Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[C:8]1([SH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>CCOCC>[CH3:7][O:6][C:1](=[O:5])[CH2:2][CH:3]([S:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:4]
Reactant: Sc1ccccc1
Reactant: C/C=C/C(=O)OC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)CC(C)Sc1ccccc1
Reaction time: 12 h

Procedure:
Methyl crotonate (150 g, 1.5 mole) is added over a period of 15 min. to a solution at 5° C of benzenethiol (165 g, 1.5 mole) and triethylamine (10 ml) in ether (500 ml). After standing for 12 hours at room temperature the reaction mixture is distilled to give β-(phenylthio)butyric acid methyl ester as an oil, b.p. 96°-98° C/<1 mm, νmaxCHCl3 1730 cm-1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:12]2OS(C(F)(F)F)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:12]2[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[F:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1ccccc1F
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(-c2ccccc2F)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
A mixture of methyl 6-benzyloxy-2-isobutyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate (10.50 g, 20 mmol), 2-fluorophenylboronic acid (3.36 g, 24 mmol) and sodium carbonate (5.30 g, 50 mmol) in toluene (50 mL), ethanol (10 mL) and water (10 mL) was stirred under an argon atmosphere at room temperature for 30 min. To the obtained mixture was added tetrakis(triphenylphosphine)palladium (1.16 g, 1 mmol) and the mixture was refluxed under heating under an argon atmosphere for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 6-benzyloxy-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (6.06 g, 65.9%) as crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[CH3:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:24]=1[CH2:25]O>>[CH3:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:24]=1[CH2:25][O:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17]
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cccc(O)c1
Reactant: Cc1cccc(C)c1CO
Product: Cc1cccc(C)c1COc1cccc(OCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Mitsunobu reaction of phenol 24 with 2,6-dimethylbenzyl alcohol gave 2-(2-(3-(2,6-dimethylbenzyloxy)phenoxy)ethyl)isoindoline-1,3-dione as yellow oil. Yield (1.2 g, 85%): 1H NMR (400 MHz, CDCl3) δ 7.85-7.88 (m, 2H), 7.71-7.74 (m, 2H), 7.12-7.18 (m, 1H), 7.01-7.10 (m, 3H), 6.60 (dd, J=8.0, 1.8 Hz, 1H), 6.57 (s, 1H), 6.51 (dd, J=8.0, 1.8 Hz, 1H), 4.99 (s, 2H), 4.09-4.24 (m, 4H), 2.38 (s, 6H).
Reaction SMILES: Br[C:2]1[N:11]=[C:5]2[CH:6]=[C:7]([Br:10])[CH:8]=[CH:9][N:4]2[N:3]=1.Cl.[F:13][CH2:14][CH2:15][NH:16][CH3:17].C(N(C(C)C)CC)(C)C>C(O)C>[Br:10][C:7]1[CH:8]=[CH:9][N:4]2[N:3]=[C:2]([N:16]([CH2:15][CH2:14][F:13])[CH3:17])[N:11]=[C:5]2[CH:6]=1
Reactant: Brc1ccn2nc(Br)nc2c1
Reactant: CNCCF
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN(CCF)c1nc2cc(Br)ccn2n1
Temperature: 130 °C
Yield: 34.5 %

Procedure:
To the solution of 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine (5 g, 18.05 mmol) and (2-fluoro-ethyl)-methyl-amine hydrochloride (20 g, 180.5 mmol) in ethanol (30 ml) was added di-isopropylethylamine (47 ml, 270.75 mmol) and the reaction mixture was heated at 130° C. in a sealed tube for 84 hours. The reaction mixture was concentrated under reduced pressure, the resulting residue was diluted with dichloromethane (100 ml). The organic layer was washed with water (2×75 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography over silicagel using 0.5% methanol/dichloromethane as eluent affording (7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(2-fluoro-ethyl)-methyl-amine (1.7 g, 34.5%) as an off white solid. MS: m/z=275.2 (M+H+).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([CH3:14])[C:12]#[N:13].[OH-].[Na+].Cl>C1COCC1>[C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([CH3:14])[C:12]#[N:13])#[CH:3]
Reactant: CC(C#N)c1ccccc1C#C[Si](C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C#Cc1ccccc1C(C)C#N

Procedure:
2-(2-(2-(Trimethylsilyl)ethynyl)phenyl)propanenitrile (2.16 g, 9 mmol) was stirred with 5N NaOH (10 mL, 50 mmol) and THF (20 mL) at room temperature for 1 hour. The reaction mixture was acidified with 5N HCl (13 mL) until the pH was about 2. The aqueous mixture was then extracted with EtOAc (3×50 mL). The combined organic layers were extracted with water (3×50 mL) and once with brine (50 mL), dried with MgSO4, and concentrated in vacuo to afford a brown oil. MS (m/z)=156 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[C:12]([N+:18]([O-])=O)[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl.CO.[Pd].[H][H]>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[C:12]([NH2:18])[CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: CNc1ccc(S(=O)(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CNc1ccc(S(=O)(=O)c2ccccc2)cc1N

Procedure:
Prepared analogously to Example 1c from (4-benzenesulphonyl-2-nitro-phenyl)-methyl-amine and palladium on activated charcoal/hydrogen in methylene chloride/methanol.
Reaction SMILES: O1C2C=CC(C(Cl)=O)=CC=2OC1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=1[F:35].[O:36]1[C:40]2[CH:41]=[CH:42][C:43]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:44][C:39]=2[O:38][CH2:37]1>C1(C)C=CC=CC=1.C(O)C>[O:36]1[C:40]2[CH:41]=[CH:42][C:43]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:44][C:39]=2[O:38][CH2:37]1.[O:36]1[C:40]2[CH:41]=[CH:42][C:43]([C:45]([NH:47][C:48]([NH:32][C:31]3[CH:33]=[CH:34][C:28]([O:27][C:18]4[C:17]5[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=5)[N:21]=[CH:20][CH:19]=4)=[C:29]([F:35])[CH:30]=3)=[S:49])=[O:46])=[CH:44][C:39]=2[O:38][CH2:37]1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1ccc2c(c1)OCO2
Agent: O=C(N=C=S)c1ccc2c(c1)OCO2
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc5c(c4)OCO5)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
1,3-Benzodioxole-5-carbonyl isothiocyanate was prepared using commercially available 1,3-benzodioxole-5-carbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 1,3-benzodioxole-5-carbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (62 mg, yield 75%).
Reaction SMILES: S(Cl)(Cl)(=O)=O.C1(C[S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[NH:21][C:22]3[C:27]([C:28](=[O:30])[CH:29]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)C=CC=CC=1.N12CCN(CC1)CC2>C(Cl)Cl>[CH:23]1[C:22]2[N:21]3[S:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:20]3=[CH:29][C:28](=[O:30])[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: O=c1cc(-c2ccccc2SCc2ccccc2)[nH]c2ccccc12
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: O=c1cc2c3ccccc3sn2c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
Sulfuryl chloride (0. 255 ml, 3.15 mmole, 1.05 equiv.) was added dropwise over 2 min to a solution of 2-[2-[(phenylmethyl)thio]phenyl]-4(1H)-quinolinone (1.03 g, 3 mmole, 1 equiv.) in dry CH2Cl2 (30 ml) at -15° C. The mixture was stirred for 0.5 hr, then 1,4-diazabicyclo[2.2.2]octane (504.8 mg, 4.5 mmole, 1.5 equiv.) was added. Stirring at -15° C. was continued for an additional 10 min, then the mixture was warmed to 25° C. After 0.5 hr at 25° C. the reaction was quenched with 10% aqueous Na2CO3 (30 ml) and extracted with CH2Cl2 . Drying (MgSO4), concentration, and silica gel chromatography (10% MeOH in 50% EtOAc/CHCl3) gave 5H-[1,2]benzisothiazolo[2,3-a]quinoline-5-one (0.28 g, 37%) as a yellow solid. Recrystallization from CHCl3 /EtOAc gave yellow, very fine needles: mp phase change at 244°-245° C., actual mp>300° C.; TLC (10% MeOH in 50% EtOAc/CHCl3) Rf 0.41; 1H NMR (CDCl3) δ8.53(m, 1H), 8.00 (app d, 1H), 7.6-7.8 (m, 3H), 7.4-7.6 (m, 3H), 7.09 (s, 1H); IR (KBr) 1618, 1593, 1571, 1544, 1483, 1464, 1445, 748 cm-1 ; MS (NH3), m/e (%) 252.1 (100, (M+H)+). Anal. Calcd for C15H9NOS: C, 71.69; H, 3.61; N, 5.57; S, 12.76. Found: C, 71.39; H, 3.51; N, 5.43; S, 12.68.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[C:7](=[O:28])[N:8]2[CH2:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([N:20]=CC3C=CC=CC=3)[CH2:16][CH2:15]2)=[O:13])=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].O>C(#N)C.Cl>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[N:31][OH:32])[C:7](=[O:28])[N:8]2[CH2:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([NH2:20])[CH2:16][CH2:15]2)=[O:13])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1C(=O)N(CC(=O)N2CCN(N=Cc3ccccc3)CC2)c2cc(Cl)ccc21
Agent: Cl
Solvent: CC#N
Solvent: O
Product: NN1CCN(C(=O)CN2C(=O)C(=NO)c3ccc(Cl)cc32)CC1
Temperature: 40 °C
Yield: 79 %

Procedure:
A mixture of 6-chloro-1-[(4-benzylideneamino-1-piperazinyl)carbonylmethyl]-2,3-indolinedione (1.5 g) and hydroxylamine hydrochloride (2.5 g) in acetonitrile (100 ml), conc. hydrochloric acid (50 ml), and water (50 ml) was heated at 40° C. for 2 hour. The reaction mixture was concentrated up to 20 ml and the precipitates appeared were filtered, and air-dried. This crude material was recrystallized from aqueous methanol at first, and for water finally to give 6-chloro-1-[(4-amino-1-piperazinyl)carbonylmethyl]-3-hydroxyimino-2-indolinone hydrochloride (0.54 g).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][C@H:3]1[OH:13].[C:14]1(=O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[O:15]1.CC1C=CC=CC=1>O>[O:15]=[C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[N:1]1[C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][C@H:3]1[OH:13]
Reactant: CCOC(=O)N1CC[C@@H](N)[C@H](O)C1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC[C@@H](N2C(=O)c3ccccc3C2=O)[C@H](O)C1

Procedure:
A mixture of 4.7 parts of ethyl trans-4-amino-3-hydroxy-1-piperidinecarboxylate, 3.7 parts of 1,3-dihydroisobenzofuran-1,3-dione and 45 parts of methylbenzene was stirred and refluxed for 2 hours using a water-separator. The reaction mixture was decanted from some insoluble tar. The methylbenzene-phase was evaporated in vacuo in a boiling water-bath. The residue was boiled in 2,2'-oxybispropane. After cooling, the solvent was decanted. The remaining oil solidified on scratching in 2,2'-oxybispropane. The product was filtered off and dissolved in dichloromethane. The solution was washed successively with a dilute hydrochloric acid solution, water, a dilute sodium hydroxide solution and again water. The organic phase was dried, filtered and evaporated in vacuo. The residue solidified on scratching in 2,2'-oxybispropane. The product was filtered off and crystallized from 2-propanol, yielding 2.12 parts of ethyl trans-4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3-hydroxy-1-piperidinecarboxylate; mp. 128.4° C. (intermediate 57).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1F)=O.O.[NH2:22][NH2:23]>CN(C1C=CN=CC=1)C>[Cl:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]2[C:14]=1[NH:23][N:22]=[C:11]2[C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: NN
Reactant: COc1ccc(C(=O)c2cccc(Cl)c2F)c(OC)c1
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(Cl)cccc23)c(OC)c1
Yield: 52.2 %

Procedure:
Prepared according to Method D Step A from (2,4-dimethoxyphenyl)[2-fluoro-3-chlorophenyl]methanone (1.20 g, 4.1 mmol), hydrazine hydrate (1.61 mL, 51.7 mmol) and DMAP (0.632 g, 5.17 mmol) to give the product (0.618 g) as a yellow solid.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[C:31]([CH3:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@H:22]([O:34][CH2:35][CH2:36][O:37][CH3:38])[C@@H:21]1[CH2:39]I)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.F.F.F.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[CH3:38][O:37][CH2:36][CH2:35][O:34][C@@H:22]1[C@H:21]([CH3:39])[C@@H:20]([CH2:19][OH:18])[O:24][C@H:23]1[N:25]1[CH:32]=[C:31]([CH3:33])[C:29](=[O:30])[NH:28][C:26]1=[O:27]
Reactant: COCCO[C@@H]1[C@H](CI)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Agent: F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCO[C@@H]1[C@H](C)[C@@H](CO)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Yield: 97.2 %

Procedure:
A solution of 5′-O-(tert-butyldiphenylsilyl)-3′-deoxy-3′-(iodomethyl)-2′-O-(2-methoxyethyl)-5-methyluridine (1.12 g, 1.65 mmol) and triethylamine trihydrofluoride (1.1 mL, 1.1 g, 6.7 mmol) in 20 mL of THF was stirred at rt for 24 h. The reaction mixture was diluted with 50 mL of ethyl acetate and washed with water and brine. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on a silica gel column. Gradient elution with 2:1, 1:2 and then 1:3 hexanes-EtOAc provided 504 mg of the title compound as a white foam.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[C:23]([O:27][C:28]([N:30]1[CH2:33][CH:32]([N:34]2[CH:38]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:36]=[N:35]2)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].COCCOC.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.C([O-])(O)=O.[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:23]([O:27][C:28]([N:30]1[CH2:33][CH:32]([N:34]2[CH:38]=[C:37]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([CH2:11][C:12]5[CH:13]=[C:14]6[C:19](=[CH:20][C:21]=5[F:22])[N:18]=[CH:17][CH:16]=[CH:15]6)=[CH:9][N:10]=4)[N:7]=3)[CH:36]=[N:35]2)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(n2cc(-c3ccc4ncc(Cc5cc6cccnc6cc5F)n4n3)cn2)C1
Temperature: 95 °C

Procedure:
A flask was charged with 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (Stage 173.1, 100 mg, 0.320 mmol), 3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyrazol-1-yl]-azetidine-1-carboxylic acid tert-butyl ester (Stage 146.3), 168 mg, 0.480 mmol), DME (2 mL), Pd(PPh3)2Cl2 (11 mg, 0.05 mmol) and 2 M K2CO3 (432 μL, 0.863 mmol). The RM was heated at 95° C. for 2 h. The cool RM was diluted with EtOAc/NaHCO3. The organic phase was separated and washed with brine (2×) then dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (CombiFlash® Companion System®, with a 4 g RediSep®: silica gel column, DCM/(DCM/MeOH 19:1)=100:0→0:100) to afford the title compound as a foam (tR 4.33 min (conditions 3), MH+=500.1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([S:17][C:18]2[N:22]4[CH:23]=[C:24]([C:27](=O)[CH3:28])[CH:25]=[CH:26][C:21]4=[N:20][N:19]=2)=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.Cl.[NH2:31][OH:32].Cl>CCO>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:8]=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([S:17][C:18]2[N:22]4[CH:23]=[C:24](/[C:27](=[N:31]/[OH:32])/[CH3:28])[CH:25]=[CH:26][C:21]4=[N:20][N:19]=2)=[CH:12][CH:11]=3)[CH2:5][CH2:6]1
Reactant: CC(=O)c1ccc2nnc(Sc3ccc4ncc(N5CCOCC5)cc4c3)n2c1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: C/C(=N\O)c1ccc2nnc(Sc3ccc4ncc(N5CCOCC5)cc4c3)n2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
To a solution of (77.3) (10 mg, 0.025 mmol) and hydroxylamine hydrochloride (6.86 mg, 0.099 mmol) in EtOH (5 ml) was added 0.01 ml of HCl (2 N) and the mixture was stirred in a sealed tube at 80° C. overnight. The mixture was evaporated to dryness and dissolved in H2O again, which was neutralized immediately by NaHCO3 until pH reached about 9. The resulted precipitate was filtered quickly. The precipitate was dissolved in DCM/MeOH (10/1) and washed again by water. The organic phase was dried over Na2SO4, filtered and evaporated to give the title compound (6.8 mg, yield 60.1%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)(O)O.[NH2:16][C:17](N)=N>O>[NH2:16][C:17]1[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[S:8](=[O:10])(=[O:9])[N:11]=1
Reactant: Nc1cccnc1S(N)(=O)=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: O
Product: NC1=NS(=O)(=O)c2ncccc2N1

Procedure:
An intimate mixture of 1 g of 3-aminopyridine-2- sulfonamide (Preparation 1) and 2.1 g of guanidine carbonate is progressively brought to the molten state (200° C.) and then heated for 24 hours at this temperature. After cooling, the residue is taken up in water. The possible insoluble material is filtered and the filtrate, treated with animal charcoal, is acidified to a pH of 7. The white precipitate is collected on a filter, washed with water and recrystallized from hot water.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[C:12]1[O:11][C:10]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:17]=3[C:27]([F:30])([F:29])[F:28])=[N:9][C:8]=1[CH2:7][CH2:6]2.B(Br)(Br)Br>ClCCl>[C:21]1([C:18]2[C:17]([C:27]([F:30])([F:29])[F:28])=[C:16]([C:10]3[O:11][C:12]4[C:13]5[C:5](=[CH:4][C:3]([OH:2])=[CH:15][CH:14]=5)[CH2:6][CH2:7][C:8]=4[N:9]=3)[O:20][N:19]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)oc1-2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)oc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of 7-methoxy-2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]oxazole (Preparation 43B, 123 mg, 0.298 mmol) in dichloromethane (3 mL) was added 1 M boron tribromide (1.491 mL, 1.491 mmol) in dichloromethane dropwise, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched by the slow addition of saturated ammonium chloride, extracted with dichloromethane, washed with water and brine. The combined aq. layers were back extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate and evaporated to give a yellow crystalline solid (quantitative yield). 1H NMR (400 MHz, CDCl3 mixed with methanol-d4) δ ppm 7.66 (2H, d, J=6.82 Hz), 7.49-7.59 (4H, m), 7.46 (1H, d, J=8.58 Hz), 6.76-6.83 (2H, m), 3.14 (2H, t, J=7.70 Hz), 3.03 (2H, t, J=7.59 Hz).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>C(OCC)(=O)C.[Pd]>[O:1]1[C:5]2([CH2:6][CH2:7][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: C1=C(c2ccccn2)CCC2(C1)OCCO2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: c1ccc(C2CCC3(CC2)OCCO3)nc1

Procedure:
To a solution of 14.6 g (67.19 mmol) of 2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine in ethyl acetate (400 mL) was added 4.6 g of 10% palladium on carbon catalyst. The resulting suspension was then hydrogenated at ambient temperature and atmospheric pressure until all the starting material was consumed (10.5 hr). The reaction mixture was filtered through celite and the filtrate was concentrated to give the product as an oily solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CCOC(C)=O>[CH3:18][N:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCN(C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCN(C)C1CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 135.8 %

Procedure:
To a solution of 4-(methyl-propyl-amino)-piperidine-1-carboxylic acid tert-butyl ester (106 mg, 0.41 mmol) in AcOEt (10 ml) was added 3N HCl (4 ml). The reaction mixture was stirred for 16 hrs at RT. The solvent was removed under reduced pressure to give the desired methyl-piperidin-4-yl-propyl-amine (87 mg, 92% yield).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[O:13][CH3:14].[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH:20]=[CH2:21]>O.[H+].[B-](F)(F)(F)F.CO.C(OCC)(=O)C>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]([O:13][CH3:14])=[C:6]([CH:11]=1)[CH:21]=[CH:20][C:19]1[CH:22]=[C:23]([C:25]([F:26])([F:28])[F:27])[CH:24]=[C:17]([C:16]([F:15])([F:29])[F:30])[CH:18]=1
Reactant: COc1ccc(Cl)cc1N
Reactant: C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(Cl)cc1C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
A solution of sodium nitrite (57 mg, 0.8 mmol) in water (1 mL) was added to a solution of 2-amino-4-chloroanisole (131 mg, 0.8 mmol) in 48% hydrogen tetrafluoroborate (0.3 mL) under ice cooling and argon atmosphere. After the mixture was stirred at 0° C. for 1 hour, a solution of 3,5-bis(trifluoromethyl)styrene (100 mg, 0.4 mmol) in methanol (3 mL) was added and the mixture was stirred at 50° C. for 1 hour. After the reaction mixture was cooled to room temperature, the residue obtained by evaporation of the solvent under reduced pressure was diluted with ethyl acetate. After the solution was washed successively with 2N hydrochloric acid, water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give the title compound (52.8 mg, 33.3%) as a white powder.