Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1C=C2[N:29]=NN(O)C2=CC=1.O.C(Cl)CCl.[NH4+].[OH-]>CN(C=O)C.CCOC(C)=O.O>[NH2:29][C:20](=[O:22])[C@H:12]([NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 0.67 h
Yield: 91.3 %

Procedure:
To a solution of N-Cbz-D-phenylalanine (1.00 g, 3.34 mmol) and HOBt hydrate (0.614 g, 4.01 mmol) in DMF (9 mL), EDC (0.834 g, 4.34 mmol) was added. The mixture was stirred for 40 min. Then conc. NH4OH (1.00 mL, ˜14 mmol) was added. It was stirred for 72 h. Water and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give (R)-benzyl 1-amino-1-oxo-3-phenylpropan-2-ylcarbamate as a solid (0.910 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:27][CH:28]2[CH2:30][CH2:29]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]([CH3:42])[C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=1.C[Si](Cl)(C)C>C(O)CCC>[CH:28]1([NH:27][C:4]2[C:5]3[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=4)=[CH:9][NH:8][C:6]=3[N:7]=[C:2]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([N:38]([CH3:42])[C:39](=[O:41])[CH3:40])=[CH:36][CH:37]=3)[N:3]=2)[CH2:29][CH2:30]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(NC4CC4)nc(Cl)nc32)cc1
Reactant: CC(=O)N(C)c1ccc(N)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N(C)c1ccc(Nc2nc(NC3CC3)c3c(-c4ccncc4)c[nH]c3n2)cc1
Temperature: 135 °C
Reaction time: 18 h
Yield: 31.8 %

Procedure:
A mixture of 2-chloro-N-cyclopropyl-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (85 mg, 0.19 mmol), N-(4-aminophenyl)-N-methylacetamide (72 mg, 0.44 mmol) and TMSCl (0.100 mL, 0.79 mmol) in nBuOH (3 mL) was stirred at 135° C. for 18 h. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (25 mg). MS 414.3 (M+H); UV 202.8, 280.8 nm.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[I-].[Li+].[C:9]([O:13][CH:14]1[CH2:18][C:17](=[O:19])[CH:16]=[CH:15]1)([CH3:12])([CH3:11])[CH3:10].[OH-].[Na+]>C1(C)C=CC=CC=1.COC(C)(C)C>[C:9]([O:13][C@@H:14]1[CH2:18][C@H:17]([OH:19])[CH:16]=[CH:15]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC1C=CC(=O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: CC(C)(C)O[C@H]1C=C[C@@H](O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
A slurry of lithium aluminum hydride (55 mg, 1.44 mmol), lithium iodide (1.65 g, 5.76 mmol), tert-butyl methyl ether (2 mL) and toluene (3 mL) is cooled to -15° C. The slurry is treated dropwise with 4-tert-butoxy-cyclopent-2-enone(430 mg, 2.79 mmol, dissolved in 1 mL of toluene) over 5 minutes. The reaction mixture is stirred at -20° C. to -12° C. for 2 hours and then allowed to warm to room temperature and is stirred for 30 minutes. The reaction mixture is then treated sequentially with sodium hydroxide (1N, 1 mL), then tert-butyl methyl ether (10 mL) and filtered. The phases of the filtrate are separated and the aqueous phase is extracted with tert-butyl methyl ether (15 mL). The organic extracts and organic phase is combined, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by chromatography (silica gel, 30 g, 33% ethyl acetate/hexane) to provide the title compound (183 mg, 42%) as a yellow oil, cis/trans/1-2+1-4 addition, 87/9.8/3.2; 1H NMR (CDCl3) 6 5.9 (m, 1H), 5.8 (m, 1H), 4.6 (m, 1H), 4.5 (m, 1H), 2.7 (m, 1H), 2.0 (d,1H, J=9.6 Hz), 1.5 (d appt, 1H, J=4.5, 14 Hz), 1.2 (s, 9H); 13C NMR (CDCl3) δ136.6, 36, 75.5, 74.4, 74, 44.6, 28.7; νmax 3395, 2974, 2938, 907, 2878, 1389, 1364, 1117, 1169, 1022 cm-1 ; MS (CI) m/e (% relative intensity) 157 (M+H+ -H2O), 57, 83 (100).
Reaction SMILES: [C:1]([N:4]([CH3:32])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:15]=2)[C:10]([OH:25])=[C:9]([C:26](OCC)=[O:27])[C:8]1=[O:31])(=[O:3])[CH3:2].[NH2:33][CH2:34][C@H:35]([OH:37])[CH3:36]>>[C:1]([N:4]([CH3:32])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH:15]=2)[C:10]([OH:25])=[C:9]([C:26]([NH:33][CH2:34][C@H:35]([OH:37])[CH3:36])=[O:27])[C:8]1=[O:31])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(C)=O)c1=O
Reactant: C[C@@H](O)CN
Product: CC(=O)N(C)CCn1c(=O)c(C(=O)NC[C@@H](C)O)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-{2-[acetyl(methyl)amino]ethyl}-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2R)-1-amino-2-propanol using methods similar to Example 574: step 2 to provide an off-white solid: 1H NMR (400 MHz, DMSO-d6@90° C.) δ ppm 1.14 (d, J=6.17 Hz, 3 H), 1.84 (s, 3 H), 2.91-2.98 (m, 3 H), 3.23-3.33 (m, 1 H), 3.40-3.50 (m, 1 H), 3.54 (t, J=6.72 Hz, 2 H), 3.85-3.88 (m, 1 H), 4.18 (s, 2 H), 4.37 (d, J=7.55 Hz, 2 H), 4.65 (d, J=5.90 Hz, 1 H), 7.12 (t, J=8.51 Hz, 2 H), 7.36-7.43 (m, 2 H), 8.07 (s, 1 H), 8.55 (s, 1 H), 10.35 (s, 1 H), 16.97-17.20 (m, 1 H); ES+ MS: 471 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=O)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: COc1ccc(-c2nnc(-c3c(-c4ccccc4)noc3C)o2)cc1
Yield: 63 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 4-methoxybenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 192 mg, 63%) which was obtained as a white foam. MS: m/e=334.2 [M+H]+.
Reaction SMILES: C[Li].CCOCC.[CH3:8][C:9]1[N:14]2[CH:15]=[C:16]([CH2:18][S:19][C:20]3[NH:21][CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:24]=3)[N:17]=[C:13]2[N:12]=[C:11]([CH3:31])[CH:10]=1.Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CS(C)=O.O>[CH3:8][C:9]1[N:14]2[CH:15]=[C:16]([CH:18]([S:19][C:20]3[NH:21][CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:24]=3)[CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:17]=[C:13]2[N:12]=[C:11]([CH3:31])[CH:10]=1
Reactant: Cc1cc(C)n2cc(CSc3nc(-c4ccccc4)c[nH]3)nc2n1
Reactant: ClCCN1CCOCC1
Agent: [Li]C
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: Cc1cc(C)n2cc(C(CCN3CCOCC3)Sc3nc(-c4ccccc4)c[nH]3)nc2n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of methyl lithium in ether (1.60 M, 0.205 mL, 0.328 mmol) was added dropwise to dimethyl sulfoxide (2.00 mL, 28.2 mmol) and the mixture left to stir for 40 minutes at room temperature. A solution of 5,7-Dimethyl-2-(4-phenyl-1H-imidazol-2-ylsulfanylmethyl)-imidazo[1,2-a]pyrimidine (0.100 g, 0.298 mmol) and N-(2-chloroethyl)morpholine (0.0666 g, 0.358 mmol) in dimethyl sulfoxide was added dropwise to the generated dimsyl anion. The resulting mixture was stirred at 80° C. for 45 minutes. After cooling to room temperature, water was carefully added and the mixture was extracted with ethyl acetate (20 mL). The combined organic extracts were dried over sodium sulfate and the solvent removed in vacuo. Column chromatography of the crude product using ethyl acetate:methanol (95:5 v/v) gave the product as a yellow oil. It was dissolved in a minimum amount of methanol and ethereal hydrogen chloride was added dropwise to precipitate the hydrochloride salt of title compound as a yellow solid which was collected by filtration and washed with ether (71 mg, 49%). LC-MS: m/z=449.3 (MH+), tR=0.37 min, method C.
Reaction SMILES: [Cl-].[Cl:2][C:3]([Cl:21])([Cl:20])[CH:4]1[O:9][CH:8]([C:10]([Cl:13])([Cl:12])[Cl:11])[C:7]2[CH:14]=[C:15]([N+]#N)[CH:16]=[CH:17][C:6]=2[O:5]1.S(=O)(=O)(O)[OH:23]>O>[OH:23][C:15]1[CH:16]=[CH:17][C:6]2[O:5][CH:4]([C:3]([Cl:21])([Cl:20])[Cl:2])[O:9][CH:8]([C:10]([Cl:13])([Cl:12])[Cl:11])[C:7]=2[CH:14]=1
Reactant: N#[N+]c1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Reactant: O=S(=O)(O)O
Agent: [Cl-]
Solvent: O
Product: Oc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Temperature: 160 °C

Procedure:
A mixture of 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-diazonium chloride (5 g.) concentrated sulphuric acid (125 ml.) and water (125 ml.) was stirred and heated at 160° C. for 20 minutes. The reaction mixture was cooled to ambient temperature and the product was filtered off, washed with water, and crystallised from cyclohexane, to give 6-hydroxy-2,4-bis(trichloromethyl)benzo[1,3]dioxin, m.p. 167°-169° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Br[C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CN(C=O)C.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]>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([N:11]2[CH2:12][CH2:13][C:14]3[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[NH:21][C:22]=3[CH:10]2[C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)=[N:25][CH:26]=1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)CCO2)NCC3
Reactant: Brc1ccc(Br)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Brc1ccc(N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)CCO3)nc1

Procedure:
1-(2,3-dihydro-5-benzofuranyl)-2,3,4,9-tetrahydro-1H-β-carboline (11.6 g, 40 mmol), 2,5-dibromopyridine (10.42 g, 44 mmol), Pd2 dba3 (1.465 g, 1.6 mmol), dppp (1.32 g, 3.2 mmol) and NaOtBu (5.38 g, 56 mmol) were stirred in 60 mL DMF at 80° C. for 3 days. The reaction mixture was filtered through a plug of Celite with CH2Cl2. The reaction mixture was then concentrated, the crude mixture was then loaded on Foxy column (110 g silica gel) and eluted with ethyl acetate/hexane (3:7). The product crystallized out in test tubes. The product was concentrated and then recrystallized from THF to yield the product as yellow crystals.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([OH:23])[CH3:22])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.N1C=CC=CC=1.S(=O)(=O)=O>ClCCl.CS(C)=O>[F:25][C:2]([F:1])([F:24])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: CC(O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: O=S(=O)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
To 1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanol (C24) (8.80 g, 25.2 mmol) in dichloromethane (168 mL) and dimethyl sulfoxide (84 mL) was added triethylamine (17 mL) and stirred in an ice bath. Pyridine.sulfur trioxide (16.0 g, 101 mmol) was added in two portions. The reaction was warmed to room temperature over 3 hours, diluted with dichloromethane, and washed with water. The aqueous layer was extracted one additional time with dichloromethane. The combined dichloromethane layers were washed with water, dried over anhydrous sodium sulfate, filtered, and adsorbed onto silica gel. Purification by flash column chromatography using 0-100% ethyl acetate/hexanes as eluent provided the title compound as a white solid (6.71 g, 73%): mp 140-141.5° C.; 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.33-8.27 (m, 2H), 8.11-8.05 (m, 2H), 7.85-7.78 (m, 2H), 7.41 (dd, J=9.0, 0.8 Hz, 2H), 2.66 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −58.01; ESIMS m/z 348 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8]P(=O)(OCC)OCC)[CH:5]=[CH:4][CH:3]=1.[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.CC(C)([O-])C.[K+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6](/[CH:8]=[CH:20]/[C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[F:17])[N:7]=1
Reactant: O=Cc1ccccc1F
Reactant: CCOP(=O)(Cc1cccc(Br)n1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1ccccc1/C=C/c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of diethyl (6-bromopyridin-2-yl)methylphosphonate (320 mg, 1.039 mmol) in tetrahydrofuran (9.4 mL) was added 2-fluorobenzaldehyde (129 mg, 1.04 mmol). The resulting solution was cooled to 0° C., and treated with potassium tert-butoxide (1M in tetrahydrofuran, 1.1 mL, 1.1 mmol). After 15 min at 0° C., the reaction was quenched by addition of saturated ammonium chloride and concentrated. The resulting residue was dissolved in ether, washed with water, then brine, dried over magnesium sulfate, and concentrated to give an oil which solidified upon standing. The solid was triturated with hexane to afford 215 mg (78%). 1H NMR (CDCl3) δ: 7.78 (d, J=16.2 Hz, 1H), 7.64 (td, J=7.6, 1.5 Hz, 1H), 7.50-7.58 (m, 1H), 7.37 (t, J=7.8 Hz, 2H), 7.29-7.34 (m, 1H), 7.15-7.26 (m, 2H), 7.12 (dd, J=10.5, 8.7 Hz, 1H). 13C NMR (CDCl3) δ: 161.1, 157.0, 142.3, 138.9, 130.1, 129.0, 128.4, 127.2, 126.5, 124.4, 124.2, 120.8, 116.1 19F NMR (CDCl3) δ: −116.28 (br. s., 1F). Mass spec.: 278.0 (MH)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[N:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH:28]4[CH2:30][CH2:29]4)=[CH:26][C:25]([CH:31]4[CH2:33][CH2:32]4)=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1>>[CH:28]1([C:27]2[C:22]([N:19]3[CH2:18][CH2:17][N:16]([C:14]([C:11]4[CH:10]=[CH:9][C:8]([N:1]5[CH2:5][CH2:4][CH2:3][C:2]5=[O:6])=[N:13][CH:12]=4)=[O:15])[CH2:21][CH2:20]3)=[N:23][CH:24]=[C:25]([CH:31]3[CH2:33][CH2:32]3)[CH:26]=2)[CH2:29][CH2:30]1
Reactant: O=C(c1ccc(Br)nc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: O=C1CCCN1
Product: O=C(c1ccc(N2CCCC2=O)nc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 48.7 %

Procedure:
Using pyrrolidin-2-one (94 mg) and (6-bromopyridin-3-yl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (427 mg) described in Preparation Example 143 and by the reaction and treatment in the same manner as in Example 1, the title compound (210 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11]1([CH2:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:18](=[O:19])[CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1cccc(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1cc(C(=O)Cc2ccccc2)cc(Cl)c1Cl
Reaction time: 17 h

Procedure:
To a stirred mixture of 2,3-dichloroanisole (62 g., 0.35 mole), phenylacetyl chloride (54 g., 0.35 mole) and carbon disulfide (250 ml.) is added portionwise aluminum chloride (47 g., 0.35 mole) with cooling at 0°-5° C. The reaction mixture is left at 25° C. for 17 hours, the carbon disulfide removed, and the residue treated with ice-water and concentrated hydrochloric acid (50 ml.) to give 68.8 g. of 2,3-dichloro-5-phenylacetylanisole which melts at 126°-129° C. on crystallization from benzene:cyclohexane, 2:1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[CH3:11][N:12]1[CH:16]=[C:15]([C:17]2[N:22]=[N:21][C:20]([N:23]3[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH:14]=[N:13]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:26]1[CH2:27][CH2:28][N:23]([C:20]3[N:21]=[N:22][C:17]([C:15]4[CH:14]=[N:13][N:12]([CH3:11])[CH:16]=4)=[CH:18][CH:19]=3)[CH2:24][CH2:25]1)[CH2:6][CH2:5]2
Reactant: Clc1ccc2c(c1)CCN2
Reactant: Cn1cc(-c2ccc(N3CCC(=O)CC3)nn2)cn1
Product: Cn1cc(-c2ccc(N3CCC(N4CCc5cc(Cl)ccc54)CC3)nn2)cn1

Procedure:
The title compound was prepared following the procedure as described in Example 5, STEP 4, reacting 5-chloroindoline and 1-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-one.
Reaction SMILES: C(ON=O)(C)(C)C.Br[CH2:9][C:10](=[CH2:14])[C:11]([OH:13])=[O:12].[N+:15]([C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=1)N)([O-:17])=[O:16].NC1C=CC=CC=1>CC#N>[N+:15]([C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=1)[CH2:9][C:10](=[CH2:14])[C:11]([OH:13])=[O:12])([O-:17])=[O:16]
Reactant: C=C(CBr)C(=O)O
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: CC(C)(C)ON=O
Solvent: Nc1ccccc1
Solvent: CC#N
Product: C=C(Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)C(=O)O
Temperature: 17.5 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and 2-(bromomethyl)acrylic acid (7.42 g, 45.0 mmol) in CH3CN (10 ml), 3,5-dinitroaniline (549 mg, 3.0 mmol) was added during 20 minutes, while maintaining the temperature of the reaction mixture at 15-20° C. At the end of the addition of the aniline extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture. After heating to 35° C. for 5 minutes, the mixture was stirred at room temperature for one hour. The volatile material in the reaction mixture was then removed at reduced pressure. The remaining crystalline residue was washed with heptane (5×50 ml) to remove unreacted 2-(bromomethyl)acrylic acid. Column chromatography (heptane-ethyl acetate-methanol-acetic acid 5:4:1:0.04) of the remaining crude product followed by crystallization from toluene gave 450 mg (60%) of 2-(3,5-dinitrobenzyl)acrylic acid as yellow needles. 1H NMR (CDCl3, 300 MHz) δ 8.93, (t, 1H, J=2.1 Hz), 8.43, (d, 2H, J=2.1 Hz), 6.56, (s, 1H), 5.93, (m, 1H), 3.85, (s, 2H).
Reaction SMILES: Cl.[F:2][C:3]1[C:9]([Cl:10])=[C:8]([F:11])[C:7]([Cl:12])=[CH:6][C:4]=1[NH2:5].[C:13](Cl)(Cl)=[O:14]>C1(C)C=CC=CC=1>[F:2][C:3]1[C:9]([Cl:10])=[C:8]([F:11])[C:7]([Cl:12])=[CH:6][C:4]=1[N:5]=[C:13]=[O:14]
Reactant: Nc1cc(Cl)c(F)c(Cl)c1F
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1cc(Cl)c(F)c(Cl)c1F
Reaction time: 2 h

Procedure:
Hydrogen chloride was passed into a well-stirred solution of 39.6 gm (0.20 mol) of 2,4-difluoro-3,5-dichloroaniline in 400 ml of toluene until a precipitate no longer separated out. The heterogeneous mixture thus obtained was cooled to 5° to 10° C. At this temperature, 40 gm (0.4 mol) of phosgene were passed in, with stirring. The mixture was then heated slowly, with stirring, so that after about two hours a temperature of 100° to 105° C. was reached. Stirring was then continued for seven hours at this temperature. During this time, a clear solution was formed, and hydrogen chloride was liberated. Nitrogen was then passed into the mixture for one hour at the same temperature to drive off the excess phosgene. Thereafter the solvent was distilled off, in vacuo at the end. The crude product which remained was distilled in a water pump vacuum.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][CH:21]=[C:22](B4OC(C)(C)C(C)(C)O4)[CH:23]=3)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:33][C:34]1[CH:39]=[C:38](Cl)[N:37]=[C:36]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[N:35]=1.C(Cl)Cl>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:33][C:34]1[N:35]=[C:36]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[N:37]=[C:38]([C:22]2[CH:23]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:10]([N:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]4)=[O:11])=[CH:13][CH:14]=3)[CH:19]=[N:20][CH:21]=2)[CH:39]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc(-c3cncc(B4OC(C)(C)C(C)(C)O4)c3)cc2)CC1
Reactant: Clc1cc(Cl)nc(-c2ccccn2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)N1CCN(C(=O)c2ccc(-c3cncc(-c4cc(Cl)nc(-c5ccccn5)n4)c3)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of (4-Isopropylpiperazin-1-yl)(4-(5-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)pyridin-3-yl)-phenyl)-methanone (Int. I) (1.5 eq, 402 mg) in DME (1 ml) and 2M sodium carbonate (0.62 ml) is treated with 4,6-dichloro-2-pyridin-2-yl-pyrimidine (Int. C) (1 eq, 139 mg) and placed under an atmosphere of argon. PdCl2(dppf).DCM (0.1 eq. 45 mg) is added and the reaction mixture is heated using microwave radiation at 90° C. for 90 minutes. After cooling to room temperature, the mixture is partitioned between DCM/water and the organic portion is separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue is purified by chromatography on silica eluting with 0-10% MeOH in DCM to afford the title compound [M+H]+=499/501 as a solid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=1Cl)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[OH2:22]>>[C:1]([NH:5][S:6]([C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=1[OH:22])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O

Procedure:
Following the general hydrolysis procedure outlined in example 15, N-(tert-butyl)-2,6-dichloro-3-nitrobenzenesulfonamide (1.67 g, 5.1 mmol), 60% NaH (612 mg, 15.3 mmol) and water (92 μL, 5l mmol) were reacted to form the crude product (1.54 g), which was carried on to the next step without purification. 1H NMR (MeOD-d4): δ 8.00 (d, 1H), 7.08 (d, 1H), 1.24 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[N:15]([C:11]1[CH:10]=[C:9]([C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:13][N:12]=1)=[C:16]=[S:17]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1ncccc1-c1ccnc(N)c1
Solvent: ClCCl
Product: COc1ncccc1-c1ccnc(N=C=S)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
To 2-methoxy-3,4′-bipyridin-2′-amine (0.53 g, 2.63 mmol) in dichloromethane (20 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.62 g, 2.7 mmol) and the reaction mixture was stirred at 40° C. for 4 hours. The reaction was cooled to room temperature and chromatographed (Biotage: 10-100% ethyl acetate/hexanes) to yield 2′-isothiocyanato-2-methoxy-3,4′-bipyridine (0.46 g, 1.9 mmol, 71.8% yield). 1H NMR (500 MHz, DMSO-D6) δ ppm 8.67 (d, J=2.44 Hz, 1 H), 8.26 (dd, J=4.88, 1.53 Hz, 1 H), 8.15 (dd, J=8.24, 2.44 Hz, 1 H), 7.89 (dd, J=7.32, 1.53 Hz, 1 H), 7.48 (d, J=8.24 Hz, 1 H), 7.15 (dd, J=7.32, 4.88 Hz, 1 H), 3.91 (s, 3 H). MS (LC/MS) R.T.=2.87; [M+H]+=244.9.