Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH:8]([OH:23])[CH:9]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:7][O:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].[CH2:26](Br)[CH:27]=[CH2:28].O>O1CCCC1>[CH3:1][C:2]1([CH:8]([O:23][CH2:28][CH:27]=[CH2:26])[CH:9]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH2:3][O:4][CH2:5][O:6][CH2:7]1
Reactant: CC1(C(O)C(Cc2ccc(Cl)cc2)n2cncn2)COCOC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(C(Cc1ccc(Cl)cc1)n1cncn1)C1(C)COCOC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.4 %

Procedure:
A solution of 23.6 g (0.07 mole) of 1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-3-(4-chlorophenyl)-propan-1-ol in 100 ml of tetrahydrofuran is added dropwise to a suspension of 2.4 g of sodium hydride in 120 ml of dry tetrahydrofuran. After stirring the mixture for 12 hours at 25° C, a solution of 9.7 g (0.08 mole) of allyl bromide in 20 ml of tetrahydrofuran is added dropwise. The reaction mixture is stirred for 36 hours, 20 ml of water are then added cautiously, and the batch is evaporated down. The residue is taken up in 350 ml of methylene chloride, the solution is washed with three times 100 ml of water, and the organic phase is dried and evaporated down. The residue is mixed with 30 ml of petroleum ether and 10 ml of ether and left to stand overnight at +3° C. The crystalline, colorless precipitate is filtered off, washed with petroleum ether and dried. 22.6 g (87.5%) of 1-(5-methyl-1,3-dioxan-5-yl)-1-allyloxy-2-(1,2,4-triazol-1-yl)-3-(4-chlorophenyl)-propane, of melting point 113°-115° C., are obtained.
Reaction SMILES: [CH2:1]([O:5][P:6](Cl)(=[O:12])[O:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH3:4].[CH2:14]([Si:18]([CH2:23][CH2:24][CH2:25][CH3:26])([CH3:22])[CH2:19][CH2:20][OH:21])[CH2:15][CH2:16][CH3:17].N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[P:6]([O:21][CH2:20][CH2:19][Si:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:23][CH2:24][CH2:25][CH3:26])[CH3:22])([O:5][CH2:1][CH2:2][CH2:3][CH3:4])([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:12]
Reactant: CCCCOP(=O)(Cl)OCCCC
Reactant: CCCC[Si](C)(CCO)CCCC
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCOP(=O)(OCCCC)OCC[Si](C)(CCCC)CCCC
Reaction time: 8 h

Procedure:
Dibutylphosphorochloridate (3.74 g) was added to a solution of 2-(di-n-butyl methylsilyl)-ethanol (3 g) and pyridine (1.04 g) in carbon tetrachloride (10 ml). The mixture was left overnight, filtered, and the filtrate passed through an alumina column (20 g), eluting with a further 3 × 20 ml of carbon tetrachloride. Removal of the solvent under vacuum left the phosphate as a colourless oil (2.7 g).
Reaction SMILES: CN1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[C:5](=O)N(C)C1=O.COC1N=C(OC)C(B2OC(C)(C)C(C)(C)O2)=CN=1.CCN(CC)CC.[CH3:46][O:47][C:48]1C=C(Br)C=[CH:50][C:49]=1[OH:55].COC1C=C(C=C(B2OC(C)(C)C(C)(C)O2)C=1OC)C=O.B([O-])([O-])[O-]>>[CH3:46][O:47][C:48]1[CH:5]=[C:6]([B:8]2[O:9][C:10]([CH3:15])([CH3:16])[C:11]([CH3:13])([CH3:14])[O:12]2)[CH:7]=[CH:50][C:49]=1[OH:55]
Reactant: COc1cc(Br)ccc1O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c(=O)n(C)c1=O
Agent: COc1cc(C=O)cc(B2OC(C)(C)C(C)(C)O2)c1OC
Agent: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Agent: [O-]B([O-])[O-]
Solvent: CCN(CC)CC
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Solution 1 was transferred under N2 to a pressure-equalising dropping funnel and added to Solution 2 over 6 h. Stirred at RT overnight before heating at 40–50° C. for ˜8 h. After stirring overnight at RT a white ppt had formed. NEt3 (149 ml; 1.07 mol) was added followed by slow addition of 2-methoxy-4-bromophenol (91.6 g; 0.451 mol). Finally, the activated catalyst (Solution 3) was added and the resultant dark brown solution was stirred at 100° C. GC analysis after 20 hours showed the desired borate compound at 11.1 minutes (62%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:26])=[C:11]([CH2:13][CH2:14][O:15]S(C3C=CC(C)=CC=3)(=O)=O)[N:12]=2)=[CH:4][CH:3]=1.[CH3:27][O:28][C:29](=[O:40])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][C:33]=1[CH3:39].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH3:27][O:28][C:29](=[O:40])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:15][CH2:14][CH2:13][C:11]2[N:12]=[C:8]([C:5]3[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[O:9][C:10]=2[CH3:26])=[CH:34][C:33]=1[CH3:39]
Reactant: COC(=O)CCc1ccc(O)cc1C
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(Cl)nc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(Cl)nc3)oc2C)cc1C
Temperature: 60 °C

Procedure:
A mixture of toluene-4-sulfonic acid 2-[2-(6-chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-ethyl ester (0.4 g, 1.0 mmol, 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.2 g, 1 mmol) and Cs2CO3 (0.49 g, 1.5 mmol) in DMF (5 mL) is heated at 60° C. overnight, cooled to room temperature, diluted with ethyl acetate, washed with water and dried. Column chromatography on silica gel gave the product (85 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([N:6]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:7][CH:8](OC)[O:9]C)[CH3:5].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CC(=O)CC>[CH3:1][O:2][C:3](=[O:23])[C@@H:4]([N:6]([C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:7][CH:8]=[O:9])[CH3:5]
Reactant: COC(=O)[C@H](C)N(CC(OC)OC)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCC(C)=O
Product: COC(=O)[C@H](C)N(CC=O)C(=O)OCc1ccccc1
Yield: 108.8 %

Procedure:
A solution of (S)-2-[benzyloxycarbonyl-(2,2-dimethoxy-ethyl)-amino]-propionic acid methyl ester (26.0 g, 80.0 mmol) and pyridinium toluene-4-sulfonate (10.0 g, 40.0 mmol) in 2-butanone (260 mL) and water (8.6 mL, 0.48 mol) was heated under reflux for 16 h, then the solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated to afford the titled compound (24.3 g), which was directly used in the next step. Yellow oil, MS (ISP)=348.3 (M+Na)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[CH:5][O:6][C:7]=1[CH2:8][N:9]1[C:14]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:17][C:13]=2[C:12](=[O:24])[N:11]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:10]1=[O:31].[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:55]=[CH:54][C:50]([C:51](O)=[O:52])=[CH:49][CH:48]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:48]=[CH:49][C:50]([C:51]([N:28]4[CH2:29][CH2:30][CH:25]([N:11]5[C:12](=[O:24])[C:13]6[S:17][C:16]([C:18]7[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=7)=[CH:15][C:14]=6[N:9]([CH2:8][C:7]6[O:6][CH:5]=[N:4][C:3]=6[CH3:2])[C:10]5=[O:31])[CH2:26][CH2:27]4)=[O:52])=[CH:54][CH:55]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: Cc1ncoc1Cn1c(=O)n(C2CCNCC2)c(=O)c2sc(-c3ccccc3)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5ocnc5C)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(4-Methyl-1,3-oxazol-5-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (253 mg; compound B94) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (207 mg; compound C10) and HATU (257 mg) in DCM (7 ml) in the presence of DIPEA (0.27 ml) according to the procedure described in example 52 to afford the title compound after purification by preparative HPLC as a solid.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:41].C(O)C.C(=O)([O-])[O-].[NH4+:49].[NH4+]>ClCCl.C(O)C>[ClH:41].[C:1]1([N:7]([CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:49])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCCOCc3ccccc3)c3ccccc3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCCOCc3ccccc3)c3ccccc3)ccc21
Yield: 61 %

Procedure:
Prepared analogously to Example 25 from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 61% of theory, C33H34N6O2 (546.7); Rf value: 0.19 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=547; (M+H+Na)++=285.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH:22]=[CH:21]1>>[C:23]([O:25][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])(=[O:24])/[CH:22]=[CH:21]\[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:26]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: O=C1C=CC(=O)O1
Product: CCCCCCCCCCCCCCCCCCOC(=O)/C=C\C(=O)OCCCCCCCCCCCCCCCCCC

Procedure:
A sample of mono octadecyl (monostearyl) maleate was prepared in a similar manner, but using 405 g octadecanol (1.5 moles) and 147 g maleic anhydride (1.5 moles).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([CH:18](C#N)[C:19]([O:21]CC)=O)([C:16]#[N:17])[C:7]1=[O:26].Br.C(O)(=[O:34])C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]2([CH2:18][C:19](=[O:21])[NH:17][C:16]2=[O:34])[C:7]1=[O:26]
Reactant: CC(=O)O
Reactant: CCOC(=O)C(C#N)C1(C#N)C(=O)N(Cc2ccc(Cl)c(Cl)c2)c2ccc(F)cc21
Agent: Br
Product: O=C1CC2(C(=O)N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccc(F)cc12

Procedure:
A solution of ethyl 2-[1-(3,4-dichlorobenzyl)-3-cyano-5-fluoro-2-oxo-3-indolinyl]-2-cyanoacetate (E) (2.0 g.) in 48% w/v hydrogen bromide in acetic acid (25 ml.) was heated under reflux for 3 hours. The solution was evaporated to half volume and poured into water (20 ml.). The mixture was extracted with ethyl acetate (2×50 ml.). The combined extracts were washed with water (2×50 ml.), brine (50 ml.), dried (MgSO4) and evaporated. The residual solid was recrystallised from 2-propanol/petrol 60-80 to give 1'-(3,4-dichlorobenzyl)-5'-fluoro-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione (0.49 g.), m.p. 253°-254° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH:10]=[CH2:11])[CH:3]=1.[BH4-].[Na+]>CO.O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([CH:10]=[CH2:11])[CH:3]=1
Reactant: C=Cc1cc(F)ccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=Cc1cc(F)ccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a mixture of 1-bromo-4-fluoro-2-vinylbenzene (0.32 g, 1.592 mmol) in tetrahydrofuran (5 mL) at −78° C. was added BuLi (0.764 mL, 1.910 mmol) dropwise. It was then stirred at this temperature for 1 h, then N,N-dimethylformamide (0.185 mL, 2.388 mmol) was added. The reaction mixture was stirred at −78° C. for 30 min, then warmed to rt and stirred at rt for 3 h. It was then quenched with NH4Cl, extracted with ether. The organic layer was dried over MgSO4, filtered and concentrated to obtain 4-fluoro-2-vinylbenzaldehyde (0.2 g) as an oil, which was used in the next step without purification. A mixture of 4-fluoro-2-vinylbenzaldehyde (200 mg, 1.332 mmol) and NaBH4 (50.4 mg, 1.332 mmol) in MeOH (2 mL) was stirred at rt for 1 h. It was then diluted with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 20% EtOac/hexane to obtain (4-fluoro-2-vinylphenyl)methanol (150 mg, 0.986 mmol, 74.0% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (dd, J=8.3, 5.9 Hz, 1H), 7.25 (dd, J=10.0, 2.7 Hz, 1H), 7.09-7.02 (m, 1H), 7.02-6.95 (m, 1H), 5.73 (d, J=17.4 Hz, 1H), 5.44 (d, J=11.0 Hz, 1H), 4.75 (d, J=4.9 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[C:8](=[O:20])[CH:7]=1.[Cl:26]N1C(=O)CCC1=O>CC(O)=O>[Cl:26][C:7]1[C:8](=[O:20])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=c1cc(OCc2ccc(F)cc2F)ccn1Cc1cccc(F)c1
Solvent: CC(=O)O
Product: O=c1c(Cl)c(OCc2ccc(F)cc2F)ccn1Cc1cccc(F)c1
Temperature: 25 °C

Procedure:
To a solution of 4-(2,4-difluorobenzyloxy)-1-(3-fluorobenzyl)-1H-pyridin-2-one (0.15 g, 0.4 mmol) in AcOH (3 mL) was added N-chlorosuccinimide (70 mg, 0.5 mmol), and the reaction mixture was heated at reflux for 10 min. The reaction mixture was cooled room temperature and the solvent was removed under reduced pressure. 1H NMR (300 MHz, CDCl3) δ 7.60-7.50 (m, 1H), 7.45-7.20 (m, 2H), 7.10-6.80 (m, 5H), 6.16 (d, J=8 Hz, 1H), 5.21 (s, 2H), 5.15 (s, 2H). ES HRMS m/z 380.0641 (M+H C19H14ClF3NO2 requires 480.0660).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[N:30]([CH3:31])[C:29]([CH:32]=O)=[CH:28][N:27]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[NH:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40]([NH2:42])=[O:41].C(O[BH3-])(=O)C.[Na+]>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[N:30]([CH3:31])[C:29]([CH2:32][N:38]5[CH2:45][CH2:44][CH2:43][C@H:39]5[C:40]([NH2:42])=[O:41])=[CH:28][N:27]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(C=O)cnc1-c1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Reactant: NC(=O)[C@@H]1CCCN1
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1c(CN2CCC[C@H]2C(N)=O)cnc1-c1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Temperature: 20 °C
Reaction time: 0.75 h

Procedure:
2-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-3-methyl-3H-imidazole-4-carbaldehyde was dissolved in dichloromethane (5 ml) containing glacial acetic acid (0.03 ml). L-prolinamide (0.028 g) was added and the mixture stirred at 20° C. for 0.75 hours. Sodium acetoxyborohydride (0.08 g) was added and the reaction stirred at 20° C. for 18 hours. The mixture was partitioned between 2N sodium carbonate and ethyl acetate, the organic phase was dried over magnesium sulphate and concentrated in vacuo. Chromatography on silica gave the title compound (0.008 g) as a yellow solid; tlc (SiO2, CH2Cl2:EtOH:NH3, 100:8:1) Rf 0.18; m/z (M+1)30 534.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:30][CH2:31]OS(C)(=O)=O)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:43][CH2:42][CH2:41][C@@H:38]1[CH2:39][OH:40].CN(C=O)C>CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:15]([CH2:30][CH2:31][N:37]3[CH2:43][CH2:42][CH2:41][C@@H:38]3[CH2:39][OH:40])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:28])([F:29])[F:27])[CH:20]=3)[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OC[C@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCOS(C)(=O)=O)CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CCC[C@@H]2CO)CC1
Yield: 100.8 %

Procedure:
Add 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-methanesulfonyloxy-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (500 mg; 1 equiv; 933 μmol); D-prolinol (3.00 equiv; 2.80 mmol; 283 mg); DMF (1 mL) and heat at 50° C. for 18 h in a sealed vessel. Dilute with EA, wash with saturated sodium bicarbonate, brine, dry MgSO4, filter and purify on 40 g silica gel with 1-10% MeOH/DCM to provide the title compound (506.9 mg; 0.94 mmol; 100%). MS (ES+): m/z=541 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:23]=[CH:22][C:21]3[N:20]4[CH2:24][CH2:25][NH:26][C:27](=[O:28])[C:19]4=[CH:18][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:23]=[CH:22][C:21]3[N:20]4[CH2:24][CH2:25][NH:26][C:27](=[O:28])[C:19]4=[CH:18][C:17]=3[CH:16]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCn2c1cc1cc(OC3CCNCC3)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
The solution of 0.45 g (1.17 mmol) 4-(1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indol-8-yloxy)-piperidine-1-carboxylic acid tert-butyl ester in 10 mL dichloromethane was cooled to 0° C. and was treated with 5 mL (7.4 g, 65.3 mmol) trifluoroacetic acid. The cooling bath was removed and after stirring at room temperature for 1 h the volatile components were removed at a rotary evaporator. The residue was taken up in dichloromethane and washed with 1 M aqueous sodium hydroxide solution. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 140 mg (42%) of the product as a white solid.
Reaction SMILES: [Cl:1]C(C=O)C(OCC)=O.BrC1C=C(Cl)N=NC=1N.Br[C:20]1[C:21]2[N:22]([C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:29]=2)[N:23]=[C:24]([Cl:26])[CH:25]=1>>[Cl:26][C:24]1[CH:25]=[C:20]([Cl:1])[C:21]2[N:22]([C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:29]=2)[N:23]=1
Reactant: CCOC(=O)c1cnc2c(Br)cc(Cl)nn12
Reactant: CCOC(=O)C(Cl)C=O
Agent: Nc1nnc(Cl)cc1Br
Product: CCOC(=O)c1cnc2c(Cl)cc(Cl)nn12
Temperature: 90 °C
Yield: 29 %

Procedure:
To a 250 mL round-bottomed flask was added ethyl 2-chloro-3-oxopropanoate (4.33 g, 28.8 mmol) and 4-bromo-6-chloropyridazin-3-amine (5 g, 23.99 mmol). The solution was heated to 90° C. for 16 hours. The solution was quenched with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by ISCO (10% ethyl acetate/dichloromethane; 80 g column) to give a mixture of ethyl 8-bromo-6-chloroimidazo[1,2-b]pyridazine-3-carboxylate and ethyl 6,8-dichloroimidazo[1,2-b]pyridazine-3-carboxylate (2.1 g, 29% yield). LC/MS, m/z 256.96 (M+1). HPLC Rt, 2.54 min. LC/MS, m/z 303.92 (M+1). HPLC Rt, 2.63 min. Waters Sunfire C18 column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[C:10]1[CH:34]=[C:33]([CH3:35])[C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)[N:16]=[N:17][C:12]=2[CH:11]=1.CCN(CC)CC.[C:43](Cl)(=[O:45])[CH3:44]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:43](=[O:45])[CH3:44])=[CH:5][C:4]=1[C:10]1[CH:34]=[C:33]([CH3:35])[C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(-c2cc(O)ccc2Cl)cc2nnc(Nc3ccc(OCCN4CCCC4)cc3)nc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(Cl)c(-c2cc(C)c3nc(Nc4ccc(OCCN5CCCC5)cc4)nnc3c2)c1
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
To a solution of 4-chloro-3-{5-methyl-3-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-benzo[1,2,4]triazin-7-yl}-phenol hydrochloride (1.0 equiv., 0.978 mmol) in DCM (30 mL) was added neat Et3N (10 equiv., 4.89 mmol) under an argon rich atmosphere and stirred for 10 minutes. Neat Acetyl chloride (1.2 equiv., 1.17 mmol) was added dropwise via syringe to the reaction mixture and allowed to stir at room temperature for 24 h. The reaction was quenched using saturated NaHCO3; the organics were dried over Na2SO4 and then concentrated down under reduced pressure. The resulting crude solid was then brought up in DCM and purified by flash chromatography using a solvent system of 85:10:5 (v/v/v) DCM/MeOH/Et3N. The fractions were concentrated under reduced pressure and precipitated out using 1:5 (v/v) DCM/hexanes to afford an orange solid (409.1 mg, 75% yield). 1H NMR (DMSO-d6): δ 1.68 (m, 4H), 2.29 (s, 3H), 2.51 (m, 4H), 2.63 (s, 3H), 2.78 (t, J=5.94 Hz, 2H), 4.07 (t, J=5.99 Hz, 2H), 6.99 (dd, J=7.05 Hz, 12.55 Hz, 2H), 7.27 (dd, J=5.90 Hz, 8.75 Hz, 1H), 7.41 (d, J=2.80 Hz, 1H), 7.67 (d, J=8.75 Hz, 1H), 7.85 (m, 1H), 7.93 (d, J=9.05 Hz, 2H), 8.17 (m, 1H), 10.83 (s, 1H). Rf=0.29 MS (ES+) m/z 520, LC retention time 2.57 minutes.
Reaction SMILES: OC1C2N=NNC=2C=CC=1.C(N=C=NC(C)C)(C)C.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([OH:27])=O.[CH3:31][C:32]1[C:36]([NH2:37])=[C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[NH:34][N:33]=1>CN(C)C=O.O>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:37][C:36]1[C:32]([CH3:31])=[N:33][NH:34][C:35]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:27]
Reactant: Cc1n[nH]c(-c2ccccc2)c1N
Reactant: COc1cccc(C(=O)O)c1
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)Nc2c(C)n[nH]c2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
311 mg of hydroxybenzotriazole and 445 μl of diisopropylcarbodiimide were added to a solution of 160 mg of 3-methoxybenzoic acid in 10 ml of dimethylformamide, after which 200 mg of 3-methyl-5-phenyl-1H-pyrazol-4-ylamine were added; the mixture was then stirred at RT for 12 h, after which water was added and the whole was extracted with methylene chloride. The organic phase was dried over magnesium sulfate, concentrated under reduced pressure and purified by means of HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The following was obtained: 4 C17H15N3O2 (293.33); MS (ESI) 294 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)=[CH:8][CH:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:26][NH2:27].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:26][NH:27][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Fc1ccc2c(-c3ccc(OCCCBr)cc3)noc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(-c3ccc(OCCCNCc4ccc(Cl)c(Cl)c4)cc3)noc2c1

Procedure:
The title compound is prepared from a mixture of 3-[4-(3-bromo-propoxy)-phenyl]-6-fluoro-benzo[d]isoxazole, 3,4-dichlorobenzylamine, potassium carbonate, potassium iodide and 4% aqueous acetonitrile essentially as described above in Example 13. Purity by LC/MS=95%, [M+H]+=445.