Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([NH2:16])[N:13]=[CH:12][N:11]=1.[CH3:17][O:18][CH2:19][C:20](O)=O.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:20]([CH2:19][O:18][CH3:17])[N:9]([C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:16])[N:15]=3)[C:3]=2[CH:4]=1
Reactant: COCC(=O)O
Reactant: Nc1ncnc(Nc2cc(Br)ccc2N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCc1nc2ccc(Br)cc2n1-c1ncnc(N)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-N-(2-amino-5-bromophenyl)-1,3,5-triazine-2,4-diamine (1.00 g, 3.56 mmol) in DMF (5 mL) was introduced methoxyacetic acid (320 mg, 3.56 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (750 mg, 3.91 mmol), 1-hydroxy-7-azabenzotriazole (533 mg, 3.91 mmol) and triethylamine (720 mg, 7.11 mmol). The reaction mixture was stirred for 18 hr at RT and concentrated in vacuo. The residue was suspended in water (100 mL) and the resulting precipitate collected by filtration. After washing the filter cake with EtOAc (10 mL) and methanol (10 mL), the crude amide was dried on the filter. The intermediate amide was dissolved in glacial acetic acid (20 mL) and warmed to 140° C. for 15 minutes (microwave heating in 4 batches of equal volume). Following concentration of the reaction mixture in vacuo, toluene (20 mL) was introduced and the suspension concentrated in vacuo (repeated twice) to furnish the crude title compound as a brown oil: LC-MS: m/z=+334.90/336.75 (M+H)+. This compound, with LC-MS purity=86% UV, was used in the next step without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1C(C)=[CH:6][S:5][C:4]=1[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10].[CH2:15]([Cl:17])[Cl:16].C(=O)(O)[O-].[Na+]>O>[ClH:16].[NH2:2][C:3]1[C:15]([Cl:17])=[CH:6][S:5][C:4]=1[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10]
Reactant: Cc1csc(C(=O)OC(C)C)c1N
Reactant: ClCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)OC(=O)c1scc(Cl)c1N
Reaction time: 8 h

Procedure:
11.75 g (50 mmol) of i-propyl 3-amino-4-methyl-thiophene-2-carboxylate hydrochloride are dissolved in 100 ml of water. 150 ml of methylene chloride are added to this solution, and sodium bicarbonate is then added a little at a time until a pH of 7 has been exceeded. The mixture is stirred for 8 hours and the organic phase is separated off, washed with water, dried with magnesium sulphate and filtered. The filtrate is concentrated using water pump vacuum and the amorphous residue is crystallized from petroleum ether.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:9].[CH3:10][O:11][S:12]([O:15]C)(=[O:14])=[O:13]>C(OCC)C>[CH3:10][O:11][S:12]([O-:15])(=[O:14])=[O:13].[CH3:10][O:9][C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N+:2]=1[CH3:1]
Reactant: CN1CCCCCC1=O
Reactant: COS(=O)(=O)OC
Solvent: CCOCC
Product: COC1=[N+](C)CCCCC1
Product: COS(=O)(=O)[O-]
Yield: 182.3 %

Procedure:
Stir 190 g of N-methylcaprolactam and 189 g of dimethylsulfate for 3 hours at 80° C. Cool the resulting reaction mixture to ambient temperature before shaking it with diethyl ether and then freeing it from solvent residue in vacuo to obtain 346 grams (g) of 2-methoxy-1-methyl-4,5,6,7-tetrahydro-3H-azepinium methylsulfate as a light yellow oil. Add this oil, drop by drop, to a solution of 110 g of dimethylamine in 600 milliliters (ml) of benzene while stirring and boil the thus-prepared admixture under reflux for 90 minutes. Collect the heavy phase and extract it several times with diethyl ether. Concentrate the produced yellowish oil in vacuo to obtain 336 g (93% of theory) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:10][CH3:11])=[CH:5][CH:4]=1.ClCCCl.[Br:26]Br.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:20][N:18]([CH3:19])[C:15]1[CH:14]=[CH:13][C:12]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:21])=[CH:8][CH:7]=2)=[C:10]([Br:26])[CH3:11])=[CH:17][CH:16]=1
Reactant: CC=C(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: Cc1ccccc1
Product: CC(Br)=C(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
Into a reactor were introduced 13.6 g (48.5 mmol) of the 1,1-bis(4-dimethylaminophenyl)propene and 54 mL of 1,2-dichloroethane under a nitrogen atmosphere. The contents were cooled to 0° C. Thereto was gradually added dropwise 7.76 g (48.5 mmol) of bromine. The resultant mixture was stirred at room temperature for 2.5 hours. Thereafter, 15.7 mL (194 mmol) of pyridine and 109 mL of toluene were added thereto and this mixture was stirred at 80° C. for 3 hours. After being cooled, the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, subsequently dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography and then crystallized from methanol to obtain 12.0 g (69%) of the target compound as green-yellow crystals.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:16]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([NH2:25])[C:19]=2[CH:18]=[N:17]1>>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:25][C:20]3[C:19]4[CH:18]=[N:17][NH:16][C:24]=4[CH:23]=[CH:22][CH:21]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[N:9]=1
Reactant: Cc1nc(N)nc(-c2cccnc2F)n1
Reactant: Nc1cccc2[nH]ncc12
Product: Cc1nc(N)nc(-c2cccnc2Nc2cccc3[nH]ncc23)n1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 22 using 4-(2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine and 1H-indazol-4-amine, and isolated as a yellow solid (13%). LCMS (API-ES) m/z 319 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 13.10 (s, 1H) 12.26 (s, 1H) 8.80 (d, J=7.82 Hz, 1H) 8.42 (d, J=4.50 Hz, 1H) 8.19 (s, 1H) 8.13 (d, J=7.43 Hz, 1H) 7.75 (br. s., 2H) 7.31 (t, J=8.02 Hz, 1H) 7.16 (d, J=8.41 Hz, 1H) 6.89-7.07 (m, 1H) 2.56 (s, 3H).
Reaction SMILES: CCN(CC)CC.[O:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=[O:18])[CH2:9]1.[CH:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)=O>CC(OC(C)=O)=O>[O:18]=[C:10]1[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:8][CH:9]1[CH2:19][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: O=C1COc2ccccc2N1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(CC2Oc3ccccc3NC2=O)cc1
Yield: 13.2 %

Procedure:
Et3N (3.18 ml, 22.8 mmol) was added to a stirring solution of 2-H-1,4-benzoxazin-3-(4H)one (2.50 g, 16.8 mmol) and methyl 4-formylbenzoate (4.59 g, 27.5 mmol) in Ac2O (20 ml). The reaction mixture was refluxed 16 h. After this mixture was cooled for 3 days, the solid was filtered and rinsed with ethyl acetate to afford the title compound 266 (657 mg, 13%) as a yellow solid. LRMS: 295.1 (Calc.); 296.0 (found).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[NH2:22]>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(N)cc1OC
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: COc1ccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)cc1OC

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 3,4-dimethoxyaniline gave N2-(3,4-dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.90 (d, 1H, J=6.6 Hz), 7.59 (bs, 1H), 7.30 (s, 1H), 7.20–7.10 (m, 2H), 7.00–6.75 (m, 4H), 6.59 (bd, 1H, J=7.8 Hz), 3.87 (s, 3H), 3.84 (s, 3H); 19F NMR (CDCl3): −47229; LCMS: ret. time: 17.77 min.; purity: 78%; MS (m/e): 357 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12](O)([CH3:14])[CH3:13])[C:4]=2[S:5][C:6]=1[CH3:7].CCN(CC)CC.CS(Cl)(=O)=O>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([CH3:14])=[CH2:13])[C:4]=2[S:5][C:6]=1[CH3:7]
Reactant: Cc1sc2c(C(C)(C)O)cccc2c1Br
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=C(C)c1cccc2c(Br)c(C)sc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39.1 %

Procedure:
A solution of 2-(3-bromo-2-methyl-benzo[b]thiophen-7-yl)-propan-2-ol (0.98 g, 3.45 mmol) in CH2Cl2 910 mL) is treated with Et3N (0.72 mL, 5.18 mmol) and MsCl (0.29 mL, 3.80 mmol) at) 0° C. The reaction is stirred at 0° C. for 10 min, and at RT overnight. It is diluted with EtOAc (50 mL), washed with 0.1 M HCl (10 m), H2O (20 mL); dried with Na2SO4, filtered and concentrated. Purification of the crude material by silica gel chromatography gives the title compound (0.36 g, 1.35 mmol, 39%). 1H NMR (CDCl3): δ) 2.23 (s, 3H), 2.56 (s, 3H), 5.40 (s, 1H), 5.49 (s, 1H), 7.28 (s, 1H), 7.41 (t, J=7.1 Hz, 1H), 7.64 (d, J=7.9 Hz, 1H) ppm.
Reaction SMILES: O=[C:2]([CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][C:5](O)=[O:6].O.[NH2:22][NH2:23].O.CCOC(C)=O>C1(C)C=CC=CC=1>[C:9]1([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:2]2[CH2:3][CH2:4][C:5](=[O:6])[NH:22][N:23]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)CCC(=O)C(c1ccccc1)c1ccccc1
Reactant: NN
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCC(C(c2ccccc2)c2ccccc2)=NN1

Procedure:
A mixture of 4-oxo-5,5-diphenylpentanoic acid (2.47 g) and hydrazine monohydrate (1.4 mL) in toluene (49 mL) was refluxed for 3.5 hours. Water and EtOAc were poured into the reaction mixture. The organic layer was separated, washed with saturated NaHCO3 aqueous solution and brine, and dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was washed with MeCN to give 6-(diphenylmethyl)-4,5-dihydropyridazin-3(2H)-one (0.85 g) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2OC(C)(C)C(C)(C)O2)[C:5](F)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[NH2:27][NH2:28].[OH-].[Na+]>C(O)(C)C.C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:9]=[N:28][NH:27][C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OC(c2cc(Cl)cnc2F)OC1(C)C
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Clc1cnc2[nH]ncc2c1
Temperature: 65 °C
Yield: 72 %

Procedure:
To a solution of 5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)pyridine, 28, (14.5 g, 55.8 mmol) and N,N-diisopropylethylamine (19.5 mL, 112.0 mmol) in isopropanol (200 mL) was added hydrazine (12.0 mL, 382.3 mmol). The mixture was heated to 65° C. overnight. LC-MS indicates desired hydrazine compound formed and the mixture was concentrated in vacuo. The crude residue was taken up in 300 mL of water and 120 mL of EtOH followed by 50 mL of 6N HCl. The resulting mixture was warmed to 45° C. overnight. Once LC-MS indicated completion of the reaction, the mixture was neutralized with 6N NaOH and the pH adjusted to 8. The mixture was concentrated in vacuo to remove volatile EtOH and extracted with EtOAc (3×). The combined organic layer was dried over Na2SO4, filtered through a plug of silica and concentrated in vacuo. Trituration with 10% aqueous acetonitrile provided the desired product (6.15 g, 72% yield, 90% purity by NMR): 1H NMR (300.0 MHz, CDCl3) δ 11.43 (s, 1H), 8.55 (d, J=2.2 Hz, 1H), 8.10 (d, J=2.2 Hz, 1H) and 8.08 (s, 1H) ppm; LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, RT=2.05 min (M+H) 153.91.
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6](C(OC(C)CC)=O)[C:7]3[C:8]([N:24]=2)=[N:9][CH:10]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]4[O:22][CH2:21][CH2:20][NH:19][CH2:18][C:17]=4[CH:23]=2)[CH:12]=3)[CH2:4][CH2:3]1.Cl[C:33]1[C:38]([CH2:39][CH:40]2[CH2:42][CH2:41]2)=[C:37]([CH3:43])[N:36]=[C:35]([CH3:44])[N:34]=1>>[CH:2]1([C:5]2[NH:6][C:7]3[C:8]([N:24]=2)=[N:9][CH:10]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]4[O:22][CH2:21][CH2:20][N:19]([C:33]5[C:38]([CH2:39][CH:40]6[CH2:41][CH2:42]6)=[C:37]([CH3:43])[N:36]=[C:35]([CH3:44])[N:34]=5)[CH2:18][C:17]=4[CH:23]=2)[CH:12]=3)[CH2:4][CH2:3]1
Reactant: CCC(C)OC(=O)n1c(C2CC2)nc2ncc(-c3ccc4c(c3)CNCCO4)cc21
Reactant: Cc1nc(C)c(CC2CC2)c(Cl)n1
Agent: Cl
Product: Cc1nc(C)c(CC2CC2)c(N2CCOc3ccc(-c4cnc5nc(C6CC6)[nH]c5c4)cc3C2)n1

Procedure:
Prepared according to the method of example 6 by using 1-methylpropyl 2-cyclopropyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate hydrochloride (reagent preparation 19) and 4-chloro-5-(cyclopropylmethyl)-2,6-dimethylpyrimidine (reagent preparation 8) in step 3. 1H NMR (400 MHz, methanol-d4) δ 8.71 (s, 1H), 8.25 (s, 1H), 7.78 (d, 1H), 7.58 (dd, 1H), 7.09 (d, 1H), 5.14 (s, 2H), 4.50 (m, 2H), 4.29 (m, 2H), 2.72 (d, 2H), 2.52 (s, 3H), 2.51 (s, 3H), 2.39 (m, 1H), 1.43 (m, 4H), 0.88 (m, 1H), 0.50 (m, 2H), 0.10 (m, 2H); MS (EI) for C28H30N6O: 467 (MH+).
Reaction SMILES: Cl.Cl.[C:3]1([C@@H:9]2[C@@H:18]3[CH2:19][CH2:20][N:21]([C:22]([C@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]4)=[O:23])[C@@H:17]3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:30]([N:38]=[C:39]=[O:40])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:32]1([CH2:31][CH2:30][NH:38][C:39]([N:25]2[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]2[C:22]([N:21]2[C@@H:17]3[C@@H:18]([C@H:9]([C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[NH:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=43)[CH2:19][CH2:20]2)=[O:23])=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C([C@H]1CCCCN1)N1CC[C@H]2[C@@H](c3ccccc3)Nc3ccccc3[C@H]21
Reactant: O=C=NCCc1ccccc1
Agent: Cl
Product: O=C(NCCc1ccccc1)N1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21

Procedure:
In the same manner as in Example 135 and using (3aS,4S,9bS)-4-phenyl-1-[(2R)-piperidin-2-ylcarbonyl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline dihydrochloride and phenethylisocyanate, the title compound was synthesized.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]=[C:5]=[O:6].[C:7]1([NH2:17])[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.ClCCNC(N)=O.CO>O1CCCC1.O>[C:7]1([NH:17][C:5]2[O:6][CH2:2][CH2:3][N:4]=2)[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cccc2c1CCCC2
Reactant: O=C=NCCCl
Agent: NC(=O)NCCCl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: c1cc2c(c(NC3=NCCO3)c1)CCCC2
Temperature: 25 °C

Procedure:
Chloroethylisocyanate (Compound 5 210 mg, 2.05 mmol) was added to a stirred solution at 5,6,7,8-tetrahydro-1-naphthylamine (302 mg, 2.05 mmol) in tetrahydrofuran (2 ml). After 30 minutes the resulting chloroethylurea was collected by vacuum filtration. Yield: 302 mg (58%) of fine white crystals: mp 101°-103°; H NMR (300 MHz, CDCl3) σ 6.98-7.30 (m, 3H); 6.08 (brs, 1H); 5.19 (br, s, 1H); 3.68 (m, 2H); 3.55 (m, 2H); 2.79 (m, 2H); 2.61 (m, 2H); 1.80 (m, 4H); Mass spectrum m/e 252.1034 (C13H17ClN2O requires 252.1029). The chloroethyl urea (237 mg, 0.94 mmol) was suspended in H2O (3 ml) and CH3OH (3 ml) and heated to reflux for 18 hours. The reaction mixture was cooled to room temperature and worked up as above to yield after recrystallization (hexane/CHCl3) 187.6 mg (87%) of the title compound: mp 160°-162° C.; 1H NMR (300 MHz, CDCl3) σ 7.23 (m, 1H); 7.08 (m, 1H; 6.75 (m, 1H); 5.55 (br, 1H); 4.35 (t, 2H); 3.70 (t, 2H); 2.70 (m, 2H); 2.58 (m, 2H); 1.80 (m, 4H); Mass spectrum m/e 216.1257 (C13H16N2O requires 216.1262).
Reaction SMILES: [CH2:1]([Si:4](OC)([O:7][CH3:8])[O:5][CH3:6])[CH2:2][CH3:3].[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[SiH4].Cl>CCOCC>[C:11]1([Si:4]([CH2:1][CH2:2][CH3:3])([O:7][CH3:8])[O:5][CH3:6])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCC[Si](OC)(OC)OC
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Agent: [SiH4]
Solvent: CCOCC
Product: CCC[Si](OC)(OC)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A 500 mL round bottomed flask was charged with propyl-trimethoxysilane (19.3 mL, 1.10×10−1 mole, Hüls) and ether (250 mL, Aldrich). A pressure equalizing addition funnel was charged with phenylmagnesium bromide (33.3 mL of a 3M solution in ether, 99.9 mmol, Aldrich) and ether (50 mL). The contents of the addition funnel were added into the silane over a 20 minute period (exotherm). A white precipitate formed. The reaction was stirred for two hours at room temperature then poured into 0.2N HCl (300 mL). The layers were separated, the product extracted into ether (2×250 mL), dried (MgSO4), and filtered. The solvent was removed via rotary evaporation resulting in 23.5 grams of crude material. Distillation under reduced pressure (b.p. 71° C., 0.6 mm Hg) provided phenyl-propyl-dimethoxysilane (18.5 g, 88.0 mmol, 88% yield); C11H18SiO2 (mw=210.34); 1H NMR (CDCl3) δ7.7 (m, 2H), 7.4 (m, 3H), 3.6 (s, 6H), 1.4 (m, 2H), 1.0 (t, 3H), 0.9 (t, 2H); 13C NMR (CDCl3) δ134.3, 133.3, 130.1, 127.9, 50.6, 17.9, 16.3, 14.8; MS m/z (relative abundance) 210 (2), 167 (100), 137 (33), 107 (17), 91 (17), 59 (10).
Reaction SMILES: O=S(Cl)Cl.[Br:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([CH:14]=1)[C:11]([OH:13])=O.CCN(C(C)C)C(C)C.[F:24][C:25]([F:35])([F:34])[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([CH:14]=1)[C:11]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([O:26][C:25]([F:24])([F:34])[F:35])=[CH:28][CH:29]=1)=[O:13]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
SOCl2 (10.84 mL, 148.5 mmol) was added to a suspension of 5-bromonicotinic acid (5 g, 24.75 mmol) in DCM (60 mL) and the RM was stirred at RT overnight. The solvent was evaporated off under reduced pressure and the residue was dissolved in DCM (40 mL), the mixture was cooled to 0° C. under a nitrogen atmosphere, DIPEA (8.65 mL, 49.5 mmol) was added dropwise, followed with a solution of 4-trifluoromethoxyaniline (3.65 mL, 27.2 mmol) in DCM (20 mL). The RM was stirred for 2 h, treated with sat. aq. Na2CO3 (100 mL), and extracted EtOAc. The combined extracts were washed with sat. solution of KH2PO4 (pH=4), brine, dried over MgSO4 and the solvent was evaporated off under reduced pressure to give a residue which was recrystallized from n-heptane/EtOAc to afford the title compound as beige needles. UPLC-MS (Condition 1) tR=2.71 min, m/z=360.9-362.9 [M+H]+, m/z=358.9-361.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.40 (d, J=8.3 Hz, 2H) 7.87 (d, 2H) 8.55 (t, J=2.1 Hz, 1H) 8.93 (d, J=2.2 Hz, 1H) 9.07 (d, J=1.7 Hz, 1H) 10.67 (s, 1H).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[C:24]2[CH:23]=[C:22]([C:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=3)[S:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.C(O)C.[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36]>C(OCC)(=O)C>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[Cl:15][C:16]1[C:24]2[CH:23]=[C:22]([C:25]3[CH2:26][CH2:27][N:28]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:7]=4[CH:8]=[CH:9][NH:10]5)[CH2:29][CH:30]=3)[S:21][C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: Clc1cccc2sc(C3=CCNCC3)cc12
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2cc3c(Cl)cccc3s2)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.129 g, 0.068 mmol) and 4-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene (0.170 g, 0.068 mmol) using ethanol as reaction solvent. Yield 0.105 g (34%) of a tan powder. FDMS m/e=438 (M+ of free base). A sample was dissolved in ethyl acetate and treated with 1.0 equivalent of oxalic acid and evaporated to an orange powder. mp 138-142° C. (dec) α[D]589=−5.3(c=1.13, dimethylsufoxide).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][O:16][CH2:17]C=C)[N:14]=1)=[O:8].C[N+]([O-])(C)C.[C:29]([O-:32])(O)=O.[Na+].C[C:35](C)=[O:36].O>O=[Os](=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][O:16][CH2:17][CH:29]([OH:32])[CH2:35][OH:36])[N:14]=1)=[O:8]
Reactant: CC(C)=O
Reactant: O=C([O-])O
Reactant: C=CCOCc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+](C)(C)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(COCC(O)CO)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(3,4-dichlorobenzyl)-3-(4-(allyloxymethyl)thiazol-2-yl)urea (Example 90, 100 mg, 0.27 mmol) in a mixture of acetone/water 10/1 (2 ml) was added TMANO (trimethylamine N-oxide, 45 mg, 0.40 mmol) and a OsO4 solution (4% in water, 0.34 mL, 5.4 μmol). The mixture was stirred at room temperature for 3 h and a saturated NaHCO3 solution was added. The solution was extracted with EtOAc (2×25 mL) and the combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford 100 mg of an off-white solid. Purification by column chromatography (SiO2, DCM/4% 7N NH3 in MeOH). 1H-NMR (300 MHz, CDCl3): δ 7.34 (s, 1H), 7.33 (d, 1H), 7.08 (d, 1H), 7.05 (bs, 1H), 6.62 (s, 1H), 4.38 (s, 2H). 4.33 (d, 2H), 3.86 (t, 1H), 3.62-3.50 (m, 4H).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[C:3]#[CH:4].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:26][C:27]1[C:28]([F:52])=[CH:29][C:30]([Cl:51])=[C:31]([CH:50]=1)[O:32][C:33]1[CH:47]=[CH:46][C:36]2[N:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[S:39][C:35]=2[C:34]=1[C:48]#[N:49]>O1CCCC1.C(OCC)(=O)C>[Cl:51][C:30]1[C:31]([O:32][C:33]2[CH:47]=[CH:46][C:36]3[N:37]=[C:38]([NH:40][C:41]([CH:43]4[CH2:45][CH2:44]4)=[O:42])[S:39][C:35]=3[C:34]=2[C:48]#[N:49])=[CH:50][C:27]([NH:26][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([C:2]([CH3:1])([CH3:5])[C:3]#[CH:4])[CH:7]=2)=[C:28]([F:52])[CH:29]=1
Reactant: N#Cc1c(Oc2cc(N)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Reactant: C#CC(C)(C)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#CC(C)(C)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3C#N)c(Cl)cc2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
To a solution of 3-(1,1-dimethylprop-2-yn-1-yl)benzoic acid (62 mg, 0.330 mmol) in tetrahydrofuran (1 mL) were added oxalyl chloride (35 μL, 0.408 mmol) and N,N-dimethylformamide (5 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (1 mL). N-[6-(5-Amino-2-chloro-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (90 mg, 0.223 mmol) produced in Example 23(vi) was added to the solution, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (15 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (7 mL) and saturated brine (7 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=20/80→80/20), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (72 mg, 56%) as a white powder.