Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]([NH:15][C@@H:16]([CH2:20][NH:21][C:22]([C:24]3[S:25][C:26]([CH2:29][CH2:30][C:31](=[O:39])[NH:32][C:33]4[NH:34][CH2:35][CH2:36][CH2:37][N:38]=4)=[CH:27][CH:28]=3)=[O:23])[C:17]([OH:19])=[O:18])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(Cl)(Cl)=O>C(O)C(C)C>[CH2:2]([O:18][C:17](=[O:19])[C@@H:16]([NH:15][C:13]([O:12][CH2:11][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:14])[CH2:20][NH:21][C:22]([C:24]1[S:25][C:26]([CH2:29][CH2:30][C:31](=[O:39])[NH:32][C:33]2[NH:34][CH2:35][CH2:36][CH2:37][N:38]=2)=[CH:27][CH:28]=1)=[O:23])[CH:1]([CH3:10])[CH3:8]
Reactant: O=C(CCc1ccc(C(=O)NC[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)O)s1)NC1=NCCCN1
Solvent: O=S(Cl)Cl
Solvent: CC(C)CO
Product: CC(C)COC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)s1)NC(=O)OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 139.2 %

Procedure:
0.38 g (0.7 mmol) of (2S)-2-(1-adamantylmethoxycarbonylamino)-3-((5-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-thiophene-2-carbonyl)-amino)-propionic acid (example 15) were dissolved in 7 ml of isobutanol. Under an inert gas atmosphere and under external ice cooling 0.19 ml of thionyl chloride were cautiously added. After stirring for 8 hours at room temperature the reaction was complete. The solvents were removed in vacuo to give a colourless foam which was purified by chromatography (silica gel; isopropanol/ethyl acetate/water (4/3/1; v/v/v)). The fractions containing the title compound were lyosphilized to give 0.30 g of a colourless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8](OCC)=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6](=[O:18])(=[O:17])[N:5]=1)[CH3:2].C[Si](C)(C)[NH:21][Si](C)(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:8]([NH2:21])=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6](=[O:18])(=[O:17])[N:5]=1)[CH3:2]
Reactant: CCOC(=O)C1=C(OCC)C(OCC)=NS1(=O)=O
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: ClCCl
Product: CCOC(=O)C1=C(N)C(OCC)=NS1(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere a solution of 1.41 g (5.3 mmol) of the Example 3 compound in 15 ml of methylene chloride is stirred in an ice bath while a solution of 1.2 g (7.9 mmol) hexamethyldisilazane in 10 ml methylene chloride is added dropwise. The solution is allowed to warm to room temperature at which temperature stirring is continued for 18 hours. The solution is then evaporated in vacuo to an oil which is redissolved in 20 ml of a mixture of methylene chloride (15)-ethanol (5). After stirring at room temperature for one hour, the solution is again concentrated in vacuo, leaving a solid, 1.1 g (85%), mp 163°-165°. Recrystallization from ethyl acetate provides analytically pure title compound, mp 172.5°-173°.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:29][C:30]1[N:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[OH:28][CH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:33]3[CH:32]=[N:31][C:30]([CH3:29])=[N:35][CH:34]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Product: Cc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@H](CO)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 75 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine to afford an off-white solid. UPLC-MS (condition 1) tR=2.37 min, m/z=474.1 [M+H]+, m/z=472.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.65 (m, 1H) 1.79-1.90 (m, 1H) 2.17-2.30 (m, 1H) 2.68 (s, 3H) 2.99 (dd, J=10.76, 6.85 Hz, 1H) 3.11-3.23 (m, 2H) 3.22-3.30 (m, 3H) 4.61 (br. s, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.04 (d, J=2.45 Hz, 1H) 8.76 (s, 2H) 8.77 (d, J=2.44 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [CH3:1][C:2]12[CH2:26][CH:6]([N:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:13][CH:12]=3)=[O:10])[CH2:8]1)[CH2:5][C:4]([CH3:28])([CH3:27])[CH2:3]2.[H-].[Na+].[CH3:31]I>C1COCC1>[CH3:31][N:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]([N:7]2[CH2:8][C:2]3([CH3:1])[CH2:26][CH:6]2[CH2:5][C:4]([CH3:28])([CH3:27])[CH2:3]3)=[O:10])=[CH:12][CH:13]=1)[C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)c3ccccc3)cc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)c1ccccc1)c1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
To a solution of N-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-benzamide (500 mg, 1.33 mmol) in dry THF (40 ml) was added sodium hydride (64 mg, 1.594 mmol in 60% mineral oil) and the mixture was stirred for 30 min. Methyl iodide (99 μl, 1.594 mmol) was added and the stirring was continued for an additional 2 hrs. The volatiles were evaporated in vacuo and the residue was purified by column chromatography (silica gel) using EtOAc-Heptane (1:1) as eluent. Pure fractions were collected and evaporated to dryness affording 300 mg (58%) of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][O:11][C:10]2=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[BrH:15]>CC(O)=O>[Br:15][CH2:12][CH2:13][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[C:10]([OH:11])=[O:14]
Reactant: Br
Reactant: O=C1OCCC1c1ccc(Cl)c(Cl)c1
Solvent: CC(=O)O
Product: O=C(O)C(CCBr)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Treat the product of Step 1 (21.25 g, 91.96 mmoles) at room temperature with 130 ml. of HOAc saturated with HBr gas. Stir at room temperature for 2 days, then pour into 800 ml. of ice-water with stirring. Store the resultant gum in a freezer for two days, then decant the liquid from the solidified gum. Triturate the solid, filter, wash with water and air dry. Yield: 26.2 g (m.p.=80°-81° C.).
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)(O)[CH3:13])[C:8]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>S(Cl)(Cl)=O.O>[F:1][C:2]1[C:10]2[N:9](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)\[CH3:13])[C:8]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCc2c(c3cccc(F)c3n2CC(C)(O)c2ccncc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=S(Cl)Cl
Product: C/C(=C\n1c2c(c3cccc(F)c31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(6-Fluoro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propan-2-ol (510 mg, 1.5 mmol) was dissolved in thionylchloride (5 mL) and stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in N-methyl-2-pyrrolidone (3 mL) and stirred for 5 min. at RT. Powdered KOH (616 mg, 10 mmol) was added, and the stirring was continued for additional 10 min. The reaction mixture was heated at 100° C. for 2 h. The progress of reaction was monitored by TLC and NMR. The reaction mixture was diluted with water and extracted with EtOAc, washed with water, concentrated to obtain the crude product which was purified by HPLC. 1H NMR (DMSO-d6, TFA salt) δ (ppm): 8.80 (d, 2H), 8.0 (d, 2H), 7.70 (s, 1H), 7.40 (d, 1H), 7.30 (m, 1H), 7.10 (m, 1H), 4.80 (m, 1H), 4.30 (m, 1H), 3.80 (m, 2H), 3.10 (m, 2H), 3.0 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:35])[C:26]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14][N:10]2[C:11](=[O:13])[N:12]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:35])[C:26]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[NH:16][CH2:15][CH2:14][N:10]2[C:11](=[O:13])[N:12]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1cc(F)c(Oc3ccc(F)cc3)c(F)c1)nc2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1nc(OCc2cc(F)c(Oc3ccc(F)cc3)c(F)c2)cc2n1CCN2

Procedure:
Prepared in a manner similar to that described for E60 using tert-butyl 7-((3,5-difluoro-4-(4-fluorophenoxy)benzyl)oxy)-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carbo-xylate (150 mg, 0.306 mmol) and TFA (2 mL, 26.0 mmol) in DCM (10 mL).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:11]=[C:12]1[NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[NH:15][CH2:14][C@@H:13]1[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>C1COCC1.CCOC(C)=O>[CH3:36][O:35][C:33](=[O:34])[CH2:32][N:18]1[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[NH:15][CH2:14][C@H:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:12]1=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Reactant: COC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A 1.0 M solution of lithium bis(trimethylsilyl)amide (3.4 ml, 3.4 mmol) in THF was added dropwise to a −78° C. solution of (3S)-2-oxo-3-tert-butoxycarbonylamino-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (0.94 g, 3.38 mmol) in 20 ml of anhydrous THF and stirred for 30 min. Methyl bromoacetate (0.44 ml, 4 mmol) was added dropwise to the reaction mixture then warmed to RT. The reaction was diluted with 100 ml of EtOAc and washed with 0.3N KHSO4 (50 ml), H2O (2×50 ml), and brine. The combined organics were dried over anhydrous Na2SO4, filtered, and evaporated to afforded a gum that was purified by flash chromatography eluzing with 3:7 EtOAc/Hex. to give 0.98 g (83%) of the title compound as a white solid. 1H NMR (CDCl3) δ 7.15-7.07 (2H, m), 6.98-6.94 (1H, m), 6.88-6.84 (1H, d), 5.62-5.55 (1H, d), 4.71-4.65 (1H, d), 4.65-4.6 (1H, m), 4.33-4.27 (1H, d), 3.96-3.90 (1H, m), 3.78 (3H, s), 3.44-3.37 (1H, m), 1.4 (9H, s).
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)=[C:7]([C:9]([OH:11])=O)[N:8]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:37]([Si:41]([CH3:58])([CH3:57])[O:42][CH:43]([C:45]1[O:46][C:47]([CH2:50][N:51]2[N:55]=[C:54]([NH2:56])[CH:53]=[N:52]2)=[CH:48][N:49]=1)[CH3:44])([CH3:40])([CH3:39])[CH3:38]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[C:37]([Si:41]([CH3:58])([CH3:57])[O:42][CH:43]([C:45]1[O:46][C:47]([CH2:50][N:51]2[N:55]=[C:54]([NH:56][C:9]([C:7]3[N:8]=[C:4]([CH3:3])[O:5][C:6]=3[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=3)=[O:11])[CH:53]=[N:52]2)=[CH:48][N:49]=1)[CH3:44])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ncc(N)n2)o1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(OC(F)(F)F)c2)o1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1nc(C(=O)Nc2cnn(Cc3cnc(C(C)O[Si](C)(C)C(C)(C)C)o3)n2)c(-c2cccc(OC(F)(F)F)c2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid (44 mg, 0.16 mmol) in CH2Cl2 (1.0 mL) was treated at rt with HOBt (25 mg, 0.19 mmol), EDC (74 mg, 0.38 mmol), DMAP (5 mg, 0.04 mmol) and the resulting mixture was stirred at rt for 30 min. 2-{2-[1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl}-2H-[1,2,3]triazol-4-ylamine (50 mg, 0.16 mmol) in CH2Cl2 (0.6 mL) was then added and the resulting mixture was stirred at rt for 16 h. CH2Cl2 (20 mL) followed by water (15 mL) were added and the aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with water, brine, dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a brown oil. LC-MS-conditions 02: tR=1.25 min, [M+H]+=593.58.
Reaction SMILES: [F-].[K+].[C:3](=O)([O-])O.[K+].OO.C[Si](C)(C[CH2:19][C:20]([CH3:26])([CH3:25])[CH2:21][CH:22]([OH:24])[CH3:23])C1C=CC=CN=1.[CH3:28][OH:29]>O1CCCC1.O>[CH3:3][C:22]([OH:24])([CH2:21][C:20]([CH3:19])([CH3:25])[CH2:26][CH2:28][OH:29])[CH3:23]
Reactant: CC(O)CC(C)(C)CC[Si](C)(C)c1ccccn1
Reactant: CO
Reactant: O=C([O-])O
Agent: OO
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)CC(C)(C)CCO
Temperature: 50 °C
Reaction time: 22 h
Yield: 99 %

Procedure:
After 69 mg (1.18 mmol) of potassium fluoride and 118 mg (1.18 mmol) of potassium hydrogen carbonate were dissolved in 1 ml of methanol, to this solution were added both 2.0 g (17.7 mol) of 30% aqueous hydrogen peroxide and a solution prepared by dissolving, in 1.5 ml of tetrahydrofuran, 165 mg (590 μmol) of dimethyl(5-hydroxy-3,3-dimethylhexyl)(2-pyridyl)silane which had been prepared in the same manner as Example 17. The solution after mixing was continued to be stirred for 22 hours at an inner temperature of 50° C. After cooling to room temperature, 10 ml of water was added to the solution after the reaction, and the mixture was extracted with three portions of 20 ml of diethyl ether. The resulting organic layers were combined together, washed with 20 ml of 15% sodium thiosulfate and dried over sodium sulfate. The solvent was evaporated off under reduced pressure to give crude 2,4,4-trimethyl-2,6-hexanediol. This was purified with a silica gel column using a mixed solvent of hexane/ethyl acetate=1/1 (volume ratio) to give 94 mg of 2,4,4-trimethyl-2,6-hexanediol in the form of colorless oil (Yield: 99%; the purity: >95%).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].[Cl:36][C:37]1[N:42]=[CH:41][CH:40]=[N:39][CH:38]=1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:41]4[CH:40]=[N:39][CH:38]=[C:37]([Cl:36])[N:42]=4)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: Clc1cnccn1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(-c4cncc(Cl)n4)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to Example 120 using (1R,2R,4R)-4-(4-Bromo-2-trifluoromethyl-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 117) and 6-chloropyrazine. Light brown solid. MS (EI): 618.3 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:10]=[C:11](/[CH:15]=[CH:16]/[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1.C([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]1([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([CH:15]3[O:34][CH:16]3[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NC/C=C/c1cccc(NCC2CCCCC2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1OC1c1cccc(NCC2CCCCC2)c1
Temperature: 25 °C

Procedure:
To a solution of (E)-tert-butyl 3-(3-(cyclohexylmethylamino)phenyl)allylcarbamate in CH2Cl2 is added MCPBA (77%) followed by Na2CO3. The reaction mixture is stirred at room temperature until no starting material is seen by TLC. Aqueous NaHCO3 (10%) is added and the product is extracted with CH2Cl2 three times. Combined organic layers are washed with brine-NaHCO3, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (10% to 50% EtOAc—hexanes gradient) gives tert-butyl (3-(3-(cyclohexylmethylamino)phenyl)oxiran-2-yl)methylcarbamate which is used in the next step without further purification.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:14](=[O:16])[CH3:15])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.O>ClCCl.CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:14](=[O:16])[CH2:15][Br:1])[CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: BrBr
Reactant: CC(=O)C1(c2ccc(Cl)cc2)CCC1
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: O=C(CBr)C1(c2ccc(Cl)cc2)CCC1
Reaction time: 0.25 h

Procedure:
A solution of bromine (8 ml) in dichloromethane (40 ml) was added at 10° C. to a solution of 1-[1-(4-chlorophenyl)cyclobutyl]ethanone (27.8 g) in methanol (30 ml). The mixture was stirred for 15 minutes and poured into a mixture of ice and water. The resulting mixture was extracted with dichloromethane. The extract was washed with water, dried and evaporated to yield an oil which was distilled (145°-160° C./1mm Hg) to give 1-[1-(4-chlorophenyl)cyclobutyl]-2-bromoethanone.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:14]N1C(=O)CCC1=O.S(=O)(=O)(O)O>BrN1C(=O)CCC1=O>[Br:14][C:3]1[CH:4]=[C:5]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCS(=O)(=O)c1ccc(C)cc1
Agent: O=S(=O)(O)O
Product: CCCS(=O)(=O)c1ccc(C)c(Br)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
A finely ground mixture of 1-methyl-4-(propylsulfonyl)benzene (Intermediate 36; 24.80 g; 0.13 mol) and N-bromosuccinimide (26.8 g; 0.15 mol) was treated with conc. sulfuric acid (115 ml; 2.15 mol). The reaction mixture was stirred for 16 h then treated with a further portion of N-bromosuccinimide (1.33 g; 0.01 mol). The reaction solution was stirred 1 h then carefully poured into 800 mL of crushed ice. The aqueous solution was extracted with 400 mL of AcOEt. The layers were separated and the organic phase was washed first with ca. 300 mL of brine, then twice with a 1N solution of NaOH in water and twice with brine. The organic phase was dried on MgSO4, filtered and concentrated under reduced pressure to give the title compound (29.3 g, 85%) as a brown oil which solidified upon standing.
Reaction SMILES: [NH2:1][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[C:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].N1C=CC=CC=1.[C:22](Cl)(=[O:24])[CH3:23].Cl>O1CCCC1.O>[C:22]([NH:1][C:2]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[C:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C(C)=C(N)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C(C)=C(NC(C)=O)c1ccccc1

Procedure:
76 g of ethyl 3-amino-2-methyl-3-phenyl-2-propenoate were maintained at 15° C. in 600 ml of tetrahydrofuran and 32.3 ml of pyridine while adding 28.44 ml of acetyl chloride in 100 ml of tetrahydrofuran. The mixture was refluxed for 1 hour, then cooled and poured into a liter of water acidified to pH 1 with 2N hydrochloric acid. After extracting with ether, washing with water, with a saturated solution of sodium bicarbonate and then with water, drying and concentrating to dryness under reduced pressure, 80 g of the expected product were obtained.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]([F:21])([F:20])[CH2:18]O>>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][CH2:18][C:17]([F:21])([F:20])[F:16])(=[O:8])=[O:9]
Reactant: OCC(F)(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reaction time: 0.5 h
Yield: 73 %

Procedure:
In a 100-ml flask equipped with a stirrer, a thermometer, a nitrogen introducing pipe and a condenser, 50 ml (0.297 mol) of trifluoromethanesulfonic anhydride and 25 ml (0.342 mole) of 2,2,2-trifluoroethanol were placed at room temperature and stirred for 30 minutes in a nitrogen atmosphose, followed by reflux for 3 hours. After distillation, 50.3 g of 2,2,2-trifluoroethyl trifluoromethanesulfonate was obtained in yield of 73%.
Reaction SMILES: [N:1]1C=CC=CC=1.[Cl:7][CH2:8][CH2:9][C:10]([N:12]=[C:13]=[O:14])=[O:11].Cl.N[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23]>CN(C)C=O>[Cl:7][CH2:8][CH2:9][C:10]([N:12]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[C:13]([NH2:1])=[O:14])=[O:11]
Reactant: O=C=NC(=O)CCCl
Reactant: C=C(C)C(=O)NCCCN
Reactant: c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: C=C(C)C(=O)NCCCN(C(N)=O)C(=O)CCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine (7.9 g, 0.1 mole) was added dropwise to a mixture of β-chloropropionylisocyanate (13.3 g, 0.1 mole) and N-(3-aminopropyl)methacrylamide hydrochloride (17.8 g, 0.1 mole) in N,N-dimethylformamide (80 ml) at 0° C. The mixture was left to stir overnight at ambient temperature. This mixture was then poured onto ice, and the product filtered. Recrystallization from absolute ethanol (400 ml) gave 1-(3-chloropropionyl)-3-methacrylamidopropyl urea, mp 131°-2° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[CH:4][C:5]([Cl:23])=[C:6]([C:8]2[C:9](=[O:22])[N:10]([CH2:20][CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)[CH:7]=1.N1C=CC=CC=1.[F:31][C:32]1[CH:37]=[C:36]([N:38]=[C:39]=[O:40])[CH:35]=[C:34]([F:41])[CH:33]=1>C(Cl)Cl>[ClH:23].[Cl:23][C:5]1[C:6]([C:8]2[C:9](=[O:22])[N:10]([CH2:20][CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)=[CH:7][C:2]([NH:1][C:39]([NH:38][C:36]2[CH:35]=[C:34]([F:41])[CH:33]=[C:32]([F:31])[CH:37]=2)=[O:40])=[C:3]([F:24])[CH:4]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NC)cc21
Reactant: O=C=Nc1cc(F)cc(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(F)cc(F)c3)c(F)cc2Cl)cc2cnc(NC)cc21
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
A 0° C. solution of Example A5 (200 mg, 0.58 mmol) and pyridine (91 mg, 1.16 mmol) in DCM (4 mL) was treated drop-wise with 1,3-difluoro-5-isocyanato-benzene (98 mg, 0.64 mmol) and stirred at RT overnight as the cooling bath expired. The mixture was concentrated to dryness and purified by prep-HPLC. The resulting solution was treated with HCl (1 mL) and lyophilized to give 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3,5-difluorophenyl)urea hydrochloride (74 mg, 26% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.94 (s, 1H), 9.03 (s, 1H), 8.54 (s, 1H), 8.14 (b s, 1H), 8.13 (d, J=8.8 Hz, 1H), 7.88 (s, 1H), 7.57 (d, J=11.2 Hz, 1H), 7.16-7.12 (m, 2H), 6.78 (t, J=8.8 Hz, 1H), 6.57 (s, 1H), 4.16-4.13 (m, 2H), 2.96 (s, 3H), 1.19 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 502.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.Cl[C:29]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[O:30].O>O1CCCC1>[CH3:35][O:34][CH2:33][CH2:32][O:31][C:29](=[O:30])[NH:12][C:10]1[S:11][C:7]2[C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1
Reactant: COCCOC(=O)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOC(=O)Nc1nc2c(OC)ccc(N3CCOCC3)c2s1
Temperature: 70 °C

Procedure:
4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine (300 mg, 1.1 mmol) and N-ethyldiisopropylamine (0.56 ml, 3.4 mmol) were dissolved in tetrahydrofurane (11 ml) and 2-methoxyethyl chloroformate (0.19 ml, 1.4 mmol) were added over 5 min. Then the mixture was heated to 70° C. for 3 h. The mixture was cooled to room temperature, water added and extracted twice with ethyl acetate. The combined organic phases were dryed with Na2SO4 and evapprated to dryness. The title compound was obtained as off-white solid (52%). MS: m/e=368 (M+H+).