Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH:6]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:12])[C:7](O)=[O:8].CCN(CC)CC.ClC(OCC)=O.[BH4-].[Na+].Cl>C1COCC1.CO>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH:6]([NH:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:17][CH:18]=1)=[O:12])[CH2:7][OH:8]
Reactant: COC(=O)CCC(NC(=O)c1ccc(-c2ccccc2)cc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCC(CO)NC(=O)c1ccc(-c2ccccc2)cc1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 30.8 %

Procedure:
2-[(Biphenyl-4-carbonyl)-amino]-pentanedioic acid 5-methyl ester (1.128 g, 3.30 mmol, 1.0 equiv.) was dissolved in THF (35 mL). The mixture was cooled to −20° C., followed by the addition of Et3N (343 mg, 3.3 mmol, 1.0 equiv.) and ethyl chloroformate (358 mg, 3.3 mmol, 1.0 equiv.). After stirring for 20 minutes, NaBH4 (375 mg, 9.9 mmol, 3 equiv.) was added and the temperature was raised to −10° C. After stirring for 5 min, MeOH (30 mL) was introduced and the mixture was further stirred for 20 min at this temperature and then at 0° C. for 20 min. 1N HCl was then added slowly to quench the reaction. Solvent was evaporated and the residue partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over MgSO4, and removed solvent by rotavap. The crude mixture was then purified by column chromatography (silica gel, 3% MeOH/CH2Cl2) to afford 333 mg of 4-[(Biphenyl-4-carbonyl)-amino]-5-hydroxy-pentanoic acid methyl ester in 31% yield. MS (ESI) m/z 328.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)Cc1ccc(Br)cc1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc(Br)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-Bromophenyl)propan-2-one (2.03 g) was dissolved in CHCl3 (40 mL), and morpholine (1.24 mL) was added thereto, followed by stirring at room temperature overnight and then at 60° C. for 4 hours. NaBH(OAc)3 (4.03 g) and acetic acid (1.1 mL) were sequentially added thereto, followed by stirring overnight. The reaction was terminated by addition of water, and the reaction solution was separated between CHCl3 and a saturated aqueous NaHCO3 solution. The residue was purified by silica gel column chromatography (mobile phase: CHCl3/EtOAc=80/20 to 60/40 (v/v)) to yield the title compound (1.67 g, colorless oil).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH3:29])=[CH:5][CH2:6][O:7][C:8]1[C:17]([C:18](=[O:20])[CH3:19])=[C:16]2[C:11]([C:12](=[O:28])[C:13]([CH3:27])=[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:15]2)=[CH:10][CH:9]=1.[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1>C(O)C.O>[CH3:27][C:13]1[C:12](=[O:28])[C:11]2[C:16](=[C:17]([C:18](=[O:20])[CH:19]=[CH:35][C:34]3[CH:37]=[CH:38][C:31]([Cl:30])=[CH:32][CH:33]=3)[C:8]([O:7][CH2:6][CH:5]=[C:4]([CH3:29])[CH3:3])=[CH:9][CH:10]=2)[O:15][C:14]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)c1c(OCC=C(C)C)ccc2c(=O)c(C)c(-c3ccccc3)oc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)=CCOc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(=O)C=Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 52.2 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 7-(3-methylbut-2-enyloxy)-8-acetyl-3-methylflavone (2.71 g, 0.0075 mol) and 4-chloro-benzaldehyde (1.05 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 1.9 g product m.p. 130-133° C., 1H-NMR (CDCl3) δ:1.69 (s, 3H), 1.72 (s, 3H), 2.19 (s, 3H), 4.65 (d. 2H), 5.31 (m, 1H), 6.97-8.42 (m, 13H).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[O:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])o1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(N)o1
Reaction time: 18 h
Yield: 52.2 %

Procedure:
A mixture of methyl 5-nitro-2-furoate (13 g, 76 mmol) and 10% Pd/C (1.3 g) in ethanol (150 mL) was shaken under an atmosphere of hydrogen at 40 psi for 18 h. The reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure to afford a crude oil. Purification by flash column chromatography (silica, 1:1 hexanes/ethyl acetate) provided methyl 5-amino-2-furoate (5.6 g): 1H NMR (500 MHz, CDCl3) δ 7.11–7.10 (m, 1H), 5.31–5.29 (m, 1H), 4.31 (br s, 2H), 3.84 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[C:4]([CH3:16])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][C:25]2[CH:38]=[CH:37][C:28]3[C@H:29]([CH2:32][C:33]([O:35]C)=[O:34])[CH2:30][O:31][C:27]=3[CH:26]=2)[CH:18]=1.CO.[OH-].[Na+].Cl>O.O1CCCC1>[CH3:16][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][C:25]2[CH:38]=[CH:37][C:28]3[C@H:29]([CH2:32][C:33]([OH:35])=[O:34])[CH2:30][O:31][C:27]=3[CH:26]=2)[CH:18]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OCCCS(C)(=O)=O)cc4C)c3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a solution of methyl [(3S)-6-({2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetate (0.438 g, 0.813 mmol) in a mixed solvent of methanol (2 mL) and tetrahydrofuran (4 mL) was added 2 M aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was diluted with water, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were recrystallized from heptane-ethyl acetate to give the title compound (0.377 g, yield 88%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:23]([O:30][C@H:31]1[CH2:35][N:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C@H:33]([CH2:41][CH2:42]Cl)[CH2:32]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C(=O)C>[CH2:39]([O:38][C:36]([N:34]1[CH2:35][C@H:31]([O:30][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:32][C@H:33]1[CH2:41][CH2:42][O:8][C:7]1[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:37])[CH3:40]
Reactant: CCOC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1CCCl
Reactant: Cc1cccc(CCc2ccccc2)c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1CCOc1c(C)cccc1CCc1ccccc1
Yield: 90.3 %

Procedure:
1200 mg of 6-methyl-2-(2-phenylethyl)phenol were dissolved in 10 ml of N,N-dimethylacetamide, allowed to react with 700 mg of potassium t-butoxide and 1600 mg of (2S,4R)-4-benzyloxy-2-(2-chloroethyl)-1-ethoxycarbonylpyrrolidine and extracted in the same manner as described in step (a) of Example 2. The resulting oily substance was purified by silica gel column chromatography, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2260 mg (yield 90%) of the title compound as an oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:22]([C:25]1[CH:34]=[C:33]2[C:28]([CH2:29][CH2:30][NH:31][CH2:32]2)=[CH:27][CH:26]=1)([O-:24])=[O:23].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[CH2:10][C:11]([N:31]1[CH2:30][CH2:29][C:28]2[C:33](=[CH:34][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)[CH2:32]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccccc1F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCc2ccc([N+](=O)[O-])cc2C1)Cc1ccccc1F

Procedure:
(3R)-3-[(tert-Butoxycarbonyl)amino]4-(2-fluorophenyl)butanoic acid (0.69 g; 2.34 mmol) and 7-nitro-1,2,3,4 tetrahydroisoquinoline (0.50 g; 2.34 mmol) were treated with EDC (0.54 g, 2.8 mmol), HOBt (0.38 g, 2.8 mmol) and N,N-diisopropylethylamine (0.60 g, 4.67 mmol) essentially following the procedure outlined in Example 1, Step A. Purification by flash chromatography (silica gel; 35% ethyl acetate/hexanes as eluant) afforded the title compound. LC/MS: 358.1 (M+1-BOC)
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][C:18]=1[C:32]1[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:3]3[C:8](=[N:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:19][C:18]=1[C:32]1[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Product: N#Cc1ccccc1-c1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Yield: 66 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (prepared as described in Example 2, steps a) to e), 90 mg, 0.28 mmol) as described in Example 7 part g), affording 2′-fluoro-5′-(7-trifluoromethyl[1,8]naphthyridin-4-yl)biphenyl-2-carbonitrile (56 mg, 66%). δH (360 MHz, CDCl3) 7.47 (1H, t, J 9.3), 7.53-7.62 (5H, m), 7.71 (1H, td, J, 7.7 and 1.4), 7.85 (1H, dd, J 7.7 and 0.7), 7.88 (1H, d, J 8.4), 8.71 (1H, d, J 8.8), 9.28 (1H, d, J 4.6). m/z (ES+) 394 [MH]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:13]1([N:18]=[C:19]=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]1>CC(C)=O.C(N(CC)CC)C>[CH:13]1([NH:18][C:19]([NH:1][CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=C=NC1CCCC1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(NCCc1c[nH]c2ccccc12)NC1CCCC1
Yield: 34.7 %

Procedure:
Tryptamine (1.04 g, 6.5 mmol) was dissolved in a mixture of acetone (20 ml) and triethylamine (1 ml) under a nitrogen atmosphere. Cyclopentyl isocyanate (795 mg, 7.15 mmol, 0.81 ml) was swiftly added dropwise at 0° C. and the mixture was then subsequently stirred for 2H, while cooling with ice, and at RT overnight. A white solid had precipitated out of the solution, and was filtered off with suction and rinsed with acetone. It was 641 mg of pure product. The filtrate was concentrated i. vac. and the residue was then stirred thoroughly with acetone (10 ml). The undissolved white solid was filtered off with suction and rinsed with acetone, and a further 612 mg of pure product were obtained in this way.
Reaction SMILES: [Cl-].[Li+].Cl[C:4]1[CH:9]=[C:8]([C:10]2[C:11]3[N:12]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:13]=[C:14]([CH3:25])[C:15]=2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:7]=[CH:6][N:5]=1.[CH2:31]([Sn](CCCC)(CCCC)C=C)[CH2:32]CC.[F-].[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.O>[CH2:29]([C:26]1[N:12]2[N:13]=[C:14]([CH3:25])[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:10]([C:8]3[CH:7]=[CH:6][N:5]=[C:4]([CH:31]=[CH2:32])[CH:9]=3)[C:11]2=[CH:28][CH:27]=1)[CH3:30]
Reactant: CCOC(=O)CCCCc1c(C)nn2c(CC)ccc2c1-c1ccnc(Cl)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cc(-c2c(CCCCC(=O)OCC)c(C)nn3c(CC)ccc23)ccn1
Reaction time: 4 h
Yield: 28.3 %

Procedure:
To lithium chloride (16.5 mg) was added a solution of ethyl 5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (65 mg) and tributyl(vinyl)stannane (56.7 mg) in dioxane (1 mL) and tetrakis(triphenylphosphine)palladium(0) (1.9 mg). The mixture was refluxed. After 4 hours, tributyl(vinyl)stannane (50 mg) and tetrakis(triphenylphosphine)palladium(0) (1.9 mg) was added. After refluxed over night, the reaction mixture was quenched with potassium fluoride (1.8 mmol) in H2O. The mixture was filtered through Celite and was washed with ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 50 mL) eluted with hexane-ethyl acetate=5-1 and 3-1 to give ethyl 5-[7-ethyl-2-methyl-4-(2-vinyl-4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (18 mg, 28.3%) as an yellow oil.
Reaction SMILES: [Cl-].[Li+].C(N([CH2:8][CH3:9])CC)C.[CH3:10][C:11]([CH3:26])([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[CH:12]=O.[Cl-].[NH4+]>C(#N)C.O.CCOCC>[CH3:10][C:11]([CH3:26])([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)/[CH:12]=[CH:25]/[C:20]([O:21][CH2:8][CH3:9])=[O:19]
Reactant: CC(C)(C=O)CCCCCOC1CCCCO1
Reactant: CCN(CC)CC
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: CCOC(=O)/C=C/C(C)(C)CCCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of triethyl phosphonoacetate (1.62 mL) in acetonitrile (8 mL) was treated with lithium chloride (0.43 g) and then cooled to 0° C. and triethylamine (1.23 mL) added dropwise as a solution in acetonitrile (2.5 mL). The reaction mixture was stirred at 0° C. for 15 minutes then a solution of 2,2-dimethyl-7-(tetrahydro-pyran-2-yloxy)-heptanal (1.65 g) in acetonitrile (6 mL) was added. The resultant mixture was allowed to warm to room temperature and was stirred for 3 hours before treating with saturated aqueous ammonium chloride solution, ether and water. The layers were separated and the aqueous phase was extracted with ether (×2) and the combined organics were washed with brine, dried over magnesium sulphate, filtered and evaporated to afford the crude product. Purification was by silica gel chromatography eluting with 0 to 40% ethyl acetate in cyclohexane to afford the subtitled compound as a colourless oil. Yield 0.89 g.
Reaction SMILES: [CH2:1]([OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:24](O)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([O:23][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCCCCCCCCCCCCCCCCCCCCCO
Reactant: O=C(O)c1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCCCOC(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 106.5 gms. (0.326 moles) of behenyl alcohol, 43.5 gms. (0.343 moles) of benzoic acid and 225 mgms. stannous oxalate was heated to 230° C. under nitrogen. The reaction was held at 230° C. for two hours, and the distillate collected. It was then cooled to 100° C. The acidity was 10.0 mg KOH/gm. The ester was then given a treatment for 30 minutes at 85° C. with 50 gms. deionized water, 2 gms. sodium carbonate, 2 gms. sodium chloride, and 1 gm. hydrogen peroxide. It was then allowed to stand and the lower aqueous layer drained off. The top layer was washed with 50 gms. water at 80°-85° C. and then separated. The solid was then vacuum stripped at 100°-105° C. to remove residual moisture. The final product was a solid benzoate ester having the following formula: ##STR14##
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][CH3:13].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl.CC(C)=O.C(Cl)Cl>[CH2:11]([NH:10][C:7]([CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1)=[O:9])[CH2:12][CH3:13]
Reactant: CCCN
Reactant: O=C(O)C1CC=CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCCNC(=O)C1CC=CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.7 %

Procedure:
Cyclohex-3-enecarboxylic acid (0.71 mmol, 90 mg), NH2CH2CH2CH3 (0.86 mmol, 70 μL) and EDC.HCl (0.86 mmol, 164 mg) were dissolved in CH2Cl2 (3 mL). DIEA (1.43 mmol, 252 μL) was added at 0° C., and the reaction was stirred for 16 h at rt. The usual workup and chromatography (Acetone/CH2Cl2/10:90) yielded N-propylcyclohex-3-enecarboxamide 26 as a white powder (65 mg, 55%). 1H NMR (400 MHz, CDCl3) δ 5.64 (m, 3H), 3.17 (dd, J=8 Hz, J=8 Hz, 2H), 2.30-1.93 (m, 5H), 1.87-1.81 (m, 1H), 1.72-1.59 (m, 1H), 1.43 (m, 2H), 0.87 (t, J=8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 175.93, 126.94, 125.61, 41.52, 41.22, 28.35, 25.97, 24.80, 23.07, 11.49.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:38]=O)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1.[Br:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[C:43]([F:48])[CH:42]=1.CC(O)=O>CCOC(C)=O.ClCCCl>[Br:40][C:41]1[CH:47]=[CH:46][C:44]([NH:45][CH2:38][C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][C:20]=2[C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)=[C:43]([F:48])[CH:42]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C=O)cn1
Reactant: Nc1ccc(Br)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(Br)cc2F)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (623 mg, 2.9 mmol) was added to a DCE solution (3 mL) of ethyl 3-(5-(5-chloro-2-formylphenyl)picolinamido)propanoate, prepared as describe in Example 6, (530 mg, 1.5 mmol), 4-bromo-2-fluoroaniline (293 g, 1.5 mmol), and AcOH (0.34 mL, 5.9 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:25]=[CH:24][CH:23]=3)=[N:14]2)=[C:9]([F:33])[CH:8]=1)(=O)=O.Cl.[F:37][C:38]1([F:44])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC([O-])(C)C.[Na+]>O1CCOCC1.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].O>[F:37][C:38]1([F:44])[CH2:43][CH2:42][N:41]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16](=[O:21])[C:15]([C:22]4[N:26]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:25]=[CH:24][CH:23]=4)=[N:14]3)=[C:9]([F:33])[CH:8]=2)[CH2:40][CH2:39]1
Reactant: FC1(F)CCNCC1
Reactant: COc1cn(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: O
Product: COc1cn(-c2ccc(N3CCC(F)(F)CC3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 24.9 %

Procedure:
A suspension of 3-fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl trifluoromethanesulfonate (408 mg, 0.8 mmol), 4,4-difluoropiperidine hydrochloride (158 mg, 1.0 mmol), Pd2(dba)3 (36.6 mg, 0.04 mmol), Xantphos (92.6 mg, 0.16 mmol), and NaOtBu (192 mg, 2.0 mmol) in 1,4-dioxane (4 mL) was stirred for 3 h at 90° C. under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane/AcOEt (1/2-0/1) and crystallized from hexane/AcOEt to give the title compound (96.0 mg, 25% yield) as a yellow-green solid: mp 192-194° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.01-2.14 (4H, m), 3.38-3.42 (4H, m), 3.89 (3H, s), 6.31 (1H, t, J=9.0 Hz), 6.47 (1H, dd, J=2.3, 9.0 Hz), 6.61 (1H, dd, J=2.6, 14.3 Hz), 7.25 (1H, d, J=1.9 Hz), 7.34-7.45 (5H, m), 7.73 (1H, d, J=2.3 Hz), 7.77 (1H, d, J=2.3 Hz). LC-MS (ESI) m/z 482 [M+H]+. Anal. Calcd for C25H22F3N5O2: C, 62.36; H, 4.61; N, 14.55. Found: C, 62.13; H, 4.62; N, 14.43.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][OH:10])#[CH:2].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[C:13]=1[CH3:19]>C1COCC1.[Cu]I.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>[Br:11][C:12]1[C:13]([CH3:19])=[C:14]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:9][OH:10])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1c(Br)cccc1Br
Reactant: C#Cc1ccccc1CO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1C#Cc1ccccc1CO
Temperature: 60 °C
Yield: 57 %

Procedure:
Step 1 A mixture of (2-ethynylphenyl)methanol (100 mg, 0.757 mmol), 1,3-dibromo-2-methylbenzene (189 mg, 0.757 mmol) and TEA (0.211 mL, 1.513 mmol) in THF (2 mL) was purged with nitrogen and treated with copper (I) iodide (2.88 mg, 0.015 mmol) and bis(triphenylphosphine)palladium(II) chloride (26.6 mg, 0.038 mmol). The mixture was heated in a sealed tube at 60° C. for 1.5 h. The mixture was filtered, the filtrate was washed with NaHCO3 (aq) and water, and dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc) to provide (2-((3-bromo-2-methylphenyl)ethynyl)phenyl)methanol as a white solid (130 mg, 57%). 1H NMR (400 MHz, chloroform-d) δ 7.44-7.58 (4H, m), 7.39 (1H, td, J=7.54, 1.43 Hz), 7.27-7.34 (1H, m), 7.00-7.09 (1H, m), 4.93 (2H, d, J=6.38 Hz), 2.64 (3H, s). Mass spectrum m/z 323, 325 (M+Na)+.
Reaction SMILES: [CH:1]1([CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:3][CH2:2]1.[C:19]([N:27]=C=O)(=[O:26])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH:1]1([CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:19]([NH2:27])=[O:26])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Nc1cc(CC(c2ccccc2)C2CC2)ccn1
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: NC(=O)Nc1cc(CC(c2ccccc2)C2CC2)ccn1
Temperature: 50 °C
Yield: 9.7 %

Procedure:
The crude 4-(2-cyclopropyl-2-phenyl-ethyl)-pyridin-2-ylamine (70 mg) is dissolved in methylene chloride (2 mL). Then benzoyl isocynate (86 mg, 0.59 mmol) is added. The reaction mixture is sealed and heated at 50° C. for 16 hour. The solvent is then carefully removed and to the residue are added ethanol (2 mL) and potassium carbonate (61 mg, 0.44 mmol). The resulting mixture is heated at 85° C. for 45 min. Then solvent is removed and the residue is partitioned between water (35 mL) and EtOAc (55 mL). The aqueous layer is separated and extracted with EtOAc (2×40 mL). The organic layers are combined and concentrated to give the crude product. Purification by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) followed by Gilson preparative HPLC affords 8 mg of the titled product.