Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][NH2:11].[F:15][C:16]([F:23])([F:22])[C:17](OCC)=[O:18]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:17](=[O:18])[C:16]([F:23])([F:22])[F:15]
Reactant: NCCNCCOc1cccc(Br)c1
Reactant: CCOC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(NCCNCCOc1cccc(Br)c1)C(F)(F)F
Reaction time: 0.25 h

Procedure:
To a stirred, 0° C., solution of N1-(2-(3-bromophenoxy)ethyl)ethane-1,2-diamine (4.7 g, 17.9 mmol) in anhydrous tetrahydrofuran (180 mL) was added ethyl trifluoroacetate [383-63-1] (2.1 mL, 17.9 mmol). The resultant solution was allowed to stir under N2 blanket for 15 minutes then evaporated to dryness to obtain N-{2-[2-(3-Bromo-phenoxy)-ethylamino]-ethyl}-2,2,2-trifluoro-acetamide as 6.3 g of yellow solid. LRMS (ESI) m/z 355.1/357.1 [(M+H)]+, calc'd for C12H14BrF3N2O2: 355.16.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([OH:27])[CH:25]=4)[NH:20][CH:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][CH:8]=1.[CH3:28][N:29]=[C:30]=[O:31]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:27][C:30](=[O:31])[NH:29][CH3:28])[CH:25]=4)[NH:20][CH:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][CH:8]=1
Reactant: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(O)cc23)CC1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)Oc1ccc2[nH]cc(CCCN3CCN(c4ncncc4OC)CC3)c2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 61.5 %

Procedure:
To a solution of 3-[3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl]-5-hydroxyindole (0.170 g, 0.46 mmol) in 6 mL of CH2Cl2 was added methyl isocyanate (60 μL, 1.0 mmol) and the mixture was stirred at room temperature for 4 days. The mixture was then evaporated and the resulting pinkish-gray foam was triturated with isopropanol-ether to give a light grey solid. This material was chromatographed (SiO2 /EtOAc-MeOH, 95:5; then 90:10) to give the title compound (0.120 g, 60%) as a light gray solid, m.p. 120°-122° C. IR (KBr) 3400, 3220, 1730 cm-1 ; 1H NMR (CDCl3, 200 MHz) δ8.33 (s, 1H), 8.06 (br s, 1H), 7.88 (s, 1H), 7.34-7.26 (m, 2H), 6.99-6.91 (m, 2H), 5.00 (br m, 1H), 3.85 (s, 3H), 3.79 (t, J=4.7 Hz, 4H), 2.91 (d, J=4.8 Hz, 3H), 2.75 (t, J=7.4 Hz, 2H), 2.54 (t, J=4.8 Hz, 4H), 2.45 (t, J=7.6 Hz, 2H), 2.04-1.83 (m, 2 H) Anal. Calcd. for C22H28N6O3 0.8H2O: C, 60.20; H, 6.80; N, 19.15. Found: C, 60.13; H, 6.40; N, 18.75.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CCN(CC)CC.CN([CH:21]=[O:22])C.[CH3:23][OH:24]>>[CH3:23][O:24][C:21](=[O:22])[C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CO
Reactant: COc1ncc(I)cc1C
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(OC)c(C)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
A solution containing 5-iodo-3-methyl-2-methoxy-pyridine (10.0 g, 40.0 mmol), Et3N (8.0 g, 80.0 mmol), and (Ph3P)4PdCl2 (2.80 g, 4.00 mmol) in 1:1 DMF/MeOH (100 mL) is cooled to 0° C. Carbon monoxide is bubbled into the cooled solution for approx. 5 min at which time the reaction mixture is sealed under a balloon of CO. The reaction mixture is allowed to warm to ambient temperature and then stirred for 16 hours. The reaction mixture is concentrated in vacuo and the residue is partitioned between water (300 mL) and EtOAc (300 mL) and the layers are separated. The organic phase is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product is purified by silica gel flash column chromatography (hexane/diethyl ether, 19:1) to provide 4.10 g (57%) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ2.20 (s, 3H), 3.88 (s, 3H), 4.00 (s, 2H), 7.96 (d, J=2.2 Hz, 1H), 8.65 (d, J=2.2 Hz, 1H) ppm; MS (ISP loop): m/z 182 (M+H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:20][CH3:21])=[C:8]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]=2)[CH2:4][NH:3]1.CCN(C(C)C)C(C)C.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:34]=1[CH2:35]Cl.[Cl-].[NH4+]>CN(C=O)C.O>[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:34]=1[CH2:35][N:3]1[CH:2]([CH3:1])[CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:20][CH3:21])=[C:8]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]=2)[CH2:4]1
Reactant: COc1cc2c(cc1OCc1ccccc1)CC(C)NC2
Reactant: COc1ccc(OC)c(CCl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(OC)c(CN2Cc3cc(OC)c(OCc4ccccc4)cc3CC2C)c1
Temperature: 80 °C
Yield: 75.9 %

Procedure:
3-Methyl-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline (338 mg, 1.2 mmol) was dissolved in anhydrous DMF (3.6 mL), DIPEA (314 mg, 2.4 mmol) and 2,5-dimethoxybenzyl chloride (279 mg, 1.5 mmol) were added. The mixture was heated to 80° C. for 20 h, cooled to room temperature and poured into water (50 mL) and ammonium chloride (saturated, 2 mL). The mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography using Flashmaster (SiO2: 20 g, hexane 100% to hexane/ethyl acetate 50/50). W8 was obtained as sticky orange oil (395 mg, 76%). 1H NMR (270 MHz, CDCl3) δ 1.14 (3H, d, J 6.3, CHCH3), 2.48 (1H, dd, J 16.3, 6.0, one of ArCH2CH), 2.86 (1H, dd, J 16.1, 4.8, one of ArCH2CH), 3.11 (1H, sext, J 6.1, CHCH3), 3.58-3.77 (4H, m, 2×ArCH2N), 3.76 (3H, s, OCH3), 3.77 (3H, s, OCH3), 3.81 (3H, s, OCH3), 5.11 (2H, s, OCH2Ph), 6.50 (1H, s, CH), 6.61 (1H, s, CH), 6.74 (1H, dd, J 8.8, 3.0, CH), 6.80 (1H, d, J 8.8, CH), 7.07 (1H, d, J 2.8, CH), 7.24-7.47 (5H, m, OCH2C6H5). 13C NMR (67.5 MHz, CDCl3): δ 15.5, 34.5, 50.0, 51.4, 52.4, 55.7, 56.0, 56.0, 71.0, 109.9, 111.3, 111.9, 114.4, 116.0, 125.8, 127.0, 127.2, 127.7, 128.4, 128.9, 137.3, 146.5, 147.7, 151.9, 153.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22](O)=[O:23])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[CH2:49]([NH:51][CH2:52][CH3:53])[CH3:50]>CN(C=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:51]([CH2:52][CH3:53])[CH2:49][CH3:50])=[O:23])[C:17]1=[O:26])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CCNCC
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)[C@H](C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid (0.015 g) in DMF (1 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.015 g), HOBT (0.01 g) and triethylamine (0.007 ml) and the mixture was stirred at room temperature for 30 min. Diethylamine (0.007 ml) was added and the resultant mixture stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by mass directed preparative h.p.l.c. to give the title compound (0.008 g) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([N:8]2[C:16]([Cl:17])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)[CH:7]=1.[S-:19][C:20]#[N:21]>>[NH2:21][C:20]1[S:19][C:3]2[CH:4]=[C:5]([F:18])[C:6]([N:8]3[C:16]([Cl:17])=[C:15]4[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]4)=[N:9]3)=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccc(F)c(-n2nc3c(c2Cl)CCCC3)c1
Reactant: N#C[S-]
Product: Nc1nc2cc(-n3nc4c(c3Cl)CCCC4)c(F)cc2s1

Procedure:
2-(5-Amino-2-fluorophenyl)-3-chloro-4,5,6,7-tetrahydro-2H-indazole (IX) is reacted with a thiocyanate and then with a halogen to give 2-(2-amino-6-fluorobenzothiazol-5-yl)-3-chloro-4,5,6,7-tetrahydro-2H-indazole (X).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:20]([O:22]CC1C=CC=CC=1)=[O:21])[CH2:3][C:4](=[O:19])[NH:5][CH2:6][C:7]1[C:16]([O:17][CH3:18])=[CH:15][C:12]([O:13][CH3:14])=[CH:11][C:8]=1[O:9][CH3:10].O.CN(C=O)C>C(O)(=O)C>[CH3:18][O:17][C:16]1[CH:15]=[C:12]([O:13][CH3:14])[CH:11]=[C:8]([O:9][CH3:10])[C:7]=1[CH2:6][NH:5][C:4](=[O:19])[CH2:3][C@@H:2]([C:20]([OH:22])=[O:21])[NH2:1]
Reactant: COc1cc(OC)c(CNC(=O)C[C@H](NC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)c(OC)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(OC)c(CNC(=O)C[C@H](N)C(=O)O)c(OC)c1
Reaction time: 2 h

Procedure:
The fully protected derivative Z-Asn(Tmob)-OBzl prepared in Step 1 (2.0 g, 3.75 mmol) was dissolved in acetic acid (50 ml), water (14 ml) and DMF (10 ml) by slight warming and vigorous stirring, nitrogen was flushed through the low pressure hydrogenation flask, 5% palladium on carbon catalyst (400 mg) was added, and a gentle stream of hydrogen continuously passed over the vigorously stirred solution for 2 hours. Nitrogen was once more flushed through the system and the catalyst removed by filtration through a doubled fluted Whatman No. 1 filter paper. The filtrate was evaporated, the residue dried in vacuo, and triturated under ethyl acetate to give a white solid. The suspension was cooled overnight to 4 degrees, then filtered and washed with ethyl acetate. Yield after drying 1.16 g (96%), Rf 0.55 single spot n-butanol/acetic acid/water (3:1:1).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]([OH:18])=[C:6]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:7]=1.[F:21][C:22]([F:34])([F:33])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:19][CH3:20])[O:18][C:30](=[O:31])[C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:33])[F:34])=[CH:28][CH:27]=1)=[C:8]2[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1
Reactant: COc1cc(O)c(C(=O)Cc2ccc(O)cc2)cc1Br
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2oc(=O)c(-c3ccc(C(F)(F)F)cc3)c(Cc3ccc(O)cc3)c2cc1Br
Temperature: 80 °C
Yield: 85.4 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-4-methoxy-phenyl)-2-(4-hydroxy-phenyl)-ethanone (0.64 g, 1.9 mmol), 4-trifluoromethylphenylacetic acid (0.78 g, 3.8 mmol), carbonyl diimidazole (0.62 g, 3.8 mmol), N,N-dimethylaminopyridine (0.12 g, 1.0 mmol), and potassium carbonate (0.52 g, 3.8 mmol) in DMF (15 mL) was heated within an 80° C. oil bath overnight. The cooled reaction mixture was poured into water and extracted with EtOAc. Organic extracts were combined and washed with water and saturated sodium chloride in succession, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material purified using silica gel flash column chromatography (1:2 EtOAc:hexanes) to provide the title compound (0.82 g, 85%). MS (ESI) m/z 505.0 (M+1)+, 507.0 (M+1+2)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[N:35]1([CH2:41]CO)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][CH2:41][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCN1CCCCC1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCN4CCCCC4)cc3)c2cc1OC
Yield: 86.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-piperidino-1-ethanol (34 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (66 mg, yield 74%).
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[CH2:13]([N:20]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[NH:21][C:22](=[O:49])[CH:23]([OH:48])[CH:24]([NH:32][C:33]([C@H:35]1[CH2:39][CH2:38][C:37](=[O:40])[N:36]1[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+].O>CS(C)=O>[CH2:13]([N:20]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[NH:21][C:22](=[O:49])[C:23](=[O:48])[CH:24]([NH:32][C:33]([C@H:35]1[CH2:39][CH2:38][C:37](=[O:40])[N:36]1[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)NC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Agent: O=C(O)c1ccccc1I(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Yield: 85.1 %

Procedure:
IBX (189 mg, 0.303 mmol, 45 wt %) was added a solution of tert-butyl 1-benzyl-2-(3-((R)-1-benzyl-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoyl)-hydrazinecarboxylate (130 mg, 0.216 mmol) in DMSO (3 mL). After stirring overnight saturated aqueous NaHCO3 solution (15 mL) and water (15 mL) were added. The mixture was extracted with EtOAc, the combined organic layers were washed with saturated aqueous NaHCO3 solution, water and dried (MgSO4). Purification by flash column chromatography (gradient 1-10% MeOH in DCM) provided the title compound (110 mg, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25]Cl)=[N:23][N:24]=2)[CH:3]=1.[I-].[Na+].[N:29]12[CH2:37][CH2:36][CH2:35][C@H:34]1[CH2:33][NH:32][CH2:31][CH2:30]2.CCN(C(C)C)C(C)C>C(#N)C.C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:32]3[CH2:31][CH2:30][N:29]4[CH2:37][CH2:36][CH2:35][C@H:34]4[CH2:33]3)=[N:23][N:24]=2)[CH:3]=1
Reactant: C1C[C@H]2CNCCN2C1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(Br)cc21
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CN4CCN5CCC[C@H]5C4)o3)cc(Br)cc21
Temperature: 70 °C
Yield: 61.2 %

Procedure:
6-Bromo-4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-(phenylsulfonyl)-1H-indazole (300 mg, 0.661 mmol) and sodium iodide (99 mg, 0.661 mmol) were weighed into a round-bottomed flask and dissolved in acetonitrile (2 ml) before (S)-1,4-diazabicyclo[4.3.0]nonane (167 mg, 1.322 mmol, available from ABCR GmbH & CO.KG) and DIPEA (0.231 ml, 1.322 mmol) were added. The mixture was heated to 70° C. for 2 h. The mixture was cooled, diluted with DCM and washed with 2 M aqueous HCl (2 ml). The organic layer was separated by hydrophobic frit. The aqueous extracts were combined and neutralised to pH 7 with NaOH then extracted with more DCM (2×10 ml) which was combined with the other organic extracts and evaporated under a stream of nitrogen to give an orange oil. This was dissolved in DCM and loaded onto the top of a 10 g silica cartridge that was subsequently eluted with 0-15% MeOH(+1% triethylamine)/DCM over 15 mins. The appropriate fractions were combined and the solvent removed in vacuo to give the title compound as a cream solid (220 mg).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[C:15]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=4)=[N:16][C:17]4[C:22]([C:23]=3[C:24](O)=[O:25])=[CH:21][CH:20]=[C:19]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:18]=4)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:41]1([C@@H:47]([NH2:49])[CH3:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.ClCCCl>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[C:15]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=4)=[N:16][C:17]4[C:22]([C:23]=3[C:24]([NH:49][C@H:47]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH3:48])=[O:25])=[CH:21][CH:20]=[C:19]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:18]=4)[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H](N)c1ccccc1
Reactant: CS(=O)(=O)c1ccc2c(C(=O)O)c(CN3CCC(N4CCCCC4)CC3)c(-c3cccc(C(F)(F)F)c3)nc2c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1c(CN2CCC(N3CCCCC3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2cc(S(C)(=O)=O)ccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
A mixture of 3-(1,4′-bipiperidin-1′-ylmethyl)-7-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.100 g, 0.174 mmol), (1S)-1-phenylethanamine (0.032 g, 0.261 mmol), EDC (0.167 g, 0.869 mmol), HOBT (0.027 g, 0.174 mmol), and N,N-diisopropylethylamine (0.303 mL, 1.74 mmol) in N,N-dimethylformamide (2 mL) and 1,2-dichloroethane (2 mL) was stirred at room temperature overnight before it was heated to 50° C. for 4 h. The solvent was removed under reduced pressure. The residue was dissolved in DMSO and purified via HPLC (Waters, 30-80% MeCN/H2O with 0.1% TFA). The fractions containing the product were neutralized with saturated aqueous NaHCO3, acetonitrile was removed under reduced pressure, and the residue was diluted with water. The solid material was collected by filtration, washed with water, and air dried to afford 3-(1,4′-bipiperidin-1′-ylmethyl)-7-(methylsulfonyl)-N-[(1S)-1-phenylethyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxamide (0.086 g, 73% yield). MS (m/z) 679.3 (M+H+).
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].[CH3:5][O-:6].[Na+].[Br:8][C:9]1[CH:10]=[C:11]2C(=[CH:17][CH:18]=1)O[CH:14]([CH:19]1[CH2:24][CH2:23][CH2:22][O:21][CH2:20]1)[CH2:13]/[C:12]/2=[N:25]\[C:26]#[N:27]>CO>[Br:8][C:9]1[CH:10]=[C:11]2[C:12]3([O:4][N:3]([CH3:2])[C:26]([NH2:27])=[N:25]3)[CH2:13][CH:14]([CH:19]3[CH2:24][CH2:23][CH2:22][O:21][CH2:20]3)[O:6][C:5]2=[CH:17][CH:18]=1
Reactant: C[O-]
Reactant: N#C/N=C1\CC(C2CCCOC2)Oc2ccc(Br)cc21
Reactant: CNO
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1OC2(CC(C3CCCOC3)Oc3ccc(Br)cc32)N=C1N
Reaction time: 0.17 h
Yield: 10 %

Procedure:
To a solution of methylhydroxylamine HCl salt (75 mg, 0.9 mmol) in anhydrous MeOH (10 mL) was added NaOMe (25 w % in MeOH, 0.13 mL), followed by (E)-N-(6-bromo-2-(tetrahydro-2H-pyran-3-yl)chroman-4-ylidene)cyanamide (300 mg, 0.9 mmol). After stirring for 10 min, the solvent was removed in vacuo. The residue was redissolved in DCM (20 mL). The mixture was filter, and the solvent was removed in vacuo. The resulting residue was purified by preparative TLC to give 20 mg of 6-bromo-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (50 mg, 10%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:17][C:18]2[CH:19]=[C:20]([CH:40]=[CH:41][CH:42]=2)[C:21]([C:23]2[N:31]3[C:26]([CH:27]=[CH:28][CH:29]=[CH:30]3)=[C:25]([CH2:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[CH:24]=2)=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(OCC)(=O)C.Cl>C(O)C.O1CCOCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:17][C:18]2[CH:19]=[C:20]([CH:40]=[CH:41][CH:42]=2)[C:21]([C:23]2[N:31]3[C:26]([CH:27]=[CH:28][CH:29]=[CH:30]3)=[C:25]([CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:24]=2)=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCCC(Nc1cccc(C(=O)c2cc(CCCC(=O)OCC)c3ccccn23)c1)c1ccc(CC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1COCCO1
Product: CCCCCC(Nc1cccc(C(=O)c2cc(CCCC(=O)O)c3ccccn23)c1)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
To a solution of ethyl 4-[3-[3-[1-(4-isobutylphenyl)hexylamino]benzoyl]indolizin-1-yl]butyrate (117 mg) in ethanol (2 ml) and 1,4-dioxane (2 ml) was added 1N aqueous solution of sodium hydroxide (1 ml). The mixture was stirred at room temperature for 3 hours, and then poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated to give 4-[3-[3-[1-(4-isobutylphenyl)hexylamino]benzoyl]indolizin-1-yl]butyric acid (98 mg) as powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Sc2ccnc3ccccc23)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Sc2ccnc3ccccc23)cc1
Yield: 58.3 %

Procedure:
4-(4-nitrophenylthio)quinoline 17.0 mmoles, 4.9 g) was dissolved in 200 ml ethanol and hydrogenated over 5 g of 5% Pd/C at 40 psi for 1 hr at room temperature. The solution was filtered through celite and the solvent removed to yield 4-(4-aminophenylthio)quinoline 2.5 g, 58%. Mass spec (FD) 253. Calculated for C15H12N2S: C, 71.40; H, 4.79, N, 11.10. Found: C, 71.12; H, 4.93N, 10.88.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.Cl[CH:15]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[CH3:33][O:32][C:24]1[CH:23]=[C:22]([CH:15]([S:3][C:4]2[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)[CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH:27]=[C:26]([O:28][CH3:29])[C:25]=1[O:30][CH3:31]
Reactant: COc1cc(C(Cl)Cn2ccnc2)cc(OC)c1OC
Reactant: COC(=O)c1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
48.5 mg of a 55% w/w suspension of sodium hydride in mineral oil were added, whilst ice-cooling, to a solution of 187 mg of methyl 4-mercaptobenzoate in 1.3 ml of dry dimethylformamide, and the reaction mixture was then stirred at room temperature for 30 minutes. To this solution was added 1.3 ml of dry dimethylformamide containing 330 mg of 1-[2-chloro-2-(3,4,5-trimethoxyphenyl)ethyl]imidazole, and the reaction mixture was heated at 60°-70° C. for 7.5 hours. At the end of this time, the resulting mixture was treated and purified by the same method as described in Example 1, to give 187.7 mg of the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[OH:28])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][C:2]2[CH:3]=[C:4]([NH:8][CH2:9][C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Brc1cccc(NCc2cccnc2)c1
Reactant: Oc1ccccc1-c1ccccc1
Product: c1ccc(-c2ccccc2Oc2cccc(NCc3cccnc3)c2)cc1

Procedure:
Using the procedure of Example 342 using N-(3-bromophenyl)pyridin-3-ylmethylamine and 2-phenylphenol (Aldrich) and purifying via preparative HPLC eluting with 90:10 to 80:20 DCM/ethyl acetate gave N-(3-(2-phenylphenoxy)phenyl)pyrid-3-ylmethylamine. Anal Calcd for C24H20N2O.0.2H2O: C, 80.96; H, 5.78; N, 7.87. Found: C, 81.07; H, 5.73; N, 7.63. MS found 353.1 [M+H]+