Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:43][O:44][C:45](=[O:63])[C@@H:46]([NH2:62])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][N:57]=[C:56]([CH3:60])[C:55]=2[CH3:61])=[CH:50][CH:49]=1>>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:19])[NH:62][C@H:46]([C:45]([O:44][CH3:43])=[O:63])[CH2:47][C:48]2[CH:49]=[CH:50][C:51]([C:54]3[CH:59]=[CH:58][N:57]=[C:56]([CH3:60])[C:55]=3[CH3:61])=[CH:52][CH:53]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccnc(C)c2C)cc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Yield: 62.8 %

Procedure:
(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (0.33 g) was coupled with (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (0.20 g) according to General Procedure L to provide (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (0.30 g). LCMS (m/z): 853.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1>>[NH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:15][CH2:16]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(N)ccn2)CC1
Yield: 33.1 %

Procedure:
Following General procedure H, 2-chloro-4-nitropyridine (500 mg, 3.1 mmol) was reacted with tert-butyl piperidin-4-ylcarbamate (695 mg, 3.5 mmol) followed by reduction to afford the desired product (300 mg, 33%) as a purple solid: ESI MS m/z 293 [C15H24N4O2+H]+.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9](N)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.N([O-])=O.[Na+].C(N)CN.[BrH:21]>[Cu]Br>[N:1]1([C:6]2[CH:12]=[CH:11][C:9]([Br:21])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Nc1ccc(-n2cncn2)cc1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: NCCN
Product: Brc1ccc(-n2cncn2)cc1
Reaction time: 0.25 h
Yield: 61 %

Procedure:
4-(1,2,4-Triazol-1-yl)aniline (400 mg, 2.5 mmol) in 48% HBr (10 ml) at -5° C. was stirred while sodium nitrite (173 mg, 2.5 mmol) was added portionwise over 5 minutes. The brown sludge was left stirring for 15 minutes and then added portionwise over 5 minutes to a refluxing mixture of copper (I) bromide (358 mg, 2.5 mmol) in 48% HBr (2 ml). The mixture was then heated at reflux for 1 minute, allowed to cool slightly, and poured into 10% ethylene diamine solution (20 ml). The aqueous solution was extracted with ethyl acetate, dried (Na2SO4), and evaporated to dryness under reduced pressure. The resulting mixture was purified by column chromatography on silica eluting with n-pentane/ethyl acetate (4-10%) to afford the title compound as a white solid (344 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][N:11]1[O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20].Cl.C([O-])(=O)C.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][N:11]1[O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)CCCON1CCNC1=Nc1c(Cl)cccc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)CCCON1CCNC1=Nc1c(Cl)cccc1Cl

Procedure:
38.80 g. of ethyl 4-{[2-[(2,6-dichlorophenyl)imino]-1-imidazolidinyl]oxy}-butyrate and 50 ml. of 25% strength hydrochloric acid are warmed to 125° for 45 minutes. The cooled solution is adjusted to pH 5 with sodium acetate and extracted with chloroform. The organic extracts are dried over magnesium sulfate and evaporated in vacuo. The residue is recrystallized from chloroform/ether, whereupon 4-{[2-[(2,6-dichlorophenyl)imino]-1-imidazolidinyl]oxy}butyric acid, m.p. 115°, is obtained.
Reaction SMILES: C([NH:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:11][O:12]C(=O)C)[CH2:6][O:7]C(=O)C)(=O)C.[OH-].[Na+].[ClH:34]>CO>[ClH:34].[NH2:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:6][OH:7])[CH2:11][OH:12]
Reactant: CCCCCCCCCCCCCCCCC(COC(C)=O)(COC(C)=O)NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCC(N)(CO)CO

Procedure:
2-Acetamido-1,3-diacetoxy-2-hexadecylpropane (1.75 g) was dissolved in 100 ml of methanol and 23.8 ml of a 1 N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed under heating for 6 hours. The mixture was neutralized with a 1 N aqueous hydrochloric acid solution and concentrated under reduced pressure. The concentrate was washed with water and ethyl acetate:hexane=1:1 in order to give 892 mg of 2-amino-2-hexadecyl-1,3-propanediol hydrochloride.
Reaction SMILES: C([O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([C@H:26]5[C@@:28]6([C:36]7[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=7)[NH:30][C:29]6=[O:39])[CH2:27]5)=[CH:23][CH:24]=4)[NH:19][N:18]=3)=[CH:13][N:12]=2)[CH2:7][CH2:6]1)(=O)C.[NH4+].[OH-]>CO>[OH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([C@H:26]5[C@@:28]6([C:36]7[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=7)[NH:30][C:29]6=[O:39])[CH2:27]5)=[CH:23][CH:24]=4)[NH:19][N:18]=3)=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(N5CCC(OC(C)=O)CC5)nc4)n[nH]c3c1)C(=O)N2
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(N5CCC(O)CC5)nc4)n[nH]c3c1)C(=O)N2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 1-(5-(6-((1R*,2S*)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-2-yl)-1H-indazol-3-yl)pyridin-2-yl)piperidin-4-yl acetate (40 mg, 0.076 mmol) and aqueous NH4OH (0.03 mL, 14 M) in MeOH (3 mL) was stirred at rt for 17 h. The crude reaction mixture was concentrated under reduced pressure to dryness, and the resulting crude product was purified by preparative HPLC to give the title compound as a yellow solid and as the TFA salt (23 mg, 62%). 1H NMR (400 MHz, MeOD) δ 8.56 (dd, J=9.6, 2.0 Hz, 1H), 8.37 (d, J=1.6 Hz, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.54 (s, 1H), 7.49 (d, J=9.6 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.60 (dd, J=8.4, 2.4 Hz, 1H), 5.60 (d, J=2.3 Hz, 1H), 4.06-3.99 (m, 3H), 3.65-3.59 (m, 2H), 3.37-3.35 (m, 1H), 3.28 (s, 3H), 2.26-2.23 (m, 1H), 2.20-2.16 (m, 2H), 2.09-2.04 (m, 2H), 1.78-1.69 (m, 2H); MS ESI 482.3 [M+H]+, calcd for [C28H27N5O3+H]+ 482.21.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](I)=[CH:9][N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[CH:5]=[CH:4][N:3]=1.[Cu][C:21]#[N:22].C1(C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C(=CC=CC=2)C=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[C:7]2[C:8]([C:21]#[N:22])=[CH:9][N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: N#C[Cu]
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nccc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(C#N)c2c(Cl)nccc21
Temperature: 110 °C
Reaction time: 18 h

Procedure:
To a mixture of C7 (1.2 g, 2.9 mmol) and copper(I) cyanide (540 mg, 6.0 mmol) in 1,4-dioxane (40 mL) were added tris(dibenzylideneacetone)dipalladium(0) (275 mg, 0.300 mmol) and 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphane) (BINAP, 540 mg, 0.87 mmol). After the reaction mixture had been stirred at 110° C. for 18 hours, it was filtered and concentrated under reduced pressure. Purification via silica gel chromatography (Gradient: 5% to 20% ethyl acetate in petroleum ether) afforded the product as a yellow solid. Yield: 380 mg, 1.2 mmol, 41%. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J=5.8 Hz, 1H), 7.80 (s, 1H), 7.43 (d, J=5.8 Hz, 1H), 5.52 (s, 2H), 3.47-3.54 (m, 2H), 0.88-0.95 (m, 2H), −0.02 (s, 9H).
Reaction SMILES: C[Al](C)C.[CH3:5][N:6]([CH3:8])[NH2:7].C[O:10][C:11]([C:13]1[O:17][N:16]=[C:15]([O:18][CH2:19][C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[N:22][O:23][C:24]=2[CH3:25])[CH:14]=1)=O.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCOCC1>[CH3:5][N:6]([CH3:8])[NH:7][C:11]([C:13]1[O:17][N:16]=[C:15]([O:18][CH2:19][C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[N:22][O:23][C:24]=2[CH3:25])[CH:14]=1)=[O:10]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)no1
Reactant: CN(C)N
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)NN(C)C)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 0.6 mL, 1.3 mmol) was added dropwise (exothermic) to a solution of N,N-dimethylhydrazine (76 mg, 1.3 mmol) in dioxane (3 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (100 mg, 0.32 mmol) in dioxane (2 mL) was added. The resulting mixture was then heated at 85-90° C. overnight, cooled to room temperature and poured into Seignette's salt and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, dichloromethane:methanol=9:1 to 7:3) afforded the title compound (86 mg, 79%) which was obtained as a white solid. MS: m/e=344.2 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([N:5]([C:10]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14]C)=[O:13])S(C)(=O)=O)(=[O:4])=[O:3].O.[OH-].[Li+]>CO>[CH3:1][S:2]([NH:5][C:10]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])=[O:4]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)cc1N(S(C)(=O)=O)S(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1cc(S(C)(=O)=O)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of methyl 2-[N,N-bis(methylsulphonyl)amino]-4-methylsulphonylbenzoate (22.9 g) and lithium hydroxide monohydrate (7.5 g) in aqueous methanol (50%) was stirred at room temperature for 18 hours. The resulting solution was acidified with concentrated hydrochloric add and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulphate), filtered and evaporated to yield 2-methylsulphonylamino-4-methylsulphonylbenzoic acid as a beige solid, NMR (acetone d6); 3.1(2s,6H), 7.57(dd,1H), 8.15(d,1H), 8.23(d,1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[O:5][N:4]=1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C([O:47][C:48](=[O:68])[C@H:49]([OH:67])[CH2:50][C@H:51]([NH2:66])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([Cl:65])[CH:60]=2)=[CH:55][CH:54]=1)C.CCO.[Li+].[OH-].O>CN(C=O)C>[Cl:65][C:61]1[CH:60]=[C:59]([C:56]2[CH:55]=[CH:54][C:53]([CH2:52][C@@H:51]([NH:66][C:8]([C:6]3[O:5][N:4]=[C:3]([O:2][CH3:1])[CH:7]=3)=[O:10])[CH2:50][C@@H:49]([OH:67])[C:48]([OH:68])=[O:47])=[CH:58][CH:57]=2)[CH:64]=[CH:63][CH:62]=1
Reactant: COc1cc(C(=O)O)on1
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(C(=O)N[C@H](Cc2ccc(-c3cccc(Cl)c3)cc2)C[C@@H](O)C(=O)O)on1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Methoxyisoxazole-5-carboxylic acid (39.4 mg, 275 μmol) and HCTU (128 mg, 310 μmol) were combined in DMF, and stirred for 10 minutes at room temperature. DIPEA (72 μL, 413 μmol) and (2R,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (50 mg, 0.1 mmol) were added, and the resulting mixture was stirred at room temperature overnight. The mixture was combined with EtOH (402 μL, 6.9 mmol) and 1 M LiOH in water (1.1 mL, 1.1 mmol). The mixture was stirred at room temperature for 1 hour, evaporated under reduced pressure, and purified by preparative HPLC to yield the title compound. MS m/z [M+H]+ calc'd for C22H21ClN2O6, 445.11. found 445.2.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:27])[CH2:15][S:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:35](Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>CC(C)=O>[C:35]([N:5]1[CH2:6][CH2:7][N:2]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:27])[CH2:15][S:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:10][CH:9]=2)[CH2:3][CH2:4]1)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: O=C(CSc1ccnc2ccccc12)c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N1CCN(c2ccc(C(=O)CSc3ccnc4ccccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
4-[2-[4-(1-Piperazinyl)phenyl]-2-oxoethylthio]-quinoline hydrochloride (Compound 51; 2.20 g, 4.66 mmol) was suspended in dry acetone (300 ml). Triethylamine (6.60 ml, 47.2 mmol) was added at -15° C. to the suspension and, after 30 minutes, pivaloylchloride (1.25 ml, 10.0 mmol) was added dropwise to the suspension. The reaction mixture was stirred at room temperature overnight and the solvent was removed under reduced pressure. The residue was chromatographed by silica gel chromatography (dichloromethane:methanol=20:1) to obtain 1.50 g of the titled compound (72.0%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])=[S:7])=[O:4].[Cl:16][CH2:17][C:18](Cl)=[O:19]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:18](=[O:19])[CH2:17][Cl:16])=[S:7])=[O:4]
Reactant: COC(=O)NC(=S)Nc1ccccc1N
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Product: COC(=O)NC(=S)Nc1ccccc1NC(=O)CCl
Temperature: 25 °C
Yield: 66.2 %

Procedure:
A suspension of 1-methoxycarbonyl-3-(2-aminophenyl)thiourea (9.00 g) in toluene (80 ml) was treated with chloroacetyl chloride (4.52 g) at room temperature and the mixture was heated to reflux for 1 hour with stirring. The mixture was then cooled to room temperature and the resultant white solid was filtered off and recrystallised from ethanol to give 1-methoxycarbonyl-3-(2-chloroacetamidophenyl)thiourea (7.98 g ), m.p. 156°-158° C.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:28](=[O:40])[N:29]([C:33]6[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=6)[N:30]=[CH:31][CH:32]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([N:42]3[CH2:47][CH2:46][CH:45]([N:48]([CH3:50])[CH3:49])[CH2:44][CH2:43]3)=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>>[CH3:49][N:48]([CH3:50])[CH:45]1[CH2:44][CH2:43][N:42]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[C:28](=[O:40])[N:29]([C:33]5[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=5)[N:30]=[CH:31][CH:32]=4)=[O:26])=[CH:20][C:19]=3[F:41])[NH:8][N:9]=2)[CH2:47][CH2:46]1
Reactant: COc1ccc(Cn2nc(N3CCC(N(C)C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C1CCN(c2n[nH]c3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A 50 mL round-bottomed flask was charged with N-(4-(1-(4-methoxybenzyl)-3-(4-(dimethylamino)piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (33.1 mg, 0.0468 mmol) and CF3COOH (5 mL). The reaction mixture was stirred at 80° C. overnight. Then the solvent was removed and the residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford the product (18.3 mg, 66.6%). LRMS (APCI pos): >99% purity, 254 nm, m/e 587 (M+1). 1H NMR (400 MHz, CDCl3) δ 11.83 (s, 1H), 10.80 (s, 1H), 8.42 (d, 1H), 8.28 (d, 1H), 8.24 (m, 1H), 7.98 (dd, 1H), 7.60 (m, 2H), 7.41 (d, 1H), 7.21-7.33 (m, 3H), 6.20 (d, 1H), 4.12 (m, 2H), 2.91 (m, 2H), 2.63 (m, 1H), 2.47 (s, 6H), 2.01 (m, 2H), 1.80 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:9]([CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[H-].[Na+].[CH3:29]I>O1CCCC1>[CH3:29][O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:9]([CH2:16][O:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: COc1ccc(COCC(Cn2ccnc2)OCCCCCCO)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCCCCCOC(COCc1ccc(OC)cc1)Cn1ccnc1
Reaction time: 1 h

Procedure:
1-[2-[(6-Hydroxyhexyl)oxy]-3-[(4-methoxyphenyl)methoxy]propyl]-1H-imidazole (Example 23) (0.3 g, 0.00086 mol) was added to a suspension of sodium hydride (0.006 g of an 80% dispersion in oil, 0.002 mol) in dry tetrahydrofuran (5 ml) at 25° C. and the resulting slurry stirred for 1 hour at this temperature. Methyl iodide (0.284 g, 0.002 mol) was then added and the resulting suspension stirred at 25° C. overnight. The suspension was then evaporated under reduced pressure and the residue poured into dilute hydrochloric acid (6N, 20 ml) and washed with ethyl acetate (2×5 ml), the aqueous phase was then basified with solid potassium carbonate and the liberated oil extracted into ethyl acetate (10 ml), the organic phase was then dried and evaporated under reduced pressure to give the product which was purified by column chromatography (silica gel, 10% methanol in ethyl acetate) to give the title compound as a pale yellow oil.
Reaction SMILES: [C:1]1([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[I-].[K+].Br[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[ClH:32]>C1(C)C=CC=CC=1.CCOC(C)=O>[ClH:32].[C:1]1([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:11][CH2:10]2)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)C1CCNCC1
Reactant: BrCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)C1CCN(CCc2ccccc2)CC1

Procedure:
A reaction mixture containing phenyl(4-piperidinyl)methanone (20.5 g, 0.108 mol), K2CO3 (33.17 g, 0.18 mol), potassium iodide (0.2 g) and 2-bromoethyl benzene (22.2 g, 0.12 mol, 16.4 ml) in toluene (250 ml) was stirred at reflux temperature for 66 h. The reaction mixture was filtered and the filtrate concentrated to a residue which was dissolved in dry Et2O (500 ml) and treated dropwise with a solution of HCl (0.11 mol) in EtOAc. The resultant precipitate was recrystallized from EtOH:CH3OH, 4:1 (500 ml) to give phenyl[1-(2-phenylethyl)-4-piperidinyl]-methanone hydrochloride, mp 258°-260° C.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:20]2C=CC=C[C:19]=2N=N1.C(Cl)Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[N:8]1[CH:19]=[CH:20][N:3]2[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=12
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Nc1cccc(N)n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccn2ccnc2c1

Procedure:
In Scheme 3, 2,6-diaminopyridine 15 is reacted with an alpha halocarbonyl 16 to give the imidazo[1,2-a]pyridine 17. The resulting amino group can be reacted with a carboxylic acid 18 using a coupling reagent such as chloro-1,3 dimethyl-4,5-dihydro-3H imidazolium chloride in the presence of a base such as TEA in a solvent such as ACN or alternatively by reacting amine 17 with an acid chloride 18 at elevated temperature in a solvent such as dichloroethane to give compound 19. Alternatively, the 2,6-diaminopyridine 15 is reacted with acid 20 using a coupling agent such as, but not limited to, BOP or DMC in an organic solvent such as DCM or DMF in the presence of an organic base such as Hunig' s base. The resulting amide 21 is reacted with alpha halocarbonyl 22 to give the imidazo[1,2-a]pyridine 23.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:15]=[C:16](/[CH:20]=[CH:21]/[C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:22](=[O:23])/[CH:21]=[CH:20]/[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:25])([F:26])[F:12])[CH:15]=1)[CH2:4]2
Reactant: O=C(O)/C=C/c1cccc(C(F)(F)F)c1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C/c1cccc(C(F)(F)F)c1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(3-trifluoromethylphenyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 271 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])[CH2:16][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:26].[K+].[K+].OO>CS(C)=O>[CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]([NH2:21])=[O:26])[CH2:16][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(C23CCCC(C2)N(Cc2ccccc2)CC3)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cccc(C23CCCC(C2)N(Cc2ccccc2)CC3)c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-benzonitrile (1.95 g, 6.16 mmol) in DMSO (55 ml) was charged with potassium carbonate (120 mg, 0.86 mmol) then 30% aqueous hydrogen peroxide (3.2 ml, 30.8 mmol). The reaction mixture was allowed to stir at room temperature for 23 h at which time it was determined not to have proceeded. Additional potassium carbonate (850 mg, 6.16 mmol) and 30% aqueous hydrogen peroxide (6.4 ml, 61.6 mmol) were introduced and stirred for 5.5 h. After a water quench (50 ml), the product was extracted with EtOAc (3×50 ml), washed with 50% saturated aqueous NaCl solution (5×50 ml), dried over Na2SO4, filtered and concentrated to a white solid which was triturated with hexanes and collected (1.0 g, 49%). (TLC 50% EtOAc/hexanes Rf 0.08); 1H NMR (400 MHz, CDCl3) δ 7.83–7.85 (m, 1H), 7.49–7.57 (m, 1H), 7.40–7.47 (m, 1H), 7.38–7.28 (m, 5H), 7.21–7.25 (m, 1H), 6.10 (brs, 1H), 5.63 (brs, 1H); 3.74–3.82 (m, 2H), 3.06–3.15 (m, 2H), 2.86–2.96 (m, 1H), 2.16–2.26 (m, 2H), 1.96–2.08 (m, 4H), 1.84–1.89 (m, 1H), 1.68–1.74 (m, 1H), 1.59–1.65 (m, 1H), 1.34–1.42 (m, 1H); APCI MS m/z 335.1 (M+1)+.