Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[OH:42].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[OH:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[NH:35][C:27]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4O)cc3)c2cc1OC
Yield: 56.3 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (105 mg) was dissolved in toluene (10 ml) with heat, after the addition of triethylamine (2 ml), triphosgene (118 mg) was added, and the admixture was refluxed with heat for 2 minutes. 2-Aminophenol (77 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 10 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted with chloroform, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was washed with chloroform and filtered to obtain 86 mg of the title compound (yield: 56%).
Reaction SMILES: Br[C:2]1[N:3]([CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[C:4]2[N:5]=[C:6]([NH2:12])[NH:7][C:8](=[O:11])[C:9]=2[N:10]=1.C(OC(=O)C)(=[O:21])C.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:12][C:6]1[NH:7][C:8](=[O:11])[C:9]2[NH:10][C:2](=[O:21])[N:3]([CH2:13][C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[C:4]=2[N:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2c(nc(Br)n2Cc2cccs2)c(=O)[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1nc2c([nH]c(=O)n2Cc2cccs2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 8-bromo-9-[(2-thienyl)methyl]guanine (see Example 5) (3.12 g; 9.56 mmol), acetic anhydride (75 ml), glacial acetic acid (75 ml) and anhydrous sodium acetate (14.9 g; 0.1816 mol) was heated to reflux for 20 hours. The dark solution which formed was then evaporated to dryness underreduced pressure. The residue was dissolved in aqueous methylamine (150 ml), stirred at room temperature for 48 hours and then heated to reflux for 2.5 hours. The methylamine was distilled off under reduced pressure and the residue was recrystallized from boiling methanol-water mixture to give 1.23 g of the analytical product, mp>300° C.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[NH2:8].C(N(CC)CC)C.[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:30][CH3:31])[C:25]=1[O:26][CH2:27][C:28]#[CH:29])[C:20](Cl)=[O:21]>C(OCC)(=O)C>[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][C:20](=[O:21])[C:19]1[CH:23]=[C:24]([O:30][CH3:31])[C:25]([O:26][CH2:27][C:28]#[CH:29])=[C:17]([F:16])[CH:18]=1
Reactant: C#CCOc1c(F)cc(C(=O)Cl)cc1OC
Reactant: CC1CCCC1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCOc1c(F)cc(C(=O)NC2CCCC2C)cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.5 %

Procedure:
To a mixture of 1 ml of ethyl acetate and 0.2 g of 2-methylcyclopentylamine hydrochloride was added 0.48 ml of triethylamine and then, a mixture of 0.24 g of 3-fluoro-5-methoxy-4-(2-propynyloxy)benzoyl chloride and 1 ml of ethyl acetate was added dropwise thereto under ice cooling. The mixture obtained was stirred at room temperature for 12 hours. Then, the reaction mixture was concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to obtain 0.21 g of N-(2-methylcyclopentyl)-3-fluoro-5-methoxy-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 70 of the present invention) represented by the formula:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH:13]12CC(C=C1)CC2CO.C1(C)C=CC=CC=1>[OH-].C([O-])(=O)C.[Zr+4].C(OCC)(=O)C>[CH:2]12[CH2:6][CH:5]([CH:4]=[CH:3]1)[CH2:11][CH2:12]2.[CH3:13][C:4]1[CH:3]=[C:2]([F:1])[CH:12]=[CH:11][C:5]=1[CH:6]=[CH:7][C:8]([O-:10])=[O:9]
Reactant: O=C(O)C=Cc1ccc(F)cc1
Reactant: OCC1CC2C=CC1C2
Agent: [Zr+4]
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C1=CC2CCC1C2
Product: Cc1cc(F)ccc1C=CC(=O)[O-]
Temperature: 145 °C
Yield: 68 %

Procedure:
10 g (60 mmol) of 4-fluoro-cinnamic acid, 7.45 g (60 mmol) of 5-norbornene-2-methanol, and 0.3 g (0.02 eq.) of zirconium(IV) acetate hydroxide were added to 50 ml of toluene and stirred. The mixture was heated to 145° C. under N2 atmosphere and azeotropically refluxed for 24 hours. After the reaction, the mixture cooled down to room temperature and was added with 100 volume % of ethyl acetate. The resulting product was extracted with 1M HCl and washed again with water. The organic layer was dried with Na2SO4 and the solvent was evaporated out to give a highly viscous material. (Yield: 68%, Purity (GC): 92%)
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@H:9]3[CH2:21][C@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[C:18](I)[CH:17]=[CH:16][N:15]=2)[N:13]=1)=[O:5])C.[ClH:22]>C(#N)C>[Cl:22][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([N:12]2[C:11]3[C@@H:10]4[CH2:21][C@@H:9]4[CH2:8][C:7]=3[C:6]([C:4]([OH:3])=[O:5])=[N:13]2)[CH:19]=1
Reactant: CCOC(=O)c1nn(-c2cc(I)ccn2)c2c1C[C@H]1C[C@@H]21
Reactant: Cl
Solvent: CC#N
Product: O=C(O)c1nn(-c2cc(Cl)ccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a solution of (1aR,5aR)-2-(4-iodo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (1.0 g, 2.53 mmol) in acetonitrile (30 mL) was added concentrated HCl solution (2 mL). The reaction was stirred at 80° C. for 20 h. After removal of acetonitrile, the aqueous residue was diluted with water and a NaHCO3 solution was added to adjust the pH to 2-3. The resulting mixture was extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was dissolved in a mixture of THF/MeOH/H2O (20/20/10) and added LiOH (61 mg). The reaction was stirred overnight and concentrated. The aqueous residue was diluted with water and an HCl solution was added to adjust the pH to 2-3. The resulting solid was filtered, washed with water and dried to give the title compound (610 mg). LCMS m/z=276.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 0.40 (dd, J=7.7, 4.5 Hz, 1H), 1.25 (td, J=7.9, 4.6 Hz, 1H), 2.25-2.30 (m, 1H), 2.71-2.75 (m, 1H), 2.76 (d, J=16.8 Hz, 1H), 2.87 (dd, J=16.4, 6.4 Hz, 1H), 7.55 (dd, J=5.4, 1.9 Hz, 1H), 7.90 (d, J=1.8 Hz, 1H), 8.52 (d, J=5.4 Hz, 1H), 12.98 (s, 1H).
Reaction SMILES: [N:1](OCCCC)=[O:2].[CH3:8][C:9]1[C:14]([CH3:15])=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:11][C:10]=1[Br:20].CC(C)([O-])C.[K+].O>CN(C)C=O.C(O)(=O)C>[Br:20][C:10]1[C:9]([CH3:8])=[C:14]([C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=1)[CH:15]=[N:1][OH:2]
Reactant: CCCCON=O
Reactant: Cc1c(Br)ccc(S(C)(=O)=O)c1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1c(Br)ccc(S(C)(=O)=O)c1C=NO
Temperature: 0 °C

Procedure:
A solution of 2.1 g (20 mmol) of n-butyl nitrite (97%) pure and 4 g (15 mmol) of 2,3-dimethyl-4-methylsulfonylbromobenzene in 50 ml of dimethylformamide is cooled to from −55 to −60° C., and a solution of 2.8 g (25 mmol) of potassium tert-butoxide in 35 ml of dimethylformamide is added dropwise at this temperature, over a period of 20 minutes. The reaction is monitored by HPLC. For work-up, initially 10 ml of water are added, and the pH is subsequently adjusted to 5-6 using approximately 9 ml of glacial acetic acid. The reaction mixture is subsequently poured into 100 ml of ice-water, and the aqueous phase is extracted with methylene chloride. The organic phase is washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated. This gives 3.6 g of an oily crude product (90% pure according to HPLC) which can be purified by recrystallization from toluene.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](I)=[CH:4][N:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([CH2:17][NH:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[O:16].CC1(C)C(C)(C)OB([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)O1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([CH2:17][NH:18][C:19](=[O:27])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[O:16])[C:5]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)=[CH:4][N:3]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: CC1(C)OB(c2cccs2)OC1(C)C
Reactant: Cc1ccc(C(=O)NCC(=O)NCCCN)cc1
Product: Cc1ccc(C(=O)NCC(=O)NCCCNc2nc(Cl)ncc2-c2cccs2)cc1

Procedure:
Preparation according to procedures 2 and 3 with the use of 2,4-dichloro-5-iodopyrimidine, N-[(3-amino-propylcarbamoyl)-methyl]-4-methyl-benzamide and 4,4,5,5-tetramethyl-2-(2-thienyl)-1,3,2-dioxaborolane.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([C:12]1[CH:16]=[C:15]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[C@H:46]([CH3:47])[CH2:45][CH2:44][CH2:43][C@@H:42]5[CH3:48])=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:14]([C:49]2[CH:50]=[C:51]([CH:60]=[CH:61][CH:62]=2)[O:52][CH2:53][CH2:54]OS(C)(=O)=O)[N:13]=1)([CH3:11])([CH3:10])[CH3:9]>C1COCC1>[C:8]([C:12]1[CH:16]=[C:15]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[C@H:42]([CH3:48])[CH2:43][CH2:44][CH2:45][C@@H:46]5[CH3:47])=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:14]([C:49]2[CH:62]=[CH:61][CH:60]=[C:51]([O:52][CH2:53][CH2:54][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:50]=2)[N:13]=1)([CH3:10])([CH3:11])[CH3:9]
Reactant: CN1CCNCC1
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Solvent: C1CCOC1
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN5CCN(C)CC5)c4)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 24 h
Yield: 38.7 %

Procedure:
1-Methylpiperazine (48 μL, 0.43 mmol) was added to a solution of Intermediate 96f (111 mg, 0.14 mmol) in THF (2 mL). The reaction was heated to 60° C. in a sealed vial overnight. 1-Methylpiperazine (48 μL, 0.43 mmol) was added and the reaction continued for a further 24 h. The mixture was cooled, evaporated in vacuo and the residue was purified by FCC, using 0-15% MeOH in DCM, then triturated with Et2O to give the title compound (42 mg, 38%) as an off-white solid. LCMS (Method 5): Rt 3.76 min, m/z 775.6 [MH+]. 1H NMR (400 MHz, do-DMSO): 0.60 (3H, d, J=6.0 Hz), 0.63 (3H, d, J=6.0 Hz), 1.28 (9H, s), 1.36-1.62 (3H, m), 1.65-1.75 (2H, m), 1.76-1.99 (3H, m), 2.03-2.12 (2H, m), 2.14-2.26 (3H, m), 2.34-2.61 (5H, m, obscured by solvent), 2.63-2.74 (3H, m), 3.11-3.24 (2H, m), 3.28-3.38 (2H, m), 4.1 (2H, t, J=5.8 Hz), 4.78-4.87 (1H, m), 5.50-5.56 (1H, m), 6.33 (1H, s), 6.93-7.00 (1H, m), 7.05-7.13 (3H, m), 7.20 (1H, dd, J=9.9, 2.4 Hz), 7.23-7.31 (2H, m), 7.34 (2H, t, J=8.0 Hz), 7.40 (1H, t, J=8.0 Hz), 7.67 (1H, d, J=9.9 Hz), 7.87-7.91 (1H, m), 8.11 (1H, s).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7](=[O:20])[CH:8]=[C:9]2[C:13]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=3[S:11][C:10]=12)([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24]>CN(C=O)C>[CH2:21]([N:25]([CH2:26][CH2:27][CH2:28][CH3:29])[C:7](=[O:20])[CH2:8][C:9]1[C:13]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=2[S:11][C:10]=1[C:5](=[O:6])[C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:22][CH2:23][CH3:24]
Reactant: COc1ccc2sc3c(C(C)(C)C)oc(=O)cc3c2c1
Reactant: CCCCNCCCC
Solvent: CN(C)C=O
Product: CCCCN(CCCC)C(=O)Cc1c(C(=O)C(C)(C)C)sc2ccc(OC)cc12

Procedure:
A solution of 21.6 mg of 1-tert-butyl-6-methoxy-3H-[1]benzothieno[2,3-c]pyran-3-one from the Step D above and 29.1 mg di-n-butyl amine in 0.75 mL anhydrous DMF was heated at 70° C. for six hours. The reaction mixture was purified on RP-HPLC using 70˜100% MeCN gradient with 0.1% TFA. The product fractions were pooled and lyophilized to give the title compound as a white solid. LC-MS: 4.53 min. (m/Z=418.3, 440.2).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].BrC[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15]O>>[CH:1]([NH:4][CH2:15][C:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[CH2:7])([CH3:3])[CH3:2]
Reactant: CO
Reactant: BrCC=Cc1ccccc1
Reactant: CC(C)N
Product: C=C(CNC(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.3 %

Procedure:
9 g of isopropylamine was dissolved in 20 ml of methanol under stirring with ice cooling, and 5 ml of the methanol containing 3.0 g (15.2 mmol), of α bromomethylstyrene obtained in Preparation Example 19 was dropped into the solution. After heating to room temperature and stirring for 18 hours, the solution was washed by concentration under reduced pressure. 150 ml of chloroform was added to the residue and the solution was washed with saturated sodium hydrogen carbonate. After drying the solution with magnesium sulfate, the solvent was distilled off. Purification was performed by silica gel column chromatography (chloroform˜chloroform:methanol=50:1). Yield: 2.14 g, % yield: 80.3%.
Reaction SMILES: C(Cl)(C(Cl)=O)=O.CS(C)=O.[CH2:11]([N:18]([C@@H:26]([CH3:29])[CH2:27][OH:28])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC.[NH4+].[Cl-]>C(Cl)Cl>[CH2:19]([N:18]([C@@H:26]([CH3:29])[CH:27]=[O:28])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@@H](CO)N(Cc1ccccc1)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: C[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
To a cold (−78° C.) solution of (COCl)2 (2M in CH2Cl2, 2.47 mL, 4.94 mmol) in CH2Cl2 (8 mL), DMSO (0.70 mL, 9.89 mmol) was added dropwise. After stirring at −78° C. for 15 min, a solution of (S)-2-(N,N-dibenzylamino)-1-propanol (1.01 g, 3.96 mmol) in CH2Cl2 (10 mL) was added dropwise. The mixture was stirred at −78° C. for 1 h, and then Et3N (2.76 mL, 19.78 mmol) was added. The reaction was warmed up to 0° C. and stirred for 15 min, followed by the addition of NH4Cl (25 mL, sat. aq.). The crude was extracted with CH2Cl2 (3×25 mL), washed successively with NaHCO3 (50 mL, sat. aq.) and brine (50 mL), dried over Na2SO4 and concentrated in vacuo. Aldehyde 4 was obtained as a yellow oil and used without further purification (928 mg, 93% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.Cl.[NH2:61][CH:62]([C:64]1[CH:65]=[CH:66][C:67]2[C:71]([CH3:73])([CH3:72])[O:70][B:69]([OH:74])[C:68]=2[CH:75]=1)[CH3:63]>CN(C=O)C.CC(=O)OCC>[OH:74][B:69]1[C:68]2[CH:75]=[C:64]([CH:62]([NH:61][C:4](=[O:5])[C:3]3[CH:7]=[CH:8][C:9]([C:11]4[CH2:15][C:14]([C:20]5[CH:21]=[C:22]([Cl:28])[C:23]([Cl:27])=[C:24]([Cl:26])[CH:25]=5)([C:16]([F:18])([F:19])[F:17])[O:13][N:12]=4)=[CH:10][C:2]=3[CH3:1])[CH3:63])[CH:65]=[CH:66][C:67]=2[C:71]([CH3:72])([CH3:73])[O:70]1
Reactant: CC(N)c1ccc2c(c1)B(O)OC2(C)C
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC(C)c1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
To a solution of 2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)benzoic acid (150 mg, 0.33 mmol), HATU (188 mg, 0.495 mmol) and Et3N (0.15 mL, 0.99 mmol) in DMF (10 mL) was added 6-(1-aminoethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (0.93 mmol). The mixture was stirred at rt overnight and EA (50 mL) was added. The mixture was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound N-(1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)ethyl)-2-methyl-4-(5-(3,4,5-tri-chlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamide (103 mg; yield 18% over 5 steps) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.00 (s, 1H), 8.82 (d, J=7.6 Hz, 1H), 7.84 (s, 2H), 7.37-7.67 (m, 6H), 5.16 (m, 1H), 4.40 (d, J=18.0 Hz, 1H), 4.33 (d, J=18.0 Hz, 1H), 2.33 (s, 3H), 1.47-1.44 (m, 9H) ppm; HPLC purity: 99.88% at 220 nm and 99.77% at 254 nm; MS: m/z=639.8 (M+1, ESI+).
Reaction SMILES: C[O-].[Na+].C[O:5][C:6](=[O:21])[CH:7]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:8]([O:10]C)=[O:9].Cl.[C:23]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)(=[NH:25])[NH2:24]>CO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][C:7]1[C:6]([OH:21])=[N:24][C:23]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[N:25][C:8]=1[OH:10].[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH:7]1[C:6](=[O:5])[NH:24][CH:23]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[NH:25][C:8]1=[O:9]
Reactant: COC(=O)C(Oc1ccccc1OC)C(=O)OC
Reactant: N=C(N)c1ccncc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1OC1C(=O)NC(c2ccncc2)NC1=O
Product: COc1ccccc1Oc1c(O)nc(-c2ccncc2)nc1O
Reaction time: 0.5 h

Procedure:
To a stirred solution of sodium methylate (9.7 g) in methanol (100 ml) a solution of dimethyl-(2-methoxyphenoxy)malonate (21.7 g) in methanol (50 ml) was added within 15 min and stirring was continued for 30 min followed by the addition of 4-amidino-pyridine hydrochloride (15 g, Referential Example 2) followed by stirring at room temperature for 20 h. The reaction mixture was concentrated in vacuo. The solid residue was stirred with diethyl ether. The obtained powder was filtered off and dissolved in water (300 ml). Acetic acid was added to pH=4. The precipitated product was filtered off, washed with water and dried in vacuo at 500C. 5-(o-methoxyphenoxy)4,6-dihydroxy-2-(4-pyridyl)pyrimidine (20.1 g, possibly also present as the tautomeric 5-(2-methoxyphenoxy)-2-(4-pyridyl)-tetrahydropyrimidine-4,6-dion) was obtained as a white powder.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:9][C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].CCN(C(C)C)C(C)C.[CH2:26]([O:33][C:34](Cl)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C.C(Cl)Cl>[CH2:26]([O:33][C:34]([NH:1][CH2:2][C@@H:3]1[CH2:9][C:6]2([CH2:7][CH2:8]2)[CH2:5][N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CC2)C[C@H]1CN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2(CC2)C[C@H]1CNC(=O)OCc1ccccc1

Procedure:
To a solution of (S)-tert-butyl 6-(aminomethyl)-5-azaspiro[2.4]heptane-5-carboxylate (prepared according to WO2011006960; 136 mg, 0.6 mmol) in acetonitrile (1.5 ml), DIPEA (156 μl, 0.9 mmol) and benzylchloroformate (100 μl, 0.7 mmol) were added. After 1 h at RT the reaction was diluted with DCM (20 ml) and washed with an aqueous satd. solution of NH4Cl; organics were evaporated to obtain an oil, which was purified on silica gel column (Cyclohexane/AcOEt from 9/1 to 7/3). Yield 168 mg, transparent oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.CS([C:18]1[N:23]=[CH:22][C:21]2=[CH:24][CH:25]=[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35])[N:20]2[N:19]=1)=O.C(N(CC)C(C)C)(C)C.COCC(O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:18]2[N:23]=[CH:22][C:21]3=[CH:24][CH:25]=[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35])[N:20]3[N:19]=2)=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Reactant: Nc1ccc(F)c(N2CCOCC2)c1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccccc1-c1ccc2cnc(Nc3ccc(F)c(N4CCOCC4)c3)nn12)S(C)(=O)=O
Yield: 37.7 %

Procedure:
4-Fluoro-3-morpholin-4-yl-phenylamine (50.0 mg, 0.255 mmol), N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (46.4 mg, 0.127 mmol) and N,N-Diisopropylethylamine (0.0666 mL, 0.382 mmol) were dissolved in 1-Methoxy-2-propanol (0.50 mL, 5.1 mmol). The reaction was irradiated at 300 watts, 200° C. for 20 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced and the crude residue was isolated and purified by Gilson prep HPLC to afford 23.77 mg of N-{2-[2-(4-Fluoro-3-morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a lyophilized powder. (M+H)=497.1. 1H NMR (400 MHz, DMSO, d6) δ 9.36 (s, 1H), 8.97 (s, 1H), 7.72 (m, 1H), 7.67 (m, 1H), 7.54 (m, 3H), 6.96 (m, 3H), 6.87 (m, 1H), 3.59 (m, 4H), 3.07 (s, 3H), 2.79 (s, 3H), 2.55 (m, 4H).
Reaction SMILES: Br[CH2:2][CH2:3]Br.Cl.[CH3:6][O:7][C:8](=[O:15])[C@@H:9]([C:11]([SH:14])([CH3:13])[CH3:12])[NH2:10].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:12][C:11]1([CH3:13])[S:14][CH2:3][CH2:2][NH:10][C@H:9]1[C:8]([O:7][CH3:6])=[O:15]
Reactant: BrCCBr
Reactant: COC(=O)[C@H](N)C(C)(C)S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1NCCSC1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.9 %

Procedure:
To a solution of 1,2-dibromoethane (6.77 g, 36 mmol) in dimethylformamide (25 ml) was added, over a period of 30 minutes, a solution of D-penicillamine methyl ester hydrochloride (6 g, 30 mmol) and 1,8-diazobicyclo[5.4.0]undeca-7-ene (13.7 g, 90 mmol) in dimethylformamide (50 ml). The resulting mixture was stirred for 18 hours at room temperature. The reaction mixture was poured into a saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed in vacuo to give 5.5 g (97%) of the product.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8]CCCCCCCCCCCC)=[N+:2]=[N-:3].[C:22]1([S:28]CC(Cl)=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][S:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: O=C(Cl)CSc1ccccc1
Agent: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=NCCNC(=O)CSc1ccccc1
Yield: 64 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 2-(phenylthio)acetyl chloride (0.222 g, 1.19 mmol) was reacted with 2-azidoethanamine (0.102 g, 1.19 mmol) and triethylamine (0.240 g, 2.37 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-2-(phenylthio)acetamide (0.179 g, 64% yield). 1H NMR (300 MHz, CDCl3) δ 7.29 (m, 4H), δ 7.18 (m, 2H), δ 3.60 (s, 2H), 3.34 (m, 4H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.6, 134.8, 129.5, 128.6, 127.1, 50.8, 39.3, 37.7 ppm; HRMS (ESI) calcd for C10H12N4OS (M+) 236.0732. found 236.0729.