Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[CH3:7][N:8]([CH3:18])[C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.[ClH:19].[C:20]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29]([CH2:33][C:34](=[O:36])[NH2:35])=[C:28](O)[CH:27]=[CH:26]2)(=[NH:22])[NH2:21].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(C(C)=O)C.O.C(O)(=O)C>[ClH:19].[ClH:19].[CH3:7][N:8]([CH3:18])[C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][C:28]2[CH:27]=[CH:26][C:25]3[C:30](=[CH:31][CH:32]=[C:23]([C:20](=[NH:21])[NH2:22])[CH:24]=3)[C:29]=2[CH2:33][C:34](=[O:36])[NH2:35])=[O:14])=[CH:11][CH:10]=1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)O
Product: CN(C)c1ccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2CC(N)=O)cc1
Reaction time: 2 h
Yield: 133.7 %

Procedure:
40 Milliliters of 20% hydrous pyridine was added to 3.0 g of 4-dimethylaminobenzoic acid, 1.77 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 2.65 g of DCC and 130.9 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 24 hours at room temperature. Then, the precipitate was collected by filtration and washed with a small amount of pyridine. To this collected precipitate were added 60 ml of DMF and 20 ml of water to dissolve the precipitate with heating, followed by stirring for 2 hours under cooling with ice. Then, insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. To the residue were added 15 ml of DMF and 10 ml of water to dissolve the residue. The solution was added dropwise to 400 ml of acetone, followed by stirring for 24 hour under cooling with ice. The precipitate was collected by filtration to obtain a crude product. Then, the product was subjected to silica gel column chromatography using methyl ethyl ketone-water-acetic acid (80:15:5) as an eluent, and the desired fractions were collected and the solvent was distilled off under reduced pressure. The residue was suspended in 15 ml of methanol, 5 ml of DMF and 0.9 ml of concentrated hydrochloric acid, and the suspension was added dropwise to a mixed liquid of 200 ml of acetone and 100 ml of ether, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 1.96 g of the desired product.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:13][C:14](=[CH2:18])[C:15](Cl)=[O:16].O>C(OCC)C>[CH3:18][C:14](=[CH2:13])[C:15]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:16]
Reactant: C=C(C)C(=O)Cl
Reactant: C1CCNC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(C)C(=O)N1CCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, pyrrolidine (3.55 g, 0.05 mole) was dissolved in ethyl ether (50 ml). Triethylamine (5.06 g, 0.05 mmole) was added and the solution cooled to and maintained at 0° C. 2-Methylacryloyl chloride (5.22 g, 0.05 mole), dissolved in ethyl ether (50 ml) was added to the reaction and the solution stirred overnight. Water (50 ml) was added, the layers were separated and the aqueous layer extracted with ethyl ether. The extracts were concentrated and the resulting product dried (6.77 g). The structure was confirmed by NMR.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16][CH2:17]O>>[CH2:16]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:2]=1[Cl:1])[CH3:17]
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(C)nc1Cl

Procedure:
A suspension of 2-chloro-6-methylnicotinic acid (7.23 mmol) and 1.2 mL of thionylchloride in 50 mL EtOH were heated to reflux overnight. The mixture was reduced to half of its volume, quenched with sat. aq. NaHCO3 solution and extracted with DCM (2×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by (KP-SIL™ from Biotage) using Hept to Hept/EtOAc (1/1) gives the desired product as colorless oil;
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.N([O-])=O.[Na+].[N-:39]=[N+:40]=[N-].[Na+]>Cl.O>[N:1]([C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1)=[N+:39]=[N-:40]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)cc(-c2ccc(N3CCC(C)CC3)cc2)c1N
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)cc(-c2ccc(N3CCC(C)CC3)cc2)c1N=[N+]=[N-]
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
A mixture of methyl 4′-amino-4″-(4-methylpiperidin-1-yl)-3-trifluoromethyl-[1,1′:3′,1″-terphenyl]-5′-carboxylate (250 mg, 0.532 mmol) in hydrochloric acid, (12 mL, 37% aqueous solution) was cooled in an ice bath and a solution of sodium nitrite (220 mg, 3.19 mmol) in water (2 mL) was added slowly. The orange-red solution was stirred for 30 min and a solution of sodium azide (208 mg, 3.19 mmol) in water (2 mL) was added dropwise. After 30 min this was partitioned between DCM and water. The organic phase washed with water and the combined organic phases were basified with 10 N aq. NaOH solution. This was extracted with DCM and the organic phases were washed with sat. NaHCO3 solution, brine, and dried with sodium sulfate. Removal of the solvent followed by silica gel chromatography (step gradient elution with DCM containing 0 to 2% MeOH) afford methyl 4′-azido-4″-(4-methylpiperidin-1-yl)-3-trifluoromethyl-[1,1′:3′,1″-terphenyl]-5′-carboxylate (128 mg, 0.26 mmol, 49% yield) as a solid. 1H NMR (500 MHz, chloroform-d) δ ppm 8.02 (1H, d, J=2.44 Hz), 7.85 (1H, s), 7.79 (1H, d, J=7.63 Hz), 7.68 (1H, d, J=2.44 Hz), 7.64 (1H, d, J=7.63 Hz), 7.59 (1H, d, J=7.63 Hz), 7.42 (2H, d, J=8.55 Hz), 7.04 (2H, d, J=8.85 Hz), 4.03 (3H, s), 3.26-3.39 (4H, m), 2.57-2.69 (4H, m), 2.38 (3H, s).
Reaction SMILES: [CH2:1]([N:3]([C:12]1[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][C:23]([CH:26]=[O:27])=[CH:24][N:25]=1)=[CH:17]2)[S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:6])=[O:5])[CH3:2].CO.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH2:1]([N:3]([C:12]1[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][C:23]([CH2:26][OH:27])=[CH:24][N:25]=1)=[CH:17]2)[S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:6])[CH3:2]
Reactant: CCN(c1ccc(C)c2cc(-c3ncc(C=O)s3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(c1ccc(C)c2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To a solution of N-ethyl-N-[2-(5-formyl-1,3-thiazol-2-yl)-4-methyl-1H-indol-7-yl]thiophene-2-sulfonamide (1.3 g) in a mixed solvent of methanol (15 ml) and tetrahydrofuran (40 ml) was added sodium borohydride (0.14 g) under ice-cooling, and the mixture was stirred at the same temperature for 2 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (0.74 g) as pale-yellow crystals. The mother liquor was concentrated, and the residue was subjected to silica gel column chromatography (ethyl acetate:hexane=3:7-6:4) to give the title compound (0.20 g) as pale-yellow crystals. total yield 0.94 g (yield 72%). melting point 166-167° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=O)[C:5]#[N:6].CS(C)=O.C(N(CC)CC)C.[SH:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]>O>[C:5]([C:4]1[CH:7]=[CH:8][C:9]2[CH:10]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[S:23][C:2]=2[CH:3]=1)#[N:6]
Reactant: N#Cc1ccc(C=O)c(F)c1
Reactant: COC(=O)CS
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc2ccc(C#N)cc2s1
Temperature: 80 °C

Procedure:
A round bottom flask was charged with 3-fluoro-4-formylbenzonitrile (9.00 g, 60.4 mmol), dimethyl sulfoxide (90 mL), triethylamine (18.0 mL, 129 mmol), and subsequently methyl 2-mercaptoacetate (5.40 mL, 60.4 mmol). The reaction mixture was heated at 80° C. for 2 hours. After cooling, the reaction mixture was poured into water and the precipitated product was collected by filtration, dried and used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:11])[CH3:10].[O:12]1[CH2:14][C@H:13]1[CH2:15]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[O:12]1[CH2:14][C@H:13]1[CH2:15][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ccccc1O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccccc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
A mixture of N-(2-hydroxyphenyl)acetamide (1.51 g, 10 mmol), (2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (2.59 g, 10 mmol) and cesium carbonate (Cs2CO3) (3.9 g, 12 mmol) in dimethylformamide (DMF) (30 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was dried over Na2SO4, filtered, concentrated and the residue was purified by silica gel flash chromatography to give the subtitled compound (1.34 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([OH:30])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.C(Cl)CCl.C(N(CC)CC)C.[P:42]([O:54][CH2:55][CH2:56][N:57]([CH2:87][CH3:88])[CH2:58][CH2:59][C@@H:60]([NH:69][C:70]1[CH:75]=[CH:74][C:73]([S:76](=[O:79])(=[O:78])[NH2:77])=[CH:72][C:71]=1[S:80]([C:83]([F:86])([F:85])[F:84])(=[O:82])=[O:81])[CH2:61][S:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[P:42]([O:54][CH2:55][CH2:56][N:57]([CH2:58][CH2:59][C@@H:60]([NH:69][C:70]1[CH:75]=[CH:74][C:73]([S:76](=[O:79])(=[O:78])[NH:77][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([C@H:14]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[OH:30])[CH2:16][CH2:17]3)=[CH:22][CH:23]=2)=[CH:72][C:71]=1[S:80]([C:83]([F:85])([F:86])[F:84])(=[O:82])=[O:81])[CH2:61][S:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[CH2:87][CH3:88])([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:43]
Reactant: O=C(O)c1ccc(N2CCC([C@@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Reactant: CCN(CCOP(=O)(OC(C)(C)C)OC(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCN(CCOP(=O)(OC(C)(C)C)OC(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a solution of (R)-4-(4-((4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 40, 88 mg, 0.20 mmol), EDC (77 mg, 0.40 mmol), and DMAP (49 mg, 0.40 mmol), triethylamine (28 μl, 0.20 mmol) in 5 ml of DCM was added (R)-di-tert-butyl 2-(ethyl(4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butyl)amino)ethyl phosphate (INTERMEDIATE 50, 150 mg, 0.20 mmol). The mixture was stirred at r.t overnight. The reaction solution was diluted with DCM (20 ml) and washed with water (30 ml). The aqueous layer was extracted with DCM (30 ml) and the combined organic layers were dried over sodium sulfate, and concentrated in vacuo to an oil. This material was purified by column chromatography (ISCO, 0→100% EtOAc/hexane followed by 0→10% MeOH/EtOAc) to provide the title compound (137 mg, yield: 59%).
Reaction SMILES: CC(C)([O-])C.[K+].Br[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH:16]=[CH2:17])=[CH:10][CH:9]=1.[CH3:18][C:19]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:20]=1[NH2:21]>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].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([NH:21][C:20]2[C:22]([CH3:27])=[CH:23][C:24]([CH3:26])=[CH:25][C:19]=2[CH3:18])=[CH:9][CH:10]=1)[CH2:15][CH:16]=[CH2:17]
Reactant: C=CCCc1ccc(Br)cc1
Reactant: Cc1cc(C)c(N)c(C)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=CCCc1ccc(Nc2c(C)cc(C)cc2C)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 80.5 %

Procedure:
A mixture of Pd2(dba)3 (517.6 mg, 5 mol % Pd), BINAP (1.06 g, 1.5 eq of Pd), and potassium tert-butoxide (3.05 g, 27.13 mmol) in 80 ml toluene was prepared in a round-bottom flask in a glove box. The 4-(4-bromophenyl)-1-butene (5.00 g, 22.6 mmol) and 2,4,6-trimethylaniline (3.80 ml, 27.13 mmol) were added by syringe, and the reaction mixture was stirred at 80° C. oil bath for 12 h. The mixture was quenched with a saturated NaHCO3(aq) solution and then concentrated under reduced pressure. The crude product was purified by column chromatography (t-butyl methyl ether/heptane (v/v)=3/97, Rf=0.3) to afford N-(4-(but-3-en-1-yl)phenyl)-2,4,6-trimethylaniline (4.83 g, 76.7%). 1H NMR (300 MHz, CDCl3): δ 6.95 (m, 4H), 6.44 (s, 1H), 6.42 (s, 1H), 5.87 (m, 1H), 5.01 (m, 2H+NH), 2.60 (t, 2H), 2.30 (s, 1H), 2.17 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 144.7, 138.8, 135.6, 135.2 (2C), 134.8, 131.5, 129.4 (2C), 129.2 (2C), 114.8, 113.6 (2C), 36.1, 34.8, 21.1, 18.5 (2C). MS (EI): m/z: calc. for C19H23N: 265.18. found 265.18.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O)[C:6]([O:8][CH3:9])=[O:7])=[O:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].N#N>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH:1]=[O:2]
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C=O)c1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: [Pd]
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C=O)c1
Temperature: 95 °C
Yield: 56 %

Procedure:
A mixture of methyl 3-formyl-4-(trifluoromethyl-sulfonyloxy)benzoate (T37.2) (7.57 g, 24.2 mmol), 2-fluoro-5-methoxy-phenylboronic acid (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) (12.4 g, 72.7 mmol), Cs2CO3 (27.6 g, 84.9 mmol), and tetrakis(triphenylphosphine) palladium (2.80 g, 2.42 mmol) in 1,2-dimethoxyethane (DME) (75 mL) was degassed with N2 at room temperature The mixture was heated at 95° C. for 9 hours. After removing solvent, the residue was purified by flash chromatography (silica gel, 1:19 EtOAc/hexane) and gave T37.3, a white solid, in 56% yield (2.9 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.88 (dd, J=4 Hz, 1H), 8.45 (s, 1H), 8.28 (m, 1H), 7.69 (d, j=8 Hz, 1H), 7.29 (t, J=9 HZ, 1H), 7.08 (m, 2H), 3.92 (s, 3H), 3.79 (s, 3H).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[ClH:19]>C(Cl)Cl.CCOCC>[Cl:19][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: O=[N+]([O-])c1ccc(N2CCN(CCO)CC2)cc1
Reactant: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(N2CCN(CCCl)CC2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
1-(2-Hydroxyethyl)-4-(4-nitrophenyl)piperazine (5 g, 0.02 mol) was dissolved in 50 mL of DCM and treated with HCl (40 mL of a 1M solution in Et2O) under a drying tube for 90 min. The solvent was evaporated, the residue dissolved in thionyl chloride (60 mL) and the mixture refluxed at 80° C. After 5 h, the reaction was complete as shown by LCMS and the thionyl chloride was removed under reduced pressure redissolving in DCM and evaporating three times to give the title compound as the HCl salt. LCMS: 93%, t=0.88 min, [MH+]=270.23.
Reaction SMILES: [Mg].II.[C:4]1([CH3:11])[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[P:12]([O-:19])(OCC)OCC.Cl>C1COCC1.C1(C)C=CC=CC=1.O>[CH3:11][C:4]1[CH:9]=[CH:8][C:7]([PH:12](=[O:19])[C:7]2[CH:8]=[CH:9][C:4]([CH3:11])=[CH:5][CH:6]=2)=[CH:6][CH:5]=1
Reactant: CCOP([O-])OCC
Reactant: Cc1ccc(Br)cc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc([PH](=O)c2ccc(C)cc2)cc1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
Under an argon atmosphere, a solution of magnesium (3.55 g, 1.0 equivalent) and a small amount of iodine in THF (30 mL) was stirred at room temperature for 1 hr. A solution of p-tolyl bromide (25 g, 0.146 moL) in THF (5 mL) was added at 30° C. The mixture was stirred at 45° C. for 30 min. and then at 5° C. for 1 hr. Diethyl phosphite (10.08 g, 0.5 equivalent) was added at 5° C. and the mixture was stirred-at 5° C. for 1 hr and at room temperature (25° C.) for 30 min. Water (10 mL) was added at 3° C., and then toluene (40 mL) and 6M-HCl (20 mL) were added. The mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned, and the organic layer was washed successively with water (10 mL), 5% aqueous NaHCO3 solution (10 mL) and 5% aqueous NaCl solution (10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered by gravity, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether-heptane to give the title compound (7.78 g, white crystals). yield 46.3%. melting point: 93.7° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][CH:16]1[CH2:21][CH2:20][CH:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:18][CH2:17]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][CH:16]2[CH2:21][CH2:20][CH:19]([N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])[CH2:18][CH2:17]2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45]
Reactant: CCN(CC)C1CCC(Nc2c(C(C)=O)cnc3ccc(Br)cc23)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: CCN(CC)C1CCC(Nc2c(C(C)=O)cnc3ccc(-c4cc(Cl)c(O)c(OC)c4)cc23)CC1
Yield: 43.3 %

Procedure:
Following general procedure D, 1-{6-bromo-4-[4-(diethylamino)cyclohexylamino]quinolin-3-yl}ethanone (42 mg, 0.100 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (57 mg, 0.200 mmol) to afford the desired product (21.5 mg, 43%) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 8.93 (s, 1H), 8.32 (d, J=1.8 Hz, 1H), 8.03 (dd, J=8.7, 1.9 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.29 (d, J=2.1 Hz, 1H), 7.22 (d, J=2.1 Hz, 1H), 4.26 (s, 1H), 3.99 (s, 3H), 3.08 (q, J=7.2 Hz, 4H), 2.69 (s, 3H), 2.44 (s, 2H), 2.14 (s, 2H), 1.79-1.64 (m, 4H), 1.29 (t, J=7.2 Hz, 6H); ESI MS m/z 496 [C28H34ClN3O3+H]+; HPLC>99% (AUC), tR=10.50 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:17]=[C:18]([F:21])[C:19]=1[F:20])[C:5]([C:7](=[CH:13]OCC)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].[CH:23]1([NH2:26])[CH2:25][CH2:24]1>C(O)(C)(C)C>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:17]=[C:18]([F:21])[C:19]=1[F:20])[C:5]([C:7](=[CH:13][NH:26][CH:23]1[CH2:25][CH2:24]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6]
Reactant: NC1CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Solvent: CC(C)(C)O
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(Cl)c1F
Temperature: 25 °C

Procedure:
A solution of 2.7 g (8.0 mmol) of ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylate, 0.46 g (8.0 mmol) of cyclopropylamine, and 40 ml of dry t-butanol was stirred at 45° C. for 21/2 hours. The mixture was cooled to room temperature and used without purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1I.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[CH:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Cu]I>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[C:23]#[C:22][C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1I
Reactant: C#Cc1ccc(Cl)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(N)c1C#Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
2-iodo-3-nitro-benzoic acid methyl ester (0.79 g, 2.84 mmol), 1-chloro-4-ethynylbenzene (0.41 g, 2.99 mmol), palladium tetrakis(triphenylphosphine) (0.16 g, 0.14 mmol), copper (I) iodide (0.03 g, 0.14 mmol), and triethylamine (1.44 g, 14.19 mmol) were dissolved in 15 mL toluene. Argon was bubbled through the resulting solution for 15 min. The reaction was stirred under argon at 80° C. for 2 h and 20 min. The reaction mixture was then washed once with water, dried (MgSO4), and concentrated in vacuo. The orange oil was purified by flash chromatography eluting with 50 to 100% CHCl3/hexanes to yield 3-amino-2-(4-chloro-phenylethynyl)-benzoic acid methyl ester, 0.76 g (94%) as a yellow oil. 1H NMR (300 MHz, d6-DMSO) δ 3.84 (s, 3H), 5.84 (br s, 2H), 6.97 (dd, J=8.1, 1.3 Hz, 1H), 7.05 (dd, J=7.5, 1.2 Hz, 1H), 7.17 (app t, J=7.5 Hz, 1H), 7.49 (d, J=8.7 Hz, 2H), 7.63 (d, J=8.7 Hz, 2H). MS (electrospray, MH+) 286.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[CH:1]([C:4]1[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(/C=C/c2cccc([N+](=O)[O-])c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1csc(/C=C/c2cccc(N)c2)n1
Temperature: 25 °C
Yield: 47.4 %

Procedure:
To a solution of 16.8 g of 4-isopropyl-2-(trans-3-nitrostyryl)thiazole dissolved in 60 ml of ethanol was added a solution of 48.4 g of stannous chloride dihydrate in 60 ml of ethanol and the mixture was refluxed for 1.5 hours. After the reaction mixture was cooled to room temperature, the mixture was adjusted to pH 13 with addition of 30% aqueous sodium hydroxide solution and then the basic portion was extracted with the use of ethyl acetate and dried over magnesium sulfate, followed by evaporation of the solvent under reduced pressure. The solid residue formed was recrystallized from ethyl ether-n-hexane to obtain 7.1 g (yield 47%) of the pale yellowish white title compound.