Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[CH:8][CH:9]=2)[C:4](=[O:19])[N:3]1[CH2:20][C:21]([O:23][CH3:24])=[O:22].[CH2:25](O)[CH2:26][CH2:27]C>CCOC(C)=O>[OH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[CH:8][CH:9]=2)[C:4]([OH:19])=[C:20]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[N:3]=1
Reactant: CCCCO
Reactant: COC(=O)CN1C(=O)c2ccc(Oc3ccccc3C)cc2C1=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1nc(O)c2ccc(Oc3ccccc3C)cc2c1O
Temperature: 95 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 2-(1,3-dioxo-5-(o-tolyloxy)isoindolin-2-yl)acetate (10.0 g, 30.8 mmol) in n-butanol (206 mL) at 95° C. was added 1 N sodium n-butoxide solution (62.0 mL, 62.0 mmol). The resulting mixture was stirred at 95° C. for 2 hours before cooling to room temperature. The solvent was partially removed and the residue was diluted with EtOAc (200 mL) and 2 N HCl (40 mL). The resulting mixture was stirred vigorously for 15 minutes at room temperature and the precipitation was collected by filtration. The filter cake was washed with H2O and then dried at 70° C. in vacuo to give a yellow solid. The solid obtained was further suspended in EtOAc (300 mL) and the slurry was heated to reflux with stirring for 2 hours. After cooling to room temperature, the precipitate was collected by filtration and then dried in vacuo to give the title compound in 1.6 g. 1H NMR (CDCl3, 200 MHz): δ=10.38 (s, 1H), 8.42-8.32 (m, 2H), 7.43 (s, 1H), 7.34-7.10 (m, 3H), 7.02 (d, 1H, J=7.6 Hz), 4.39 (t, 2H, J=6.6 Hz)), 2.20 (s, 3H), 1.84-1.38 (m, 4H), 0.99 (t, 3H, J=7.2 Hz).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]2=[O:29])=[CH:2]1.[CH:30]1(O)[CH2:35]CC[CH:32]([OH:36])[CH2:31]1>CN(C)C(=O)C.[Zn]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH:27]3[CH2:35][CH2:30][CH2:31][CH:32]([OH:36])[CH2:28]3)=[O:25])[C:12]2=[O:29])=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Reactant: OC1CCCC(O)C1
Agent: [Zn]
Solvent: CC(=O)N(C)C
Product: O=C(OC1CCCC(O)C1)C1=C(Nc2ccc(F)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 8.6 %

Procedure:
A solution of the compound (0.10 g, 0.25 mmol) of Example 21, 1,3-cyclohexanediol (0.44 g, 3.8 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.018 g, 0.019 mmol) in N,N-dimethylacetamide (1.0 mL) was stirred at 130° C. for 1.5 days. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.010 g, y. 13%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:20][N:8]2[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.O.[NH2:32][NH2:33]>CO>[CH2:12]([O:11][C:10]1[C:9](=[O:19])[N:8]2[CH:20]=[C:21]([CH2:24][N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH:22]=[CH:23][C:7]2=[N:6][C:5]=1[C:3]([NH:32][NH2:33])=[O:2])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1nc2ccc(CN3CCOCC3)cn2c(=O)c1OCc1ccccc1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)c1nc2ccc(CN3CCOCC3)cn2c(=O)c1OCc1ccccc1
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a solution of 3-benzyloxy-7-morpholin-4-ylmethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid methyl ester (AU2007001980) (1 g, 2.44 mmol) in methanol (15 ml), hydrazine hydrate (1.44 g, 85% content, 24.4 mmol) was added at room temperature. The mixture was stirred for 1 hour. After most of the solvent was evaporated under reduced pressure, 15 ml of water was added. The mixture was extracted with dichloromethane three times, and the extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness to give the titled product (807 mg, 80.7%).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1.C1C(=O)N([Br:26])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:26][CH2:11][C:10]1[C:5]2[C:6](=[N:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:9]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2nc(F)ccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1nc(CBr)c2ccc(F)nc21
Temperature: 25 °C

Procedure:
A stirring solution of 8.88 g (35.2 mmol) of 37-4, 6.88 g (38.7 mmol) of NBS and 851 mg (3.52 mmol) of benzoyl peroxide in 250 mL of CCl4 was heated to reflux for 6 hours. The reaction was stopped after a 66% conversion of starting material as determined by LC/MS. The reaction mixture was cooled to room temperature, filtered through a pad of Celite to remove precipitated succinimide, and the filtrate concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-70% ethyl acetate/hexanes) to afford the title product as a solid. 1H NMR (CDCl3): 1.75 (s, 9H), 4.75 (s, 2H), 7.00 (d, 1H), 8.30 (t, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([NH:22]C=O)[CH:6]=[C:7]([CH2:11][P:12]([O:18]C(C)C)([O:14]C(C)C)=[O:13])[CH2:8][CH2:9][F:10])[CH3:2].C[Si](C)(C)Br.C(O)C>ClCCl>[CH2:1]([O:3][C:4](=[O:25])[CH:5]([NH2:22])[CH:6]=[C:7]([CH2:11][P:12]([OH:14])([OH:18])=[O:13])[CH2:8][CH2:9][F:10])[CH3:2]
Reactant: CCOC(=O)C(C=C(CCF)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(N)C=C(CCF)CP(=O)(O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.52 g (1.36 mmol) of 4-diisopropylphosphonomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester is dissolved in 3.5 ml of dichloromethane, and 0.7 ml (5.45 mmol) of trimethylbromosilane is added dropwise at room temperature. The mixture is left to stand at room temperature for 24 hours, 3.5 ml of ethanol are added dropwise, the mixture is left to stand for a further 24 hours and is concentrated by evaporation in a rotary evaporator, the residue is dissolved in 2.4 ml of ethanol, and a mixture of 0.6 ml of propylene oxide and 0.6 ml of ethanol is added. A suspension forms, which is stirred for a further 2 hours at room temperature and for 2 hours with ice cooling and is then filtered with suction. 2-amino-6-fluoro-4-phosphonomethyl-hex-3-enoic acid ethyl ester having a melting point of 222° (decomp.) is obtained.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:13][C:12]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[C:21]([O:35][CH:36]4[CH2:39][CH2:38][CH2:37]4)=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]([C:30]([O:32][CH3:33])=[O:31])[C@@H:25]([CH3:34])[CH2:24][CH2:23]4)[N:19]=2)([OH:14])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:40]I.O>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:13][C:12]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[C:21]([O:35][CH:36]4[CH2:37][CH2:38][CH2:39]4)=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]([C:30]([O:32][CH3:33])=[O:31])[C@@H:25]([CH3:34])[CH2:24][CH2:23]4)[N:19]=2)([O:14][CH3:40])[CH2:11]1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CI
Reactant: COC(=O)N1c2ccc(-c3csc(C4(O)CN(C(=O)OC(C)(C)C)C4)n3)c(OC3CCC3)c2CC[C@@H]1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N1c2ccc(-c3csc(C4(OC)CN(C(=O)OC(C)(C)C)C4)n3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.012 g, 0.30 mmol) was added to a solution of (S)-methyl 6-(2-(1-(tert-butoxycarbonyl)-3-hydroxyazetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.100 g, 0.19 mmol) in N,N-dimethylformamide (2 mL), and the resulting mixture was stirred for 30 min at room temperature. Methyl iodide (0.014 mL, 0.23 mmol) was added, and the resulting mixture s stirred overnight at room temperature. The reaction mixture was poured into 10 mL of water, extracted with 3×10 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-TLC with ethyl acetate/petroleum ether (13). This resulted in 70 mg (68%) of (S)-methyl 6-(2-(1-(tert-butoxycarbonyl)-3-methoxyazetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate as colorless oil. MS (ESI, pos. ion) m/z 544 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=3)[C:6]=2[N:7]=1.[CH3:20][NH2:21]>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH3:20])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=3)[C:6]=2[N:7]=1
Reactant: CN
Reactant: Fc1cc(F)cc(C2CCc3c(Cl)nc(Cl)nc32)c1
Solvent: CO
Product: CNc1nc(Cl)nc2c1CCC2c1cc(F)cc(F)c1
Yield: 30.6 %

Procedure:
A solution of 2,4-dichloro-7-(3,5-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (200 mg, 0.664 mmol) and methanamine (0.664 mL, 1.328 mmol) in MeOH (3 mL) was stirred at rt for 1 h. The solvent was removed in vacuum and the crude product was purified by column chromatography on silica gel to give 2-chloro-7-(3,5-difluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (60 mg, 0.203 mmol, 30.5% yield). LC-MS (M+H)+=296.1.
Reaction SMILES: [C:1]1([C:7]2[CH:25]=[C:24]3[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]4[S:23][CH2:22][C:16]5([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]5)[O:15][C:14]=43)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1>>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][N:19]2[CH2:20][CH2:21][C:16]3([O:15][C:14]4[C:24]5[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]=4[S:23][CH2:22]3)=[CH:9][CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:25]=5)[CH2:17][CH2:18]2)=[CH:31][CH:32]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1C(=O)c2ccc(-c3ccccc3)cc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccc(-c3ccccc3)cc2C2=C1SCC1(CCN(Cc3ccc(F)cc3)CC1)O2

Procedure:
Compound 148 was synthesized using 9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione and 1-(bromomethyl)-4-fluorobenzene and conditions outlined in procedure V. M.p.=197-198° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.95 (m, 2H), 7.87 (d, J=7.6 Hz, 1H), 7.74 (d, J=6.8 Hz, 2H), 7.60 (m, 2H), 7.52 (m, 1H), 7.34 (m, 2H), 7.10 (t, J=8 Hz, m, 2H), 3.5 (s, 2H), 3.10 (s, 2H), 2.71 (m, 2H), 2.39 (m, 2H), 2.03 (m, 2H), 1.84 (m, 2H); LCMS: 486 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([O:8][C:9](=[O:18])[NH:10][CH2:11][C@@H:12]2[CH2:17][C@@H:16]3[C@@H:14]([CH2:15]3)[NH:13]2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C([O-])=O.CCN(CC)CC.[N:34]([C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]([C:46]([NH2:48])=[O:47])[CH:38]=1)=[C:35]=[O:36]>C1COCC1>[Cl:1][C:2]1[C:3]([F:19])=[C:4]([O:8][C:9](=[O:18])[NH:10][CH2:11][C@@H:12]2[CH2:17][C@@H:16]3[C@@H:14]([CH2:15]3)[N:13]2[C:35](=[O:36])[NH:34][C:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([C:46](=[O:47])[NH2:48])[CH:38]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)n1cc(N=C=O)c2ccccc21
Reactant: O=C(NC[C@@H]1C[C@H]2C[C@H]2N1)Oc1cccc(Cl)c1F
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)n1cc(NC(=O)N2[C@H](CNC(=O)Oc3cccc(Cl)c3F)C[C@H]3C[C@H]32)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of [(1R,3S,5R)-1-(2-aza-bicyclo[3.1.0]hex-3-yl)methyl]-carbamic acid 3-chloro-2-fluoro-phenyl ester, trifluoroacetate (60.0 mg, 0.211 mmol) and Et3N (88 μl, 0.62 mmol) in THF (5 mL) was added 3-isocyanato-indole-1-carboxylic acid amide (43.0 mg, 0.211 mmol; prepared as described in Scheme A1). The solution was stirred at RT under a nitrogen atmosphere for 3 days. Purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min) afforded after lyophilization of the purified HPLC fractions the title compound. MS (LC/MS): 486.0 [M+H]+; tR (HPLC conditions k): 3.57 min.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2].Cl[C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([CH2:23][N:24]3[CH2:29][CH2:28][N:27]([CH:30]4[CH2:33][CH2:32][CH2:31]4)[CH2:26][CH2:25]3)[N:19]2[CH3:22])=[C:15]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[N:14]=1>>[CH:30]1([N:27]2[CH2:26][CH2:25][N:24]([CH2:23][C:18]3[N:19]([CH3:22])[C:20]4[C:16]([N:17]=3)=[C:15]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[N:14]=[C:13]([N:7]3[C:6]5[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=5[N:4]=[C:3]3[CH2:1][CH3:2])[N:21]=4)[CH2:29][CH2:28]2)[CH2:33][CH2:32][CH2:31]1
Reactant: Cn1c(CN2CCN(C3CCC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CCc1nc2ccccc2[nH]1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C4CCC4)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-ethylbenzimidazole and 4-(2-chloro-8-((4-cyclobutylpiperazin-1-yl)methyl)-9-methyl-9H-purin-6-yl)morpholine were reacted to give 444. LCMS m/z: 516.3 (MH+)
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[C:38]([CH3:47])([CH3:46])[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].CCOC(/N=N/C(OCC)=O)=O.C([O-])(=O)C(C)C>C1COCC1>[C:42]([O:41][C:39](=[O:40])[C:38]([CH3:47])([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][C:7]1[CH:16]=[CH:17][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:46])([CH3:45])([CH3:44])[CH3:43]
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2O)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)O
Agent: CC(C)C(=O)[O-]
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 95.5 %

Procedure:
To a solution of 388A (1.70 g, 7.35 mmol) and PPh3 (5.80 g, 22.1 mmol) in anhydrous THF (35 ml) was added t-butyl 2-hydroxyisobutyrate (3.83 ml, 22.1 mmol) followed by DEAD (3.47 ml, 22.1 mmol), the reaction mixture was stirred at rt for 19 h. More reagents PPh3 (1.16 g, 4.41 mmol), isobutyrate (0.77 ml, 4.41 mmol) and DEAD (0.69 ml, 4.41 mmol) were added, and the mixture was stirred for another 50 h, concentrated and purified by silica gel flash column chromatography to afford 388B (2.62 g, 96%) as a light pink crystalline solid (50%-80% CH2Cl2-hexanes).
Reaction SMILES: [C:1]([CH2:4][C:5]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])([OH:12])[CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1)(=[O:3])[NH2:2].[H-].[Na+].Cl[C:24]([O:26][CH3:27])=[O:25]>O1CCCC1>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:5]([OH:12])([CH2:4][C:1](=[O:3])[N:2]([C:24]([O:26][CH3:27])=[O:25])[C:24]([O:26][CH3:27])=[O:25])[CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1
Reactant: COC(=O)Cl
Reactant: NC(=O)CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N(C(=O)CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl)C(=O)OC
Reaction time: 1 h
Yield: 4.8 %

Procedure:
3-Carbamoyl-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (0.94 g., 3 mmole) was added to a suspension of oil-free sodium hydride (0.14 g., 5.8 mmole) in dry tetrahydrofuran (10 ml). The suspension was stirred for one hour and then a solution of methyl chloroformate (0.6 g., 6.3 mmole) in dry tetrahydrofuran (10 ml) was added dropwise over 15 minutes. The mixture was stirred at room temperature for three hours and then the solvent was evaporated in vacuo. The residue was partitioned between saturated aqueous sodium bicarbonate solution (10 ml) and ethyl acetate (40 ml), and the organic phase was separated, washed with brine (10 ml), dried (MgSO4) and evaporated. The residue was chromatographed on silica eluting with ethyl acetate/methanol 95:5 (v:v), and the fractions containing the product were combined and evaporated and recrystallized from ethyl acetate-hexane to give the title compound, (62 mg, 5%), m.p. 155°-156° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]([C:28]1[S:29][CH:30]=[CH:31][N:32]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26])=[N:15][CH:14]=[C:13]2[F:27])(=[O:9])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:46][C:47]#[N:48]>CN(C=O)C.C(OCC)(=O)C>[C:47]([CH2:46][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:16]1[C:17]2[C:12](=[CH:11][C:10]([S:7]([N:6]([CH2:5][C:4]3[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:3]=3[O:2][CH3:1])[C:28]3[S:29][CH:30]=[CH:31][N:32]=3)(=[O:8])=[O:9])=[CH:19][CH:18]=2)[C:13]([F:27])=[CH:14][N:15]=1)#[N:48]
Reactant: N#CCBr
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4O)ncc(F)c3c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4OCC#N)ncc(F)c3c2)c(OC)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
N-(2,4-dimethoxybenzyl)-4-fluoro-1-(2-hydroxyphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.078 g, 0.141 mmol) was dissolved in DMF (0.7 mL) and cesium carbonate (0.148 g, 0.456 mmol) was added, followed by bromoacetonitrile (10.58 μl, 0.152 mmol). The reaction was heated to 60° C. and stirred overnight. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 12 g, gradient elution 0-100% EtOAc:Heptane) to afford 1-(2-(cyanomethoxy)phenyl)-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide. (ESI) 591.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]1[CH2:15][CH2:14][C:12](=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].[NH:16]1[CH2:19][CH2:18][CH2:17]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[N:16]1([CH:12]2[CH2:14][CH2:15][CH:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:4])([CH3:3])[CH3:1])[CH2:10][CH2:11]2)[CH2:19][CH2:18][CH2:17]1
Reactant: C1CNC1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(N2CCC2)CC1
Reaction time: 0.25 h
Yield: 33.6 %

Procedure:
To a stirred solution of N-4-boc-aminocyclohexanone (500 mg, 2.34 mmol) in DCM (7 mL) was added azetidine (220 ul, 3.26 mmol) and the mixture stirred for 15 minutes. Sodium acetate (193 mg, 2.34 mmol) was added, followed by careful addition of sodium triacetoxyborohydride (746 mg, 3.52 mmol) The reaction mixture was stirred, at ambient temperature, under nitrogen for 3 hours, diluted with DCM to 25 mL total volume and filtered. The filtrate was poured onto and SCX-2 (10 g) cartridge and the cartridge washed with methanol (75 mL) then eluted with 2M ammonia in methanol (75 mL). The ammoniacal solution was evaporated, to give a waxy off white solid (200 mg). The SCX cartridge wash was resubmitted to a second SCX-2 cartridge (10 g) and the cartridge again washed with methanol (75 mL) and eluted with 2M ammonia/methanol (75 mL). The ammoniacal solution was evaporated to a colourless gum. Solid products were combined and triturated with isohexane. The resultant crystalline solid was collected by suction filtration and dried to yield the title compound as a white solid (104 mg). A second crop crystallised from the filtrate. This was again collected and dried to give the title compound as fine white needles (260 mg).
Reaction SMILES: C([N:11]1[CH2:25][CH2:24][N:14]2[C:15]3[C:20]([NH:21][C:22](=[O:23])[CH:13]2[CH2:12]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)(OCC1C=CC=CC=1)=O.Cl.[H][H]>[Pd].C(O)C>[CH2:24]1[N:14]2[C:15]3[C:20]([NH:21][C:22](=[O:23])[CH:13]2[CH2:12][NH:11][CH2:25]1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: [H][H]
Reactant: O=C1Nc2ccccc2N2CCN(C(=O)OCc3ccccc3)CC12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C1Nc2ccccc2N2CCNCC12

Procedure:
A mixture of 3.0 g. of 3-carbobenzoxy-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one, 2 g. of hydrogen chloride, 3 g. of 10% palladium on carbon and 200 ml. of ethanol is hydrogenated on a Parr apparatus for 18 hours at 46 p. s. i. hydrogen pressure. The catalyst is filtered and the filtrate is concentrated. The residue is recrystallized from ethanol to give 0.55 g. of the product as the hydrogen chloride salt, m.p. 288°-290°.
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:29])[C@:7]1([CH3:28])[C@:23]2([CH3:24])[CH:10]([CH:11]3[C:20](=[CH:21][CH2:22]2)[C@:19]2([CH3:25])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][C@H:8]1[CH3:27])(=O)C.C[O-].[Na+]>CO>[OH:4][CH2:5][C:6]([C@:7]1([CH3:28])[C@:23]2([CH3:24])[CH:10]([CH:11]3[C:20](=[CH:21][CH2:22]2)[C@:19]2([CH3:25])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][C@H:8]1[CH3:27])=[O:29]
Reactant: CC(=O)OCC(=O)[C@@]1(C)[C@H](C)CC2C3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CC2C3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]2(C)[C@@]1(C)C(=O)CO

Procedure:
2-oxo-2-((10S,13S,16R,17S)-10,13,16,17-tetramethyl-3-oxo-2,3,6,7,8,10,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl acetate (144 g) is stirred in 1500 ml methanol and treated with sodium methoxide (25%, 5 ml) for 30 minutes. The mixture is partitioned between methylene chloride and sodium bicarbonate. The organic phase is separated and washed with sodium bicarbonate, dried over sodium sulfate, and concentrated to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH2:15])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[C:18](=S)=[S:19]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:18]([SH:19])=[N:15][N:14]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ncc(-c2cccc(F)c2)nn1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Fc1cccc(-c2cnc3nnc(S)n3n2)c1
Temperature: 25 °C
Yield: 50 %

Procedure:
To a suspension of [6-(3-fluoro-phenyl)-[1,2,4]triazin-3-yl]-hydrazine (400 mg, 0.789 mmol) in ethanol (12 mL) was added 2 N aqueous potassium hydroxide (1 mL) followed by carbon disulfide (1 mL). The reaction mixture was stirred at reflux for 1 h, then cooled to room temperature and concentrated in vacuo. The residue was dissolved with 1 N aqueous potassium hydroxide, heated and sonicated then the insolubles were filtered. The filtrate was acidified to pH 2-3 with 1 N aqueous HCl. The resulting precipitate was filtered, washed with water, and dried in vacuo to return title compound as an orange solid (242 mg, 50% yield): 1H NMR (DMSO-d6): δ 7.52 (dt, 1H), 7.70 (dt, 1H), 7.97-8.04 (m, 2H), 9.36 (s, 1H), 14.05 (s, 1H); MS (m/z) 248 [M+H+]+.
Reaction SMILES: [F:1]/[C:2](=[C:5](/[C:8]1[C:17]([O:18][CH2:19][O:20][CH3:21])=[CH:16][C:15]2[C:14]([CH3:23])([CH3:22])[CH2:13][CH2:12][C:11]([CH3:25])([CH3:24])[C:10]=2[CH:9]=1)\[CH2:6][CH3:7])/[CH:3]=O.[OH-].[Na+].[CH3:28][C:29]([CH3:31])=[O:30]>>[F:1]/[C:2](=[C:5](/[C:8]1[C:17]([O:18][CH2:19][O:20][CH3:21])=[CH:16][C:15]2[C:14]([CH3:22])([CH3:23])[CH2:13][CH2:12][C:11]([CH3:24])([CH3:25])[C:10]=2[CH:9]=1)\[CH2:6][CH3:7])/[CH:3]=[CH:28]/[C:29](=[O:30])[CH3:31]
Reactant: CC/C(=C(\F)C=O)c1cc2c(cc1OCOC)C(C)(C)CCC2(C)C
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC/C(=C(F)/C=C/C(C)=O)c1cc2c(cc1OCOC)C(C)(C)CCC2(C)C
Reaction time: 5 h
Yield: 95 %

Procedure:
To a solution of (E)-2-fluoro-3-(3-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-pent-2-enal (Intermediate 17, 880 mg, 2.5 mmol) in acetone (10 mL) was added 1M NaOH (7.5 mL) at 0° C. The mixture was stirred for 5 h, quenched with 2M H2SO4 (10 mL), and was stirred for 30 min. The mixture was then extracted with EtOAc (×3). The combined organic layer was washed successively with brine, NaHCO3, was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5% EtOAc-hexane) to give the title compound as a yellow solid (930 mg, 95%).