Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:10]([F:13])([F:12])[F:11].Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[F:32][C:31]([F:34])([F:33])[C:28]1[CH:29]=[CH:30][C:25]([O:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][C:15](=[O:16])[N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[O:9][C:10]([F:11])([F:12])[F:13])=[CH:19][CH:20]=2)=[N:26][CH:27]=1
Reactant: CNc1ccccc1OC(F)(F)F
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Product: CN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)c1ccccc1OC(F)(F)F

Procedure:
The title product was prepared from N-methyl-2-(trifluoromethoxy)-aniline and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative HPLC (method C) (49%, colourless oil). HPLC-MS m/z=473.2 (M+1), Rt: 5.18 min.
Reaction SMILES: C(N[C:5]1[C:6]([N+:16]([O-:18])=[O:17])=[C:7]([C:11]([Cl:15])=[CH:12][C:13]=1[Cl:14])[C:8]([OH:10])=[O:9])(=O)C.[OH-:19].[K+].Cl>O.C(OCC)(=O)C>[Cl:14][C:13]1[CH:12]=[C:11]([Cl:15])[C:7]([C:8]([OH:10])=[O:9])=[C:6]([N+:16]([O-:18])=[O:17])[C:5]=1[OH:19]
Reactant: [OH-]
Reactant: CC(=O)Nc1c(Cl)cc(Cl)c(C(=O)O)c1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1c(Cl)cc(Cl)c(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
3-Acetamido-4,6-dichloro-2-nitrobenzoic acid (9.7 g, 0.033 mol) was added to a solution of KOH (18.7 g, 0.034 mol) in H2O (85 mL). The solution was heated under reflux for 18 h and cool to room temperature. Conc HCl was added to adjust the pH to 0. The mixture was diluted with ethyl acetate and H2O and left to stir at room temperature for 30 min. The layers were separated; the aqueous layer was extracted with ethyl acetate (3×), the extracts combined with the original organic layer, washed with brine, dried and concentrated to yield 4,6-dichloro-3-hydroxy-2-nitrobenzoic acid as a dark red solid (7.4 g, 89%); m.p. 188-189° C. (lit. m.p. (Linderberg, M., Hellberg, S., Bjork, S. et al, Eur. J. Med. Chem., 1999, 34, 729-744): 186° C. (dec)).
Reaction SMILES: C([SiH](CC)CC)C.[F:8][C:9]1[CH:25]=[CH:24][C:12]2[C:13]3([CH3:23])[C:18](=[CH:19][CH2:20][C:11]=2[CH:10]=1)[N:17]([CH3:21])[C:16](=[O:22])[CH2:15][CH2:14]3.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:8][C:9]1[CH:25]=[CH:24][C:12]2[C:13]3([CH3:23])[CH:18]([CH2:19][CH2:20][C:11]=2[CH:10]=1)[N:17]([CH3:21])[C:16](=[O:22])[CH2:15][CH2:14]3
Reactant: CN1C(=O)CCC2(C)C1=CCc1cc(F)ccc12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)CCC2(C)c3ccc(F)cc3CCC12
Temperature: 0 °C
Reaction time: 96 h

Procedure:
Triethylsilane (1 ml; 6.12 mmol) was added to 8-fluoro-4,10b-dimethyl-1,2,3,4,6,10b-hexahydrobenzo[f]quinolin-3-one (500 mg; 2.04 mmol) in CH2Cl2 (15 ml) at room temperature. The reaction mixture was cooled to 0° C. and trifluoroacetic acid (2.6 ml) was added. After stirring at room temperature for four days, the reaction mixture was diluted with CH2Cl2 and treated with saturated NaHCO3. The resulting layers were separated and the organic layer was washed with saturated NaHCO3, dried over MgSO4 and concentrated under vacuum to a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].Cl.CN.Cl.[CH2:16]([N:18]=C=NCCCN(C)C)C.O.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:18][CH3:16])=[O:6]
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(F)c(Cl)c1
Temperature: 23 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
To a suspension of 3-chloro-4-fluorobenzoic acid (25.0 g, 143 mmol), Methylamine hydrochloride (11.60 g, 172 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (41.2 g, 215 mmol), and 1H-benzo[d][1,2,3]triazol-1-ol hydrate (32.9 g, 215 mmol) in DMF (Volume: 150 mL) was added 4-methylmorpholine (79 mL, 716 mmol) at 23° C. The reaction was stirred at 23° C. for 3 hr. The reaction mixture was diluted with water (500 mL) to furnish a yellow-orange solution. The solution was stirred overnight at 23° C. affording a suspension. The suspension was filtered, washed with H2O (3×100 mL), and the resulting solid was dried in vacuo at 30° C. to provide 3-chloro-4-fluoro-N-methylbenzamide (14.24 g, 76 mmol, 53.0% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.78 (d, J=4.55 Hz, 3H) 7.53 (t, J=8.97 Hz, 1H) 7.86 (ddd, J=8.59, 4.80, 2.27 Hz, 1H) 8.04 (dd, J=7.20, 2.15 Hz, 1H) 8.51-8.65 (m, 1H). ESI-MS: m/z 188.0 (M+H)+. Mp=108.3-110.0° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].Cl.[CH3:30][C:31]1[N:32]=[C:33]([CH2:36][N:37]2[C:42]3[CH:43]=[C:44]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[S:45][C:41]=3[C:40](=[O:52])[N:39]([CH:53]3[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]3)[C:38]2=[O:59])[S:34][CH:35]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:56]4[CH2:57][CH2:58][CH:53]([N:39]5[C:40](=[O:52])[C:41]6[S:45][C:44]([C:46]7[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=7)=[CH:43][C:42]=6[N:37]([CH2:36][C:33]6[S:34][CH:35]=[C:31]([CH3:30])[N:32]=6)[C:38]5=[O:59])[CH2:54][CH2:55]4)=[O:21])=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: Cc1csc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nc(C)cs5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
The title compound is prepared analogously as described for example 1 using 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (159 mg; compound C10), 1-[(4-methyl-1,3-thiazol-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (190 mg; compound B38), HBTU (167 mg) (additional 76 mg of HBTU are added after 90 min), DIPEA (0.28 ml) and DCM (3 ml). The crude product is purified by flash column chromatography (amino phase silica gel, eluent: EtOAc) and subsequent preparative thin layer chromatography [eluent: DCM/MeOH/triethylamine, 95/5/0.5 (v/v/v)] to yield the title compound as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[N:26])=[C:16]3[N:15]=[C:14](Cl)[CH:13]=2)[CH:6]=1)[CH3:2].[C:29]1([NH2:36])[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=1>CN1C(=O)CCC1.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[N:26])=[C:16]3[N:15]=[C:14]([NH:35][C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([NH2:36])[CH:30]=3)[CH:13]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Nc2cc(Cl)nc3c(CCCCC#N)cnn23)c1
Reactant: Nc1cccc(N)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(Nc2cc(Nc3cccc(N)c3)nc3c(CCCCC#N)cnn23)c1
Temperature: 160 °C
Yield: 123.9 %

Procedure:
A mixture of compound (14a) (0.63 g. 1.6 mmol) and benzene-1,3-diamine (69 mg, 0.636 mmol) in 2 mL of NMP was heated at 160° C. overnight. The reaction mixture was diluted with EtOAc (50 mL) and washed with saturated aq NaHCO3 and brine and dried over anhydrous Na2 SO4. HPLC purification provided 3-[5-(3-amino-phenylamino)-3-(4-cyano-butyl)-pyrazolo[1,5-a]pyrimidin-7-ylamino]-benzoic acid ethyl ester (15a) (0.37 g. 50%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1([CH:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:19][NH2:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[O:6]
Reactant: NCC(c1ccccn1)N1CCOCC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(c1ccccn1)N1CCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and (2-morpholin-4-yl-2-pyridin-2-ylethyl)amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[C:14]([C:16]([O:18]C)=[O:17])[N:15]=3)[S:10][C:3]=12.[OH-].[Na+].Cl>CCOC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=3)[S:10][C:3]=12
Reactant: COC(=O)c1csc(-c2cc3nccc(Cl)c3s2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1csc(-c2cc3nccc(Cl)c3s2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of methyl 2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-thiazole-4-carboxylate (0.200 g, 0.62 mmole), prepared by the method described in PC10795A, section A, example 26, in EtOAc (5 ml) was added 1N aqueous NaOH solution (1.85 ml, 1.85 mmole). The reaction mixture was stirred at 50° C. for 1 h, cooled to room temperature, diluted with H2O (10 ml) and acidified with 1N HCl to pH˜2. The resulting solution was extracted with 10% MeOH in CH2Cl2 (5×10 ml), dried over MgSO4 and concentrated and dried under vacuum to give yellow solid (0.181 g, 98%). 1H NMR (300 MHz, DMSO-d6) □ 7.67 (1H, d, J=5.09 Hz) 8.41 (1H, s) 8.65 (1H, s) 8.71 (1H, bs); ESIMS (MH+): 309.95.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([NH2:18])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1.N1C(C)=CC=CC=1C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([NH:18][S:2]([CH3:1])(=[O:4])=[O:3])[C:14]([F:16])([F:17])[F:15])=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@@H](c1ccc(Br)cc1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)N[C@@H](c1ccc(Br)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.1 %

Procedure:
Add methanesulfonyl chloride (16.42 mL, 0.21 mol) drop-wise to a mixture of (1S)-1-(4-bromophenyl)-2,2,2-trifluoroethanamine (49 g, 0.19 mol), 4-dimethylaminopyridine (1.18 g, 9.0 mmol), 2,6-lutidine (67 mL, 0.57 mol) in DCM (250 mL) at 0° C. Warm the mixture to ambient temperature and stir at that temperature for 20 hours. Dilute the reaction mixture with DCM (300 mL) and wash it sequentially with 2M HCl (2×200 mL), water (250 mL), then brine (250 mL). Collect the organic phase and dry over magnesium sulphate; filter; and concentrate the filtrate under reduced pressure. Triturate the residue with hexane (200 mL) for 10 min; filter; and dry the solid under reduced pressure to give the title compound as a pale brown solid (60 g, 93% yield, 98% ee). MS (m/z): 332 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:14][CH2:13][CH:12]2[CH:8]1[CH2:9][C:10](=[O:15])[CH2:11]2.C(=O)([O-])[O-:17].[Na+].[Na+].[Mn]([O-])(=O)(=O)=O.[K+]>>[C:2]([CH2:3][CH2:4][CH2:5][CH:6]=[C:7]1[CH2:14][CH2:13][CH:12]2[CH:8]1[CH2:9][C:10](=[O:15])[CH2:11]2)([OH:17])=[O:1]
Reactant: O=C([O-])[O-]
Reactant: O=C1CC2CCC(CCCCCO)C2C1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Product: O=C(O)CCCC=C1CCC2CC(=O)CC12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-(5-Hydroxypent-1-yl)bicyclo[3.3.0]octan-7-one {hexahydro-4-(5-hydroxyheptyl)-2(1H)-pentalenone} (0.5 g, 2.4 mmoles) is mixed with a 10% solution of sodium carbonate (0.51 ml). The reaction is cooled in an ice bath and solution of potassium permanganate (0.48 g dissolved in 12 ml water) is slowly added over 10 minutes. The ice bath is then removed and the reaction mixture stirred at room temperature for 12 hour, after which time the precipitated manganese dioxide is filtered off and the filtrate partitioned between ether. The solution is acidified with dilute sulfuric acid and the organic layer separated. The aqueous phase is extracted with ether (2×20 ml), and the ether extracts combined and dried over anhydrous sodium sulfate. The solvent is removed under vacuum leaving a clear colorless oil. The crude product is chromatographed on silica gel and subsequently kugelrohred under reduced pressure leaving a clear, colorless oil (0.050 g, 0.22 mmoles).
Reaction SMILES: OC1C=CC([C:8]2[NH:9][C:10](=O)[C:11]3[C:16]([CH:17]=2)=[CH:15][C:14](OC)=[CH:13][C:12]=3OC)=CC=1.C([Li])CCC>C1COCC1>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:8][N:9]=1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(O)cc3)cc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc2cnccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a suspension of 2-methyl-4,6-dimethoxy benzoic acid (2.8 g, 14.27 mmol) in CH2Cl2 (30 mL), oxalyl chloride (3.62 g, 28.54 mmol) was added and the mixture was stirred at rt for 16 h. The solvent and excess of oxalyl chloride were removed at reduced pressure. The solid was dissolved in CH2Cl2 (10 mL) and methyl amine hydrochloride (1.33 g, 42.81 mmol) was added on cooling and the mixture was stirred at rt for 4 h. The solvent was removed and the crude product was purified by chromatography by using 5% methanol in CH2Cl2, to give 1.3 g of the amide intermediate in 43% yield. To a solution of the amide intermediate (1.29 g, 6.16 mmol) in THF (30 mL), n-butyl lithium (5.6 mL, 14.18 mmol, 2.5 M solution in hexane) was added slowly under N2 with cooling (ice-salt bath) maintaining the temperature below 20° C. The mixture was stirred for 1 h at 0° C., then cooled to −50° C. and a solution of 4-O-TBDMS-benzonitrile (1.58 g, 6.78 mmol) in THF (10 mL) was added quickly. The cooling bath was removed and allowed to warm to rt and stirred for 16 h at rt. Saturated aqueous NH4Cl solution was added with cooling, and the layers were separated. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to give the crude intermediate, which was purified by chromatography using 5% methanol in CH2Cl2, to give two products (1) 678 mg of isoquinoline in 26% yield and (2) 780 mg of quinalone product in 27% yield. To a suspension of the above quinalone product (2) (780 mg, 1.65 mmol) in ethanol (20 mL), conc. HCl (2 ml) was added and the mixture was heated at 70° C. for 2 h. The reaction mixture was cooled to rt and the solvent was removed and purified by chromatography using 5% methanol in CH2Cl2 to give 3-(4-hydroxyphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (215 mg, 44%). MS (ES) m/z: 297.93 (M); Mp. 245-247° C.
Reaction SMILES: [C@H:1]([OH:10])([C:7]([OH:9])=[O:8])[C@H:2]([OH:6])[C:3]([OH:5])=[O:4].C(O)(=O)C(C(C(O)=O)O)O.N[C@@H](C(O)=O)C(S)(C)C>>[C:7]([OH:9])(=[O:8])[C@@H:1]([C@H:2]([C:3]([OH:5])=[O:4])[OH:6])[OH:10]
Reactant: O=C(O)[C@@H](O)[C@@H](O)C(=O)O
Agent: CC(C)(S)[C@@H](N)C(=O)O
Agent: O=C(O)C(O)C(O)C(=O)O
Product: O=C(O)[C@H](O)[C@@H](O)C(=O)O

Procedure:
Via chiral HPLC the absolute amounts of meso-tartaric acid and DL-tartaric acid were determined. (Column used: Chirex 3126 (D)-penicillamine (ligand exchange)) (see Table 4).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]([OH:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)[CH3:4].F[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1.O>CN(C=O)C>[CH2:3]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]([O:17][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)[CH3:4]
Reactant: CCc1cc2cc(OC)ccc2c(O)c1-c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc2cc(OC)ccc2c(Oc2ccc(C=O)cc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.8 %

Procedure:
To a suspension of NaH (60% in mineral oil, 78 mg, 1.95 mmol) in DMF (15 mL) at 0° C. was added a solution of 3-ethyl-6-(methyloxy)-2-phenyl-1-naphthalenol (57) (0.52 g, 1.86 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 10 min. 4-Fluorobenzaldehyde (0.47 g, 3.72 mmol) in DMF (3 mL) was added and the resulting mixture was heated at 70° C. for 36 h. Cooled to room temperature, the mixture was poured into water (50 mL) and extracted with EtOAc. The extracts were combined and washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a dark brown oil. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (25:1) to give 0.61 g (86%) of compound 58 as a light yellow foam. 1H NMR (400 MHz, CDCl3): δ 1.13 (t, J=7.5 Hz, 3H), 2.57 (q, J=7.5 Hz, 2H), 3.94 (s, 3H), 6.68 (d, J=8.6 Hz, 2H), 7.06 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 7.08-7.15 (m, 2H), 7.17-7.27 (m, 4H), 7.58-7.64 (m, 3H), 7.67 (d, J=9.2 Hz, 1H), 9.79 (s, 1H). LCMS (APCI): m/z 383 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][C:28]4[CH:37]=[C:36]5[C:31]([CH2:32][CH2:33][NH:34][CH2:35]5)=[CH:30][CH:29]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:39][CH2:40][O:41][Si](C(C)(C)C)(C)C.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH2:27][C:28]3[CH:37]=[C:36]4[C:31]([CH2:32][CH2:33][N:34]([CH2:39][CH2:40][OH:41])[CH2:35]4)=[CH:30][CH:29]=3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(Cc3ccc4c(c3)CNCC4)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnn2c(Cc3ccc4c(c3)CN(CCO)CC4)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 50 °C
Reaction time: 8 h
Yield: 14.7 %

Procedure:
5-(2-Benzyl-2H-indazol-6-yl)-7-(1,2,3,4-tetrahydro-isoquinolin-7-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (200 mg, 0.41 mmol) was dissolved in DMF (4 mL) and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (0.15 g, 0.62 mmol) was added followed by triethylamine (0.17 mL, 1.26 mmol) and sodium iodide (0.006 g, 0.004 mmol). The resulting mixture was stirred at 50° C. overnight. The mixture was concentrated, dried using a vacuum pump for 2 hours. The residue was dissolved in 2 mL dichloromethane and TFA (0.30 mL) was added and the resulting solution was stirred overnight, concentrated and purified by preparative HPLC to afford 32 mg (15%) of the title compound. 1H-NMR (CD3OD-d4) 8.36-8.33 (m, 1 H), 7.81 (s, 1 H), 7.76 (dd, 1H), 7.63-7.61 (m, 1 H), 7.38-7.29 (m, 5 H), 7.19 (dd, 1 H), 7.11-6.98 (m, 3 H), 6.46 (s, 1 H), 5.65 (s, 2 H), 4.24 (s, 2 H), 3.76 (t, 2 H), 3.67 (s, 2 H), 2.93-2.79 (m, 4 H), 2.69 (t, 2 H); LC-MS [M+H]+=530.3, RT=2.36 min.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1([CH2:16][O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH:12]1[CH:14]=C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl.C1CCCCC1.C(OCC)(=O)C>[C:18]([O:17][CH2:16][C:11]1([CH2:10][O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH:12]1[CH2:14][OH:26])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[O+][O-]
Reactant: C=CC1CC1(COC(=O)c1ccccc1)COC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(OCC1(COC(=O)c2ccccc2)CC1CO)c1ccccc1
Reaction time: 1.5 h
Yield: 36 %

Procedure:
A solution of 11 g (33 mmoles) of 1,1-bis(benzoyloxymethyl)-2-vinylcyclopropane in 200 ml of CH2Cl2 was cooled to -70° and stirred while a stream of O3 was introduced over a period of 30 minutes, at which time a permanent blue color was obtained. TLC in cyclohexane-ethyl acetate (4:1) indicated that the starting material was no longer present and several new more polar products (Rf 0.55, 0.5, 0.47, 0.4) had been formed. The reaction mixture was treated with 6.6 g (174 mmoles) of NaBH4 and the cooling bath was removed. Stirring was continued for 1.5 hours and TLC showed the formation of a more polar (Rf 0.2) product. The reaction mixture was acidified by the continuous dropwise addition of 200 ml of 2N HCl. The mixture was concentrated to remove the CH2Cl2 and the aqueous layer was extracted with three 100 ml portions of EtOAc which was washed with 50 ml of water, 100 ml of saturated NaHCO3 and 50 ml of saturated NaCl. The EtOAc layer was dried (MgSO4), filtered and concentrated to give 11.3 g of crude product which was chromatographed on 600 ml of silica gel; first eluting with 2400 ml of cyclohexane-ethyl acetate (5:2) and finally with 1600 ml of 2:1 cyclohexane ethyl acetate. Fractions containing only product were combined and concentrated to give 4 g (36%) of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]([CH3:15])[CH2:13][C:12]3[C:8]4[C:9](=[N:27][CH:28]=[CH:29][C:7]=4[C:6]=2[CH:30]=1)[N:10](S(C1C=CC(C)=CC=1)(=O)=O)[C:11]=3[I:16].[OH-].[Na+].O>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]([CH3:15])[CH2:13][C:12]3[C:8]4[C:9](=[N:27][CH:28]=[CH:29][C:7]=4[C:6]=2[CH:30]=1)[NH:10][C:11]=3[I:16]
Reactant: Cc1ccc(S(=O)(=O)n2c(I)c3c4c(ccnc42)-c2cc(F)ccc2N(C)C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN1Cc2c(I)[nH]c3nccc(c23)-c2cc(F)ccc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of Example 41D (2.0 g, 3.75 mmol) in dioxane (30 mL) was added 1M aqueous sodium hydroxide (15 mL, 15 mmol) and the mixture was stirred at 50° C. overnight. Water was added and the precipitate was filtered, washed with water and hexanes and dried in vacuo to afford the title compound. LC-MS: 380 (M+H)+.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1>ClCCl>[Cl:14][C:15]1[N:20]=[C:19]([NH:4][CH:1]([CH3:3])[CH3:2])[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1nc(Cl)ncc1[N+](=O)[O-]
Yield: 90.4 %

Procedure:
Isopropylamine (4.5 ml) and N,N-diisopropylethylamine (13.2 ml) were dissolved into 150 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitropyrimidine (10.0 g) in dichloromethane (30 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for half an hour. Purification was conducted by a column chromatography to obtain a bright-yellow solid (10.1 g) in a yield of 90.4%. 1H NMR (400 MHz, CDCl3): δ 9.03 (s, 1H), 8.24 (s, 1H), 4.53 (m, 1H), 1.34 (d, J=6.8 Hz, 6H) ppm.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=O.[CH2:15]([NH2:18])[CH2:16][NH2:17]>>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([C:5]2[NH:17][CH2:16][CH2:15][N:18]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: NCCN
Reactant: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Product: Cc1cccc(C2=NCCN2)c1[N+](=O)[O-]
Temperature: 190 °C

Procedure:
A solution of methyl 3-methyl-2-nitrobenzoate 3.13 g (16.1 mmol) in ethylenediamine (15 mL) was heated at reflux for 1.5 hours, at which point the solvent was removed at 130° C. under reduced pressure. The residue was then heated at 190° C. for 1.25 hours before being cooled on ice and purified by flash column chromatography (silica gel, 1% to 10% methanol in dichloromethane) to give the title compound of Step A (0.35 g) as a brown oil.