Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([NH2:10])=[O:9].Br[C:13]1[S:14][C:15]([CH3:18])=[CH:16]N=1>>[CH3:18][C:15]1[S:14][C:13]2=[N:11][C:6]3[C:7]([C:8](=[O:9])[N:10]2[CH:16]=1)=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3
Reactant: Cc1cnc(Br)s1
Reactant: NC(=O)c1c(N)cccc1Cl
Product: Cc1cn2c(=O)c3c(Cl)cccc3nc2s1
Yield: 78.1 %

Procedure:
10.2 g of 6-chloroanthranilamide and 10.74 g of 2-bromo-5-methylthiazole were stirred at 140° C. for 2 hours. After working up in the conventional manner there was obtained 11.7 g (78%) of the above compound; m.p. 235°-236° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16](O)[N:17]=2)[C:12](=[O:21])[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]1.C1(P([N:41]=[N+:42]=[N-:43])(C2C=CC=CC=2)=O)C=CC=CC=1.C(OCC)(=O)C.Cl>N1C=CC=CC=1.C(OCC)C.O>[N:41]([C:16]1[N:17]=[C:18]2[C:13]([C:12](=[O:21])[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]2[C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:14][C:15]=1[F:20])=[N+:42]=[N-:43]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(O)c(F)cc2c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N=[N+]=[N-])c(F)cc2c1=O
Yield: 82.3 %

Procedure:
In 5 ml of pyridine was suspended 500 mg of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylate, and 770 mg of diphenylphosphoryl azide was added thereto, after which the resulting mixture was subjected to reaction at 80° C. for 4 hours. The solvent was thereafter removed by distillation under reduced pressure, and to the residue thus obtained were added 10 ml of ethyl acetate and 10 ml of water, after which the pH of the resulting mixture was adjusted to 2.0 with 6N hydrochloric acid. The organic layer was then separated, washed successively with 5 ml of saturated aqueous sodium hydrogencarbonate solution and 5 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the residue thus obtained was added 5 ml of diethyl ether, after which the crystals thus deposited were collected by filtration to obtain 440 mg (yield 82.3%) of ethyl 7-azido-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 176°-177.5° C. The physical properties of this compound were identical with those of the compound obtained in Example 44.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[CH:10][C:11]=2[CH3:13])[S:6][CH2:5][CH2:4]1.[CH3:15]O.S(=O)(=O)(O)O>CCCCCC.C(OCC)(=O)C>[CH3:15][O:1][CH2:2][CH:3]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[CH:10][C:11]=2[CH3:13])[S:6][CH2:5][CH2:4]1
Reactant: CO
Reactant: Cc1ccc(C)c2c1SCCC2CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COCC1CCSc2c(C)ccc(C)c21
Temperature: 25 °C
Yield: 60 %

Procedure:
To a mixture of 1.32 g (6.33 mmol) of 4-hydroxymethyl-5,8-dimethylthiochroman with 13 ml of methanol was added 0.1 ml of concentrated sulfuric acid, and the mixture was reacted at reflux under heat for 10 hours. The reaction mixture was cooled to room temperature, poured into ice water and extracted with ethyl acetate. The extract was washed with water and with a saturated sodium chloride aqueous solution. An organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off. The residue was purified by column chromatography (silica gel; hexane/ethyl acetate=2/1)to give 0.84 g (yield 60%) of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4](O)=[O:5].[NH2:15][C:16](N)=[O:17]>>[F:12][C:11]([F:14])([F:13])[C:7]1[CH:8]=[CH:9][CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:15][C:16](=[O:17])[NH:1]2
Reactant: NC(N)=O
Reactant: Nc1cccc(C(F)(F)F)c1C(=O)O
Product: O=c1[nH]c(=O)c2c(C(F)(F)F)cccc2[nH]1

Procedure:
Prepared according to general method C from 2-amino-6-trifluoromethylbenzoic acid (1.0 g) and urea (2.92 g). Yield: 948 mg (85%) of a solid. 1H-NMR (DMSO-δ6) δ (ppm) 11.43 (br s, 2H), 7.78 (t, J=7.9 Hz, 1H), 7.58 (d, J=7.4 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][CH2:8][C:9](OCC)=[O:10].O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(OCC)(=O)C.ClCCl.O>[OH:10][CH2:9][CH2:8][O:7][CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)COCc1ccco1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCCOCc1ccco1
Reaction time: 2 h

Procedure:
Combine ethyl 2-fur-2-ylmethoxyaceate (1.2 g, 6.5 mmol) and tetrahydrofuran (10 mL). Cool in an ice-bath. Add dropwise a solution of lithium aluminum hydride (8.0 mL, 1.0 M in THF, 8.0 mmol). After 2 hours, add water (0.3 mL), add 15% sodium hydroxide solution (0.3 mL), and add water (0.9 mL). Stir vigorously. After 15 minutes, filter the reaction mixture and dry the filtrate over Na2SO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 2% ethyl acetate/dichloromethane to give fur-2-ylmethyl 2-hydroxyethyl ether: Rf =0.22 (silica gel, 5% acetone/dichloromethane) Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine (1.71 g, 5.2 mmol), fur-2-ylmethyl 2-hydroxyethyl ether (0.74 g, 5.2 mmol), and triphenylphosphine (1.67 g, 6.4 mmol) in tetrahydrofuran (20 mL). Add diethyl azodicarboxylate (1.0 mL, 6.35 mmol). After 21 hours, evaporate the reaction mixture in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% acetone/dichloromethane to give 1-(t-butoxycarbonyl)-4-(1-(2-fur-2-ylmethoxy-ethyl)-1H-benzimidazole-2-carbonyl)piperidine: Rf =0.30 (silica gel, 5% acetone/dichloromethane).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[O:21]1[CH2:26][CH2:25][O:24][C:23]2[CH:27]=[C:28]([S:31](Cl)(=[O:33])=[O:32])[CH:29]=[CH:30][C:22]1=2>ClCCl>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:31]([C:28]2[CH:29]=[CH:30][C:22]3[O:21][CH2:26][CH2:25][O:24][C:23]=3[CH:27]=2)(=[O:32])=[O:33])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3c(c2)OCCO3)CC1
Temperature: 0 °C
Yield: 100.2 %

Procedure:
1-Boc-piperazine (250 mg, 1.34 mmol, 1 equiv.) was dissolved in dichloromethane (2.5 mL) and cooled in an ice bath under nitrogen atmosphere. Triethylamine (375 μl, 2.68 mmol, 2.0 equiv.) was added followed by portionwise addition of 2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonyl chloride (346 mg, 1.48 mmol, 1.1 equiv.). The reaction was stirred in the ice bath for one hour, then quenched with saturated aqueous ammonium chloride (˜3 mL). The organic layer was washed twice with saturated ammonium chloride, once with brine, dried over sodium sulfate and concentrated in vacuo and then purified on silica gel chromatography using a 95/5-5/95, hexane/EtOAc (v/v) gradient to give 1-boc-4-(2,3-dihydrobenzo[b][1,4]dioxin-6-ylsulfonyl)piperazine as a white powder (516 mg, 89% yield).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]2=[O:29])=[CH:2]1.C(O)C[OH:32]>CN(C)C(=O)C.[Zn]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[C:13]([C:24]([O:26][CH2:27][CH2:28][OH:32])=[O:25])[C:12]2=[O:29])=[CH:2]1
Reactant: OCCO
Reactant: CCOC(=O)C1=C(Nc2ccccc2Cl)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: [Zn]
Solvent: CC(=O)N(C)C
Product: O=C(OCCO)C1=C(Nc2ccccc2Cl)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 29.4 %

Procedure:
A solution of the compound (0.10 g, 0.24 mmol) of Example 15, ethylene glycol (0.14 mL, 2.5 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.012 g, 0.012 mmol) in N,N-dimethylacetamide (2.0 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 130° C. for 1 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.030 g, y. 29%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][C:14](OB(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(OCC)(=O)C>[N:11]1[CH:16]=[CH:15][C:14]([C:2]2[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)Oc1ccncc1
Reactant: COC(=O)c1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccncc2)s1
Yield: 54.2 %

Procedure:
To a solution of methyl 5-bromo-2-thiophenecarboxylate (884 mg), 4-pyridyl boric acid (500 mg), tetrakistriphenylphosphine palladium(0) (250 mg) in dimethoxyethane (15 ml) was added 2 M sodium carbonate solution (4 ml) and the solution was heated for 15 hours under reflux. The reaction solution was diluted with ethyl acetate and the organic layer was separated, washed with water and extracted with 1 N hydrochloric acid. The extract was made alkaline with sodium hydroxide solution and extracted with ethyl acetate. The extract was dried and concentrated to give pale yellow solid of methyl 5-(4-pyridyl)-2-thiophenecarboxylate (428 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][Cl:13])=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(O)nc1
Product: Oc1ccc(CCl)cn1

Procedure:
A 100 ml RBF was charged with 6-hydroxynicotinic acid (4 g) and 20 ml of thionyl chloride. The mixture was refluxed for 1 hr. Excess thionyl chloride was then evaporated in vacuo to obtain the 6-hydroxynicotinyl chloride. A 200 ml RBF was charged with 1.13 g of 6-hydroxynicotinyl chloride in 100 ml of methylene chloride, cooled and stirred at 0° C. Piperidine (8.6 mM=0.85 ml) in 10 ml methylene chloride was added dropwise and the resulting mixture was stirred at room temperature for 15 hours. The mixture was then concentrated under vacuum. To the residue was added 25 ml of methylene chloride and stirred at 30° C. for 5 minutes. Solid was filtered and residue was chromatographed using CH2C12:MeOH:NH3=200:10:1. The product was recrystallized from CH2Cl2 and petroleum ether to furnish 0.92 g (62%) of product. 1H NMR (CDCl3, 400 MHz) 6: 7.61 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 6.55 (d, J=8.6 Hz, 1H), 3.50 (bs, 4H), 1.65 (m, 2H), 1.57 (m, 4H). 13C NMR (CDCl3, 400 MHz) δ:166.5, 164.8, 141.3, 135.7, 119.7, 116.1, 26.0, 24.4. IR (CHCl3) cm−1: 3346, 3050, 3004, 1655, 1615, 1473, 1115, 841, 780, 627. HREIMS m+/z (%) : C11H14N2O2 (calc)=206.1055; C11Hl14N2O2 (obs)=206.1061 (70).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:10])[CH2:4][CH2:3]1.CN.[B-][C:23]#[N:24].[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH3:23][NH:24][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:10])[CH2:4][CH2:3]1
Reactant: [B-]C#N
Reactant: O=C1CCC(NC(=O)c2ccc3[nH]ncc3c2)CC1
Agent: CN
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CNC1CCC(NC(=O)c2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Acetic acid (0.096 ml) was added to a solution of the N-(4-oxocyclohexyl)-1H-indazole-5-carboxamide (40.0 mg, 0.155 mmol) obtained in Example 160 in methanol (1.2 ml), and the resulting solution was maintained at room temperature for 30 minutes. To this solution was added a 40% aqueous methylamine solution (60.0 mg, 0.777 mmol), and the resulting mixture was maintained at room temperature for another 2 hours. Then, a solution of sodium cyanotrihydroborate (48.7 mg, 0.777 mmol) in methanol (0.6 ml) was added dropwise thereto, and the resulting mixture was stirred for 22 hours while being maintained at room temperature. A 1N aqueous sodium hydroxide solution (0.8 ml) was added to the reaction solution, and the resulting mixture was stirred while being maintained at room temperature, and was then concentrated to dryness. The resulting crude product residue was purified by a silica gel column chromatography (eluent: chloroform/methanol/aqueous ammonia=10/1/0.1) to obtain N-[4-(methylamino)cyclohexyl]-1H-indazole-5-carboxamide (an isomer having a lower polarity) (12.2 mg, 29%) and N-[4-(methylamino)cyclohexyl]-1H-indazole-5-carboxamide (an isomer having a higher polarity) (28.3 mg, 67%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1)CCC.N#N.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)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].C1COCC1>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([C:29]4[N:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[CH:3][C:4]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Agent: [Pd]
Agent: N#N
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ncccn4)cc3C)c(C)nc12
Temperature: 55 °C
Yield: 32.9 %

Procedure:
A solution of 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.30 g, 0.76 mmol), 2-tributylstannanyl-pyrimidine (0.34 g, 0.92 mmol) and THF (5 mL) is de-gassed with N2 for 10 minutes Triphenylarsine (0.047 g, 0.15 mmol) and Pd2(dba)3 (0.035 g, 0.038 mmol) is added and the solution heated at 55° C. for 48 hours and concentrated. The residue is purified by ISCO column chromatography (15%-30% EtOAc/hexane gradient), dissolved in acetonitrile (20 mL), washed with hexane (3×20 mL) and concentrated to furnished the title compound (0.097 g, 0.25 mmol, 32%). 1H NMR (CDCl3), δ 0.88 (t, J=7.4 Hz, 6H), 1.74-1.92 (m, 4H), 2.18 (s, 3H), 2.51 (s, 3H), 2.52 (s, 3H), 3.29-3.38 (m, 1H), 6.67 (s, 1H), 7.08 (t, J=4.8, 1H), 7.93 (s, 1H), 8.69 (s, 2H). LC/MS (m/z): calcd. for C22H25N5S (M+H)+: 392.3; found: 392.2.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:31])([F:30])[F:29])[NH:17][C:18]3=[O:21])=[CH:13][CH:12]=2)[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.Cl>O1CCCC1>[NH2:1][CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:29])([F:31])[F:30])[NH:17][C:18]3=[O:21])=[CH:13][CH:12]=2)[CH2:6]1
Reactant: [N-]=[N+]=NCC1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCC1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 40 °C
Reaction time: 14 h
Yield: 97.9 %

Procedure:
The 7-(5-azidomethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (50.0 mg, 0.116 mmol) obtained in Example 1-30 was dissolved in tetrahydrofuran (387 μl). Thereafter, triphenylphosphine (33.6 mg, 0.128 mmol) and water (20.9 μl) were added to the obtained solution, and the obtained mixture was then stirred at 40° C. for 14 hours. Thereafter, 1 N hydrochloric acid (0.5 ml) was added to the reaction solution, followed by washing with ethyl acetate. A 1 N sodium hydroxide aqueous solution (1.0 ml) was added to the residual water layer, followed by extraction with ethyl acetate. The extract was washed with a saturated saline solution, and was then dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The obtained residue was purified by column chromatography using Bond Elut (registered trademark) NH2 (Varian; 1g), so as to obtain 7-(5-aminomethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (45.8 mg; yield: 98%) in the form of a colorless foaming substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11](F)[CH:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1.[NH2:23][C:24]1[C:25]([C:32](O)=[O:33])=[N:26][C:27]([Br:31])=[C:28]([F:30])[CH:29]=1>>[NH2:23][C:24]1[C:25]([C:32]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)=[O:33])=[N:26][C:27]([Br:31])=[C:28]([F:30])[CH:29]=1
Reactant: Nc1cc(F)c(Br)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)NC1CN(c2ccncc2N)CCC1F
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2nc(Br)c(F)cc2N)C1
Yield: 40 %

Procedure:
Following Method 11 of Example 305, (+/−)-tert-butyl 1-(3-aminopyridin-4-yl)-4-fluoropiperidin-3-ylcarbamate and 3-amino-6-bromo-5-fluoro-picolinic acid were reacted yielding (S)-tert-butyl 1-(3-(3-amino-6-bromo-5-fluoro-picolinamido)pyridin-4-yl)piperidin-3-ylcarbamate (40%). LCMS (m/z): 509.0 (MH+), LC Rt=3.04 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:17]([OH:19])=[O:18])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][N:3]=1.Cl[CH:21]([C:24]1([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[N:33]=[CH:32][CH:31]=[CH:30]3)[CH2:26][CH2:25]1)[CH:22]=O>C(O)C>[N:33]1[C:34]2[C:29](=[CH:28][C:27]([C:24]3([C:21]4[N:7]5[CH:6]=[C:5]([C:8]6[CH:9]=[CH:10][C:11]([C:14]7([C:17]([OH:19])=[O:18])[CH2:16][CH2:15]7)=[CH:12][CH:13]=6)[CH:4]=[N:3][C:2]5=[N:1][CH:22]=4)[CH2:26][CH2:25]3)=[CH:36][CH:35]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Reactant: Nc1ncc(-c2ccc(C3(C(=O)O)CC3)cc2)cn1
Solvent: CCO
Product: O=C(O)C1(c2ccc(-c3cnc4ncc(C5(c6ccc7ncccc7c6)CC5)n4c3)cc2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
A mixture of 1-[4-(2-aminopyrimidin-5-yl)phenyl]cyclopropanecarboxylic acid (0.22 g, 0.86 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.21 g, 0.86 mmol) in ethanol (8 mL) was stirred at 100° C. overnight. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product (0.12 g, 31%). LCMS: (M+H)=447.1.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:13]3[CH2:15][CH:16]([CH3:19])[CH2:17][CH2:18][C:12]=3[C:11]([CH3:21])([CH3:20])[O:10][C:9]=2[CH:8]=[C:7]([CH:22]([CH3:30])[CH:23]([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:6]=1)(=[O:3])[CH3:2].C(Cl)(Cl)Cl.C(O)(=[O:37])C>>[C:1]([O:4][C:5]1[C:14]2[C:13]3[CH2:15][CH:16]([CH3:19])[CH2:17][C:18](=[O:37])[C:12]=3[C:11]([CH3:20])([CH3:21])[O:10][C:9]=2[CH:8]=[C:7]([CH:22]([CH3:30])[CH:23]([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CCCCCC(C)C(C)c1cc(OC(C)=O)c2c(c1)OC(C)(C)C1=C2CC(C)CC1
Solvent: ClC(Cl)Cl
Product: CCCCCC(C)C(C)c1cc(OC(C)=O)c2c(c1)OC(C)(C)C1=C2CC(C)CC1=O

Procedure:
To a stirring mixture of 1-acetoxy-3-(1,2-dimethylheptyl)-7,8,9,10-tetrahydro-6,6,9-trimethyl-6H-dibenzo[ b,d]pyran (5.21 g., 12.6 mmole) in 35 ml. of 50% acetic acid and 10 ml. of chloroform under a nitrogen atmosphere, was added dropwise a solution of ceric ammonium nitrate (27.63 g., 50.4 mmole) in 70 ml. of 50% acetic acid. After the addition was complete, the reaction mixture was stirred over a steam bath. After 3 hours the mixture was poured onto ice with stirring. It was extracted into ether and the organic solvents were removed under reduced pressure. The residue was again taken up in ether, washed to neutrality with 5% NaHCO3, washed with water and dried over Na2SO4. Evaporation of the solvents in vacuo left 8.34 g. (23%) of crude product whose tlc showed a blue fluorescent spot (silica gel, Rf 0.66, 1:1 EtOAc/hexane).
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16]([C:20]4[CH:21]=[CH:22][C:23]5[NH:24][C:25]6[C:30]([C:31]=5[CH:32]=4)=[CH:29][CH:28]=[CH:27][CH:26]=6)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:34]1[C:35]2[S:42][C:41]3[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=3[C:36]=2[N:37]=[CH:38][N:39]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.CC([O-])(C)C.[Na+]>C1(C)C=CC=C(C)C=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]>[C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16]([C:20]4[CH:21]=[CH:22][C:23]5[N:24]([C:34]6[C:35]7[S:42][C:41]8[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=8[C:36]=7[N:37]=[CH:38][N:39]=6)[C:25]6[C:30]([C:31]=5[CH:32]=4)=[CH:29][CH:28]=[CH:27][CH:26]=6)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ncnc2c1sc1ccccc12
Reactant: c1ccc(-n2c3ccccc3c3cc(-c4ccc5[nH]c6ccccc6c5c4)ccc32)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1cccc(C)c1
Product: c1ccc(-n2c3ccccc3c3cc(-c4ccc5c(c4)c4ccccc4n5-c4ncnc5c4sc4ccccc45)ccc32)cc1
Temperature: 150 °C
Yield: 44 %

Procedure:
9-phenyl-9H,9′H-3,3′-bicarbazole (3.05 g, 7.47 mmol), 4-chlorobenzo[4,5]thieno[3,2-d]pyrimidine (1.812 g, 8.21 mmol), Pd2dba3 (0.342 g, 0.373 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (S-Phos) (0.307 g, 0.747 mmol), and sodium 2-methylpropan-2-olate (1.794 g, 18.67 mmol) were charged to a 250 mL RBF, diluted in m-Xylene (Volume: 74.7 mL), degassed with nitrogen and heated to reflux at 150° C. overnight. The reaction was quenched with aqueous ammonium chloride and filtered through a plug of Celite® with dichloromethane (DCM). The crude was purified by column chromatography and then recrystallized from toluene/ethanol to give 4-(9′-phenyl-9H,9′H-[3,3′-bicarbazol]-9-yl)benzo[4,5]thieno[3,2-d]pyrimidine (1.95 g, 44% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:3]=1[C:4]([P:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])[O:7]C)=[O:5].[I-].[Na+:23]>C(C(C)=O)C>[CH3:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:3]=1[C:4]([P:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:7])[O-:9])=[O:5].[Na+:23]
Reactant: COP(=O)(C(=O)c1c(C)cc(C)cc1C)c1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: Cc1cc(C)c(C(=O)P(=O)([O-])c2ccccc2)c(C)c1
Temperature: 55 °C
Reaction time: 2.5 h

Procedure:
60.5 parts by weight of methyl 2,4,6-trimethylbenzoylphenylphosphinate (as described in U.S. Pat. No. 4,265,723) and 33 parts by weight of sodium iodide were dissolved in 560 parts by volume of methyl ethyl ketone, and the solution was stirred for 2.5 hours at 55° C. The resulting precipitate was filtered off, washed with methyl ethyl ketone and dried, the desired product being obtained.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][OH:25]>CN(C=O)C>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[O:15][CH2:23][CH2:24][OH:25])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: OCCBr
Reactant: O=C1c2ccccc2Cc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of anthrone (5.0 g, 25.7 mmole) in 34 mL anhydrous DMF under an inert atmosphere was added potassium carbonate (7.47 g, 54.1 mmole). To the resulting reaction mixture was added 2-bromoethanol (2.0 mL, 28.3 mmole). The resulting reaction mixture was stirred for 1 hr at room temperature, then 3 hrs at 80° C. The reaction was then cooled to room temperature and quenched with saturated NaHCO3. Ethyl acetate was added and the organic layer was collected and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was purified via flash chromatography.