[C:18]([F:20])[CH:19]=1)[O:16][CH2:15][CH2:14][CH2:13]2)[C:23]([OH:25])=[O:24])([CH3:28])([CH3:29])[CH3:30]
Reactant: Cc1nc2cc(N)nn2c(-c2cc(F)c3c(c2C)CCCO3)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(N=C=O)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)Nc2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(-c4cc(F)c5c(c4C)CCCO5)n3n2)cc1

Procedure:
A mixture of Example 1 (22 mg, 0.050 mmol), 1-isocyanato-4-methylbenzene (7.28 mg, 0.055 mmol), Hunig's base (0.026 mL, 0.149 mmol) in THF (2 mL) was stirred at rt for 16 h. It was then concentrated and purified by prep HPLC (TFA/MeOH). The fractions were combined and adjusted pH=6 using 1N NaOH. The residue was adjusted pH=3-4 by adding 1-2 drops of 1N HCl. It was then extracted with EtOAc, dried, filtered and concentrated to obtained Example (18 mg, 60%) as light yellow solid. LCMS (M+H)=576.31.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:37])=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O.Cl.[CH3:39][NH:40][CH3:41].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[C:3]([CH3:37])=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:20])[CH3:21])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][N:40]([CH3:41])[CH3:39]
Reactant: CNC
Reactant: Cc1c(F)c(NCCCOS(C)(=O)=O)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(F)c(NCCCN(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Temperature: 50 °C
Reaction time: 24 h
Yield: 71.3 %

Procedure:
1.02 g (1.89 mmol) of the above 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-methanesulfonyloxypropylamino)-7-methyl-4H-1-benzopyran-4-one was dissolved in 30 mL of dimethylformamide, 1.54 g (18.9 mmol) of dimethylamine hydrochloride and 2.60 g (18.9 mmol) of potassium carbonate were added and the mixture was stirred at 50° C. for 24 hours. Water was added to the reaction solution and the mixture was extracted once with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol:=100:1-9:1) to give 660 mg of 6,8-difluoro-5-(3-dimethylaminopropylamino)-2-(3-fluoro-4-pivaloylaminophenyl)-7-methyl-4H-1-benzopyran-4-one (yield: 71%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27](Cl)[C:26]=1[N+:32]([O-:34])=[O:33].[CH3:36][N:37]([CH3:43])[CH2:38][CH2:39][CH2:40][NH:41][CH3:42]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:41]([CH2:40][CH2:39][CH2:38][N:37]([CH3:43])[CH3:36])[CH3:42])[C:26]=1[N+:32]([O-:34])=[O:33]
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cccc(Cl)c1[N+](=O)[O-]
Reactant: CNCCCN(C)C
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cccc(N(C)CCCN(C)C)c1[N+](=O)[O-]

Procedure:
In an analogous procedure to that described in the fifth paragraph of the portion of Note a) which is concerned with the preparation of starting materials, N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-3-chloro-2-nitrobenzamide was reacted with N-(3-dimethylaminopropyl)-N-methylamine to give N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-3-[N-(3-dimethylaminopropyl)-N-methylamino]-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 1.44-1.58 (m, 2H), 2.06 (s, 6H), 2.15 (t, 2H), 2.21 (s, 3H), 2.69 (s, 3H), 3.02 (t, 2H), 3.48-3.53 (m, 4H) 3.69-3.73 (m, 4H), 7.1 (d, 1H), 7.19-7.25 (m, 2H), 7.44-7.62 (m, 3H), 7.74-7.64 (m, 1H), 7.94 (d, 1H), 8.26 (d, 1H), 10.13 (s, 1H), 10.32 (s, 1H); Mass Spectrum: M+H+ 576.