Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C1C(=O)N([Cl:27])C(=O)C1>CN(C=O)C>[Cl:27][C:7]1[CH:6]=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[C:8]=1[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[O:18][CH3:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccnn1C(C)C
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1-c1c(Cl)cnn1C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.1 %

Procedure:
To a stirred, ice-cooled solution of 1-isopropyl-5-(2-methoxy-5-nitro-phenyl)-1H-pyrazole from Example 1.81, Step C (1.0 g, 3.83 mmol) in DMF (10 mL) was added NCS (0.56 g, 4.22 mmol) over a period of 10 minutes. The reaction mixture was warmed to ambient temperature and stirred at 55° C. for 6 h. The reaction mixture was cooled and poured into an ice-water mixture with vigorous stirring to form a white solid, which was filtered and washed with cold water until free of DMF. The solid was dried in vacuo to yield 4-chloro-1-isopropyl-5-(2-methoxy-5-nitro-phenyl)-1H-pyrazole (1.1 g, 97%). LCMS m/z (%)=296 M+H+, (35Cl, 100), 298 (37Cl, 28.5). 1H NMR (400 MHz, CDCl3) δ: 8.4 (dd, J1=9.09 Hz, J2=2.78 Hz, 1H), 8.19 (d, J=2.8 Hz), 7.6 (s, 1H), 7.14 (d, J=9.18 Hz, 1H), 4.10 (m, 1H), 3.94 (s, 3H), 1.49 (d, J=6.62 Hz, 3H), 1.36 (d, J=6.62 Hz, 3H).
Reaction SMILES: [F:1][CH:2]([F:9])[C:3](=[O:8])[CH2:4][C:5](=O)[CH3:6].O.[NH2:11][NH2:12]>O1CCCC1>[F:1][CH:2]([F:9])[C:3]1([OH:8])[NH:12][N:11]=[C:5]([CH3:6])[CH2:4]1
Reactant: CC(=O)CC(=O)C(F)F
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: CC1=NNC(O)(C(F)F)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1,1-difluoropentane-2,4-dione (2.5 g, 0.018 mol) in tetrahydrofuran (32 mL) was added hydrazine hydrate (0.98 mL, 0.020 mol) in tetrahydrofuran (32 mL) dropwise. The reaction was stirred at 25° C. for 16 hours and then concentrated in vacuo. The residue was used in the next reaction without further purification. 1H NMR (CDCl3): δ 5.68-5.96 (t, 1H), 5.50-5.80 (br s, 1H), 2.98 (dd, 1H), 2.68 (dd, 1H), 2.01 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=O)[CH2:24][C:25](=[O:32])[CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=[S:43])[CH2:24][C:25](=[O:32])[CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)CC(=O)C1CCOCC1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(=O)C1CCOCC1

Procedure:
In analogy to the procedure described in example 192f, (2S,4R)-1-[3-oxo-3-(tetrahydro-pyran-4-yl)-propionyl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with Lawesson's reagent to give the title compound as yellow oil. MS (ESI): m/z=508.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Cl[CH2:21][C:22](=O)[CH2:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][C:25]1=[O:37].CCN(C(C)C)C(C)C>C(O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]2[S:10][CH:21]=[C:22]([CH2:23][N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:26][C:25]3=[O:37])[N:11]=2)=[N:6][CH:7]=1
Reactant: NC(=S)Nc1ncc(Br)cc1Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)CCl)C(=O)C1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2csc(Nc3ncc(Br)cc3Oc3ccc(F)cc3)n2)C(=O)C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 25.1 %

Procedure:
In a 20 mL scintillation vial equipped with magnetic stirrer 1-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (0.25 g, 0.73 mmol) was suspended in ethanol (5 ml) and tert-butyl 4-(3-chloro-2-oxopropyl)-3-oxopiperazine-1-carboxylate (0.32 g, 1.10 mmol) was added followed by DIEA (0.22 mL, 1.28 mmol). Resulting mixture was heated to 60° C. and agitated for 3 hours. Mixture was then diluted with ethyl acetate and washed with sodium bicarbonate solution, brine, dried and evaporated. Purified by column chromatography on silica gel, eluting with 50-100% ethyl acetate/hexane to give the title compound (0.106 g, 25.1% yield). 1H NMR (CDCl3) δ 1.41 (s, 9H), 2.79-3.42 (m, 6H), 6.55 (s, 2H), 7.03-7.12 (m, 4-H), 8.12 (s, 1H), 8.95 (bs, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:17][C:18]1[C:23]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][N:19]=1>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:8]1[C:4]2[CH:3]=[C:2]([C:21]3[CH:22]=[C:23]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])[C:18]([Cl:17])=[N:19][CH:20]=3)[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7]1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3)c2)OC1(C)C
Reactant: Brc1ccc2ncoc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(-c2ccc3ncoc3c2)cnc1Cl)c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 39.6 %

Procedure:
To a microwave vial equipped with a stirbar and charged with 6-bromobenzo[d]oxazole (0.050 g, 0.25 mmol), cesium carbonate (0.25 g, 0.76 mmol), PdCl2(dppf)*DCM (0.037 g, 0.045 mmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (0.10 g, 0.25 mmol) in THF (3 ml) was added water (0.5 ml). The vial was capped and placed into CEM Microwave for 10 minutes at 100° C., while 100 watts of energy was supplied via Powermax® (Simultaneous heating while cooling technology). The progress of the reaction was monitored by LC/MS, which showed desired material in the mixture. The mixture was diluted with water and the organic layer was extracted with DCM and brine solution. The organics were collected, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was recrystallized from 5:1 DCM/MeOH and Hexanes to give N-(5-(benzo[d]oxazol-6-yl)-2-chloropyridin-3-yl)-4-fluorobenzenesulfonamide (0.040 g, 39% yield) as a tan crystalline solid. MS (ESI pos. ion) m/z: 404 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:7][C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(Br)cc1
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: Brc1ccc(C=Cc2ccc(Br)cc2)cc1

Procedure:
To a three neck 50 ml round bottom, 4-bromostyrene (14.490 g, 0.0786 mol) was added. To the solution, a magnetic stir bar along with dichloromethane (DCM) (10 mL) were added. To the solution, Grubb's catalyst (0.500 mg, 5.8×10−4 mol) along with DCM (25 mL) was added. The solution was allowed to react for 24 hours at room temperature. The precipitate was filtered and placed into a vial for storage.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:22]([CH2:34][CH:35]=O)[CH2:23][N:24]([CH3:33])[C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:18]=[CH:19][C:20]=1[Cl:21].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([CH:22]([CH2:34][CH2:35][N:5]2[CH2:6][CH2:7][C:2]([OH:1])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:3][CH2:4]2)[CH2:23][N:24]([CH3:33])[C:25](=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: CN(CC(CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CC(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
A solution of 4-hydroxy-4-phenyl-piperidine (1.99 g) in methanol (20 mL) was cooled to 0° C. and the pH was adjusted to 8 by adding acetic acid. To this solution was added N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide (3.57 g) in methanol (20 mL), and the resulting reaction mixture was treated with sodium cyanoborohydride (0.765 g). Upon warming to the room temperature, the reaction mixture was stirred for 16 hours and treated with saturated sodium bicarbonate solution. The solution was extracted with dichloromethane, dried (anhydrous sodium sulfate) and evaporated. The resulting material was purified by chromatography, with dichloromethane:methanol (90:10) as the eluent, to give the piperidine (2.42 g); NMR (CDCl3): 1.5-2.5 (m, 10), 2.68 (broad, 4), 3.47 (s, 3), 3.5-3.57 (m, 1), 6.8-7.5 (m, 13); MS: m/z=511(M+1). This material was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([OH:16])=O)[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.S(Cl)(Cl)=O.N1CCCCC1.[NH2:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][C:37]=1[F:38])[N:34]([CH2:39][C@H:40]1[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]1)[C:33]([C:47]([CH3:51])([CH3:50])[CH2:48][OH:49])=[CH:32]2.C(N(CC)CC)C>CN(C=O)C.ClCCl>[F:17][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:28][C:29]4[CH:30]=[C:31]5[C:35](=[CH:36][C:37]=4[F:38])[N:34]([CH2:39][C@H:40]4[CH2:44][O:43][C:42]([CH3:45])([CH3:46])[O:41]4)[C:33]([C:47]([CH3:51])([CH3:50])[CH2:48][OH:49])=[CH:32]5)=[O:16])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: O=C(O)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: CC1(C)OC[C@H](Cn2c(C(C)(C)CO)cc3cc(N)c(F)cc32)O1
Solvent: C1CCNCC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](Cn2c(C(C)(C)CO)cc3cc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)c(F)cc32)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.1 %

Procedure:
DMF (3 drops) was added to a stirring mixture of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (187 mg, 0.8 mmol) and thionyl chloride (0.13 mL, 1.8 mmol). After 30 minutes a clear solution had formed. A small amount was mixed piperidine to test that the acid chloride had been formed. The solution was concentrated on the rotovap and then toluene (1 mL) was added and the mixture was concentrated again. The toluene step was repeated once more and the residue was placed on high vacuum for 10 minutes. The acid chloride was then dissolved in dichloromethane (2 mL) and added to a mixture of (S)-2-(5-amino-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-1H-indol-2-yl)-2-methylpropan-1-ol (200 mg, 0.6 mmol) and triethylamine (0.25 mL, 1.8 mmol) in dichloromethane (4 mL). The reaction was stirred at room temperature for 45 minutes. The reaction was washed with 1N HCl solution, saturated NaHCO3 solution and brine, dried over MgSO4 and concentrated to yield the product as a black foamy solid (320 mg, 96%). ESI-MS m/z calc. 560.6, found 561.5 (M+1)+. Retention time 2.05 minutes. NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.53 (s, 1H), 7.42-7.40 (m, 2H), 7.34-7.30 (m, 3H), 6.24 (s, 1H), 4.84 (t, J=5.5 Hz, 1H), 4.51-4.46 (m, 1H), 4.41-4.32 (m, 2H), 4.08 (dd, J=6.0, 8.3 Hz, 1H), 3.71-3.67 (m, 1H), 3.58-3.50 (m, 2H), 1.48-1.45 (m, 2H), 1.40 (s, 3H), 1.34-1.33 (m, 6H), 1.18 (s, 3H) and 1.14-1.12 (m, 2H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:30]I.O>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:13]([O:15][CH3:30])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1CNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)c(CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 3,4-bis((tert-butoxycarbonylamino)methyl)benzoic acid (380 mg, 1 mmol) in THF (5 mL) was added NaH (200 mg, 60%). After stirring at room temperature for 20 min, MeI (4 eq) was added and the resultant solution stirred at room temperature overnight. Water was added and the aqueous phase extracted with EtOAc. The organic phase was washed with brine, dried and concentrated in vacuo to afford methyl 3,4-bis((tert-butoxycarbonylamino)methyl)benzoate (368 mg). The ester was hydrolyzed following the procedure described in step 1e of Example 14 to afford 3,4-bis((tert-butoxycarbonyl(methyl)amino)methyl)benzoic acid (300 mg).
Reaction SMILES: [C:1]([C:3]([S:10][C:11](=[S:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:9])[CH2:4][CH2:5][C:6]([OH:8])=[O:7])#[N:2].CCN=C=NCCCN(C)C.[N:30]([CH2:33][CH2:34][CH2:35]O)=[N+:31]=[N-:32]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([C:3]([S:10][C:11](=[S:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH3:9])[CH2:4][CH2:5][C:6]([O:8][CH2:35][CH2:34][CH2:33][N:30]=[N+:31]=[N-:32])=[O:7])#[N:2]
Reactant: CC(C#N)(CCC(=O)O)SC(=S)c1ccccc1
Reactant: [N-]=[N+]=NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C#N)(CCC(=O)OCCCN=[N+]=[N-])SC(=S)c1ccccc1
Reaction time: 0.08 h
Yield: 84.6 %

Procedure:
4-cyano-4-thiobenzoylsulfanyl-pentanoic acid (CTP, 1.0 g, 3.6 mmol) and DMAP (439.8 mg, 3.6 mmol) were dissolved in anhydrous DCM (50 mL). The solution was stirred for 5 min in ice bath, and EDCI (690.1 mg, 3.6 mmol) was added and stirred for 30 min. 3-Azidopropanol (364 mg, 3.6 mmol) was added and the solution was stirred in ice bath for 30 min and at room temperature for another 8 h. After reaction, the solution was washed with NaHCO3 aq. (satd.) and then H2O. The organic layer was dried (Na2SO4), solvent removed by rotary evaporation and the crude product was purified by column chromatography (silicagel 60 Å, 200-400 mesh, ethyl acetate:hexane, 1:4) to give rose-red oil in 84.6% yield. The structure of this compound was confirmed by 1H NMR and 13C NMR spectroscopy. 1H NMR (300 MHz, CDCl3, δ in ppm): 1.90-1.93 (m, 5 H, —CH2CH2N3, —CH3), 2.45-2.60 (m, 2 H, C(CN)CH2—), 2.68 (m, 2 H, C(CN)CH2CH2—), 3.40 (t, 2 H, —CH2N3), 4.21 (t, 4 H, —OCH2CH2—), 7.39 (m, 2 H, PH-2H), 7.57 (m, 1 H, PH-4H), 7.89 (m, 2 H, PH-3H). 13C NMR (75 MHz, CDCl3, δ in ppm): 222.40, 171.43, 144.74, 133.29, 128.82, 126.91, 118.68, 62.22, 48.34, 45.93, 33.60, 29.98, 28.27, 24.41.
Reaction SMILES: C([O:3][C:4](=[O:23])/[CH:5]=[C:6](\[CH3:22])/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:21])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[C:16]([CH3:19])[O:15][C:14]=1[CH3:20])C.[OH-].[K+].C(O)(=O)C>C(O)C.O>[CH3:22]/[C:6](/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:21])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[C:16]([CH3:19])[O:15][C:14]=1[CH3:20])=[CH:5]\[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(C)/C=C/c1c(C)oc(C)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(/C=C/c1c(C)oc(C)c1C)=C\C=C\C(C)=C\C(=O)O
Temperature: 25 °C

Procedure:
(E,E,E,E)-3,7-Dimethyl-9-(2,4,5-trimethyl-3-furyl)-2,4,6,8-nonatetraenoic acid ethyl ester (2.8 g.) was dissolved in ethanol (50 ml.) treated with potassium hydroxide (1.6 g.) in water (5 ml.) and heated at reflux for 30 minutes. After cooling to room temperature, water followed by acetic acid (until acid) was added and the solids were filtered off. Crystallization from ethylacetate gave pure (E,E,E,E)-3,7-dimethyl-9-(2,4,5-trimethyl-3-furyl)-2,4,6,8-nonatetraenoic acid (1.5 g.) m.p. 213°-214°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C([Li])CCC.Cl[CH2:26][O:27][CH3:28]>C1COCC1>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]([CH2:26][O:27][CH3:28])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: COc1ccc(CNC(=O)OC(C)(C)C)c(OC)c1
Reactant: COCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCN(Cc1ccc(OC)cc1OC)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 104.4 %

Procedure:
Tert-butyl 2,4-dimethoxybenzylcarbamate (3.96 g, 14.8 mmol) was dissolved in THF (74 mL) and cooled to −78° C. The solution was treated with butyl lithium (7.44 mL, 16.3 mmol) dropwise over a five minute period to afford a pale-yellow solution. The solution was allowed to stir for 15 minutes before the chloro(methoxy)methane (1.35 mL, 17.8 mmol) was added dropwise (neat). The reaction was stirred at −78° C. for 10 minutes, then allowed to warm slowly to ambient temperature overnight. The reaction was concentrated in vacuo to afford a yellow gel which was partitioned between half-saturated NH4Cl solution and ether. The aqueous layer was extracted once, and the organics were combined. The organic layer was washed with water, then brine, separated, dried over Na2SO4, filtered, and concentrated in vacuo. 1H NMR supports the desired near-pure (>90%) tert-butyl 2,4-dimethoxybenzyl(methoxymethyl)carbamate (4.81 g, 104% yield) as a pale-yellow oil which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:5]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:4]=2[N:3]=1.[C:21](OC)(=[O:24])[C:22]#[CH:23]>CO>[Cl:20][C:17]1[CH:18]=[CH:19][C:4]2[N:3]3[CH:23]=[CH:22][C:21](=[O:24])[N:1]=[C:2]3[CH2:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])[C:5]=2[CH:16]=1
Reactant: NC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Reactant: C#CC(=O)OC
Solvent: CO
Product: O=c1ccn2c(n1)CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2

Procedure:
In the manner given in Example 1, 2-amino-7-chloro-5-(o-chlorophenyl)-3H-1,4-benzodiazepine, methyl propiolate and methanol were refluxed. The mixture was chromatographed to give 9-chloro-7-(o-chlorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([OH:24])=O)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=2)[CH2:6][C@@H:5]1[CH3:34])(=[O:3])[CH3:2].[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][NH2:39].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>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([NH:39][CH2:38][CH2:37][N:36]([CH3:40])[CH3:35])=[O:24])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=2)[CH2:6][C@@H:5]1[CH3:34])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(CCC(=O)O)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: CN(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3ccc(CCC(=O)NCCN(C)C)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of 3-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)propanoic acid (for a preparation See Intermediate 10)(58 mg, 0.128 mmol) and N1,N1-dimethylethane-1,2-diamine (22.50 mg, 0.255 mmol) in DMF (3 mL) were added HATU (72.8 mg, 0.191 mmol) and DIPEA (0.067 mL, 0.383 mmol). The resulting mixture was stirred for 30 min, then reaction mixture partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc (×3), the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was dissolved in 1:1 MeOH/DMSO and was purified by MDAP (formate). The appropriate fractions were combined and concentrated in vacuo to give 3-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)-N-(2-(dimethylamino)ethyl)propanamide (34.6 mg, 48%) as a viscous colourless oil. LCMS (Formate, 2 min), Rt=0.71 min, MH+=525.
Reaction SMILES: F[C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].SC1SC2C(C(F)(F)F)=CC=CC=2N=1.[Cl:27][C:28]1[S:29]C2C=CC(Cl)=CC=2N=1>>[Cl:27][C:28]1[S:29][C:2]2[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1
Reactant: Clc1ccc2sc(Cl)nc2c1
Reactant: Nc1cccc(C(F)(F)F)c1F
Agent: FC(F)(F)c1cccc2nc(S)sc12
Product: FC(F)(F)c1cccc2nc(Cl)sc12
Temperature: 90 °C

Procedure:
The title compound was prepared from 2-fluoro-3-trifluoromethylaniline via 2-mercapto-7-trifluoromethyl-1,3-benzothiazole as described for 2,5-dichloro-1,3-benzothiazole except that in the first step the reaction mixture was heated to 90° C. for 4 h.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I.CS[C:28]1[NH:29][CH2:30][CH2:31][N:32]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[NH:32]1[CH2:31][CH2:30][N:29]=[C:28]1[N:22]1[CH2:23][CH2:24][N:19]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[CH:12]=[CH:11][N:10]3[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[CH2:20][CH2:21]1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(N3CCNCC3)cccc21
Reactant: CSC1=NCCN1
Agent: I
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccccc1)n1ccc2c(N3CCN(C4=NCCN4)CC3)cccc21
Temperature: 50 °C

Procedure:
A solution of 1-(phenylsulfonyl)-4-piperzin-1-yl-1H-indole (71 mg, 0.18 mmol) in dioxane is treated with 2-methylthio-2-imidazoline hydroiodide (52.7 mg, 0.22 mmol) and N,N-diisopropylethylamine (62 μl, 0.36 mmol), heated at 50° C. for 16 hr., cooled and concentrated in vacuo to give a residue. The residue is purified by HPLC to give the title product, 15 mg, identified by HPLC and mass spectral analyses (2.57 min; 410 M+H) using the LCMS conditions described in Table I.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12]([OH:18])=[N:13][CH:14]=[CH:15][C:16]=2[Cl:17])[CH:9]=1)[C:5]#[N:6].Br[CH2:20][C:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[N:23](C(OC(C)(C)C)=O)[N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12](=[O:18])[N:13]([CH2:20][C:21]3[C:29]4[C:24](=[N:25][CH:26]=[CH:27][CH:28]=4)[NH:23][N:22]=3)[CH:14]=[CH:15][C:16]=2[Cl:17])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccnc2O)c1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccn(Cc3n[nH]c4ncccc34)c2=O)c1
Temperature: 55 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-chloro-5-[(4-chloro-2-hydroxypyridin-3-yl)oxy]benzonitrile (150 mg, 0.534 mmol) in DMF (3 mL) was added tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (167 mg, 0.534 mmol) and potassium carbonate (73.8 mg, 0.534 mmol) and the mixture warmed to 55° C. for 60 minutes. After this time, the reaction mixture was purified by preparative HPLC using a Luna reverse phase column (10μ, C18, 250×21.2 mm) and eluting with a gradient of 5-95% ACN/water (0.5% TFA). The desired fractions were combined and the solvent evaporated in vacuo. The residue was dissolved in TFA (10 mL) and allowed to stand at room temperature for 15 minutes and then the solvent was evaporated in vacuo to give a white solid. This solid was suspended in ACN (10 mL) and the solvent evaporated in vacuo to give the title compound. 1H NMR (DMSO-d6) δ=13.64 (s, 1H), 8.52 (dd, 1H, J=1.6 and 4.5 Hz), 8.15 (dd, 1H, J=1.4 and 8.06 Hz), 7.90 (d, 1H, J=7.5 Hz), 7.73 (dd, 1H, J=1.7 and 1.4 Hz), 7.50 (dd, 1H, J=2.5 and 1.2 Hz), 7.41 (dd, 1H, J=3.2 and 1.9 Hz), 7.18 (dd, 1H, J=4.5 and 8.06 Hz), 6.61 (d, 1H, J=7.5 Hz) and 5.48 (s, 2H) ppm. HRMS (M+1): 412.0372.