Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[OH-:12].[Na+].Cl.[NH2:15][OH:16]>O>[C:7]([C:6]1[CH:10]=[CH:11][C:3]([CH2:2][N:15]([CH2:2][C:3]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=2)[OH:16])=[CH:4][CH:5]=1)([OH:8])=[O:12]
Reactant: [OH-]
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(CN(O)Cc2ccc(C(=O)O)cc2)cc1
Temperature: 45 °C
Yield: 39 %

Procedure:
A filtered solution of 4-(chloromethyl)benzoic acid (33.0 g, 186 mmol) and NaOH (7.43 g, 186 mmol) was added over a 5 minute period to a solution of hydroxylamine hydrochloride (6.45 g, 92.8 mmol), NaOH (3.7 g, 92.8 mmol) and water (100 mL). The solution was stirred mechanically, and heated to 45° C. The pH of the solution was kept at 8-10 by the addition of aqueous NaOH. When the pH of the solution stopped decreasing, the solution was filtered, then acidified with concentrated H2SO4 to a pH of 4. The resulting white solid was isolated by filtration and washed with copious amounts of water until no cloudiness was observed when the filtrate was treated with aqueous silver nitrate. The product was dried in vacuo then dissolved in boiling N,N-dimethylformamide (DMF) (60 mL) and the hot solution treated with water until slightly turbid. The solution was cooled and the white solid which formed was isolated by filtration, washed with water, and dried in vacuo at 70° C. at 0.01 Torr to give 10.9 g (39%) product. The product met the following criteria: 1H NMR (DMSO-d6) δ 12.87 (br, s, 2H), 7.86 (d, J=7.5 Hz, 4H), 7.45 (d, J=7.5 Hz, 4H), 3.87 (s, 4H). 13C {1H} NMR (DMSO-d6) δ 167.3, 143.6, 129.4, 129.1, 129.0, 63.5. Analyzed for C16H15NO5 : C, 63.78; H, 5.02; N, 4.65. Found: C, 63.62; H, 5.11; N, 4.84.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH3:24][N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[C:18](=[O:21])[CH2:19][CH3:20]
Reactant: CCC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=O)N(C)c1cccc(-c2ccc3nnc(C)n3n2)c1
Temperature: 25 °C

Procedure:
A mixture of 2.52 g of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]propanamide, 100 ml of dimethylformamide and 0.43 g of sodium hydride (60% in oil) was stirred at room temperature. A 1.53 g portion of methyl iodide in 10 ml of dimethylformamide was added and the procedure of Example 1 was followed, giving 1.15 g of the desired product, mp 150°-152° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([CH3:10])=[N:3]1.C(Cl)(=O)C(Cl)=O.[NH2:17][C:18]1[CH:19]=[C:20]([CH:37]=[CH:38][CH:39]=1)[O:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([CH:28]=[C:29]([NH:31][C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])[N:30]=2)[N:27]=1.[OH-].[Na+]>ClCCl.CN(C)C=O.CN1CCCC1=O>[CH:34]1([C:32]([NH:31][C:29]2[N:30]=[C:25]3[CH:24]=[CH:23][C:22]([O:21][C:20]4[CH:19]=[C:18]([NH:17][C:7]([C:5]5[C:4]([CH3:10])=[N:3][N:2]([CH3:1])[CH:6]=5)=[O:8])[CH:39]=[CH:38][CH:37]=4)=[N:27][N:26]3[CH:28]=2)=[O:33])[CH2:35][CH2:36]1
Reactant: Cc1nn(C)cc1C(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nn(C)cc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.4 %

Procedure:
To a suspension of 1,3-dimethyl-1H-pyrazole-4-carboxylic acid (140 mg, 1.0 mmol) in dichloromethane (10 mL) were added N,N-dimethylformamide (2 drops) then oxalyl chloride (0.171 mL, 2.0 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure. The residue was diluted with N-methylpyrrolidone (5 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (155 mg, 0.50 mmol) was added thereto, and the mixture was stirred at room temperature for 6 hr. To the reaction mixture was added 0.5N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→70/30). The objective fraction was concentrated under reduced pressure, and the residue was washed with diisopropyl ether to give the title compound (126 mg, yield 58%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[C:14]1([C:20]2[O:21][CH2:22][CH:23]([OH:32])[CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:25]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCCl>[C:14]1([C:20]2[O:21][CH2:22][CH:23]([O:32][C:10](=[O:11])[NH:9][C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:4][CH:5]=3)[CH:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:25]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OC1COC(c2ccccc2)=NC1c1ccccc1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: ClCCCl
Product: O=C(Nc1ccc(C(F)(F)F)cc1)OC1COC(c2ccccc2)=NC1c1ccccc1
Yield: 74.4 %

Procedure:
4-(Trifluoromethyl)phenyl isocyanate (0.8 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (4RS, 5RS)-2,4-diphenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.26 g) in 1,2-dichloroethane (30 cc). The solution obtained is heated to reflux for 5 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica (0.063-0.2 mm; 40 g) contained in a column 1 cm in diameter, collecting 20-cc fractions. Fractions 2 and 3, eluted with a mixture of ethyl acetate and cyclohexane (3:7 by volume), are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in petroleum ether, (4RS, 5RS)-2,4-diphenyl-5-[4-(trifluoromethyl)phenylcarbamoyloxy]-5,6-dihydro-4H-1,3-oxazine (1.4 g), m.p. 140° C., is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[CH:27]=1)=[O:25])(C)(C)C>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:22](=[O:21])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[CH:27]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N
Product: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)ccc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-4-chloro-phenyl)-carbamic acid tert-butyl ester (Example J4) (182 mg, 0.75 mmol) and 3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light brown substance (316 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@@:4]2([CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:37])[C@H:19]([NH:29]C(=O)OC(C)(C)C)[CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:13]2)[C:3]1=[O:38].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:29][C@H:19]([CH2:20][CH2:21][O:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:18]([N:14]1[CH2:15][CH2:16][CH2:17][C@:4]2([C:3](=[O:38])[N:2]([CH3:1])[CH2:6][C@H:5]2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)=[O:37]
Reactant: CN1C[C@@H](c2ccccc2)[C@@]2(CCCN(C(=O)[C@@H](CCOc3ccccc3)NC(=O)OC(C)(C)C)C2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C[C@@H](c2ccccc2)[C@@]2(CCCN(C(=O)[C@H](N)CCOc3ccccc3)C2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Tert-butyl (R)-1-((4S,5R)-2-methyl-1-oxo-4-phenyl-2,7-diazaspiro[4.5]decan-7-yl)-1-oxo-4-phenoxybutan-2-ylcarbamate (242 mg; 0.464 mmol) was solubilised in DCM (1 ml). TFA (0.894 ml; 11.60 mmol) was added and the solution stirred at RT for 20 minutes before being concentrated in vacuo. The residual oil was dissolved with methanol (3 ml) and passed through a 10 g SCX-2 cartridge eluting with 2M NH3 in methanol (70 ml). The solvent was removed in vacuo yielding (4S,5R)-7-((R)-2-amino-4-phenoxybutanoyl)-2-methyl-4-phenyl-2,7-diazaspiro[4.5]decan-1-one.
Reaction SMILES: C(N(C(C)C)/[CH:5]=[C:6](\[F:9])/[CH:7]=O)(C)C.NC1C(C(ON2C3C=CC=CC=3N=N2)=O)=C2N=CC(CC#N)=CN2N=1.[NH2:38][C:39]1[C:43]([C:44]([NH:46][C:47]2[CH:48]=[N:49][CH:50]=[CH:51][C:52]=2[N:53]2[CH2:58][CH2:57][N:56]([CH3:59])[CH2:55][CH2:54]2)=[O:45])=[C:42]([NH2:60])[NH:41][N:40]=1.O>CS(C)=O>[NH2:60][C:42]1[C:43]([C:44]([NH:46][C:47]2[CH:48]=[N:49][CH:50]=[CH:51][C:52]=2[N:53]2[CH2:58][CH2:57][N:56]([CH3:59])[CH2:55][CH2:54]2)=[O:45])=[C:39]2[N:38]=[CH:5][C:6]([F:9])=[CH:7][N:40]2[N:41]=1
Reactant: CN1CCN(c2ccncc2NC(=O)c2c(N)n[nH]c2N)CC1
Reactant: CC(C)N(/C=C(\F)C=O)C(C)C
Agent: N#CCc1cnc2c(C(=O)On3nnc4ccccc43)c(N)nn2c1
Solvent: O
Solvent: CS(C)=O
Product: CN1CCN(c2ccncc2NC(=O)c2c(N)nn3cc(F)cnc23)CC1
Temperature: 140 °C
Reaction time: 0.42 h

Procedure:
A mixture of (Z)-3-(diisopropylamino)-2-fluoro-prop-2-enal (Tetrahedron Letters (1992), 33(3), 357-60) (22.81 mg, 0.1317 mmol), 4-methylbenzenesulfonic acid (Water (1)) (30.05 mg, 0.1580 mmol), 3,5-diamino-N-[4-(4-methylpiperazin-1-yl)-3-pyridyl]-1H-pyrazole-4-carboxamide (50 mg, 0.1580 mmol) in DMSO (1 mL)/H2O (0.5 mL) was stirred at 140° C. for 25 min. The crude mixture was purified by Fractionlynx HPLC. The aqueous fractions were combined and lyophilised to yield 2-amino-6-fluoro-N-(4-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. (10 mg, 21%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([F:30])=[C:21]([NH:23][C:24](=[O:29])C(F)(F)F)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[Li+].[OH-].[F:33][C:34]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:35]=1C(Cl)=O.C(O)C(N)(CO)CO>CN(C=O)C.O.C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([F:30])=[C:21]([NH:23][C:24](=[O:29])[C:35]4[C:34]([F:33])=[CH:42][CH:41]=[CH:40][C:39]=4[F:43])[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1cc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)ccc1F)C(F)(F)F
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: NC(CO)(CO)CO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)ccc1F)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.9 %

Procedure:
A solution of N-{5-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorophenyl}-2,2,2-trifluoroacetamide (300 mg, 0.69 mmol) and 1M LiOH (4.13 ml, 4.13 mmol) in 10:1 THF:H2O (15 mL) was heated at 50° C. overnight. The reaction was washed with brine (25 mL) and the aqueous layer was extracted with EtOAc (25 mL). The organic layers were combined, filtered through a cotton plug, and solvent removed by rotary evaporation. After high vacuum removal of residual solvent, the crude mixture was dissolved in DCM (10 mL) and to this was added 2,6-difluorobenzoyl chloride (519 mg, 2.94 mmol). After stirring 3 h at ambient temperature, DMF (25 mL) was added to dissolve any suspended solids followed by the addition of excess polymer-bound trisamine resin. Upon overnight stirring, the amine resin was removed by vacuum filtration, rinsed with MeOH (50 mL), and filtrate concentrated under reduced pressure to afford the desired amide (162 mg, 49%) as an off-white solid. ESIMS (M+H)+=480.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=1)#[CH:10]>C(#N)C.[Cu]I.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>[CH2:17]([C:14]1[CH:13]=[CH:12][C:11]([C:9]#[C:10][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1)[CH2:18][CH2:19][CH3:20]
Reactant: C#Cc1ccc(CCCC)cc1
Reactant: Nc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: CCCCc1ccc(C#Cc2ccc(N)cc2)cc1
Temperature: 85 °C
Reaction time: 24 h
Yield: 48.5 %

Procedure:
To a stirred solution of 4-iodoaniline (20 g, 91 mmol, Aldrich) and 1-eth-1-ynyl-4-butylbenzene (16.7 g, 105 mmol, Aldrich) in dry acetonitrile (300 mL) under nitrogen was added CuI (0.83 g, 4.3 mmol), TEA (27.7 g, 273 mmol) followed by Pd(PPh3)2Cl2 (3 g, 4.3 mmol). The reaction mixture was stirred at 85° C. for 24 hours and the solvent was removed under reduced pressure. The residue was diluted with Et2O (200 mL) and washed with water, brine and dried (MgSO4). The solvent was removed under reduced pressure and the crude product was purified by chromatography (Pet Ether/EtOAc (4/1) to give 11 g (47%) of the title compound as a solid. TLC-Pet ether/EtOAc (4/1): Rf=0.35. HPLC purity >98%.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:17]([F:19])[F:18])[N:6]2[CH2:13][C:14]([OH:16])=O.CCN=C=NCCCN(C)C.Cl.[F:32][C:33]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:34]=1[C:35]([NH:37][NH2:38])=O.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>ClCCCl>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:17]([F:19])[F:18])[N:6]2[CH2:13][C:14]1[O:16][C:35]([C:34]2[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:33]=2[F:32])=[N:37][N:38]=1
Reactant: N#Cc1ccc2c(cc(C(F)F)n2CC(=O)O)c1Cl
Reactant: NNC(=O)c1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCCl
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2nnc(-c3ccc(F)cc3F)o2)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 37.3 %

Procedure:
To a suspension of [4-chloro-5-cyano-2-(difluoromethyl)-1H-indol-1-yl]acetic acid (0.020 g, 0.070 mmol) in DCE (3 mL), under N2, was added EDCl (0.016 g, 0.081 mmol) and stirred at rt. After 5 min, 2,4-difluorobenzohydrazide (0.014 g, 0.081 mmol) was added and stirring was continued at rt. After 30 min, TsCl (0.016 g, 0.084 mmol) and P-BEMP (loading 2.2 mmol/g, 0.127 g, 0.28 mmol) were added and the mixture was heated at 100° C. for 20 min. The reaction was monitored by LC/MS. Subsequently, the mixture was heated at 120° C. for 30 min. Additional TsCl (0.020 g, 0.105 mmol) and P-BEMP (0.127 g, 0.28 mmol) were added and the mixture was heated at 120° C. another 20 min. Upon cooling, the resin was filtered off and washed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (10-70% EtOAc-hexanes gradient). The product was crystallized from CH2Cl2-hexanes to afford the title compound as a white solid (0.011 g, 38% yield): MS (ES) m/z 421 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([OH:33])([C:31]#[CH:32])[CH3:30])=[N:27][CH:28]=1.C(N(CC)CC)C>CS(C)=O.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>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:32]#[C:31][C:29]([C:26]4[CH:25]=[CH:24][C:23]([F:22])=[CH:28][N:27]=4)([OH:33])[CH3:30])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1
Reactant: C#CC(C)(O)c1ccc(F)cn1
Reactant: Nc1nccc(-n2c(OCCO)nc3ccc(Br)cc32)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(O)(C#Cc1ccc2nc(OCCO)n(-c3ccnc(N)n3)c2c1)c1ccc(F)cn1
Temperature: 25 °C
Yield: 1.5 %

Procedure:
A mixture of 2-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]ethan-1-ol (200 mg, 0.57 mmol), 2-(5-fluoropyridin-2-yl)but-3-yn-2-ol (940 mg, 5.69 mmol), bis(triphenylphosphine)palladium(II) dichloride (200 mg, 0.28 mmol) and triethylamine (0.5 mL) in dimethylsulfoxide (1 mL) was irradiated with microwave radiation under nitrogen for 1 hr at 120° C. The reaction mixture was cooled to room temperature then filtered through a frit filter to remove the catalyst. The filtrate was concentrated under vacuum and the crude product (80 mg) was purified by preparative HPLC to give 3.7 mg (1%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-fluoropyridin-2-yl)but-3-yn-2-ol as a light yellow solid: 1H NMR (300 MHz, DMSO) delta 8.54 (d, J=2.7 Hz, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.15 (d, J=1.2, 1H), 7.84 (q, 1H), 7.78-7.72 (m, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.24 (q, 1H), 7.10-7.04 (m, 3H), 6.37 (s, 1H), 5.03 (s, 1H), 4.60 (t, J=4.5 Hz, 2H), 3.81 (d, J=4.5 Hz, 2H), 1.82 (s, 3H); LC-MS: m/z=+435 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[CH3:13][C:14]([CH3:18])([CH3:17])[CH:15]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl>[CH3:13][C:14]([CH3:18])([CH3:17])[CH2:15][NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: CC(C)(C)C=O
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(NCC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
4-Methoxy-2-nitroaniline (10 g, 59.5 mmol, 1.0 equiv.) and trimethyl-acetaldehyde (9.73 g, 113 mmol, 1.9 equiv.) were dissolved in anhydrous dichloromethane (100 ml). The resulting solution was then treated with acetic acid (18.72 ml, 327 mmol, 5.5 equiv.), followed by sodium triacetoxyborohydride (30.3 g, 143 mmol, 2.4 equiv.). The mixture was stirred at room temperature. When LCMS showed completion of the reaction, the mixture was treated with saturated aqueous NaHCO3, then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to give the crude N-(2,2-dimethylpropyl)-4-methoxy-2-nitroaniline (1-3), which was used without purification. LRMS m/z (M+H) 239.0 found, 238.1 required.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1C(OC)=O.CN1CCNCC1.CN1C(=O)CCC1.C(O[CH:28]=[C:29]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])C>CC#N>[S:4]1[CH:5]=[CH:6][C:2]([NH:1][CH:28]=[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:3]1
Reactant: COC(=O)c1sccc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CN1CCNCC1
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(=CNc1ccsc1)C(=O)OCC
Temperature: 25 °C

Procedure:
A mixture of methyl 3-aminothiophene-2-carboxylate 1 (5.0 g, 32 mmol, 1.0 eq), N-methyl piperazine (6.5 g, 64 mmol, 2.0 eq) and NMP (30 mL) was heated to reflux for 16 hours. After the decarboxylation was complete, the reaction mixture was allowed to cool to room temperature and diethyl 2-(ethoxymethylene)-malonate (7.0 g, 32 mmol, 2.0 eq) was added. The reaction mixture was heated to reflux for 4 h. The product was purified using SiO2 column chromatography (Hex/EtOAc; 100:0 to 80:20%) to obtain a light yellow powder, 5.0 g (31%). LC/MS (10-99% CH3CN/0.05% TFA gradient over 5 min): m/z 270.2, retention time 1.52 minutes. 1H NMR (DMSO-d6) δ: 10.80 (d, 1.0 H, J=13.87 Hz, NH), 8.30 (d, 1.0 H, J=13.94 Hz), 7.60 (dd, 1.0H, J=3.0 Hz, J′=2.0 Hz), 7.40 (dd, 1.0 H, J=1.5 Hz, J′=3.13 Hz), 7.28 (dd, 1.0 H, J=1.5 Hz, J′=5.2 Hz), 4.20 (q, 2H, J=7.0 Hz), 4.10 (q, 2H, J=7.0 Hz), 1.30 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:27][CH2:26][CH2:25][CH2:24][Br:23])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: BrCCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CCCCBr)CC3)noc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (12 g, 55 mmol), K2CO3 (13 g) and 1,4-dibromobutane (20 g, 9.3 mmol, 1.7 eq) in acetonitrile (300 ml) was stirred at room temperature overnight. The inorganic material was filtered. The solution was concentrated to -80 ml, when crystals crashed out. The product was filtered to yield 14.16 g (73%), m.p.=243°-245° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([NH2:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[N:20]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[N:11]=[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:1])([F:21])[F:22])[CH:5]=1)[CH:19]=[CH:18]2)=[C:24]=[O:26]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cccc2ccc(-c3cccc(OC(F)(F)F)c3)nc12
Solvent: Cc1ccccc1
Product: O=C=Nc1cccc2ccc(-c3cccc(OC(F)(F)F)c3)nc12
Reaction time: 48 h

Procedure:
2-(3-(trifluoromethoxy)phenyl)quinolin-8-amine (252 mg, 0.830 mmol) in toluene (10 mL) was added a mixture of triphosgene (82 mg, 0.275 mmol) in toluene (5 mL). The mixture was stirred for 2 days to obtain 8-isocyanato-2-(3-(trifluoromethoxy)phenyl)quinoline, which was used without isolation.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:48]1[C:43](=[CH:44][C:45]([Cl:58])=[C:46]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[CH:47]=1)[O:42][C:41]([CH2:60][OH:61])([CH3:59])[CH2:40]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl.[H][H]>CO.C1COCC1.[OH-].[OH-].[Pd+2]>[Cl:58][C:45]1[CH:44]=[C:43]2[O:42][C:41]([CH2:60][OH:61])([CH3:59])[CH2:40][C@@:10]3([C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]3)[C:48]2=[CH:47][C:46]=1[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=1
Reactant: [H][H]
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)OC(C)(CO)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: CCc1ccc(Cc2cc3c(cc2Cl)OC(C)(CO)C[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 37.7 %

Procedure:
To a solution of 51 (13 mg, 15.5 μmol) in a mixture of MeOH (1.2 mL) and THF (0.4 mL) was added Pd(OH)2/C (15 mg) and 1,2-dichlorobenzene (20 μL). A balloon of hydrogen gas was attached for 0.5 h with vigorous stirring. LC/MS indicated that de-protection was complete. The reaction mixture was filtered through Celite, concentrated to a residue, and purified via preparatory TLC (5% MeOH in DCM) to give 52 (2.8 mg, 38%). 1H NMR (300 MHz, CD3OD) δ 7.34 (s, 1H), 7.07 (s, 4H), 6.81 (s, 1H), 3.97 (s, 2H), 3.85 (dd, J=2.1, 11.1 Hz, 1H), 3.67-3.74 (m, 3H), 3.44-3.56 (m, 3H), 3.23 (t, J=9.3 Hz, 1H), 2.58 (q, J=7.5 Hz, 2H), 2.45 (d, J=15.3 Hz, 1H), 2.16 (d, J=15.6 Hz, 1H), 1.42 (s, 3H), 1.19 (t, J=7.5 Hz, 3H). LCMS m/z 479 (M+H), 501 (M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:15][CH:14]=1)[C:5]2=O.O.[NH2:28][NH2:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)=[CH:7][NH:29][N:28]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: O=c1c(-c2ccc(-c3ccc(F)cc3)cc2)coc2cc(O)c(Cl)cc12
Reactant: NN
Solvent: O
Product: Oc1cc(O)c(-c2n[nH]cc2-c2ccc(-c3ccc(F)cc3)cc2)cc1Cl
Yield: 63.7 %

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-3-(4′-fluorobiphenyl-4-yl)-7-hydroxy-chromen-4-one (0.12 g, 0.33 mmol), Hydrazine hydrate (5 ml). The quenched reaction was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give 4-Chloro-6-[4-(4′-fluoro-biphenyl-4-yl)-1H-pyrazol-3-yl]-benzene-1,3-diol as a white solid (0.08 g, 63.7%).