Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[NH:24])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH:25]([CH:27]([CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=1)[C:28](OC)=O)=[O:26].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[Cl:23][C:15]1[CH:14]=[C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:28]=[C:27]([CH2:32][C:33]4[CH:34]=[N:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=4)[C:25](=[O:26])[N:24]=3)=[CH:11][CH:10]=2)[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=1
Reactant: N=C(N)OCCc1ccc(Oc2cc(Cl)cc(C(F)(F)F)c2)cc1
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4cc(Cl)cc(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 130 °C
Yield: 14.5 %

Procedure:
To the solution of 2-(4-{[3-chloro-5-(trifluoromethyl)phenyl]oxy}phenyl)ethyl imidocarbamate (230 mg, 0.488 mmol) and methyl 2-formyl-3-[2-(methyloxy)-5-pyrimidinyl]propanoate (131 mg, 0.585 mmol) in NMP (3 mL) was added K2CO3 (270 mg, 1.950 mmol). The mixture was heated with a microwave reactor at 130° C. for 1 h. Purification via MDAP then afforded the title compound (38 mg, 0.071 mmol, 14.63% yield). LCMS: rt=3.68 min, [M+H+]=533
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:27]([OH:29])=[O:28])[NH:4][C:5](=[O:26])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([NH:14][CH2:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[CH:19][NH:20]3)=[O:13])=[CH:8][C:7]=1[Cl:25].C1C=NC2N(O)N=NC=2C=1.C(N=C=NC(C)C)(C)C.[S:49]1[CH:53]=[CH:52][CH:51]=[C:50]1[C:54](O)=[O:55]>CN1CCCC1=O>[S:49]1[CH:53]=[CH:52][CH:51]=[C:50]1[C:54]([NH:1][CH2:2][C@@H:3]([C:27]([OH:29])=[O:28])[NH:4][C:5](=[O:26])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([NH:14][CH2:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH2:18][CH2:19][NH:20]3)=[O:13])=[CH:8][C:7]=1[Cl:25])=[O:55]
Reactant: O=C(O)c1cccs1
Reactant: NC[C@H](NC(=O)c1ccc(C(=O)NCc2cccc3[nH]ccc23)cc1Cl)C(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2cccnc21
Solvent: CN1CCCC1=O
Product: O=C(NCc1cccc2c1CCN2)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Reaction time: 2 h

Procedure:
To 3-amino-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine on Wang resin (Example 69; 100 mg) was added a solution of HOAT (70 mg, 0.51 mmol), diisopropylcarbodiimide (80 μL, 0.51 mmol), and thiophene-2-carboxylic acid (70 mg, 0.55 mmol) in 1-methyl-2-pyrrolidinone (1 mL). The mixture was agitated for 2 h and then the resin was filtered and washed extensively with dichloromethane and methanol. Cleavage of the product was effected with triethylsilane/trifluoroacetic acid/dichloromethane (2:1:1; 1 mL) at room temperature for 30 min. The solvent was evaporated and the residue was purified by HPLC to give 3-(thiophene-2-carbonyl)amino-N-[2-chloro-4-[[(2,3-dihydro-1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine (10.7 mg).
Reaction SMILES: CO.[ClH:3].C([O:11][C:12]1[C:13]([C:32]#[N:33])=[C:14]2[C:19](=[CH:20][CH:21]=1)[C@@H:18]([OH:22])[C@@H:17]([N:23](CC1C=CC=CC=1)[CH3:24])[CH2:16][CH2:15]2)C1C=CC=CC=1>[H][H].[Pd]>[ClH:3].[C:32]([C:13]1[C:12]([OH:11])=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][C@H:17]([NH:23][CH3:24])[C@@H:18]2[OH:22])#[N:33]
Reactant: CN(Cc1ccccc1)[C@H]1CCc2c(ccc(OCc3ccccc3)c2C#N)[C@H]1O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN[C@H]1CCc2c(ccc(O)c2C#N)[C@H]1O

Procedure:
In 30 ml. of methanol are suspended 250 mg. of cis-6-benzyloxy-2-(N-benzyl-N-methylamino)-5-cyano-1-hydroxy-1,2,3,4-tetrahydronaphthalene hydrochloride and 5 % palladium-on-carbon, and the mixture is agitated in hydrogen streams at room temperature for 30 minutes. After the reaction, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The procedure provides cis-5-cyano-1,6-dihydroxy-2-methylamino-1,2,3,4-tetrahydronaphthalene hydrochloride as a white precipitate. Recrystallization from ethanol-ethyl acetate provides colorless crystals melting at 226°-227° C(decomp.). Yield 112 mg.
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5](=O)[NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>O>[S:1]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5](=[S:19])[NH:4][CH2:3][CH2:2]1
Reactant: O=C1NCCSc2ccsc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: O
Product: S=C1NCCSc2ccsc21

Procedure:
acb) 1.0 g of 3,4-dihydro-thieno[2,3-f][1,4]thiazepin-5(2H)-one was heated under reflux for 5 hours together with 15 ml of pyridine and 1.35 g of phosphorus pentasulfide. After cooling the mixture was poured into 90 ml of water and the crystals were removed by filtration,. After chromatography on silica gel, the product was recrystallized from ethyl acetate. There was obtained 3,4-dihydro-thieno-[2,3-f][1,4]thiazepine-5(2H)-thione as yellow crystals of m.p. 138°-139°.
Reaction SMILES: C(OC[C@H]1OC(=O)C[C@@H]1C1OCCO1)(=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O1CCO[CH:24]1[C@@H:28]([CH2:33][CH2:34][OH:35])[C@H:29]([OH:32])[CH2:30][OH:31].C(CO)C>CCOCC.C1COCC1.CCOCC.C1COCC1.O.Cl.C(Cl)(Cl)Cl.O1CCOC1[C@@H](CCO)[C@H](O)CO.CO>[OH:32][C@H:29]1[C@H:28]2[C@H:24]([O:35][CH2:34][CH2:33]2)[O:31][CH2:30]1
Reactant: OCC[C@H](C1OCCO1)[C@H](O)CO
Agent: CC(=O)OC[C@H]1OC(=O)C[C@@H]1C1OCCO1
Agent: Cl
Agent: [Al+3]
Solvent: O
Solvent: CCCO
Solvent: C1CCOC1
Product: O[C@@H]1CO[C@H]2OCC[C@H]21
Yield: 64 %

Procedure:
According to the above general procedure, a solution containing 1.44 mg (6.26 mmol) (4S,5S)-5-(acetyloxymethyl)-4-[1,3]dioxolan-2-yldihydrofuran-2-one (3c) in Et2O:THF 1:1 (20 mL) was reduced with 522 mg (13.75 mmol) LiAlH4 in Et2O (100 mL) to give the crude protected triol (4) (1.12 mg, 93%). The crude triol (4) was cyclized in 60 mL THF water (5:1) and 5 mL 1N hydrochloric acid. Column chromatography (silica gel 20 g, ethyl methanol in CHCl3 10%) gave compound (5) (515 mg, 64%) as a colorless solid, Rf=0.35, [α]25D −25.1°, c 1.0, MeOH.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:21]([O:23]CC)=[O:22])[C:6](=[O:20])[N:7]2[C:12]=1[CH:11]=[C:10]([N:13]1[CH2:18][CH2:17][NH:16][CH:15]([CH3:19])[CH2:14]1)[CH:9]=[CH:8]2)[CH3:2].[OH-].[Na+].[ClH:28]>C1COCC1>[ClH:28].[CH2:1]([C:3]1[CH:4]=[C:5]([C:21]([OH:23])=[O:22])[C:6](=[O:20])[N:7]2[C:12]=1[CH:11]=[C:10]([N:13]1[CH2:18][CH2:17][NH:16][CH:15]([CH3:19])[CH2:14]1)[CH:9]=[CH:8]2)[CH3:2]
Reactant: CCOC(=O)c1cc(CC)c2cc(N3CCNC(C)C3)ccn2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1cc(C(=O)O)c(=O)n2ccc(N3CCNC(C)C3)cc12
Temperature: 65 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a suspension of 0.686 g (2 mmol) of ethyl 1-ethyl-8-(3-methyl-1-piperazinyl)-4H-quinolizin-4-one-3-carboxylate, from Step 1, in 8 mL of THF was added 8.0 mL of a 1.0N aqueous sodium hydroxide solution and the reaction mixture was heated, with stirring, at 65° C. for 3 hours. The THF was removed from the reaction mixture by distillation during the reaction. The concentrated reaction mixture was cooled to ambient temperature and adjusted to pH 1-2 with 16 mL of 1N aqueous hydrochloric acid solution. The aqueous solution was concentrated in vacuo to remove the water and the residue was suspended in 10 mL of water. The solid was collected by filtration and dried in vacuo to afford the 385 mg (55% yield) of the title compound, m.p.>295° C.; MS DCI-NH3 : 316 (M-Cl)+ ; IR (KBr): 3420 (OH), 1720 (C=O) cm-1 ; 1H NMR (TFA) d 1.50 (t, 3H, J=7.5 Hz), 1.70 (d, 3H, J=6 Hz), 3.00 (q, 2H, J=7.5 Hz), 3.70-4.10 (m, 6H), 4.55 (m, 1H), 4.60 (m, 1H), 7.40 (d, 1H, J=3.0 Hz), 7.68 (dd, 1H, J=3.0 Hz, 8.4 Hz), 8.18 (s, 1H), 9.19 (d, 1H, J=8.4 Hz). Analysis calculated for C17H22 ClN3O3 +H2O: C, 55.21; H, 6.54; N, 11.36. Found: C, 55.19; H, 6.07; N, 11.34.
Reaction SMILES: C([NH:4][C@@H:5]([C:21]([OH:23])=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)(=O)C>Cl>[C:13]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH2:6][C@H:5]([C:21]([OH:23])=[O:22])[NH2:4])(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)N[C@H](Cc1cccc(C(=O)c2ccccc2)c1)C(=O)O
Agent: Cl
Product: N[C@H](Cc1cccc(C(=O)c2ccccc2)c1)C(=O)O
Yield: 86.9 %

Procedure:
A suspension of 2.0 g of N-Acetyl-m-benzoyl-D-phenylalanine in 15 ml of 8N hydrochloric acid was heated to 100° in the steam bath for 4 h. The suspension was filtered hot, solid was washed with 8N hydrochloric acid, then water. The filtrate was neutralized with 1N sodium hydroxide and yielded 1.503 g of m-benzoyl-D-phenylalanine after water washing and drying under nitrogen, m.p. 230°-231°, [α]D25 =+3.3±0.8 C=0.90 g/100 ml 1N HCl. Anal.: Calcd. for C16H15NO3 : C, 71.36; H, 5.61; N, 5.20. Found: C, 70.43; H, 5.34; N, 5.37.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=3)[N:12]=[C:11]([C:22](O)=[O:23])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)=N2)C=CC=1>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=3)[N:12]=[C:11]([C:22]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=[O:23])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1cccc(-n2nc(C(=O)O)cc2-c2ccc(F)c(Cl)c2)c1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Solvent: O=CO
Product: N#Cc1cccc(-n2nc(C(=O)N3CNC(=O)C3)cc2-c2ccc(F)c(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 108A with the addition of 0.1% formic acid in the preparative HPLC in analogy to the synthesis of the compound of Example 23. 8 mg (35% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[C:12]2[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:22])[C:13]=2[N:14]=[CH:15][N:16]=1)[CH3:2].[C:30](Cl)(=[O:32])[CH3:31]>>[C:30]([N:27]1[CH2:26][CH2:25][CH:24]([NH:23][C:21]([C:17]2[C:13]3[N:14]=[CH:15][N:16]=[C:11]([C:5]4[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:4]=4[O:3][CH2:1][CH3:2])[C:12]=3[NH:19][C:18]=2[CH3:20])=[O:22])[CH2:29][CH2:28]1)(=[O:32])[CH3:31]
Reactant: CCOc1ccc(F)cc1-c1ncnc2c(C(=O)NC3CCNCC3)c(C)[nH]c12
Reactant: CC(=O)Cl
Product: CCOc1ccc(F)cc1-c1ncnc2c(C(=O)NC3CCN(C(C)=O)CC3)c(C)[nH]c12

Procedure:
Starting from 4-(2-ethoxy-5-fluorophenyl)-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f17) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C(Cl)Cl.[NH2:4][C:5]1[C:10]2=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=4[F:40])=[O:28])=[C:22]([F:41])[CH:21]=3)[CH:12]=[C:13]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:9]2[N:8]=[CH:7][N:6]=1.[CH3:42][N:43]=[C:44]=[O:45]>C1COCC1>[NH2:4][C:5]1[C:10]2=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:28])[NH:29][C:30]4[CH:35]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:33]=[CH:32][C:31]=4[F:40])=[C:22]([F:41])[CH:21]=3)[CH:12]=[C:13]([CH:14]3[CH2:19][CH2:18][N:17]([C:44]([NH:43][CH3:42])=[O:45])[CH2:16][CH2:15]3)[N:9]2[N:8]=[CH:7][N:6]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Reactant: CN=C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)N1CCC(c2cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 60.3 %

Procedure:
To a flask containing 3 ml of methylene chloride was added 1-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (Example 111) (75 mg, 0.141 mmol, 1.0 eq). To this suspension was added THF dropwise until complete dissolution occurs. To this solution was added methyl isocyanate (8.8 μl, 0.148 mmol, 1.05 eq.) and reaction allowed to stir at room temperature for 17 h. Reaction solution was concentrated to dryness and residue dissolved in EtOAc. Wash 2× with saturated sodium bicarbonate, 1× brine, layers separated, organics dried (Na2SO4), filtered, condensed and purified via flash chromatography (1:1 THF:hexanes). The purified fractions collected and concentrated to dryness. Residue was stirred in hexanes and filtered to obtain title compound (50 mg, 60.2% yield). 1H-NMR (DMSO-d6) δ 9.41 (d, J=2.8 Hz, 1H), 9.25 (d, J=2.3 Hz, 1H), 8.65 (dd, J=7.5, 2.4 Hz, 1H), 8.25 (t, J=8.6 Hz, 1H), 7.90 (s, 1H), 7.51 (m, 1H), 7.41 (m, 1H), 7.32 (dd, J=12.4, 2.0 Hz, 1H), 7.23 (dd, J=8.5, 1.4 Hz, 1H), 6.57 (s, 1H) 6.44 (q, J=4.3 Hz, 1H), 4.05 (d, J=13.3 Hz, 2H), 3.28 (m, 1H), 2.80 (t, J=12.2 Hz, 2H), 2.56 (d, J=4.5 Hz, 3H), 1.95 (d, J=11.3 Hz, 2H), 1.52 (m, 2H); MS [M+H]+=589; LCMS RT=3.11 min.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH:19]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].O1CCCC1.[Cl:41]N1C(=O)CCC1=O>CO.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[S:6][C:7]([Cl:41])=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][CH:19]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:16][CH:17]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cs1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(CCc2ccc(NC(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)c(Cl)s1
Temperature: 25 °C
Reaction time: 29 h
Yield: 69.3 %

Procedure:
Di-tert-butyl {[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamate (150 mg) prepared in a similar manner according to Step 5 of Production Example 18 was dissolved in methanol (1.5 ml) and tetrahydrofuran (3 ml) under nitrogen atmosphere. Then N-chlorosuccinimide (59.7 mg) was added to the solution at 0° C. The reaction mixture was stirred at room temperature for 29 hours, and diluted in ethyl acetate. The organic solution was washed with saturated sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual solid was washed with ethyl ether to give di-tert-butyl {[(4-{2-[2-(acetylamino)-5-chloro-1,3-thiazol-4-yl]ethyl}phenyl)amino]methylidene}biscarbamate (111 mg) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([S:10][CH2:11][CH3:12])[C:3]=1N.[H+].[B-](F)(F)(F)F.N(OCCC(C)C)=O.O[PH2]=O>CCO>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([S:10][CH2:11][CH3:12])[CH:3]=1
Reactant: CCSc1nc(CC)cc(Br)c1N
Agent: CC(C)CCON=O
Agent: F[B-](F)(F)F
Agent: O=[PH2]O
Solvent: CCO
Product: CCSc1cc(Br)cc(CC)n1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
4-Bromo-6-ethyl-2-ethylsulfanyl-pyridin-3-ylamine (476 mg, 1.82 mmoles) was dissolved into EtOH (5 mL) and chilled to −10° C. under nitrogen. At −10° C. 48% wt. aq. HBF4 (1.0 mL) was added and the temperature was further lowered to −25° C. At −25° C. isoamyl nitrite (0.256 mL, 1.9 mmoles) was slowly added (over 1 min), and the temperature was allowed to warm to −5° C. The reaction was stirred at −5° C. for 30 min. After this period the reaction mix was chilled to −25° C. and an excess of 50% aqueous H3PO2 (5.0 mL) was added. The mix was then allowed to warm to ambient temperature and was stirred at this temperature for 1 hour (vigorous bubbling is observed). After this period the reaction was combined with 40 mL of diethyl ether followed (carefully) by saturated NaHCO3 (10 mL). The mix was then extracted with diethyl ether (2×20 mL) and the resultant ether layer was washed with brine. After drying over anhydrous MgSO4 the ethereal layer was evaporated in vacuo to yield crude product. The crude product was purified using flash silica chromatography (0-10% EtOAc/Hexane) to yield 4-bromo-2-ethylsulfanyl-6-ethylpyridine (340 mg, 76%) as a golden-yellow liquid. 1H-NMR (CDCl3): δ 7.09 (br d, J=1.3 Hz, 1H), 6.90 (br d, J=1.5 Hz, 1H), 3.0 (q, J=7.3 Hz, 2H), 2.73 (q, J=7.6 Hz, 2H), 1.39 (t, J=7.3 Hz, 3H), 1.27 (t, J=7.6 Hz, 3H).
Reaction SMILES: [I-:1].F[C:3]1[CH:12]=[CH:11][C:10]2[N+:9]3[CH:13]=[C:14]4[CH:23]=[CH:22][C:21]5[CH:20]=[C:19]([CH2:24][CH2:25][CH3:26])[CH:18]=[CH:17][C:16]=5[N:15]4[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C)C=O>[I-:1].[N:27]1([C:3]2[CH:12]=[CH:11][C:10]3[N+:9]4[CH:13]=[C:14]5[CH:23]=[CH:22][C:21]6[CH:20]=[C:19]([CH2:24][CH2:25][CH3:26])[CH:18]=[CH:17][C:16]=6[N:15]5[C:8]=4[CH:7]=[CH:6][C:5]=3[CH:4]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C1CCNCC1
Reactant: CCCc1ccc2c(ccc3c[n+]4c5ccc(F)cc5ccc4n32)c1
Agent: [I-]
Solvent: CN(C)C=O
Product: CCCc1ccc2c(ccc3c[n+]4c5ccc(N6CCCCC6)cc5ccc4n32)c1

Procedure:
A stirred mixture of 3.62 g. of 3-fluoro-10-propylimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide, 20 ml. of dimethylformamide and 2.0 ml. of piperidine is heated at 72° C. for 94 hours, then evaporated at reduced pressure. The residue is dissolved in methanol along with 2.0 g. of triethylamine hydroiodide. The solution is diluted with water and the resulting precipitate is collected by filtration and suspended in 125 ml. of 0.5% triethylamine hydroiodide. The solid 3-(1-piperidinyl)-10-propylimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration, triturated with 2-propanol and dried; m.p. 148°-153° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([NH:13][C:14](=[O:23])[C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[C:24]#[N:25].[C:26]([O-:29])(=[O:28])[CH3:27].[Na+].O>CN(C)C=O>[C:26]([O:29][CH2:2][C:3]1[C:12]2[C:7](=[C:8]([NH:13][C:14](=[O:23])[C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[C:24]#[N:25])(=[O:28])[CH3:27]
Reactant: N#Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CBr
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1c(C#N)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
A mixture of 4-bromomethyl-8-(2,6-dichlorobenzoylamino)-3-cyanoquinoline (238 mg) and sodium acetate (94 mg) in dimethylformamide (1 ml) was stirred at ambient temperature overnight. To the residue was added water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (n-hexane-dichloromethane) to give 4-acetoxymethyl-3-cyano-8-(2,6-dichlorobenzoylamino)quinoline (54 mg).
Reaction SMILES: II.[CH3:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].C(O)(=[O:15])C>>[CH3:3][C:4]1[C:5](=[O:12])[C:6]([CH3:11])=[CH:7][C:8](=[O:15])[C:9]=1[CH3:10]
Reactant: CC(=O)O
Reactant: Cc1ccc(C)c(O)c1C
Agent: II
Product: CC1=CC(=O)C(C)=C(C)C1=O
Yield: 94.7 %

Procedure:
Halogenation and subsequent oxidation were conducted in the same manner as in Example 8 except for adding 0.068 g of iodine to the acetic acid solution of 2,3,6-trimethylphenol upon chlorination. Thus, there was obtained 14.2 g (94.7 percent in yield) of 2,3,6-trimethyl-p-benzoquinone.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:11][CH2:12][C@@:13]1([C:32]#[CH:33])[O:17][C@@H:16]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:15][C@H:14]1OS(C)(=O)=O)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.CC(OC(C)=O)=O>C1COCC1.CO.CN(C1C=CN=CC=1)C.CO>[C:3]([O:11][CH2:12][C@@:13]1([C:32]#[CH:33])[O:17][C@@H:16]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH:15]=[CH:14]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C#C[C@]1(COC(=O)c2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1OS(C)(=O)=O
Agent: CN(C)c1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: C#C[C@@]1(COC(=O)c2ccccc2)C=C[C@H](n2cc(C)c(=O)[nH]c2=O)O1
Temperature: -70 °C
Yield: 127.9 %

Procedure:
A mixture of NaBH4 (628 mg, 16.6 mmol) and MeOH (50 ml) was cooled and stirred at −70° C. To this was added a mixture of 5 (3.39 g, 8.3 mmol) and CeCl3.7H2O (3.1 g, 8.3 mmol) in THF/MeOH=1/1 (50 ml) dropwise over 15 min. The resulting suspension was stirred for 1 h at the −70□. The reaction was quenched by adding AcOH (ca. 1 mL). The reaction mixture was evaporated. The residue was suspended in MeCN (15 ml). To this suspension were added DMAP (1.02 g, 8.3 mmol), i-Pr2NEt (1.45 mL, 8.3 mmol) and Ac2O (1.57 mL, 16.6 mmol). The mixture was stirred for 30 min at 0° under positive pressure of dry Ar, and partitioned between CH2Cl2 and sat. aqueous NaHCO3. The organic layer was dried (Na2SO4), evaporated, and chromatographed on a silica gel column (hexane/EtOAc=4/1). This gave 6 (3.74 g, 100%) as an oil.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([O:8][C:9]1[CH:42]=[CH:41][C:12]2[O:13][CH2:14][C:15]3[N:40]=[CH:39][CH:38]=[CH:37][C:16]=3[C:17](=[CH:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][C:24]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)([OH:27])[C:23]([CH3:36])([CH3:35])[CH2:22]3)[C:11]=2[CH:10]=1)([CH3:7])[CH3:6])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)(=O)C>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:24]2([OH:27])[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH:18]=[C:17]3[C:16]4[CH:37]=[CH:38][CH:39]=[N:40][C:15]=4[CH2:14][O:13][C:12]4[CH:41]=[CH:42][C:9]([O:8][C:5]([CH3:6])([CH3:7])[CH2:4][OH:3])=[CH:10][C:11]3=4)[CH2:22][C:23]2([CH3:36])[CH3:35])=[CH:29][CH:30]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(CO)Oc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a cooled (0° C.) solution of 2-(5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yloxy)-2-methyl-propionic acid ethyl ester (117 mg, 0.193 mmol) in tetrahydrofuran (5 mL) was added lithium aluminum hydride (1.0 M solution in tetrahydrofuran, 0.39 mL, 0.39 mmol). The reaction was allowed to stir at 0° C. for 2 h. Excess hydride was quenched by the addition of a saturated aqueous potassium/sodium tartrate solution. The mixture was stirred at rt until two clear phases formed. The mixture was diluted with ethyl acetate and shaken. The extracts were dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (methylene chloride—90:10 methylene chloride/methanol gradient) to afford the titled compound (102 mg, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]#[N:17])[O:13][N:12]=2)[CH2:7][CH2:6]1.[N-:23]=[N+:24]=[N-:25].[Na+].[Cl-].[NH4+]>CN(C=O)C.[OH-].[Na+]>[Br:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[N:15]=[C:14]([C:16]3[NH:25][N:24]=[N:23][N:17]=3)[O:13][N:12]=2)[CH2:9][CH2:10]1
Reactant: N#Cc1nc(N2CCC(Oc3cc(F)ccc3Br)CC2)no1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(Br)c(OC2CCN(c3noc(-c4nnn[nH]4)n3)CC2)c1
Temperature: 100 °C

Procedure:
A mixture of 3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazole-5-carbonitrile (8 g, 21.79 mmol), sodium azide (2.125 g, 32.7 mmol) and ammonium chloride (5.83 g, 109 mmol) in DMF (43.6 ml) was heated at 100° C. for 0.5 h. The mixture was cooled to RT, diluted with 1N NaOH (50 mL), washed with Et2O (2×50 mL). The aqueous layer was acidified to pH about 1 with 2N HCl and extracted with EtOAc (3×75 mL). The combined organic fractions were washed with water (2×50 mL) then dried over Na2SO4. The solvent was evaporated under reduced pressure, the product dissolved in a small amount of EtOAc and precipitated with hexanes. The solid was filtered and washed with hexanes to afford the title compound. MS: m/z 410, 412 (MH+).