Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N2C(C(F)(F)F)=C([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=[CH2:30])=[CH:23][CH:22]=5)C=N2)C=CC=CC=1.C(C1C=C2C(=CC=1)C(=NO)CCC2)=C.[C:45]1([C:51]2[S:55][N:54]=[C:53](C(OC)=O)[C:52]=2[C:60]([F:63])([F:62])[F:61])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[C:45]1([C:51]2[S:55][N:54]=[C:53]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=[CH2:30])=[CH:23][CH:22]=5)[C:52]=2[C:60]([F:63])([F:62])[F:61])[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: COC(=O)c1nsc(-c2ccccc2)c1C(F)(F)F
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Agent: C=Cc1ccc2c(c1)CCCC2=NO
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1nsc(-c2ccccc2)c1C(F)(F)F

Procedure:
The titled compound was prepared using the experimental protocol described for Preparation 89A employing 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate I-1) and methyl 5-phenyl-4-(trifluoromethyl)isothiazole-3-carboxylate (Preparation 105B) as starting materials. The compound had an HPLC retention time=4.30 min. (condition C); LC/MS M+1=424.9.
Reaction SMILES: [NH2:1][C:2](=[O:18])[C@H:3]([NH:10]C(=O)OC(C)(C)C)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:19]>O1CCOCC1>[ClH:19].[NH2:10][C@H:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:2]([NH2:1])=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(N)=O)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)[C@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The solid (R)-tert-butyl 2-amino-2-oxo-1-phenylethylcarbamate (446 mg) was dissolved in dioxane (5 mL), aq. 6N HCl (8 mL) was added. After being stirred at room temperature for 20 h, the mixture was concentrated in vacuo to give (R)-2-amino-2-phenylacetamide hydrochloride as a solid (329 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>O>[CH:5]1[C:6]2[NH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH:15]=[C:3]([CH:2]=[O:1])[N:4]=1
Reactant: OCc1cc2c(cn1)[nH]c1ccccc12
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: O
Product: O=Cc1cc2c(cn1)[nH]c1ccccc12
Temperature: 80 °C
Yield: 82.7 %

Procedure:
A mixture of 3.3 g of 3-hydroxymethyl-beta-carboline, 300 ml of water-free pyridine and 9.9 g of lead tetra-acetate is heated in an oil bath for 4 h at about 80° C. After cooling and evaporation, 150 ml of water is added. The crystalline residue is filtered off, washed with a 5% aqueous potassium carbonate solution and then again with water. The air-dried product (3.5 g) is boiled in 0.7 liters of 2-propanol with activated carbon and is filtered hot. After evaporation, 2.7 g of beta-carboline-3-carboxaldehyde is obtained, with a melting point of 270° C. (decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][C:29]=1[O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42].C(N(CC)CC)C.C(OC(C)(C)C)=O>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([CH3:27])=[C:29]([O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[CH:30]=2)[CH:15]([CH3:16])[CH3:17])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCOc1cc(C(=O)O)ccc1C
Reactant: CC(C)NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(C)(C)O[SiH2]C(C)(C)C
Agent: CC(C)(C)OC=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(C)(C)O[SiH2]C(C)(C)C)C(C)C)ccc1C

Procedure:
From (3S,4R)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-(isopropylamino-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (5 g, 12.9 mmol), 4-methyl-3-(3-methoxy-propoxy)-benzoic acid (4.06 g, 18.1 mmol), BOPCI (4.6 g, 18.1 mmol) and triethylamine (7.2 mL, 51.7 mmol). TLC, Rf (AcOEt)=0.7. MS (LC-MS): 493 [M+H-Boc]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[CH2:10]([O:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[CH3:11].C1C=CC=CC=1>O>[CH3:2][C:1](=[N:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:21])=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC(=O)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(N=C(C)c2ccccc2)cc1

Procedure:
A solution of acetophenone (44 ml), ethyl-p-aminobenzoate (60 g), benzene (100 ml) was refluxed in the presence of molecular sieve (100 g) with continuous removal of water. The crude product was purified by crystallizing it from ethanol to give N-(α-methyl benzylidene)-p-carbethoxy aniline (XI). XI had a m.p. of 87° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>C(#N)C>[NH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NCCCN
Solvent: CC#N
Product: NCCCNc1ccc([N+](=O)[O-])cn1
Reaction time: 7.5 h

Procedure:
A solution of 2-chloro-5-nitropyridine (3.16 g, 20 mmol) in dry acetonitrile (40 ml) was added dropwise to a solution of 1,3-diaminopropane (5.0 ml) in acetonitrile (20 ml) at room temperature. After 7.5 hour, a yellow solid precipitated in the reaction mixture. The solvent was removed in vacuo and the residue was partitioned between 2.5 M aqueous sodium hydroxide and dichloromethane. The layers were separated and the aqueous portion was extracted 3× with dichloromethane. The combined organic layers were back-extracted with a saturated sodium chloride solution, then dried and concentrated in vacuo using a Buchi rotary evaporator Model R-124 to give (3-aminopropyl)(5-nitro(2-pyridyl))amine as a yellow solid (2.55 g). The amine (1.14 g, 6 mmol) was shaken with benzotriazole carboxamidinium 4-methylbenzenesulfonate (2.0 g, 6 mmol) and diisopropylethyl amine (DIEA) (1.05 ml, 6 mmol) in acetonitrile (10 ml) at room temperature over two days. Dilution with ether gave the amino-{3-[(5-nitro(2-pyridyl))amino]propyl}carboxamidinium 4-methylbenzenesulfonate as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:18](=[O:19])[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2cccnc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cccnc2)n1
Yield: 95.1 %

Procedure:
Following the procedure in Example 118A, 3-tert-butyl-1-(pyridin-3-yl)-1H-pyrazol-5-amine (665 mg, 3.08 mmol) and phenyl chloroformate (705 mg, 4.5 mmol) were reacted to give phenyl 3-tert-butyl-1-(pyridin-3-yl)-1H-pyrazol-5-ylcarbamate (984 mg, 2.93 mmol, 95%). 1H NMR (300 MHz, DMSO-d6) δ 7.42-7.39 (m, 3H), 7.30-7.26 (m, 5H), 6.85 (t, 1H), 6.82 (d, 2H), 1.21 (s, 9H); LC-MS (ESI) m/z 337 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:3]=1[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8](=[O:16])(=[O:15])[N:7]([C:17]2[CH:22]=[C:21]([CH3:23])[C:20]([O:24]C)=[C:19]([CH3:26])[CH:18]=2)[C:6]1=[O:27].B(Br)(Br)Br.OC1C(C)=CC(N2C(=O)N(CC3C(F)=CC(F)=CC=3F)C3C=CC=CC=3S2(=O)=O)=CC=1C>>[Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:3]=1[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8](=[O:15])(=[O:16])[N:7]([C:17]2[CH:18]=[C:19]([CH3:26])[C:20]([OH:24])=[C:21]([CH3:23])[CH:22]=2)[C:6]1=[O:27]
Reactant: COc1c(C)cc(N2C(=O)N(Cc3c(F)cccc3Cl)c3ccccc3S2(=O)=O)cc1C
Agent: BrB(Br)Br
Agent: Cc1cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc(C)c1O
Product: Cc1cc(N2C(=O)N(Cc3c(F)cccc3Cl)c3ccccc3S2(=O)=O)cc(C)c1O
Yield: 54.2 %

Procedure:
The title compound (0.12 g, 0.26 mmol) was prepared from (81) (0.23 g, 0.48 mmol) and boron tribromide (1.0M solution in DCM, 0.60 mL, 0.60 mmol) using the methods of (114).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:72]=[CH:71][C:70]([C:73]([F:76])([F:75])[F:74])=[CH:69][C:68]=2[CH3:77])[C:56]=1[CH3:78].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:72]=[CH:71][C:70]([C:73]([F:74])([F:75])[F:76])=[CH:69][C:68]=4[CH3:77])[C:56]=3[CH3:78])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1cc(C(F)(F)F)ccc1-c1nc2cc(F)cc(F)c2c(Cl)c1C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1cc(C(F)(F)F)ccc1-c1nc2cc(F)cc(F)c2c(Nc2cc(N3CCOCC3)cnc2N2CCOCC2)c1C

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.018 g, 0.039 mmol), 2,5-dimorpholinopyridin-3-amine (0.077 g, 0.29 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(2-methyl-4-(trifluoromethyl)phenyl)quinoline (0.090 g, 0.24 mmol), Pd2dba3 (7.74 mg, 8.46 μmol) and sodium tert-butoxide (0.058 g, 0.61 mmol) in toluene (2.4 mL) at 120° C. for 4 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(2-methyl-4-(trifluoromethyl)phenyl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 7.75 (1H, br. s), 7.58-7.66 (4H, m), 7.38 (1H, m), 7.06 (1H, m), 6.26 (1H, br. s.), 3.93 (4H, br. s), 3.80 (4H, app t, J=4.1 Hz), 3.20 (4H, br. s.), 3.01 (4H, app t, J=4.4 Hz), 2.25 (3H, s), 1.94 (3H, s). Mass Spectrum (ESI) m/e=600.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].CCO[CH:18]=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[CH2:28]([O:27][C:25]([C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][NH:14][NH:13][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=1[Cl:12])=[O:26])[CH3:29]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CCO
Product: CCOC(=O)C(=CNNc1c(Cl)cc(C(F)(F)F)cc1Cl)C(=O)OCC

Procedure:
##STR79## 24.5 g (0.1 mol) of 2,6-dichloro-4-trifluoromethylphenyl hydrazine and 21.6 g (0.1 mol) of diethyl ethoxymethylene malonate are stirred for 24 hours at room temperature in 150 ml of ethyl alcohol, the solvent removed by vacuum, and the crystalline residue stirred with petroleum ether. Suctioning off and air-drying results in a yield of 33 g (79.5% of the theoretical) of N-[2,2-bis-(ethoxy-carbonyl)-vinyl]-N'-(2,6-dichloro-4-trifluoromethylphenyl) hydrazine with a melting point of 86° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH:23]([NH:26][CH2:27][CH2:28][OH:29])([CH3:25])[CH3:24]>>[OH:29][CH2:28][CH2:27][N:26]([CH:23]([CH3:25])[CH3:24])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:20]
Reactant: CC(C)NCCO
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 2-(isopropylamino)ethanol (1.2 equiv) to give 209 (10.8 mg, M+1 399.1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[C:7]2[OH:13].[CH3:14][NH:15][C:16]([CH3:19])([CH3:18])[CH3:17]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:15]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:14])[NH:8][C:7]2=[O:13]
Reactant: CNC(C)(C)C
Reactant: Oc1nc(Cl)nc2c(Br)cccc12
Solvent: CN1CCCC1=O
Product: CN(c1nc2c(Br)cccc2c(=O)[nH]1)C(C)(C)C
Temperature: 150 °C
Yield: 24.7 %

Procedure:
A mixture of 8-bromo-2-chloroquinazolin-4-ol (407c, 0.20 g, 0.77 mmol) in N-methyl-tert-butylamine (Aldrich; 0.919 mL, 7.71 mmol) and 1 mL NMP was sealed and heated to 150° C. in an oil bath for 6 h. The reaction was heated for 3 days. The reaction was partitioned between sat'd aq. NH4Cl and EtOAc. The organic layer was washed with sat'd aq. NH4Cl once, sat'd aq. NaCl once, and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with 10% MeOH in DCM, adsorbed onto 1.5 g silica gel, and purified by silica gel chromatography (24 g column) using 0-50% EtOAc/hexanes. The product-containing fractions were concentrated to afford 8-bromo-2-(tert-butyl(methyl)amino)quinazolin-4(3H)-one (0.060 g, 0.19 mmol, 25% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.36 (1H, br. s.), 7.76-8.03 (2H, m), 6.95-7.14 (1H, m), 2.97 (3H, s), 1.55 (9H, s). m/z (ESI, +ve ion) 310.0/312.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:21]=1)[C:18]1[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([OH:20])=[CH:9][CH:10]=1.[CH:22]1([C:25]#[CH:26])[CH2:24][CH2:23]1>[Cu]I.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>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:21]=1)[C:18]1[CH:17]=[C:16]([C:26]#[C:25][CH:22]3[CH2:24][CH2:23]3)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([OH:20])=[CH:9][CH:10]=1
Reactant: NC1=N[C@]2(CO1)c1cc(O)ccc1Oc1ccc(Br)cc12
Reactant: C#CC1CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: NC1=N[C@]2(CO1)c1cc(O)ccc1Oc1ccc(C#CC3CC3)cc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A vial was charged with (R)-2-amino-2′-bromo-5H-spiro[oxazole-4,9′-xanthen]-7′-ol (1.00 g, 2.88 mmol), cyclopropyl acetylene (0.732 mL, 8.64 mmol), copper(i) iodide (0.110 g, 0.576 mmol), and DIPA (14.40 mL). Tetrakis(triphenylphosphine)palladium(0) (0.333 g, 0.288 mmol) was added, the vial was flushed with argon, and the reaction was heated to 50° C. and stirred overnight. The reaction was diluted with ethyl acetate and filtered through Celite. The solution was concentrated and purified via column chromatography (RediSep 40 g, gradient elution 0-10% MeOH:DCM) to afford (S)-2-amino-2′-(cyclopropylethynyl)-5H-spiro[oxazole-4,9′-xanthen]-7′-ol as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(N1CCOCC1)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.[Br:48][C:49]1[CH:50]=[CH:51][C:52]([CH3:61])=[C:53]([CH:60]=1)[O:54][CH:55]([CH3:59])[C:56](O)=[O:57]>CN(C=O)C.[Cl-].[Na+]>[Br:48][C:49]1[CH:50]=[CH:51][C:52]([CH3:61])=[C:53]([CH:60]=1)[O:54][CH:55]([CH3:59])[C:56]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1)=[O:57]
Reactant: CC#CC(CC(=O)OCC)c1ccc(N)cc1
Reactant: Cc1ccc(Br)cc1OC(C)C(=O)O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC#CC(CC(=O)OCC)c1ccc(NC(=O)C(C)Oc2cc(Br)ccc2C)cc1
Reaction time: 72 h

Procedure:
A solution of 150 mg (0.56 mmol) of ethyl 3-(4-aminophenyl)hex-4-ynoate, 193 mg (1.68 mmol) of N-ethylmorpholine, 103 mg (0.67 mmol) of HOBt hydrate and 104 mg (0.67 mmol) of EDAC in 3 ml of DMF was added to a solution of 160 mg (0.62 mmol) of 2-(5-bromo-2-methylphenoxy)propionic acid in 2 ml of DMF. After 3 days at room temperature, the reaction mixture was diluted with sodium chloride solution and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. This gave ethyl 3-{4-[2-(5-bromo-2-methylphenoxy)propionylamino]phenyl}hex-4-ynoate.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:4][N+:3]=1[O-].[C:21]([O:24]C(=O)C)(=[O:23])[CH3:22]>C(O)C>[C:21]([O:24][CH2:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:4][N:3]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(OCCOCc2ccccn2)cc[n+]([O-])c1C
Solvent: CCO
Product: CC(=O)OCc1nccc(OCCOCc2ccccn2)c1C
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture comprising 0.60 g of 2,3-dimethyl-4-(2-pyridylmethoxyethoxy)pyridine N-oxide and acetic anhydride was stirred at 100° C. for 0.5 hour and cooled, followed by the addition of 40 ml of ethanol. The obtained mixture was stirred at a room temperature for 0.5 hour and distilled to remove the solvent. The residue was dried in a vacuum to obtain 0.47 g of crude 2-acetoxymethyl-3-methyl-4-(2-pyridylmethoxyethoxy)pyridine as an oil.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:30]([F:33])([F:32])[F:31])[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24]O)=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:30]([F:31])([F:32])[F:33])[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][N:40]4[C:36](=[O:46])[C:37]5[C:38](=[CH:42][CH:43]=[CH:44][CH:45]=5)[C:39]4=[O:41])=[C:20]([C:26]([F:27])([F:28])[F:29])[CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Reaction time: 3 h
Yield: 49.2 %

Procedure:
[6-{3-[3,5-Bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-4-(trifluoromethyl)pyridin-3-yl]methanol (0.98 g), phthalimide (0.30 g, 2.04 mmol) and triphenylphosphine (0.58 g) were dissolved in tetrahydrofuran (50 ml), and to the solution was added diethyl azodicarboxylate (40% toluene solution, 1.0 ml) at room temperature. After stirring the mixture for 3 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the target compound (0.60 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)[CH2:9][C:8]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[N:7]1)[CH3:2].[CH:27]1[C:35]2[C:34]3[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=3[O:32][C:31]=2[C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:39]3[C:33]4[O:32][C:31]5[CH:30]=[CH:29][CH:28]=[CH:27][C:35]=5[C:34]=4[CH:36]=[CH:37][CH:38]=3)=[CH:13][CH:12]=2)[CH2:9][C:8]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[N:7]1)[CH3:2]
Reactant: CCOC(=O)CN1N=C(c2ccc(OC)cc2)CC1c1ccc(Br)cc1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CN1N=C(c2ccc(OC)cc2)CC1c1ccc(-c2cccc3c2oc2ccccc23)cc1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
A solution of [5-(4-bromo-phenyl)-3-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-acetic acid ethyl ester (0.417 g, 1.0 mmol) and 4-dibenzofuranboronic acid (0.233 g, 1.1 mmol) in toluene (15 mL, X M) was treated with 2 N aq K2CO3 (1.5 mL, xx mmol) and Pd[PPh3]4 (0.058 g, 0.05 mmol). The resulting solution was heated to reflux for 2 h, cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. Purification by flash column chromatography (10% ethyl acetate in heptane) provided [5-(4-Dibenzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-acetic acid ethyl ester (0.394 g, 78%) as a white crystalline solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13](Cl)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[O:25]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13]([NH:36][C:35]3[CH:34]=[CH:33][C:32]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:38][CH:37]=3)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1C
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C
Reaction time: 12 h
Yield: 75.2 %

Procedure:
To a solution of compound 1D (26 mg, 0.10 mmol) in DMF (2 mL) were added K2CO3 (138 mg, 1.00 mmol) and p-phenoxyaniline (20 mg, 0.11 mmol) at 25° C. The reaction mixture was stirred for 12 h and then diluted with dichloromethane (15 mL) and washed with water (10 mL) and brine (10 mL). The organic phase was dried over Na2SO4 and concentrated and the resulting residue was triturated with methanol to afford 31 mg (76% yield) of the desired compound as a yellow solid. HPLC: 100% at 4.62 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 413.12 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][N:8]([CH3:12])[CH2:9][C:10]=2[CH:11]=1.S(=O)(=O)(O)O.[Br:18]Br.[OH-].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[C:3]([Br:18])=[N:4][C:5]2[CH2:6][CH2:7][N:8]([CH3:12])[CH2:9][C:10]=2[CH:11]=1
Reactant: CN1CCc2ncc(N)cc2C1
Reactant: BrBr
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CN1CCc2nc(Br)c(N)cc2C1
Reaction time: 0.42 h

Procedure:
D4 (978 mg, 6 mmol) was dissolved in acetic acid (10 ml) containing 2M sulphuric acid (2 ml). Bromine (0.31 ml, 6 mmol) was added dropwise with stirring over a period of approximately 25 min. After 2 h, the precipitated solid was removed by filtration and washed with ether to give a pale yellow solid which was dissolved in water. The solution was basified with 2M NaOH and extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4) and evaporation in vacuo gave the crude product as a pale yellow solid (444 mg). The above filtrate from the reaction mixture was concentrated by evaporation in vacuo, diluted with water and made basic with 2M sodium hydroxide. The mixture was extracted with dichloromethane and the extract dried (MgSO4) and evaporated to give a crude brown solid which was purified by chromatography on silica gel eluting with dichloromethane:methanol:aq. ammonia (0.880) (ratio 19:1:0.1). The title compound was obtained as a white solid (248 mg).