Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[OH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[NH2:27].CCN(C(C)C)C(C)C>>[OH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[NH:27][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@@H]2CCCC[C@H]2O)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (1R,2R)-2-hydroxy-cyclohexylamine and DIEA to give 2-((1R,2R)-2-hydroxy-cyclohexylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 354 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18]([C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)C.[OH-].[Na+]>CCO>[C:21]([C:18]1[O:17][C:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([CH:6]=[CH:5][C:4]([OH:29])=[O:3])[CH:12]=[CH:11][CH:10]=2)=[O:15])=[CH:20][CH:19]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(C(=O)c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C=Cc1cccc(NC(=O)c2ccc(C(=O)c3ccccc3)o2)c1

Procedure:
The ester (10) (28 mg, 0.072 mmol) was hydrolysed using Method C, except that EtOH (0.15 mL) and 1M NaOH (0.15 mL) were used. After the reaction, the solvent was removed under a stream of nitrogen gas and the residue acidified to pH 5 using 1N HCl. The precipitate was filtered off and dried to give the title compound. Yield: 8 mg, 31%; LC-MS tr 1.95 min; HPLC Purity: 98%; MS (ES+) m/z 362 (M+H); 1H NMR (400 MHz; DMSO): δ 6.4 (d, 1H), 7.10 (d, 1H), 7.20-7.40 (m, 2H), 7.55 (m, 1H), 7.60-7.80 (m, 3H), 7.80-7.90 (d, 1H), 7.95 (s, 1H), 7.95-8.10 (m, 3H)
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH:8]=[C:9](Br)[S:10][C:6]=2[C:5]([C:12]([NH2:14])=[O:13])=[CH:4][N:3]=1.Br[C:16]1[S:20][C:19]([CH3:21])=[C:18]([CH2:22][CH2:23][C:24]#[N:25])[CH:17]=1>>[NH2:1][C:2]1[C:7]2[CH:8]=[C:9]([C:16]3[S:20][C:19]([CH3:21])=[C:18]([CH2:22][CH2:23][C:24]#[N:25])[CH:17]=3)[S:10][C:6]=2[C:5]([C:12]([NH2:14])=[O:13])=[CH:4][N:3]=1
Reactant: Cc1sc(Br)cc1CCC#N
Reactant: NC(=O)c1cnc(N)c2cc(Br)sc12
Product: Cc1sc(-c2cc3c(N)ncc(C(N)=O)c3s2)cc1CCC#N

Procedure:
62 was prepared from 4-amino-2-bromo-thieno[3,2-c]pyridine-7-carboxylic acid amide 17 and 3-(5-bromo-2-methyl-thiophen-3-yl)-propionitrile 61 as a white solid in a similar manner to the procedure described in Example 14. 1H NMR (400 MHz, d6-DMSO) δ: 2.40 (s, 3H), 2.81 (s, 4H), 7.15 (s, 2H), 7.23 (s, 1H), 7.24 (br s, 1H), 7.70 (s, 1H), 7.80 (br s, 1H), 8.46 (s, 1H). MS (EI) m/z (M+H+) 343.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]2[O:11][CH:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][O:23][CH3:24])=[CH:17][CH:16]=3)[CH:9]3[CH2:25][C:26](=[O:28])[CH2:27][CH:8]3[C:7]=2[CH:6]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO.C1COCC1.CCOC(C)=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]2[O:11][CH:10]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][O:23][CH3:24])=[CH:19][CH:20]=3)[CH:9]3[CH2:25][CH:26]([OH:28])[CH2:27][CH:8]3[C:7]=2[CH:6]=1
Reactant: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(=O)CC32)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(O)CC32)cc1
Yield: 100 %

Procedure:
To a solution of cyclopentanon 23 (60 mg, 0.16 mmol) in 1 mL of MeOH and 0.5 mL of THF was added NaBH4 (15 mg, 0.40 mmol). After stirring for 2 hrs saturated aqueous ammonium chloride was added. The solution was diluted with EtOAc. The aqueous solution was extracted 2× with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to give 60 mg (0.16 mmol, 100%) of alcohol 25. HRMS (ES+) calc for C22H30NO6: 404.2073, found: 404.2082 (M+NH4).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:10][C:9]([P:11]([O:16][CH2:17][CH3:18])(=[O:15])[O:12][CH2:13][CH3:14])=[CH:8][CH:7]=1)CCC.I[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=1[N+:37]([O-:39])=[O:38]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:34]([C:31]1[CH:32]=[C:33]([C:6]2[O:10][C:9]([P:11]([O:12][CH2:13][CH3:14])(=[O:15])[O:16][CH2:17][CH3:18])=[CH:8][CH:7]=2)[CH:28]=[C:29]([N+:37]([O-:39])=[O:38])[CH:30]=1)([O-:36])=[O:35]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(P(=O)(OCC)OCC)o1
Reactant: O=[N+]([O-])c1ccc(I)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOP(=O)(OCC)c1ccc(-c2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)o1
Temperature: 80 °C

Procedure:
A mixture of diethyl 5-tributylstannyl-2-furanphosphonate (1 mmol), 1-iodo-2,4-dinitrobenzene (1 mmol) and tetrakis(triphenylphosphine)-palladium(0) (0.05 mmol) in 6 mL of dioxane was heated at 80° C. for 16 h. Evaporation of solvent and chromatography provided diethyl 5-(3,5-dinitrophenyl)-2-furanphosphonate as solid foam.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH2:15][CH2:16][CH:17]=O)=[CH:13][C:12]([CH2:19][CH2:20][CH3:21])=[N:11]2)=[CH:6][CH:5]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][N:34]([CH2:17][CH2:16][CH2:15][C:14]2[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:23])([F:22])[F:1])=[CH:5][CH:6]=3)[N:11]=[C:12]([CH2:19][CH2:20][CH3:21])[CH:13]=2)[CH2:33][CH2:32]1
Reactant: CCCc1cc(CCC=O)n(-c2ccc(OC(F)(F)F)cc2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc(OC(F)(F)F)cc2)n1

Procedure:
100 mg (80.6%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-trifluoromethoxyphenyl)-3-propyl-1H-pyrazol-5-yl)propanal (82.5 mg, 0.253 mmol), 1-(2-fluorophenyl)piperazine (60 mL, 0.379 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5](C(Cl)(Cl)Cl)[O:4][N:3]=1.[CH2:11]([NH2:15])[CH2:12][CH2:13][CH3:14]>>[CH2:11]([NH:15][C:5]1[O:4][N:3]=[C:2]([CH3:1])[N:6]=1)[CH2:12][CH2:13][CH3:14]
Reactant: Cc1noc(C(Cl)(Cl)Cl)n1
Reactant: CCCCN
Product: CCCCNc1nc(C)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methyl-5-trichloromethyl-1,2,4-oxadiazole (43 g, 0.21 mole) was added to n-butylamine (46.75 g, 0.63 mole) and stirred at room temperature overnight. Excess amine was removed under vacuum and the residue distilled (oil bath 110° C./0.5 mm Hg). Recrystallisation fromm petroleum ether 60°-80° C. gave the title compound as white plates 26 g, m.p. 62°-65° C.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:88]=[C:89]([F:91])[CH:90]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[N:67][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH3:77])[CH2:73][CH2:72]5)=[CH:69][CH:70]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:88]=[C:89]([F:91])[CH:90]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[N:67][C:68]([N:71]5[CH2:72][CH2:73][N:74]([CH3:77])[CH2:75][CH2:76]5)=[CH:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(N5CCN(C)CC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cc(F)cc(F)c6)c5)c4c3)cn2)CC1
Yield: 41.7 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (95 mg, 0.148 mmol) was hydrolyzed with lithium hydroxide (17 mg, 0.399 mmol) in THF/methanol/water (2/2/1 mL) to yield 30 mg (81.0% yield) of the titled compound. 1H NMR (CDCl3, 300 MHz): δ 9.14 (s, 1H), 8.49-8.46 (dd, 2H), 8.11 (s, 1H), 7.87 (s, 1H), 7.77-7.71 (m, 2H), 7.449-7.443 (d, 1H), 6.80-6.76 (m, 3H), 5.36 (s, 2H), 3.65-3.62 (m, 4H), 2.58-2.55 (m, 4H), 2.37 (s, 3H). MS: m/z=486.1 (M+1), HPLC: 93.44% in method B.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[Se](=O)=[O:19]>C(Cl)Cl>[C:12]1([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([CH:1]=[O:19])=[CH:3][CH:4]=3)[N:9]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[Se]=O
Reactant: Cc1ccc2ccc(-c3ccccc3)nc2c1
Solvent: ClCCl
Product: O=Cc1ccc2ccc(-c3ccccc3)nc2c1
Temperature: 160 °C

Procedure:
A mixture of 7-methyl-2-phenylquinoline (2.49 g, 11.4 mmol) and selenium dioxide (1.92 g, 17.3 mmol, 1.5 eq.) is heated to 160° C. (bath temp.) for 22 h. The cooled melt is suspended in CH2Cl2 with the aid of sonication and filtered through Celite and then through a plug of silica gel. This effectively removes the red color and the major lower spots. The material thus obtained is crystallized from hexanes/CHCl3, yielding a pale beige solid, mp. 108° C. The mother liquor is concentrated and chromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with hexanes:CH2Cl2 1:1 (1-25)→1:3 (26-53)→CH2Cl2 (54-73)→3% EtOAc in CH2Cl2 (74-85)] to obtain the title compound as a pale yellow solid, mp. 109° C.; 1H NMR (CDCl3, 400 MHz) δ 7.48-7.60 (m, 3H), 7.94 (d, J=8.8 Hz, 1H), 8.01-8.05 (m, 2H), 8.18-8.23 (m, 2H), 8.29 (d, J=8.8 Hz, 1H), 8.64 (s, 1H), 10.26 (s, 1H) MS (ES+): m/z 234.2 (100) [MH+]; HPLC: tR=3.0 min (MicromassZQ, nonpolar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.IC.[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH3:14])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC#N)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1cccc(C(C)C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (3-methoxyphenyl)acetonitrile (1.0 g, 6.79 mmol) and iodomethane (0.42 mL, 6.79 mmol) in THF (10 mL) at 0° C. was added sodium bis(trimethylsilyl)amide (1M in THF; 6.8 mL, 6.8 mmol). The reaction was warmed to room temperature and stirred for 1 hour. The mixture was partitioned between H2O and EtOAc and acidified with 1N aqueous HCl, and then extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the desired product.
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]1([CH2:15][CH2:16][CH2:17][NH:18][C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])[CH:14]=[CH:13][N:12]=[CH:11]1.C(=O)(O)[O-].[Na+].[ClH:29]>ClCCl.CCOCC.C(N(CC)CC)C>[ClH:9].[ClH:29].[C:1]([O:21][CH2:20][C:19]([NH:18][CH2:17][CH2:16][CH2:15][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)([CH3:23])[CH3:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(CO)NCCCn1ccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(COC(=O)c1ccccc1)NCCCn1ccnc1
Temperature: 0 °C

Procedure:
A solution of benzoyl chloride (0.36 g) in dichloromethane (1.5 ml) was added dropwise to a mixture of 2-[3-(imidazol-1-yl)propylamino]-2-methyl-1-propanol (0.5 g) and triethylamine (0.5 g) in dichloromethane (5 ml) with stirring under nitrogen at 0° C. The mixture was stirred at 0° C. for 1 hour and then allowed to warm up to ambient temperature and stirred at this temperature for 3 hours. Saturated aqueous sodium bicarbonate (5 ml) was added. The mixture was shaken and the organic layer separated. The aqueous layer was extracted with further dichloromethane. The combined organic extracts were dried, filtered and evaporated to give an oil which was dissolved in ether and treated with ethereal hydrogen chloride to give 2-[3-(imidazol-1-yl)propylamino]-2,2-dimethylethyl benzoate dihydrochloride, m.p. 198-199° C., after recrystallisation from ethanol.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11]([OH:20])(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH2:14].C([O-])([O-])=O.[K+].[K+].C(OCCO)C.Cl>O>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[NH:14][C:13]1[C:12](=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([OH:20])=[O:19])([OH:6])=[O:5]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(O)c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCCO
Product: O=C(O)c1ccccc1Nc1ccccc1C(=O)O
Reaction time: 2 h
Yield: 84 %

Procedure:
A mixture of 2-chlorobenzoic acid (100 g), anthranilic acid (90 g), anhydrous powered K2CO3 (135 g), Cu/CuO (2 g) and 2-ethoxyethanol (200 ml) was heated with swirling on the steam bath until gas evolution ceased and then stirred at 145° for a further 21/2 hours. The thick reaction mixture was diluted with water, acidified (HCl) and then the crude product was collected and washed well with hot water. This was dissolved in hot dilute aqueous Na2CO3 treated liberally with charcoal-celite and filtered through a celite pad. The hot filtrate was diluted with half the volume of EtOH and then slowly acidified (HCl). The pale yellow product which separated was collected when still warm, washed well with hot water, benzene and dried, providing material (84% yield) of sufficient purity for use in the next step (lit, m.p. 295° dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CO.Cl.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]>[ClH:1].[C:23]1([C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Clc1cc(Nc2cccc(N3CCCC3)n2)c2nccn2n1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: c1ccc(-c2cc(Nc3cccc(N4CCCC4)n3)c3nccn3n2)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 68.9 %

Procedure:
A mixture of 6-chloro-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (52 mg, 0.17 mmol), phenylboronic acid (31 mg, 0.25 mmol), Pd2(dba)3 (10 mg, 0.017 mmol), X-phos (32 mg, 0.067 mmol) and K2CO3 (69 mg, 0.5 mmol) in dioxane (5 mL) and water (0.5 mL) was heated to 100° C. with stirring for 4 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=180:1) to give crude product as a yellow solid. The solid was further purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 40% acetonitrile/60% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give a light yellow solid. This was dissolved in methanol and three drops of concentrated HCl added. The mixture was stirred for 5 minutes, then concentrated in vacuo to give the final product 6-phenyl-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine hydrochloride (46 mg, 78%) as an HCl salt. 1H NMR (300 MHz, CD3OD): δ 8.81 (s, 1H), 8.31 (s, 1H), 8.04-7.96 (m, 3H), 7.56-7.50 (m, 4 h), 6.38 (d, 1H, J=7.8 Hz), 6.20 (d, 1H, J=8.4 Hz), 3.54-3.49 (m, 4 h), 2.08-2.03 (m, 4 h). LC-MS: [M+H]+, 357.1, tR=1.912 min, HPLC: 95.34% at 214 nm, 99.67% at 254 nm, tR=7.083 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH3:9])=[N:6][CH:7]=1.[CH3:10][S-:11].[Na+]>CN(C=O)C.C(OCC)C>[CH2:8]([C:5]1[CH:4]=[CH:3][C:2]([S:11][CH3:10])=[CH:7][N:6]=1)[CH3:9]
Reactant: C[S-]
Reactant: CCc1ccc(Br)cn1
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCc1ccc(SC)cn1
Temperature: 100 °C
Yield: 56.4 %

Procedure:
A solution of 5-bromo-2-ethylpyridine (see part (i)) (3.0 g, 16.2 mmol) in dry DMF (4.5 ml) was treated with sodium methanethiolate (1.8 g, 24.3 mmol) and the suspension heated at 100° C. for 3 hours. The cooled mixture was diluted with diethyl ether (200 ml), washed with water (4×100 ml), then dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica by elution with dichloromethane. The appropriate fractions were combined and evaporated under reduced pressure. The resulting oil was distilled under reduced pressure (60 mm) at an oven temperature of 150° C. using a Kugelrohr (trade mark) apparatus to give the title compound, (1.4 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][C:36](=[O:39])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][C:36]([OH:39])([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 49 %

Procedure:
Diisopropylamine (25.2 mL, 0.18 mol) in anhydrous THF (500 mL) was cooled to 0° C. and n-butyllithium (112.5 mL of a 1.6 M solution in THF, 0.18 mol) was added dropwise over 20 minutes to the cooled solution. The reaction mixture was stirred for an additional 15 minutes at 0° C. and then tri-n-butyltinhydride (48.4 mL, 0.18 mol) was added dropwise over 30 minutes. The reaction mixture was then stirred for one hour and then cooled to −78° C. N-(t-butoxycarbonyl)-4-piperidone (30.0 g, 0.15 mol) in THF (500 mL) was then added dropwise to the cooled solution over one hour. After addition was complete, the reaction was stirred for 2 hours at −78° C. and then quenched with buffer (pH 6). The mixture was extracted with ethyl acetate, the organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography (5% ethyl acetate/hexane to provide 1-(t-butoxycarbonyl)-4-hydroxy-4-tributylstannyl piperidine (36.06 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1([CH3:28])[O:25][CH:24]([CH2:26][OH:27])[CH2:23][O:22]1.O[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:20][C:21]1([CH3:28])[O:25][CH:24]([CH2:26][O:27][C:30]2[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=2)[CH2:23][O:22]1
Reactant: CC1(C)OCC(CO)O1
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OCC(COc2ccc(C=O)cc2)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
39.3 g (150 mmol) of triphenylphosphine are added to a solution of 13.2 g (100 mmol) of 1,2-O-isopropylideneglycerol in 250 ml of dry THF, and the mixture is stirred at RT for 30 min. The mixture is cooled to about 0° C., and 12.2 g (100 mmol) of 4-hydroxybenzaldehyde and 31.9 g (150 mmol) of diisopropyl azodicarboxylate (DIAD) are added. The yellow reaction solution is stirred at RT for 16 h. The mixture is then concentrated using a rotary evaporator, and the residue is added to 150 ml of sat. sodium bicarbonate solution. The mixture is extracted with ethyl acetate (three times, 150 ml each), and the combined organic phases are dried over sodium sulphate. After removal of the solvent on a rotary evaporator, the crude product is purified chromatographically on silica gel 60 (mobile phase gradient cyclohexane→cyclohexane/ethyl acetate 2:1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:13]=[CH:14][C:15]([CH2:19][C:20]3[CH:21]=NC=[CH:24][CH:25]=3)=[C:16]([OH:18])[CH:17]=2)=[CH:4][CH:3]=1.CC(C)([O-:29])C.[K+]>C(O)(C)(C)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:13]=[CH:14][C:15]([CH2:19][CH:20]3[CH2:25][CH2:24][O:29][CH2:21]3)=[C:16]([OH:18])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: Nc1ccc(-c2ccc(Cc3cccnc3)c(O)c2)c2ccccc12
Agent: [K+]
Solvent: CC(C)(C)O
Product: Nc1ccc(-c2ccc(CC3CCOC3)c(O)c2)c2ccccc12
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 19 %

Procedure:
To a solution of 200 mg of tert-butyl naphthyl carbamate (Example 6) (0.59 mmol, 1 equiv.) in 1.6 mL anhydrous tert-butanol was added 200 mg of 3-tetrahydrofuroic aldehyde from above (excess) and 1.78 mL potassium tert-butoxide solution in tert-butanol (1.0 M, 1.78 mmol, 3 equiv.). The mixture was heated to 40° C. overnight, then cooled and quenched with NH4Cl saturated aqueous solution. The product was extracted with a dichloromethane/MeOH mixture (3×100 mL). The combined extracts were washed with brine, dried over MgSO4, and concentrated. 1H NMR analysis revealed that only 10% of the enone was consumed. The residue (300 mg) was dissolved in 4.0 mL dichloromethane and treated with 4 mL of a 1:1 mixture dichloromethane: TFA. The mixture was stirred for 1.5 h, then neutralized with saturated NaHCO3 aqueous solution, basified with 4 N NaOH solution and extracted with dichloromethane/MeOH (3×100 mL). The combined organic extracts were washed with brine, dried (MgSO4) and filtered and concentrated. The crude product was purified by column chromatography on silica gel using 10 to 50% EtOAc in hexane eluent mixtures to give the title compound (35 mg 0.11 mmol, 19% of theoretical yield).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[Cl:5][C:6]1[CH:11]=[C:10](Cl)[N:9]=[C:8]([S:13]([CH3:16])(=[O:15])=[O:14])[N:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:5][C:6]1[CH:11]=[C:10]([NH:4][O:3][CH3:2])[N:9]=[C:8]([S:13]([CH3:16])(=[O:15])=[O:14])[N:7]=1
Reactant: CS(=O)(=O)c1nc(Cl)cc(Cl)n1
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CONc1cc(Cl)nc(S(C)(=O)=O)n1
Temperature: 90 °C

Procedure:
40 g (0.48 mol) of O-methylhydroxylamine hydrochloride is added to a solution of 100 g (0.44 mol) of 4,6-dichloro-2-methylsulfonylpyrimidine in 400 ml of N,N-dimethylformamide. 66 g (0.48 mol) of potassium carbonate is added and the whole is heated at 90° C. for 10 hours. The mixture is allowed to cool, is evaporated down, the residue is taken up in 10% strength aqueous hydrochloric acid and dichloromethane, the phases are separated, dried and concentrated in a rotary evaporator. The 4-chloro-6-methoxyamino-2-methylsulfonylpyrimidine obtained as byproduct may be separated by chromatography on silica gel (developer: cyclohexane/ethyl acetate). There is obtained 39 g (45%) of the title compound as a white crystalline mass of m.p. 135° C.