Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.[Br:11][C:12]1[CH:13]=[C:14]([O:19][CH3:20])[CH:15]=[C:16](F)[CH:17]=1.O>CN(C=O)C>[Br:11][C:12]1[CH:17]=[C:16]([CH:15]=[C:14]([O:19][CH3:20])[CH:13]=1)[O:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1
Reactant: CN1CCC(O)CC1
Reactant: COc1cc(F)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Br)cc(OC2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 600 mg, 15.0 mmol) in DMF (20 mL) at 65° C. was slowly added a solution of 4-hydroxy-1-methylpiperidine (1.15 g, 10 mmol) in DMF (7.0 mL). After stirring for 30 minutes, a solution of 3-bromo-5-fluoroanisole (2.05 g, 10 mmol) in DMF (7.0 mL) was added and the reaction mixture was stirred at 65° C. for 24 h. The reaction mixture was allowed to cool to ambient temperature then was poured into water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were loaded onto a SCX-2 cartridge, which was then washed with acetonitrile then eluted with 2N ammonia in methanol. Concentration of the basic methanolic fractions in vacuo gave the title compound (1.5 g, 50%). 1H NMR (CDCl3, 400 MHz): 6.65 (dd, J=2.2, 1.6 Hz, 1H), 6.63 (dd, J=2.3, 1.6 Hz, 1H), 6.37 (dd, J=2.3, 2.1 Hz, 1H), 4.29-4.21 (m, 1H), 3.75 (s, 3H), 2.70-2.61 (m, 2H), 2.31-2.21 (m, 5H), 2.01-1.93 (m, 2H), 1.86-1.75 (m, 2H). LCMS (Method B): RT=2.1 min, M+H+=300.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[NH2:20].N1C=CC=CC=1.[C:27](Cl)(Cl)=[O:28]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[C:3]([N:20]=[C:27]=[O:28])=[CH:4][C:5]([O:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:14])[CH3:15])=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cc(N)c(Br)cc1Cl
Reactant: O=C(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCOc1cc(N=C=O)c(Br)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-phenylamine (0.15 g, 0.393 mmol) in toluene (3 ml) was added pyridine (0.038 ml, 0.472 mmol), DMAP (0.048 g, 0.393 mmol) and 20% phosgene in toluene (0.224 ml, 0.433 mmol). The mixture was stirred at room temperature for two hours. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure to give [2-(4-bromo-2-chloro-5-isocyanato-phenoxy)-ethoxy]-tert-butyl-dimethyl-silane (0.155 g) as a white solid, which was used directly in the next step.
Reaction SMILES: S(=O)(=O)(O)O.O.[CH3:7][N:8]([CH3:26])[S:9]([C:12]1[C:20]2[O:19]C(C(C)(C)C)=[N:17][C:16]=2[CH:15]=[CH:14][C:13]=1[Cl:25])(=[O:11])=[O:10]>O1CCOCC1>[NH2:17][C:16]1[C:20]([OH:19])=[C:12]([S:9]([N:8]([CH3:7])[CH3:26])(=[O:10])=[O:11])[C:13]([Cl:25])=[CH:14][CH:15]=1
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc2nc(C(C)(C)C)oc12
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Yield: 96.1 %

Procedure:
11 ml (205 mmol; 1.20 V) of sulfuric acid and 11 ml of water were added dropwise to a solution of 9.12 g (28.8 mmol; 1.0 eq) of 2-tert-butyl-6-chlorobenzooxazole-7-sulfonic acid dimethylamide in 41 ml of 1,4-dioxane. The reaction medium was refluxed for six and a half hours. The reaction medium was concentrated and 440 ml of 1 N sodium hydroxide were added (pH at 8). The solution was extracted with ethyl acetate. The organic phases were combined, dried over magnesium sulfate, filtered and evaporated. 6.94 g of 3-amino-6-chloro-2-hydroxy-N,N-dimethylbenzenesulfonamide were obtained in the form of a brown solid. Yield=96%.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([O:21][CH3:22])[CH:13]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([Si:5]([CH3:7])([CH3:6])[O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([O:21][CH3:22])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(OCCO[Si](C)(C)C(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(OCCO[Si](C)(C)C(C)(C)C)ccc1N
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
Step C A suspension of tert-butyl-[2-(3-methoxy-4-nitro-phenoxy)-ethoxy]-dimethyl-silane (1 g, 3.05 mmol) and Pd/C (Aldrich, 10%, 0.1 g) in ethyl acetate (25 mL) was vigorously shaken in a Parr under atmosphere of H2 (50 psi) for 0.5 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2-methoxy-phenylamine as a light yellow oil (0.9 g, 99%).
Reaction SMILES: O.Cl[C:3]1[C:12]([CH:13]=[O:14])=[C:11]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[C:10]2[CH:9]=[C:8]3[O:23][CH2:24][CH2:25][O:26][C:7]3=[CH:6][C:5]=2[N:4]=1.[I-:27].[Na+].Cl>C(#N)C>[I:27][C:3]1[C:12]([CH:13]=[O:14])=[C:11]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[C:10]2[CH:9]=[C:8]3[O:23][CH2:24][CH2:25][O:26][C:7]3=[CH:6][C:5]=2[N:4]=1
Reactant: CN1CCN(Cc2c(C=O)c(Cl)nc3cc4c(cc23)OCCO4)CC1
Reactant: [I-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CN1CCN(Cc2c(C=O)c(I)nc3cc4c(cc23)OCCO4)CC1
Temperature: 25 °C

Procedure:
A 4-necked 12-L round-bottom flask is equipped with a mechanical stirrer and water-cooled condenser. Under nitrogen, the flask is charged with 7-chloro-9-(4-methyl-piperazin-1-yl-methyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-carbaldehyde (120 g, 346 mmol), prepared as in example 13f, sodium iodide (1.04 kg, 6.92 mmol), and 3 L of acetonitrile. To the yellow suspension is added concentrated hydrogen chloride (59.7 mL, 726 mmol) over 5 min. The white slurry is refluxed for 15 hr. The solvent is mostly removed by short-path distillation in vacuo. The resultant thick slurry is cooled to ambient temperature and treated with 2.5 L of water and 2.5 L of methylene chloride. The organic layer is separated and the aqueous layer is extracted with methylene chloride (3×2 L). The combined organic layers are washed with brine (2.5 L), dried over anhydrous sodium sulfate, concentrated and dried in vacuo at 30° C. yielding 7-iodo-9-(4-methyl-piperazin-1-yl-methyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-carbaldehyde as a yellow solid. This crude product is used for the next step without further purification. Recrystallization from CH2Cl2 --MeOH (1:1) gave an analytical sample as an off-white solid: 198°-200° C. (dec.). 1H NMR (CDCl3, 200 MHz) δ2.30 (s, 3H), 2.43, 2.57 (m, 8H), 3.93 (s, 2H). 4.40(s, 4H), 7.47 (s, 1H), 7.50 (s, 1H), 10.1 (s, 1H). Elemental analysis: Calculated for C18H20IN3O3 : C 47.70, H 4.45, N 9.27. Found: C 47.78, H 4.45, N 9.26.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[S:47](N)([NH2:50])(=[O:49])=[O:48]>O1CCOCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:50][S:47]([N:43]1[CH2:44][CH2:45][CH:40]([C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:39])[CH2:41][CH2:42]1)(=[O:49])=[O:48]
Reactant: NS(N)(=O)=O
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)N1CCC(C(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Temperature: 130 °C
Yield: 6.9 %

Procedure:
To a solution of N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) (10.0 mg, 0.018 mmol) in 1,4-dioxane (1.0 mL) was added sulfamide (17.1 mg, 0.18 mmol) and the mixture was heated to 130° C. in a microwave for 10 minutes. Purification by preparative LCMS (pH 2) gave the desired compound (0.8 mg, 7% yield). LCMS for C24H27ClN7O3S (M+H)+: m/z=528.2.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][C:7]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:6]1=[O:16])=[O:4].[BH4-].[Na+].Cl>CO.[Cl-].[Na+].O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][C:7]2([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[C@H:6]1[OH:16])=[O:4]
Reactant: COC(=O)C1CCCC2(CCCCC2)C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: COC(=O)[C@@H]1CCCC2(CCCCC2)[C@H]1O
Yield: 20.9 %

Procedure:
To a solution of 1-oxo-spiro[5.5]undecane-2-carboxylic acid methyl ester (13.02 g) obtained in Step 2 in methanol (300 mL), sodium borohydride (2.2 g) was added in small portions under ice-cooling, followed by stirring the reaction mixture under ice-cooling for 30 minutes. Then, after addition of saturated brine, 2N aqueous hydrochloric acid solution was further added dropwise to the reaction mixture until the evolution of gases ceased, followed by extraction with ethyl acetate twice. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:8 to 1:5) to give trans-1-hydroxy-spiro[5.5]undecane-2-carboxylic acid methyl ester (2.74 g).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:43][CH:44]1[C@H:48]2[C@H:49](OC3CCCCO3)[N:50](C(OC(C)(C)C)=O)[C:51]3[CH:58]=[C:57]([O:59][CH3:60])[CH:56]=[CH:55][C:52]=3[C:53](=[O:54])[N:47]2[CH2:46][CH2:45]1)[CH2:9][CH2:10][O:11][CH:12]1[C@H:16]2[C@H:17](OC3CCCCO3)[N:18](C(OC(C)(C)C)=O)[C:19]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:20]=3[C:21](=[O:22])[N:15]2[CH2:14][CH2:13]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:8]([O:43][CH:44]1[C@@H:48]2[CH:49]=[N:50][C:51]3[CH:58]=[C:57]([O:59][CH3:60])[CH:56]=[CH:55][C:52]=3[C:53](=[O:54])[N:47]2[CH2:46][CH2:45]1)[CH2:9][CH2:10][O:11][CH:12]1[C@@H:16]2[CH:17]=[N:18][C:19]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:20]=3[C:21](=[O:22])[N:15]2[CH2:14][CH2:13]1
Reactant: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)[C@@H](OC1CCCCO1)[C@@H]1C(OCCCOC3CCN4C(=O)c5ccc(OC)cc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)CCN1C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2c(c1)N=C[C@H]1C(OCCCOC3CCN4C(=O)c5ccc(OC)cc5N=C[C@@H]34)CCN1C2=O
Reaction time: 1 h
Yield: 75 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 8a (80 mg, 0.08 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 9a (31 mg, 0.06 mmol, 75%) as a solid: [α]20D=+515° (c=0.10, CHCl3);—1H NMR (CDCl3, 400 MHz): δ 2.01-2.11 (m, 4H, 2-H, 2′-H), 2.28-2.36 (m, 4H, 1-H, 1′-H), 2.38-2.45 (m, 2H, 13-H), 3.52-3.61 (m, 2H, 3-H, 3′-H), 3.67-3.75 (m, 2H, 11a-H, 11a′-H), 3.77-3.85 (m, 2H, 3-H, 3′-H), 3.90 (s, 6H, 7-OMe, 7′-OMe), 4.23-4.30 (m, 4H, 12-H, 12′-H), 6.79 (s, 2H, 9-H, 9′-H), 7.53 (s, 2H, 6-H, 6′-H), 7.65 (d, 2H, J=4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 29.0, 29.6, 46.6, 53.7, 56.0, 65.6, 109.6, 112.9, 120.2, 140.7, 146.9, 151.8, 162.3, 164.6; IR (neat): 3350, 2956, 1599, 1506, 1447, 1385, 1262, 1216, 1091 cm−1; MS (FAB) m/z (relative intensity) 597 ([M+2×MeOH]+., 22), 565 ([M+MeOH]+., 25), 533 (M+., 100).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29]OS(C)(=O)=O)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:35][C:36]([NH2:38])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:39]#[N:40].[Na+].[I-].[Na+]>CN(C)C=O>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][C:39]#[N:40])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:35][C:36]([NH2:38])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCC1CCN(c2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)CC1
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCCC1CCN(c2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
20 mg of 4-(benzylamino)-6-({4-[4-(2-methylsulfonyloxyethyl)piperidino]phenyl}amino)pyridine-3-carboxyamide (the compound of Example 58) was dissolved in 0.5 mL of N,N-dimethylformamide, to which 3 mg of sodium cyanide and 9 mg of sodium iodide were added, and stirred overnight at 120° C. After cooling, the solvent was evaporated, water was added to the residue, and extracted with chloroform. The extract was washed with water and dried on anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=8:1) to obtain 6 mg (29%) of the title compound as a light yellow crystalline powder.
Reaction SMILES: Cl[Si](C)(C)C.Br[C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1([CH2:24][NH:25][CH2:26][CH2:27][C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)C2C=CC=CC=2N=N1>O1CCCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[C:7]([F:14])([F:13])[CH2:24][NH:25][CH2:26][CH2:27][C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)[CH3:12]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: c1csc(CCNCn2nnc3ccccc32)c1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)CNCCc1cccs1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28.1 %

Procedure:
To a mixture of 3.5 g (0.054 g-atom) of zinc powder (−325 mesh) and 60 mL of anhydrous tetrahydrofuran was added 5.1 mL (0.041 mole) of chlorotrimethylsilane in one portion. After stirring for 20 minutes, a solution of 5.2 mL (0.041 mole) of ethyl bromodifluoroacetate in 5 mL of tetrahydrofuran was added dropwise at a rate to keep the internal temperature below 35 degrees. The mixture was stirred for 20 minutes and then cooled to −10 to 0 degrees. A solution of 7 g (0.027 mole) of benzotriazol-1-ylmethyl-(2-thiophen-2-yl-ethyl)-amine in 20 mL of tetrahydrofuran was added dropwise at a rate to keep the internal temperature at −10 to 0 degrees. After 10 minutes the reaction mixture was warmed to room temperature and stirred for 3 hours at room temperature. The solution was cooled to −10 to 0 degrees and quenched by the addition of saturated aqueous sodium bicarbonate at a rate to maintain the internal temperature −10 to 0 degrees. Ether was added, the mixture was stirred for 15 minutes at room temperature and then filtered through Celite, washing with ether. The filtrate was extracted 3 times with ether. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Ether and hexane were added to the residue, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (gradient, 100:0-80:20) to give 2 g of 2,2-difluoro-3-(2-thiophen-2-yl-ethylamino)-propionic acid ethyl ester as a oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:26])[CH2:18][C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:27][C:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:26])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:32]4[CH:31]=[CH:30][N:29]=[C:28]([Cl:27])[CH:33]=4)=[CH:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(I)cc3)nc2)CC1
Reactant: OB(O)c1ccnc(Cl)c1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(Cl)c4)cc3)nc2)CC1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a sealed tube was added N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-iodophenyl)acetamide 177-2 (100 mg, 0.22 mmol), 2-chloropyridin-4-ylboronic acid 177-3 (52 mg, 0.33 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), saturated Na2CO3 (1 mL), ethanol (1 mL) and toluene (3 mL). The reaction was heated to 110° C. and stirred for 16 hours. The reaction was cooled down to room temperature, then extracted with ethyl acetate. The crude product was purified by silica-gel flash chromatography, eluted with ethyl acetate to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(2-fluoropyridin-4-yl)phenyl)acetamide 177 as off-white solid. MS m/z 450.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.51 (s, 1H), 8.40 (d, 1H), 7.97 (d, 1H), 7.87 (d, 1H), 7.78 (d, 1H), 7.76 (d, 2H), 7.69 (dd, 1H), 7.43 (d, 2H), 7.37 (dd, 1H), 3.68 (s, 2H), 3.52 (m, 4H), 3.09 (t, 2H), 3.02 (t, 2H), 1.97 (s, 3H).
Reaction SMILES: C(O)(=O)C.O.[I:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[C:9]([N+:15]([O-])=O)[CH:8]=1>[Fe].C(O)C>[I:6][C:7]1[CH:8]=[C:9]([NH2:15])[C:10]([NH:13][CH3:14])=[CH:11][CH:12]=1
Reactant: CNc1ccc(I)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CNc1ccc(I)cc1N
Temperature: 70 °C
Yield: 89.7 %

Procedure:
A mixture of an iron powder (1.7 g), acetic acid (2.2 ml), ethanol (80 ml), and water (25 ml) was stirred at 70° C. To the reaction mixture was added dropwise a mixture of (4-iodo-2-nitro-phenyl)-methyl-amine (2.0 g) and ethanol (20 ml). After that, the mixturee was stirred at 70° C. for 6 hours. Then, the reaction mixture was filtrated and thoroughly washed with THF. The resulting filtrate was concentrated under reduced pressure. To the resulting residue was poured saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 4-iodo-N1-methyl-benzene-1,2-diamine (1.6 g)
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:21][CH:20]=2)[N:13]=1>N1C=CC=CC=1>[C:1]([O:18][C:17]1[C:12]([F:11])=[N:13][C:14]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:21][CH:20]=2)=[CH:15][CH:16]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)Cl
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)c(F)n2)cc1
Solvent: c1ccncc1
Product: CCCCCCCCOc1ccc(-c2ccc(OC(=O)CCCCCCC)c(F)n2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.3 %

Procedure:
1.2 ml (7.1 mmol) of octanoyl chloride are added dropwise at 0° C. to 1.5 g (4.7 mmol) of 2-fluoro-3-hydroxy-6-(4-octyloxyphenyl)pyridine (prepared as described in Example 3) in 20 ml of pyridine, and the mixture is stirred at 0° C. for 3 hours. It is then poured onto ice water, filtered off and the residue is purified by chromatography (silica gel, 9:1 hexane/ethyl acetate) and by recrystallization from acetonitrile, giving 1.34 g of 2-fluoro-6-(4-octyloxyphenyl)pyridine-3-yl octanoate. ##STR20##
Reaction SMILES: Cl.O[CH2:3][C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][N:5]=1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH2:3][C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][N:5]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1nccc2c1CCCC2
Agent: Cl
Solvent: ClC(Cl)Cl
Product: ClCc1nccc2c1CCCC2
Temperature: 50 °C

Procedure:
To a solution of l-hydroxymethyl-5,6,7,8-tetrahydroisoquinoline hydrochloride (0.42 g) in chloroform (10 ml) was added dropwise a solution of thionyl chloride (1.1 ml) in chloroform (5 ml) at room temperature and heated for 2 hours at ca. 50° C. The reaction mixture was concentrated in vacuo and the residue was taken up with ethyl acetate. The organic layer was washed with saturated sodium carbonate aqueous solution, dried over sodium sulfate, filtered and concentrated in vacuo to give 1-chloromethyl-5,6,7,8-tetrahydroisoquinoline (0.22 g) as a brown oil.
Reaction SMILES: FC(F)(F)C(O)=O.[BH4-].[Na+].[Cl:10][C:11]1[C:24]([C:25](=O)[C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[CH:23][C:14]2[CH2:15][CH:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:17][C:13]=2[C:12]=1[Cl:34]>C(Cl)Cl>[Cl:10][C:11]1[C:24]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=2)=[CH:23][C:14]2[CH2:15][CH:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:17][C:13]=2[C:12]=1[Cl:34]
Reactant: CCOC(=O)C1Cc2cc(C(=O)c3ccc(O)cc3)c(Cl)c(Cl)c2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1Cc2cc(Cc3ccc(O)cc3)c(Cl)c(Cl)c2O1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To trifluoroacetic acid (120 ml.) under a nitrogen atmosphere were added sodium borohydride pellets (5.39 g.) over a period of 30 minutes at 5° C. A solution of ethyl 6,7-dichloro-2,3-dihydro-5-(p-hydroxybenzoyl)-benzofuran-2-carboxylate (7.35 g.) in methylene chloride (50 ml.) was then added dropwise over 30 minutes, and the mixture stirred at room temperature for 22 hours.
Reaction SMILES: C[N:2]([CH3:21])[CH:3]=[C:4]([C:10](=[O:20])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1F)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:22](OCC)[CH3:23].C1(N)CC1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH:21]1([N:2]2[C:12]3[C:11](=[CH:16][C:15]([F:17])=[C:14]([F:18])[CH:13]=3)[C:10](=[O:20])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3]2)[CH2:23][CH2:22]1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)cc1F
Reactant: CCOCC
Agent: NC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A solution of ethyl 3-(dimethylamino)-2-(2,4,5-trifluorobenzoyl)acrylate (Example 48a) (75 g, 249 mmol) in a mixture of Ethanol (100 mL)/Diethyl ether (200 mL) was added to cyclopropanamine (34.5 mL, 498 mmol). After 2 h of stirring at rt, LCMS showed complete disappearance of starting material. The reaction mixture was evaporated under reduced pressure, the oily residue was dissolved in N,N-Dimethylformamide (DMF) (250 mL) and potassium carbonate (103 g, 747 mmol) was then added. The reaction mixture was stirred at 100° C. for 2 h, and LCMS showed completion of reaction. Cold water was added to the mixture. The precipitates were collected by filtration and dried to afford ethyl 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (71 g, 242 mmol, 97% yield) as a pale yellow solid. LCMS: [M+H]+: 294.1.