Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B(O)O)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Br[C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:15]3[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: Nc1ccc(Br)nc1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1ncc2cc(-c3ccc(N)cn3)ccc21
Temperature: 110 °C

Procedure:
In a 10-20 mL reaction vial, the 1-methyl-1H-indazol-5-ylboronic acid (250 mg, 1.34 mmol) and the 6-bromopyridin-3-amine (250 mg, 1.34 mmol) were dissolved in dioxane (7 mL) and water (1.5 mL) under argon atmosphere. The mixture was bubbled with argon for 5 min and then potassium carbonate (368 mg, 2.67 mmol) and Pd(PPh3)4 (231 mg, 0.2 mmol) were added sequentially. The resulting reaction mixture was then sealed and heated in oil bath at 110° C. for 3 h. Reaction was then partitioned between EtOAc (30 mL) and water (30 mL).The organic phase was washed with water (3×20 mL) and was concentrated. Residue was purified on silica gel column with 0-75% EtOAc/Hex to afford the title compound. LCMS-ESI+: calc'd for: C13H12N4: 225.1 (M+H+); found: 225.2 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[S:4][CH:3]1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].Br[CH2:19][C:20]#[N:21].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CS(C)=O>[C:20]([CH2:19][N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[S:4][CH:3]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]1=[O:1])#[N:21]
Reactant: N#CCBr
Reactant: CCOC(=O)CC1Sc2ccccc2NC1=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CS(C)=O
Product: CCOC(=O)CC1Sc2ccccc2N(CC#N)C1=O
Temperature: 25 °C
Reaction time: 40 h
Yield: 82.8 %

Procedure:
After 1.82 g of ethyl 2-(3,4-dihydro-3-oxo-2H-1,4-benzothiazin-2-yl)acetate, 1.31 g of bromoacetonitrile and 146 mg of potassium iodide were dissolved in dimethylsulfoxide (18 ml), 1.50 g of potassium carbonate was added to the solution. The mixture was stirred at room temperature for 40 hours. After saturated ammonium chloride aqueous solution was added to the reaction mixture, the mixture was extracted with ethyl acetate. After the organic phase was washed with saturated sodium chloride aqueous solution, the organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The resulting semicrystalline residue was dissolved in benzene. After insoluble matters were filtered off, the solvent was distilled off. Isopropyl ether was added to the residue for crystallization to give 1.74 g of the title compound. The structural formula and physical data of this compound are shown in Table 5.
Reaction SMILES: [C:1]1([C:7]23[CH2:15][CH:11]4[CH2:12][CH:13]([CH2:14]2)[C:9]([NH2:16])([CH2:10]4)[CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]([N:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[C:32]#[N:33])=[O:26]>CS(C)=O.CCOC(C)=O>[C:1]1([C:7]23[CH2:15][CH:11]4[CH2:10][C:9]([NH:16][CH2:24][C:25]([N:27]5[CH2:31][CH2:30][CH2:29][C@H:28]5[C:32]#[N:33])=[O:26])([CH2:8]2)[CH:13]([CH2:12]4)[CH2:14]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC12CC3CC1CC(c1ccccc1)(C3)C2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(c1ccccc1)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.7 %

Procedure:
To a stirred mixture of the compound obtained from step II (0.2 g, 0.94 mmol) and K2CO3 (0.39 g, 2.8 mmol) in DMSO (4.0 mL) at ice bath temperature under nitrogen atmosphere (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.16 g, 0.94 mmol) was added. After stirring the reaction mixture for 3 h at r.t., it was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-[N-(2-phenylhexahydro-2,5-methanopentalen-3a(1H)-yl)glycyl]pyrrolidine-2-carbonitrile as off-white solid (0.16 g) in 48% yield. m/z (M+1) 350; 1H NMR (CDCl3) 300 MHz δ 7.35-7.16 (m, 5H), 4.4.85-4.76 (m, 1H), 3.76-3.40 (m, 2H), 3.50 (s, 2H), 2.48-2.41 (m, 1H), 2.36-2.27 (m, 2H), 2.23-2.0 (m, 6H), 1.94-1.68 (m, 4H), 1.66-1.60 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[ClH:29].[CH3:30][N:31]([CH2:33][C:34]1[CH:35]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:37]=[CH:38][CH:39]=1)[CH3:32].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>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].C(Cl)Cl.O>[ClH:29].[CH3:30][N:31]([CH2:33][C:34]1[CH:39]=[C:38]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]3[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)[CH:37]=[CH:36][CH:35]=1)[CH3:32]
Reactant: CN(C)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2cccc(CN(C)C)c2)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for example 33 using from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (200 mg, 0.449 mmol), 3-(N,N dimethylaminomethyl)phenylboronic acid pinacol ester hydrochloride (170 mg, 0.571 mmol), potassium phosphate (300 mg, 1.413 mmol), dioxane (12 mL), water (3 mL), and PdCl2(dppf)-CH2Cl2 adduct (50 mg, 0.061 mmol). The product was obtained as a light tan solid (204 mg, 85% yield). 1H NMR (400 MHz, DMSO-d6) δ=11.67 (br. s., 1H), 10.97 (br. s., 1H), 8.68 (t, J=5.1 Hz, 1H), 8.38 (s, 1H), 8.30 (s, 1H), 8.16 (s, 1H), 8.00-7.94 (m, 1H), 7.92 (d, J=1.0 Hz, 1H), 7.65-7.53 (m, 2H), 5.96 (s, 1H), 5.18 (dt, J=6.6, 13.3 Hz, 1H), 4.43 (d, J=5.1 Hz, 2H), 4.38 (d, J=5.6 Hz, 2H), 2.74 (d, J=4.8 Hz, 6H), 2.61-2.52 (m, 2H), 2.15 (s, 3H), 1.59-1.52 (m, 2H), 1.51 (d, J=6.6 Hz, 6H), 0.90 (t, J=7.3 Hz, 3H); LC-MS(ES)+ m/e 500.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)[CH3:13]>CN1C(=O)CCC1.CCOC(C)=O.O>[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[N+:9]([O-:11])=[O:10])=[CH:21][CH:22]=1)[CH3:13]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)Cc1ccc(Nc2ccc(Br)cc2[N+](=O)[O-])cc1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
A mixture of 1-bromo-4-fluoro-3-nitrobenzene (MATRIX SCIENTIFIC) (10.7 g, 48.7 mmol) and 4-aminophenylacetic acid ethyl ester (8.7 g, 48.7 mmol) in NMP (50 mL) is stirred for 48 h at 110° C. The reaction mixture is allowed to cool at rt, diluted with EtOAc and H2O. The layers are separated and the aqueous phase is extracted with EtOAc. The combined organic phase is washed brine, dried (Na2SO4), filtered and concentrated. Silica gel column chromatography purification (Hexane/EtOAc, 4:1) of the crude product affords the title compound as an orange oil: ES-MS: 380.9 [M+2]+; single peak at tR=5.75 min (System 1); Rf=0.27 (Hexane/EtOAc, 4:1).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].O>ClCCl>[Br:1][CH2:2][C:3]([NH:6][C:7]1[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])=[O:4]
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: O
Product: O=C(CBr)Nc1ccccc1C(=O)c1ccccc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A solution of bromoacetyl bromide (100 mL, 1.15 mol, Aldrich) dissolved in dichloromethane (300 mL) was added over 30 min to a solution of 2-aminobenzophenone (197 g, 1.0 mol, Fluka) dissolved in dichloromethane (1.3 L) and water (100) mL) cooled to -10° C. under vigorous mechanical stirring. The resulting mixture was stirred for an additional 1 h at --5° C. and then was allowed to warm to ambient temperature. The layers were separated, and the organic extract was washed with dilute sodium bicarbonate, then was dried over sodium sulfate. Evaporation afforded 309.8 g (95%) of 2-bromoacetamidobenzophenone as off-white crystals.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=O)=[CH:11][CH:12]=2)[CH:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][CH:5]1[CH3:30])(=[O:3])[CH3:2].Cl.C1C=CC2N(O)N=[N:38][C:36]=2C=1.CN.O1CCCC1.C(=O)([O-])O.[Na+]>ClCCl.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:38][CH3:36])=[O:16])=[CH:11][CH:12]=2)[CH:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[CH:20][CH:19]=2)[CH2:6][CH:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2C(Nc2ccc(N3CCOCC3)cc2)CC1C
Agent: CN
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2c(c1)C(Nc1ccc(N3CCOCC3)cc1)CC(C)N2C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
72 mg of 1-acetyl-4-[(4-morpholinophenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (compound of Step 3 of Example 111), 51 mg of WSCD.HCl, and 36 mg of HOBt.H2O were dissolved in 2 mL of dichloromethane, and 0.4 mL of a 2 M methylamine/tetrahydrofuran solution was added to the solution. The resulting mixture was stirred overnight at room temperature. After completion of the reaction, a saturated aqueous solution of sodium hydrogen carbonate was added to the mixture, and the mixture was extracted three times with chloroform. The extraction product was washed with saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (methanol:chloroform=1:10), and thus 52 mg (cis:trans=4:1, 70%) of the title compound was obtained as a yellow solid.
Reaction SMILES: [O:1]=[C:2]([CH3:21])[CH2:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:5].[H-].[Na+].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>C1COCC1>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][CH:3]([C:2](=[O:1])[CH3:21])[C:4]([C@H:6]2[CH2:10][CH2:9][CH2:8][N:7]2[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])=[O:5])=[CH:27][CH:26]=1
Reactant: CC(=O)CC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Clc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)C(Cc1ccc(Cl)cc1)C(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 60 °C
Yield: 20.7 %

Procedure:
A solution of (R)-benzyl 2-(3-oxobutanoyl)pyrrolidine-1-carboxylate (1 g, 3.5 mmol) in THF (50 mL) was added sodium hydride (130 mg, 5.3 mmol) followed by 4-chlorobenzyl bromide (710 mg, 3.5 mmol). The reaction mixture was then heated at 60° C. for 6 h. After concentrating the reaction mixture in vacuo, the resulting residue was purified by silica gel column chromatography (hexanes ethyl acetate) to afford (2R)-benzyl 2-(2-(4-chlorobenzyl)-3-oxobutanoyl)pyrrolidine-1-carboxylate (300 mg, 21%). LCMS: 8.04 and 8.14 min, calculated: 413, found (MH+): 414.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[N:16][O:17][C:11]=3[C:10]3[S:18][CH:19]=[CH:20][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:30][C:31]1[CH:32]=[CH:33][C:34]([CH3:40])=[C:35]([CH:39]=1)[C:36](Cl)=[O:37]>ClCCl>[O:17]1[C:11]2[C:10]3[S:18][CH:19]=[CH:20][C:9]=3[N:8]([C:6]([C:5]3[CH:21]=[CH:22][C:2]([NH:1][C:36](=[O:37])[C:35]4[CH:39]=[C:31]([F:30])[CH:32]=[CH:33][C:34]=4[CH3:40])=[CH:3][CH:4]=3)=[O:7])[CH2:14][CH2:13][C:12]=2[CH:15]=[N:16]1
Reactant: Nc1ccc(C(=O)N2CCc3cnoc3-c3sccc32)cc1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2CCc3cnoc3-c3sccc32)cc1

Procedure:
As described for Example 1, a solution of 2 mmol of 5,6-dihydro-6-(4-aminobenzoyl)-4H-isoxazolo [5,4-d]thieno[3,2-b]azepine and 5 mmol of triethylamine is reacted with 2.2 mmol of 5-fluoro-2-methylbenzoyl chloride in 10 ml of dichloromethane under argon for 16 hours to give the product as a solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].C(N(CC)CC)C.C([O:43][CH:44]=[CH:45][CH3:46])C.O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:8][C:7]1[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)[C:5](=[O:19])[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=2)=[O:21])=[CH:3][C:2]=1[C:44](=[O:43])[CH2:45][CH3:46]
Reactant: CC=COCC
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
A solution of 5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (Example 1 (d), 1500 mg, 2.5 mmol), bis[1,2-bis(diphenylphosphino)ethane]palladium(0) (230 mg, 0.25 mmol), triethylamine (7.5 ml, 54 mmol) and ethylpropenyl ether (900 μl, 7.5 mmol) in DMF (45 ml) was heated at 100° C. overnight. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate and the solvent was removed under reduced pressure. The crude product was then dissolved in DMF (25 ml) and 2M HCl (25 ml) and then stirred for 1.5 h. The reaction mixture was then poured into aqueous NaHCO3 and extracted with ethyl acetate. The extracts were separated, evaporated under reduced pressure, and the residue was chromatographed on silica using ethyl acetate/heptane (2/1, 4/1, 10/1) as eluent. Fractions containing the product were combined and evaporated to give the title compound (1.3 g, >99%).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[C:12]1(/[C:18](/[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[I-:32].[Na+].O>CC(C)=O>[I:32][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]/[CH:19]=[C:18](\[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)/[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: ICCCCC/C=C(\c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
p-Toluenesulfonate of (E)-7-phenyl-7-(3-pyridyl)-6-hepten-1-ol (15 g, 36 mmoles) and sodium iodide (18 g, 120 mmoles) were dissolved in acetone (100 ml) and the solution was stirred at room temperature for 3 hours. Water (200 ml) was added to the mixture and the product was extracted twice with ethyl ether. The organic layer was washed with water, dried (magnesium sulfate) and concentrated under reduced pressure to give (E)-1-iodo-7-phenyl-7-(3-pyridyl)-6-heptene (13 g, 96%) as an oil.
Reaction SMILES: O=[Si]=O.[F:4][C:5]1[C:10]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[OH:12])=[CH:9][CH:8]=[CH:7][N:6]=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[F:4][C:5]1[C:10]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: CCOC(OCC)c1ccccc1C(O)c1cccnc1F
Agent: [Cr+6]
Agent: O=[Si]=O
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(OCC)c1ccccc1C(=O)c1cccnc1F
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 11.8 g of dicalite in 100 ml of dry methylene chloride was added 7.38 g of chromium trioxide. The suspension was stirred for 30 min then a solution of (2-fluoropyridin-3-yl)-2-(diethoxymethyl)-phenylmethanol in 100 ml of methylene chloride was added. The supension was stirred overnight. The suspension was filtered through dicalite and washed with methylene chloride. The filtrate was washed with 100 ml portions of 1 M sodium hydroxide solution, water and brine and evaporated and azeotroped with toluene. Flash chromatography eluting with 30 to 50% ethyl acetate in heptane afforded (2-fluoropyridin-3-yl)-2-(diethoxymethyl)-phenylmethanone as a gum; 1H-NMR (200 MHz, CDCl3) d 5.60 (CHOEt),
Reaction SMILES: Cl[CH:2]([C:7]1[CH:26]=[CH:25][C:10]2[O:11][C:12]3[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH3:24])=[CH:18][C:13]=3[CH2:14][O:15][C:16](=[O:17])[C:9]=2[C:8]=1[O:27][CH3:28])[CH2:3][CH:4]([CH3:6])[CH3:5].CN1CCCN2C1=NCCC2>CN(C)C=O.[Cu-]=O>[CH3:28][O:27][C:8]1[C:9]2[C:16](=[O:17])[O:15][CH2:14][C:13]3[CH:18]=[C:19]([CH3:24])[CH:20]=[C:21]([O:22][CH3:23])[C:12]=3[O:11][C:10]=2[CH:25]=[CH:26][C:7]=1[CH:2]=[CH:3][CH:4]([CH3:6])[CH3:5]
Reactant: COc1cc(C)cc2c1Oc1ccc(C(Cl)CC(C)C)c(OC)c1C(=O)OC2
Agent: O=[Cu-]
Agent: CN1CCCN2CCCN=C12
Solvent: CN(C)C=O
Product: COc1cc(C)cc2c1Oc1ccc(C=CC(C)C)c(OC)c1C(=O)OC2

Procedure:
1.1 g (3.0 mmol) of the compound from Example 95 in 10 ml of dimethylformamide, 2.2 ml (15.3 mmol) of 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene and 0.65 g of copper(I) oxide are stirred at 80° C. for 12 h in an argon atmosphere. After filtering, the mixture is evaporated in vacuo, the residue is taken up with methylene chloride, 1N aqueous hydrochloric acid is added, then the mixture is washed with water, dried and evaporated. Chromatography on silica gel Si60 in petroleum ether/ether=3:1 yields 730 mg (65% of theory) of glassy solid.
Reaction SMILES: [CH2:1]([C@@H:4]1[C@:12]([C:14]2[C:15]([F:21])=[N:16][CH:17]=[C:18]([Br:20])[CH:19]=2)([CH3:13])[N:11]=[C:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:6]2([CH2:9][CH2:8][CH2:7]2)[S:5]1(=[O:31])=[O:30])[CH:2]=C.C(=O)(O)[O-:33].[Na+].[BH4-].[Na+]>C(Cl)Cl.CO>[Br:20][C:18]1[CH:19]=[C:14]([C@@:12]2([CH3:13])[N:11]=[C:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:6]3([CH2:9][CH2:8][CH2:7]3)[S:5](=[O:31])(=[O:30])[C@@H:4]2[CH2:1][CH2:2][OH:33])[C:15]([F:21])=[N:16][CH:17]=1
Reactant: C=CC[C@@H]1[C@@](C)(c2cc(Br)cnc2F)N=C(NC(=O)OC(C)(C)C)C2(CCC2)S1(=O)=O
Reactant: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(Br)cnc2F)[C@@H](CCO)S(=O)(=O)C12CCC2
Reaction time: 0.08 h
Yield: 101 %

Procedure:
To a solution of tert-butyl ((6R,7R)-6-allyl-7-(5-bromo-2-fluoropyridin-3-yl)-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-9-yl)carbamate (2.0 g, 3.87 mmol) in DCM (40 mL) and MeOH (10 mL) was added sodium bicarbonate (0.651 g, 7.75 mmol) and the resulting mixture was brought to −78° C. To this mixture was bubbled O3 for 15 min until the starting material was consumed. A stream of oxygen was passed through the solution for 5 min, then solid sodium borohydride (0.293 g, 7.75 mmol) was added to the mixture. The flask was removed from the bath and allowed to reach rt and stirred for 30 min. The mixture was carefully quenched with saturated NH4Cl, water was added and extracted with DCM. The combined organics were dried over Na2SO4, filtered, and concentrated to afford a white solid as tert-butyl ((6R,7R)-7-(5-bromo-2-fluoropyridin-3-yl)-6-(2-hydroxyethyl)-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-9-yl)carbamate (2.035 g, 3.91 mmol, 101% yield). LC/MS (ESI+) m/z=541.8 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.C1C(=O)N([Cl:20])C(=O)C1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:20])=[C:7]([OH:12])[CH:6]=[CH:5]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1ccc2cc(Br)ccc2c1
Solvent: C1CCOC1
Product: Oc1ccc2cc(Br)ccc2c1Cl

Procedure:
The title compound was prepared by reacting 6-bromo-2-naphthol (3 g, 13.4 mmol) and NCS (2.47 g, 18.5 mmol) in THF (50 mL) according to method C to yield 2.2 g (64%) of yellow solid: 1H NMR (DMDO-d6): δ 7.34 (1H, d, J=8.87 Hz), 7.69 (1H, dd, J=1.75 Hz, J=6.09 Hz), 7.79 (1H, d, J=8.96 Hz), 7.96 (1H, d, J=9.03 Hz), 8.17 (1H, d, J=1.75 Hz), 10.68(1H, s); MS (ESI) m/z255/2571259 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:15]#[N:16].Br[CH2:18][CH2:19][O:20][CH3:21].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:18][CH2:19][O:20][CH3:21])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:15]#[N:16]
Reactant: N#Cc1cc(-c2ccc(O)cc2)ccc1F
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COCCOc1ccc(-c2ccc(F)c(C#N)c2)cc1

Procedure:
A mixture of 4-fluoro-4′-hydroxy-1,1′-biphenyl-3-carbonitrile (0.50 g, 2.35×10−3 mol), 1-bromo-2-methoxyethane (0.33 g, 2.35×10−3 mol), potassium iodide (0.04 g, 2.35×10−4 mol) and potassium carbonate (1.30 g, 9.40×10−3 mol) in butanone (20 cm3) was reacted, worked up and purified as described for compound 3 in Example 2. Yield 0.26 g (40%), GC purity (100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([O:15][CH2:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:31](=[O:33])[CH3:32])=[CH:3][CH:4]=2)=[CH:9][C:10]=1[O:15][CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24]
Reactant: Nc1ccc(-c2cnc(N)c(OCc3c(Cl)cccc3Cl)c2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2cnc(N)c(OCc3c(Cl)cccc3Cl)c2)cc1
Temperature: 25 °C

Procedure:
To a solution of 5-(4-amino-phenyl)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (100 mg, 0.28 mmol) in acetonitrite (3 mL) at 0° C., was added pyridine (0.035 mL, 1.5 eq.) and acetic anhydride (0.03 mL, 0.28 mmol). The mixture was stirred at room temperature over night, and the precipitate was filtered to provide N-{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-acetamide as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH:19]1([NH2:22])[CH2:21][CH2:20]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:22][CH:19]1[CH2:21][CH2:20]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: NC1CC1
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CC1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (300 mg, 1.13 mmol) was treated with cyclopropylamine following general procedure B to afford 4-cyclopropylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (200 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (170 mg) following general procedure E. The above ethylamide (0.6 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 1-cyclopropyl-3-ethyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (15 mg). LCMS: m/z 312 [M+1]+.