Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4].Br[C:31]1[CH:32]=[CH:33][C:34]([CH:37]([NH:41][S:42]([C:44]([CH3:47])([CH3:46])[CH3:45])=[O:43])[CH2:38][C:39]#[N:40])=[N:35][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[C:39]([CH2:38][CH:37]([NH:41][S:42]([C:44]([CH3:47])([CH3:46])[CH3:45])=[O:43])[C:34]1[CH:33]=[CH:32][C:31]([C:15]2[CH:16]=[CH:17][C:12]([C@H:8]3[O:7][C:6]([CH3:27])([CH3:28])[N:5]([C:3](=[O:4])[CH:2]([F:1])[F:29])[C@@H:9]3[CH2:10][F:11])=[CH:13][CH:14]=2)=[CH:36][N:35]=1)#[N:40]
Reactant: CC1(C)O[C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CF)N1C(=O)C(F)F
Reactant: CC(C)(C)S(=O)NC(CC#N)c1ccc(Br)cn1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)O[C@H](c2ccc(-c3ccc(C(CC#N)NS(=O)C(C)(C)C)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Temperature: 80 °C
Yield: 51.6 %

Procedure:
To a stirred solution of 2,2-Difluoro-1-{(4S,5R)-4-fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-3-yl}-ethanone (0.312 g, 0.758 mmol) and 2-Methyl-propane-2-sulfinic acid [1-(5-bromo-pyridin-2-yl)-2-cyano-ethyl]-amide (0.25 g, 0.758 mmol) in toluene:Ethanol:water (10:10:10 mL) is added Na2CO3 (0.16 g, 1.515 mmol) at room temperature. Resulting reaction mixture is degassed with nitrogen for 15 minutes followed by addition of Pd(PPh3)4 (0.087 g, 0.076 mmol). Resulting reaction mixture is heated to 80° C. for 3 hours. Solvent is evaporated in vacuo then diluted with water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combi-flash chromatography using 50% ethyl acetate in hexane to afford the title compound (0.21 g): 1H-NMR (400 MHz, DMSO-d6) δ: 1.19 (s, 9H), 1.53 (s, 3H), 1.60 (S, 3H), 2.98-3.04 (m, 1H), 3.17-3.22 (m, 1H), 4.54-4.58 (m, 0.5H), 4.66-4.70 (m, 1H), 4.78-4.84 (m, 1.5H), 4.89-4.95 (m, 1H), 5.26-5.27 (m, 1H), 6.12 (d, J=9 Hz, 1H), 6.64 (t, J=52.4 Hz, 1H), 7.53-7.64 (m, 2H), 7.76 (d, J=8.2 Hz, 1H), 7.82 (d, J=8.12 Hz, 2H), 8.89 (d, J=1.84 Hz, 1H), 8.86 (d, J=2.08 Hz, 1H). LC-MS (m/z): [M+H]=537.2.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].CCN=C=NCCCN(C)C.C1[CH:40]=[C:39]2[N:41]=NN(O)[C:38]2=CC=1.O.CCN(C(C)C)C(C)C.CC(N)C.Cl>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:41][CH:39]([CH3:40])[CH3:38])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Solvent: O
Product: CC(C)NC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
Combined 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (100 mg, 0.327 mmol), EDCI (94 mg, 0.490 mmol), HOBT hydrate (75 mg, 0.490 mmol) in DMF (1 mL) and then add Hunig's base (127 mg, 0.980 mmol). Then propan-2-amine (28.9 mg, 0.490 mmol) was added and the mixture was stirred at ambient temperature for 16 h. The mixture was diluted with water (4 mL) and acidified with 1N HCl to pH=5-6 to give a solid. The solid was collected by filtration, washed with water (2 mL), and recrystallized from hot MeOH (3-6 mL) to give the title compound (62.0 mg, 54.7% yield) as an off-white solid. MS m/z [M+H]+ 348.
Reaction SMILES: [Cl:1][C:2]1[N: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][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:18][CH:17]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:27].[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[N: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][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:20][CH:21]=2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(CCN(C)C)cc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(CCN(C)C)cc1
Yield: 39.9 %

Procedure:
Following general procedure II, 1-(6-chloro-4-{4-[2-(dimethylamino)ethyl]phenylamino}-1,5-naphthyridin-3-yl)ethanone (40 mg, 0.11 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.15 mmol) followed by formation of the dihydrochloride salt to afford the desired product (17 mg, 28%) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 9.30 (s, 1H), 8.43 (d, J=9.0 Hz, 1H), 8.33 (d, J=9.0 Hz, 1H), 7.52 (br s, 2H), 7.42 (d, J=8.5 Hz, 2 H), 7.37 (d, J=8.5 Hz, 2H), 3.40-3.32 (m, 2H), 3.22-3.13 (m, 2H), 2.96 (s, 6H), 2.79 (s, 3H); ESI MS m/z 495 [M+H]+; HPLC>99% (AUC), tR=9.91 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Cl.[CH3:14]O>>[CH3:14][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccc(O)c(Cl)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 3-chloro-4-hydroxyphenyl acetic acid (20 mmol) in methanol (50 mL) was added concentrated HCl solution (5 mL), and stirred for 1 h at 50° C. After excess solvents were removed under vacuum, the residue was dissolved in EtOAc (50 mL) and washed with sat. NaHCO3 solution (2×30 mL), brine (30 mL) and dried over anhydrous Na2SO4. This afforded methyl 3-chloro-4-hydroxy acetate 3 as a colorless oil (4.0 g, 99%). 1H NMR (CDCl3) 6.9–7.0 (d, 1H), 6.8–6.9 (d, 1H), 5.4 (s, 1H), 3.6 (s, 3H), 3.4 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([O:26][CH3:27])[O:24][CH3:25])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:3]=1.[O:28]1[CH2:33][CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:8]([C:7]1[C:2]([C:31]2[CH2:32][CH2:33][O:28][CH2:29][CH:30]=2)=[CH:3][C:4]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([O:26][CH3:27])[O:24][CH3:25])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:5][CH:6]=1)#[N:9]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(Cl)c(C#N)cn1)CCC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(C3=CCOCC3)c(C#N)cn1)CCC2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
N-(4-chloro-5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2J, 60 mg, 0.155 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (65.0 mg, 0.309 mmol), PdCl2(PPh3)2 (10.9 mg, 0.015 mmol), Na2CO3 (2 M in water, 0.232 ml, 0.464 mmol) and DME (2 ml) were charged into a sealed vial under argon. The mixture was stirred at 100° C. for 1 h, cooled to room temperature, diluted in EtOAc and washed with sat. aq. NaHCO3 (2×) and brine. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) the product fractions were concentrated to give the title compound as a white solid. (UPLC-MS 3) tR 1.19 min; ESI-MS 436.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>O1CCCC1.CN(C)C=O>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:24]([NH:23][C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)=[O:25])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccnc(N)c2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccn1
Reaction time: 1 h

Procedure:
After dissolving 0.53 g of 2-amino-4-(4-aminophenoxy)pyridine in a mixture of 20 ml of tetrahydrofuran and 10 ml of dimethylformamide, 0.36 ml of p-fluorophenyl isocyanate was added and the mixture was stirred for 1 hour. NH type silica gel was added to the reaction solution, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (chloroform:methanol=20:1, followed by 10:1). The solvent was distilled off under reduced pressure to obtain 610 mg of the target substance as a white powder.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][N:10]=1.CS(Cl)(=O)=O.[F:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CN(C)C=O>[Cl:8][C:9]1[CH:14]=[C:13]([CH2:15][O:16][C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[CH:12]=[CH:11][N:10]=1
Reactant: OCc1ccnc(Cl)c1
Reactant: Oc1ccc(F)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Fc1ccc(OCc2ccnc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
Triethylamine (1.2 mL, 8.4 mmols) was added to a mixture of (2-chloro-4-pyridinyl)methanol (1.0 g, 7.0 mmols), methanesulfonyl chloride (0.6 mL, 7.7 mmols) and ethyl acetate (20 mL) under cooling with ice, and stirred at room temperature for 2 hours. Filtering the reaction liquid, the filtrate was concentrated. To the resulting residue, 4-fluorophenol (0.94 g, 8.4 mmols), potassium carbonate (1.93 g, 14.0 mmols) and N,N-dimethylformamide (20 mL) were added and s at 80° C. for 20 hours. Cooling the reaction liquid to room temperature, ethyl acetate was added thereto, followed by washing with saturated aqueous sodium hydrogencarbonate solution and saturated brine and drying over anhydrous sodium sulfate. Concentrating the solvent under reduced pressure, the residue was purified on silica gel column chromatography (KP-Sil, FLASH 40+M, chloroform) to provide the title compound (845 mg, 51%).
Reaction SMILES: [Br:1][C:2]1[C:3]([I:11])=[C:4]([OH:10])[C:5]([I:9])=[CH:6][C:7]=1[I:8].[F:12][C:13]([F:24])([C:17]([F:23])([Br:22])[C:18]([F:21])([F:20])[Br:19])[C:14](Cl)=[O:15]>N1C=CC=CC=1>[I:11][C:3]1[C:2]([Br:1])=[C:7]([I:8])[CH:6]=[C:5]([I:9])[C:4]=1[O:10][C:14](=[O:15])[C:13]([F:12])([F:24])[C:17]([F:23])([Br:22])[C:18]([F:21])([F:20])[Br:19]
Reactant: Oc1c(I)cc(I)c(Br)c1I
Reactant: O=C(Cl)C(F)(F)C(F)(Br)C(F)(F)Br
Solvent: c1ccncc1
Product: O=C(Oc1c(I)cc(I)c(Br)c1I)C(F)(F)C(F)(Br)C(F)(F)Br

Procedure:
20.3 grams of 3-bromo-2,4,6-triiodophenol (m.p. 155°-157° C.) were dissolved in 50 ml of pyridine 13.0 grams of 2,2,3,4,4-pentafluoro-3,4-dibromo-butyryl chloride were added dropwise through a dropping funnel with stirring. The mixture was stirred overnight at room temperature. The mixture was washed in a separatory funnel twice with 250 ml of DI water, then filtered through a column of silica and the solvent evaporated. The material was then chromatographed on a column of silica using FREON 113 (trichlorotrifluroethane) as eluent. The sample (25 grams), which slowly crystallized at room temperature, was shown to be pure ester (97%) by gc/ms. It is suitable for use as a fluid above its melting point of 56-57° C. m/e (chemical ionization) 129 (21%, CF2Br); 131 (100, CF2Br and C3F5); 140 (13%, C5HBr); 142 (13%, C5HBr); 188 (14%, C5HI); 267, 269 (11%, 10% C5BrIH); 315 (4%, C5I2H); 422, 424 (6%, 7%, C6I2HBrO); 549, 551 (5%, 4%, C6I3HBrO); 866, 868, 870, 872 (0.2%, 0.6%, 0.4%, 0.2%, molecular ion). I.R.(ν, in cm-1)=3080 (Ar--H); 1800 (C=O); 1550, 1520 (Ar C=C).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:17][CH2:16]3)[N:10]=2)=[CH:5][CH:4]=1.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH:21]1([N:18]2[CH2:17][CH2:16][CH:15]([CH2:14][C:11]3[N:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][N:35]5[CH2:36][CH2:37][N:32]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)[CH2:33][CH2:34]5)=[CH:4][CH:5]=4)[O:13][N:12]=3)[CH2:20][CH2:19]2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: ClCc1ccc(-c2nc(CC3CCN(C4CCCC4)CC3)no2)cc1
Product: c1ccc(N2CCN(Cc3ccc(-c4nc(CC5CCN(C6CCCC6)CC5)no4)cc3)CC2)cc1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 23, starting from 4-[5-(4-chloromethylphenyl) [1,2,4]oxadiazol-3-ylmethyl]-1-cyclopentyl-piperidine and 1-phenylpiperazine.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:15][O:16][CH2:17][C:18]([NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O>C1(C)C(C)=CC=CC=1>[CH3:15][O:16][CH2:17][C:18]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][N:20]=1
Reactant: COCC(=O)NCCc1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Product: COCC1=NCCc2ccccc21

Procedure:
Phosphorous pentoxide (25 g, 0.176 mol) was added to a stirred solution of the product from (a) above (14.47 g, 0.075 mol) in xylene (35 ml) and the resulting mixture heated under reflux for 2.5 hours. The solvent was decanted from the resulting black gum which was triturated with xylene and then, when cool, with ether. Water was then carefully added, with ice-cooling, and the resulting mixture basified with 2M aqueous sodium hydroxide solution and then extracted with ether. The extract was washed with water, dried (MgSO4) and evaporated under reduced pressure to give a brown oil (13.4 g) which was purified by chromatography on silica gel, using ether as eluent, to afford the required compound (5.88 g) as an orange oil. Rf 0.28 (SS 2).
Reaction SMILES: [Br-].[F:2][C:3]([F:31])([F:30])[C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.O=[C:38]1[CH2:43][CH2:42][N:41]([C:44]2[CH:54]=[CH:53][C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=2)[CH2:40][CH2:39]1>C1COCC1>[F:31][C:3]([F:2])([F:30])[C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH:6]=[C:38]1[CH2:39][CH2:40][N:41]([C:44]2[CH:54]=[CH:53][C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=2)[CH2:42][CH2:43]1
Reactant: FC(F)(F)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ccc(N2CCC(=O)CC2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N2CCC(=Cc3ccccc3C(F)(F)F)CC2)cc1
Temperature: 25 °C

Procedure:
A suspension of 2-(trifluoromethyl)benzyl triphenylphosphonium bromide (prepared according to the procedure described in J. Chem. Soc. Perkin Trans. 11995, 18, 2293-2308) (0.737 g) in THF (10 mL) was treated with n-butyllithium (724 μL of a 1.6M solution in hexanes) at 0° C., treated with ethyl 4-(4-oxo-1-piperidinyl)benzoate (prepared according to the procedure described in Synthesis 1981, 606-608, 0.32 g), and gradually warmed to room temperature overnight. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NH4Cl and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were dried (MgSO4), filtered, and concentrated. The resulting residue was purified by silica gel chromatography eluting with 10% ethyl acetate in hexanes to give the desired product.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:16])[CH2:9][C:10](OC)([O:12][CH3:13])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OC(C)C)(C)C>[CH3:13][O:12]/[C:10](/[CH3:11])=[CH:9]\[C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:16]
Reactant: COC(C)(CC(=O)Nc1ccccc1)OC
Solvent: CC(C)OC(C)C
Product: CO/C(C)=C\C(=O)Nc1ccccc1
Temperature: 60 °C
Yield: 47.3 %

Procedure:
558 g of N-phenyl-3,3-dimethoxybutyramide were heated for 1 hour at 195° C at a vacuum of 60 mm Hg and after cooling to 60° C, it was added to 500 ml of isopropyl ether. The mixture was cooled and vacuum filtered to obtain 226 g of 3-methoxy-crotonanilide in the form of white crystals melting at 111--112° C.
Reaction SMILES: COC(C1C=CC(C(O)=O)=NC=1)=O.COC1N=CC(N)=CC=1.[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28]([NH:31][C:32]([C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40]C)=[O:39])=[CH:36][N:35]=2)=[O:33])=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28]([NH:31][C:32]([C:34]2[CH:43]=[CH:42][C:37]([C:38]([OH:40])=[O:39])=[CH:36][N:35]=2)=[O:33])=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(OC)nc2)nc1
Agent: COC(=O)c1ccc(C(=O)O)nc1
Agent: COc1ccc(N)cn1
Product: COc1ccc(NC(=O)c2ccc(C(=O)O)cn2)cn1

Procedure:
250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to 6-methoxypyridin-3-amine via Procedure G. Crude methyl 6-(6-methoxypyridin-3-ylcarbamoyl)nicotinate was hydrolyzed via Procedure M to yield 196 mg of 6-(6-methoxypyridin-3-ylcarbamoyl)nicotinic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(6-methoxypyridin-3-ylcarbamoyl)nicotinic acid via Procedure G. The crude product was recrystallized to yield pure N5-(4-chloro-3-(pyridin-2-yl)phenyl)-N2-(6-methoxypyridin-3-yl)pyridine-2,5-dicarboxamide. MS (Q1) 460 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][C:14]([OH:18])=[C:15]([Br:17])[CH:16]=[C:11]2[N:10]=[N:9]1.[CH3:19][N:20]1[C:24]([CH2:25]Cl)=[N:23][CH:22]=[N:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][C:14]([O:18][CH2:25][C:24]3[N:20]([CH3:19])[N:21]=[CH:22][N:23]=3)=[C:15]([Br:17])[CH:16]=[C:11]2[N:10]=[N:9]1
Reactant: Cn1ncnc1CCl
Reactant: Oc1nc2c(cc1Br)nnn2-c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nc2c(cc1Br)nnn2-c1ccccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.4 %

Procedure:
A mixture of 3-(2-fluorophenyl)-5-hydroxy-6-bromo-1,2,3-triazolo[4,5-b]pyridine (0.91 g, 2.94 mmol), 2-methyl-3-chloromethyl-1,2,4-triazole (0.46 g, 3.53 mmol) and caesium carbonate (1.40 g, 4.29 mmol) in dry DMF (15 ml) was stirred at room temperature under nitrogen for 18 h. The mixture was poured into water (150 ml) and extracted with ethyl acetate (2×100 ml). The extracts were dried (Na2SO4), filtered and concentrated. Flash column chromatography on silica gel, eluting with 4% methanol-dichloromethane, gave 3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-bromo-1,2,3-triazolo[4,5-b]pyridine (1.05 g, 88%) as a beige solid. δH (360 MHz; CDCl3) 3.96 (3H, s), 5.59 (2H, s), 7.37-7.43 (2H, m), 7.56-7.64 (1H, m), 7.68 (1H, dd, J=7 and 7), 7.87 (1H, s) and 8.62 (1H, s); m/z (ES+) 404, 406 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][N:5]([C:21](=[O:40])[C@H:22]([CH2:34][C:35]1[N:39]=[CH:38][NH:37][CH:36]=1)[NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1.O[Li].O>C1COCC1.O>[C:28]1([CH2:27][O:26][C:24]([NH:23][C@H:22]([C:21]([N:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:12]=2)[CH2:4][C:3]([OH:41])=[O:2])=[O:40])[CH2:34][C:35]2[N:39]=[CH:38][NH:37][CH:36]=2)=[O:25])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)CN(Cc1ccc(OCc2ccccc2)cc1)C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN(Cc1ccc(OCc2ccccc2)cc1)C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 110.6 %

Procedure:
To a solution of the ester from Step 2 (1.53 g, 2.75 mmol) in THF (15 mL) and H2O (5 mL) at 0° C. was added LiOH hydrate (0.14 g, 3.30 mmol) and the solution was stirred 5 hours at 0° C. The solution was concentrated, the residue taken up in H2O, and the pH was adjusted to 4-5 with 1N HCl. The resulting mixture was concentrated and dried in vacuo to afford 1.65 g of the title compound as a white solid;
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:50])[CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:37][CH:38]=[C:39]([CH2:41][O:42]C3CCCCO3)[N:40]=2)[CH:31]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]2[N:7]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]4[O:37][CH:38]=[C:39]([CH2:41][OH:42])[N:40]=4)[CH:31]=3)[CH2:28][C:27](=[O:50])[NH:20][C:9]=2[CH:10]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)co2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)co3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.16 g) (Example J8) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-2-yl]-phenyl]-propionic acid tert-butyl ester (0.22 g) (Example K11) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.10 g).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.C1(S([O-])(=O)=O)C=CC=CC=1>>[CH:1]1[CH:2]=[CH:3][C:4]([C@@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:5][CH:6]=1
Reactant: NC(C(=O)O)c1ccccc1
Agent: O=S(=O)([O-])c1ccccc1
Product: N[C@@H](C(=O)O)c1ccccc1

Procedure:
These objects are accomplished by a process wherein DL-α-phenylglycine in the form of a benzensulfonate salt is subjected to resolution to give the D-α-phenylglycine salt and the L-α-phenylglycine salt, the D-salt is purified and neutralized to give D-α-phenylglycine (salt free) and the L-salt is subjected to racemization and reused as a raw material in the processing sequence.
Reaction SMILES: [N:1]1([C:7](=[S:9])[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][CH2:11][C:12](=O)[CH2:13]Cl.C(=O)([O-])O.[Na+]>C(O)C>[Cl:10][CH2:11][C:12]1[N:8]=[C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[S:9][CH:13]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)N1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: ClCc1csc(N2CCCCC2)n1
Yield: 66.6 %

Procedure:
A mixture of piperidine-1-carbothioamide (1.0 g), 1,3-dichloro-2-propanone (0.91 g) and ethanol (30 mL) was heated under reflux for 1 hr. After concentration of the reaction mixture, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 1-(4-chloromethyl-1,3-thiazol-2-yl)piperidine as a colorless oil (1.00 g, yield 67%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).