Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([CH3:11])([CH3:10])[CH:4]([OH:9])[CH2:5][C:6]([OH:8])=[O:7])#[N:2].[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.Cl>CN(C=O)C.C1(C)C=CC=CC=1>[C:1]([C:3]([CH3:11])([CH3:10])[CH:4]([OH:9])[CH2:5][C:6]([O:8][CH3:12])=[O:7])#[N:2]
Reactant: CC(C)(C#N)C(O)CC(=O)O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COC(=O)CC(O)C(C)(C)C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
4-Cyano-3-hydroxy-4-methylpentanoic acid (7.7 g, 49 mmol) was dissolved in DMF (50 mL) and potassium carbonate (10.16 g, 73.5 mmol) was added. Dimethyl sulfate (8.03 g, 63.7 mmol) was dropwise added with vigorous stirring. The mixture was stirred at room temperature for 2 hr and toluene (50 mL) was added. 2N Aqueous hydrochloric acid solution (40 mL, 80 mmol) was dropwise added with vigorous stirring. After partitioning, a toluene layer was separated and an aqueous layer was extracted again with toluene (25 mL). The toluene layers were combined and concentrated under reduced pressure to give methyl 4-cyano-3-hydroxy-4-methylpentanoate (7.13 g, 41.6 mmol). The yield was 85% relative to 4-cyano-3-hydroxy-4-methylpentanoic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>N1C=CC=CC=1>[CH3:35][S:36]([O:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]3)=[CH:22][CH:21]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:17][CH2:16]2)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: Oc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCCN2)cc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCCN2)cc1
Reaction time: 5 h
Yield: 12.5 %

Procedure:
To a solution containing 2-(4-fluorophenyl)-1-{4-[(2-piperidyl)ethoxy]benzyl}-1,2,3,4-tetrahydroisoquinolin-6-ol (0.100 g, 0.2 mmol) in pyridine (0.4 ml) was added methyl sulfonyl chloride (25 μl, 0.32 mmol). After stirring for five hours, solvent was removed and the reaction was basified with aqueous sodium bicarbonate solution. The reaction was extracted with dichloromethane and concentrated. The product was purified by semipreparative HLPC (C-18 column, 10-100% acetonitrile/water with 0.1% trifluoroacetic acid). The acetonitrile was removed from the HPLC fractions containing the desired product. Ethyl acetate was added and the solution neutralized using saturated sodium bicarbonate. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound (0.0135 g, 13% yield): 1H NMR (CDCl3) 6.7-7.1 (m, 11H), 4.78 (t,1H), 4.1 (t, 3H), 3.45-3.62 (m, 2H), 2.62-3.18 (m, 8H), 2.58 (m, 4H), 1.63 (m, 4H), 1.43 (m, 2H); ES−MS (m/z) 539 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]3[N:14]=[CH:13][N:12]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17](B5OC(C)(C)C(C)(C)O5)[CH:16]=4)[C:9]3=[N:10][CH:11]=2)=[CH:2]1.Br[C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[C:33]#[N:34].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.ClCCl.CO.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:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]3[N:14]=[CH:13][N:12]([C:15]4[CH:16]=[C:17]([C:31]5[C:32]([C:33]#[N:34])=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH:18]=[CH:19][CH:20]=4)[C:9]3=[N:10][CH:11]=2)=[CH:2]1
Reactant: N#Cc1ccccc1Br
Reactant: CC1(C)OB(c2cccc(-n3cnc4cc(-c5ccoc5)cnc43)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccccc1-c1cccc(-n2cnc3cc(-c4ccoc4)cnc32)c1
Temperature: 80 °C
Yield: 39 %

Procedure:
A degassed mixture of crude 6-(furan-3-yl)-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-3H-imidazo[4,5-b]pyridine (85 mg), 2-bromobenzonitrile (54 mg, 0.3 mmol), tetrakis(triphenylphosphine)palladium(0) (10 mg) and potassium phosphate (85 mg, 0.4 mmol) in N,N-dimethylformamide (1.5 ml) was heated at 80° C. for 16 hours. The reaction was cooled to ambient temperature, diluted with dichloromethane (10 ml) and methanol (10 ml) and pre-adsorbed onto silica. Purification by silica gel chromatography eluting with dichloromethane/methanol/concentrated ammonia (96:3.5:0.5) furnished the title compound as a cream-coloured solid (31 mg). This was converted to its oxalate salt and crystallised from hot ethanol; δH (400 MHz, d6-DMSO) 7.16-7.17 (1H, m), 7.66 (1H, td, J 8 and 1), 7.70-7.72 (1H, m), 7.78-7.81 (3H, m), 7.87 (1H, td, J 8 and 1), 8.02 (1H, dd, J 8 and 1), 8.17-8.19 (1H, m), 8.25-8.26 (1H, m), 8.36 (1H, s), 8.51 (1H, d, J 2), 8.78 (1H, d, J 2), 9.02 (1H, s); m/z (ES+) 363 (M++H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[O:7][CH:8]=[CH:9][N:10]=1.[N+:11]([CH:14]=[C:15](SC)[S:16][CH3:17])([O-:13])=[O:12]>>[N+:11]([CH:14]=[C:15]([S:16][CH3:17])[NH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[O:7][CH:8]=[CH:9][N:10]=1)([O-:13])=[O:12]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCCSc1ncco1
Product: CSC(=C[N+](=O)[O-])NCCCSc1ncco1
Yield: 63 %

Procedure:
Hydrochloric acid (90 ml) was added to potassium thiocyanate in ethanol (1.8 1.) with stirring. Following filtration from inorganic material, glycollaldehyde (35.9 g) was added and the resulting solution was heated under reflux for 24 hours. Concentration, followed by cooling afforded a white solid, which following recrystallisation from ethanol afforded oxazole-2-thiol (30 g), m.p. 143°-144°. (ii) 3-Bromopropylphthalimide (13.4g) was added to a stirred solution of sodium ethoxide (from 1.15 g sodium) and oxazole-2-thiol (5.1 g) in ethanol (100 ml). The resultant solution was heated under reflux for 2.5 hour and concentrated under reduced pressure. The residue was triturated with water (100 ml) to afford 2-(3-phthalimidopropylthio)oxazole (14 g), m.p. 101°. Recrystallisation from ethanol gave the pure oxazole, m.p. 102°-103°. (iii) Hydrazine hydride (5.3 g) was added carefully to a solution of 2-(3-phthalimidopropylthio)oxazole (10 g) in ethanol (173 ml) with stirring. The solution was then heated under reflux for 25 minutes. After cooling, and filtration from phthalhydrazide, the filtrate was concentrated under reduced pressure and the residue was re-evaporated with ethanol to yield crude 2-(3-aminopropylthio)oxazole. (iv) By the procedure of Example 8(i), 2-(3-aminopropylthio)oxazole (2.1 g) is reacted with 1-nitro-2,2-bis-methylthioethylene (2.0 g) to give 1-nitro-2-methylthio-2-[3-(2-oxazolylthio)propylamino]ethylene (2.1 g) which, on reaction with methylamine by the procedure of Example 8(ii) gives the title product (1.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]O)[CH:5]=[CH:6][CH:7]=1.[CH2:31]([N:33](CC)[CH2:34]C)C.CS(Cl)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:33]([CH3:34])[CH3:31])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: CCc1ccc2c(-c3cccc(Cl)c3)c(CCCCCO)c(-c3ccccc3)nn12
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCc1ccc2c(-c3cccc(Cl)c3)c(CCCCCN(C)C)c(-c3ccccc3)nn12
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a solution of 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol (55 mg) and triethylamine (19.9 mg) in dichloromethane (3 mL) was added methanesulfonyl chloride (16.5 mg) under ice-water cooling and the mixture was stirred at 0° C. for 1 hour. The solution was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. To the residue in 1,2-dichloroethane (3 mL) was added 2 M dimethylamine in tetrahydrofuran (3 mL) and the mixture was stirred at 60° C. for 120 hours. The solution was diluted with chloroform, washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1–5:1) to give 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N,N-dimethyl-1-pentanamine as an yellow oil (38 mg).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:26])=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2)(=[O:14])=[O:13].N(OC(C)(C)C)=O>CC(O)=O>[Cl:26][C:19]1[CH:18]=[C:17]2[C:16](=[C:25]3[C:20]=1[CH:21]=[CH:22][CH:23]=[N:24]3)[NH:15][S:12](=[O:13])(=[O:14])[C:3]1[C:2]2=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][CH:4]=1
Reactant: Nc1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1ccc(Cl)c2cccnc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Product: O=S1(=O)Nc2c(cc(Cl)c3cccnc23)-c2cc(C(F)(F)F)ccc21
Yield: 32.9 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-N-(5-chloro-quinolin-8-yl)-4-trifluoromethyl-benzenesulfonamide (Intermediate 302) (350 mg, 0.87 mmol), t-butyl nitrite (0.16 ml, 1.30 mmol) and AcOH (3.5 ml) gave the title compound (110 mg, 33%) after purification by column chromatography with DCM/MeOH/NH3 (99:1:2 drops) as the eluent.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH3:20])=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>CN(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>[CH3:20][NH:19][C:17]([C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)[CH:3]=3)[CH:9]=[N:10][C:11]=2[CH:16]=1)=[O:18]
Reactant: OB(O)c1cccs1
Reactant: CNC(=O)c1ccc2c(c1)ncn2-c1cccc(Br)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: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2c(c1)ncn2-c1cccc(-c2cccs2)c1

Procedure:
To a solution of 1-(3-bromophenyl)-N-methyl-1H-benzimidazole-5-carboxamide (20 mg, 0.06 mmol) and thiophene-2-boronic acid (9.0 mg. 0.073 mmol) in anhydrous DMF (0.6 mL) was added Pd(PPh3)4 (3.5 mg, 0.003 mmol) followed by a solution of Na2CO3 (19 mg, 0.18 mmol) in water (0.16 mL). The reaction was irradiated in the microwave for 10 min (200 W, 150° C.). After cooling, the reaction mixture was filtered through Celite and washed with EtOAc (15 mL). The combined organic layer was washed with saturated aqueous NaHCO3 solution (10 mL) followed by saturated aqueous solution brine (3×10 mL), dried (MgSO4) and evaporated to dryness. The crude product was purified by solid-phase extraction (Isolute SAX, followed by Isolute SCX), giving N-methyl-1-(3-thien-2-ylphenyl)-1H-benzimidazole-5-carboxamide as an off-white solid; 1H NMR (400 MHz, MeOH-d4): δ 8.57 (s, 1H), 8.27 (d, J=2 Hz, 1H), 7.89-7.86 (m, 2H), 7.78 (d, J=7.8 Hz, 1H), 7.66-7.62 (m, 2H), 7.52-7.54 (m, 2H), 7.45 (d, J=5.1 Hz, 1H), 7.12 (dd, J=3.5 Hz, 1.5 Hz, 1H), 2.97 (s, 3H); MS (ES+): m/z 333.9 (100%) [MH+].
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[O:1]([CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)c1ccc(C(C)O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)Oc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 54.6 %

Procedure:
To a solution of methyl 4-(1-hydroxyethyl)benzoate (0.9 g, 5 mmol), phenol (525 mg, 5.6 mmol), triphenylphosphine (2198 mg, 8.4 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (1695 mg, 8.4 mmol) at 0° C. The mixture was stirred at 20° C. for 12 hours. Water (15 mL) was added to the mixture and then the mixture was extracted with ethyl acetate (35 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give methyl 4-(1-phenoxyethyl)benzoate (700 mg, 54%). 1H NMR (300 MHz, d6-DMSO): δ 8.02-7.98 (m, 2H), 7.46-7.43 (m, 2H), 7.23-7.16 (m, 2H), 6.91-6.80 (m, 3H), 5.36 (q, J=6.0 Hz, 1H), 3.90 (s, 3H), 1.64 (d, J=6.6 Hz, 3H).
Reaction SMILES: [C:1]([CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[OH:3][CH:1]([CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:5]1)[CH3:2]
Reactant: CC(=O)C1CN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
To a 100 ml round bottom flask was added tert-butyl 3-acetylazetidine-1-carboxylate (2.06, 10.3 mmol) and 30 ml MeOH. NaBH4 (0.403 g, 10.6 mmol) was added in portions. The resulting reaction mixture was stirred at room temperature for 15 minutes. The volatiles were removed under vacuum. The residue was treated with 50 ml 10% KOH and extracted with 2×50 ml ethyl acetate. The organics were combined and dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel column eluted with 1:4 to 1:2 E/H to give 2.06 g desired product as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1.[Br:15][CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](O)=[O:18].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[Br:15][CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]([NH:10][C:8]1[S:9][C:5]([CH2:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[Cl:1])=[CH:6][N:7]=1)=[O:18]
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: Nc1ncc(Cc2ccccc2Cl)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1ncc(Cc2ccccc2Cl)s1)C(Br)c1ccccc1
Reaction time: 16 h
Yield: 75 %

Procedure:
5-(2-Chloro-benzyl)-thiazol-2-ylamine (450 mg, 2.0 mmol) and bromo-phenyl-acetic acid (430 mg, 2.0 mmol) were dissolved in acetonitrile (20 mL) containing triethylamine (280 μL, 2.0 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (836 mg, 2.2 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by silica gel chromatography using a gradient of 10-30% ethyl acetate in hexanes to yield a pale yellow solid (633 mg, 1.50 mmol, 75.0%). ESI-MS m/z calc. 420.0. found 421.2 (M+1)+ Retention time 3.63 minutes.
Reaction SMILES: [Br:1][C:2]1[N:3]=[N:4][C:5](Br)=[CH:6][CH:7]=1.[CH:9]1([NH2:13])[CH2:12][CH2:11][CH2:10]1.CCN(CC)CC>O1CCOCC1>[Br:1][C:2]1[N:3]=[N:4][C:5]([NH:13][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: NC1CCC1
Reactant: Brc1ccc(Br)nn1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Brc1ccc(NC2CCC2)nn1
Yield: 55.2 %

Procedure:
Into a solution of 3,6-dibromopyridazine (1.19 g, 5 mmol) in dioxane (5 mL) was added cyclobutylamine (0.39 g, 5.5 mmol), and Et3N (0.60 g, 6 mmol). The reaction was microwave at 90° C., 150W for 0.45 h. The reaction was monitored by TLC and the crude product was purified by silica gel chromatography (eluent: 30% Ethyl acetate in n-hexane), to give the desired product (0.63 g, 55.3%). 1H NMR (300 MHz, CDCl3) δ: 7.25-7.28 (1 H, d, J=9.0 Hz), 6.49-6.52 (1 H, d, J=9.0 Hz), 5.27 (1 H, s), 4.16-4.24 (1 H, m), 2.40-4.49 (2 H, m), 1.87-1.95 (2 H, m), 1.75-1.84 (2 H, m).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=[O:23]>>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]3=[O:23])=[N:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1ccc(C#Cc2ccccc2)cn1
Reactant: O=C1CCCCN1
Product: O=C1CCCCN1Cc1ccc(C#Cc2ccccc2)cn1

Procedure:
The title compound, brown oil, MS: m/e=291.2 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from (5-phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) and piperidin-2-one.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1
Reactant: COc1ccc2c(O)cc(-c3ccccc3)nc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)cc(-c3ccccc3)nc2c1
Reaction time: 0.25 h

Procedure:
The product of Step 1a (21.7 g, 86.4 mmole) was suspended in POCl3 (240 mL). The suspension was refluxed for 2 hours. After removal of the POCl3 in vacuo, the residue was partitioned between EtOAc (IL), and cold aqueous NaOH (generated from 1.0N 200 mL NaOH and 20 mL 10.0 N NaOH) and stirred for 15 min. The organic layer was washed with water (2×200 mL), brine (200 mL), dried (MgSO4), and concentrated in vacuo to supply 4-chloro-2-phenyl-7-methoxyquinoline (21.0 g, 90%) as a light brown solid. 1H NMR (DMSO-d6) δ: 3.97 (s, 3H), 7.36 (dd, J=9.2, 2.6 Hz, 1H), 7.49-7.59 (m, 4H), 8.08 (d, J=9.2 Hz, 1H), 8.19 (s, 1H), 8.26-8.30 (m, 2H); 13C NMR (DMSO-d6) δ: 55.72, 108.00, 116.51, 119.52, 120.48, 124.74, 127.26, 128.81, 130.00, 137.58, 141.98, 150.20, 156.65, 161.30. LC-MS (retention time: 1.547, Method D), MS m/z 270 (M++1).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>C1COCC1>[CH2:12]([NH:14][C:15]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)=[O:16])[CH3:13]
Reactant: CCN=C=O
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNC(=O)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
NaH (0.9 g, 37.5 mmol) was added in portions to a 0° C. cooled solution of indole (2.93 g, 25 mmol) in THF (100 mL). After 30 min, ethyl isocyanate (1.78 g, 25 mmol) was added dropwise. The reaction mixture was stirred at RT overnight, then was quenched with 25% citric acid in water (50 mL) and extracted with ethyl acetate (3 X). These organic extracts were combined, dried (MgSo4), and recrystallized from ether/hexanes to afford 1.3 g of N-(ethylaminocarbonyl)indole as a tan solid, a 28% yield. m.p. 71-73° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](N(CC)CC)[CH3:11].C(OC(ON=C(C#N)C(N)=O)=O)C.O>O1CCCC1>[C:1]([O:9][CH2:10][CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)ON=C(C#N)C(N)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccccc1

Procedure:
To a solution of benzoic acid (1.22 g) and triethylamine (2.8 ml) in dry tetrahydrofuran (20 ml), 2-ethoxycarbonyloxyimino-2-cyanoacetic acid amide (1.85 g) is added at room temperature while stirring, and the resulting mixture is stirred at room temperature for 2 hours. The reaction mixture is admixed with water and extracted with ethyl acetate. The extract is washed with water, an aqueous solution of sodium hydrogencarbonate, 1 N hydrochloric acid and water in order, dried and concentrated to give ethyl benzoate (1.3 g) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]([C:19]#[N:20])([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].[BH4-].[Na+].ClCCl.CO>CO.O.O.O.O.O.O.[Co](Cl)Cl>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][C:8](=[O:9])[NH:20][CH2:19]1)[CH3:2]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1cccnc1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CC1(c2cccnc2)CNC(=O)C1
Reaction time: 18 h

Procedure:
Combine 3-cyano-3-(pyrid-3-yl)pentanedioic acid diethyl ester (50 g, 172 mmol) and cobalt(II)chloride hexahydrate (81.8 g, 344 mmol) in methanol (500 mL). While maintaining the temperature at or below 20° C. with an ice-bath, add portionwise sodium borohydride (65.1 g, 1.72 mol). After the addition is complete, allow the reaction mixture to stand at ambient temperature. After 18 hours, evaporate the reaction mixture in vacuo to obtain a residue. Quench the reaction mixture by adding ammonium chloride and 0.5 M aqueous sodium hydroxide solution. Adjust the pH of the quenched reaction mixture to about 8 using 1 M aqueous hydrochloric acid solution. Filter through celite and extract the aqueous filtrate twice with dichloromethane. Combine the organic layers, dry over Na2SO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with dichloromethane/methanol 10/1 to give the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(Cl)Cl.[C:11]([C:13]1[CH:14]=[C:15]([C:19]2[CH:33]=[C:32]([CH2:34][NH:35][S:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)(=[O:38])=[O:37])[CH:31]=[CH:30][C:20]=2[O:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])[CH:16]=[CH:17][CH:18]=1)#[N:12]>>[C:11]([C:13]1[CH:14]=[C:15]([C:19]2[CH:33]=[C:32]([CH2:34][NH:35][S:36]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)(=[O:38])=[O:37])[CH:31]=[CH:30][C:20]=2[O:21][CH2:22][C:23]([OH:25])=[O:24])[CH:16]=[CH:17][CH:18]=1)#[N:12]
Reactant: CC(C)(C)OC(=O)COc1ccc(CNS(=O)(=O)c2ccc(F)cc2)cc1-c1cccc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(-c2cc(CNS(=O)(=O)c3ccc(F)cc3)ccc2OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a solution of TFA/DCM (1:3, 6 mL) was added t-butyl 2-(2-(3-cyanophenyl)-4-((4-fluorophenylsulfonamido)methyl)phenoxy)acetate (8) (51 mg, 0.10 mmol, 1 eq) and the mixture was stirred at room temperature for 2 h. The organic solvent was removed in vacuo and the crude product was purified by reversed phase preparative HPLC to give 36 mg (82%) of 2-(2-(3-cyanophenyl)-4-((4-fluorophenylsulfonamido)methyl)phenoxy)acetic acid (Example 9).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][CH:10]=[C:7]([CH:8]=O)[C:6]=1[OH:13])([CH3:4])([CH3:3])[CH3:2].[C:14]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)#[CH:15]>C(O)C.C(O)(=O)C>[C:1]([C:5]1[CH:12]=[CH:11][CH:10]=[C:7]([CH:8]=[N:20][C:19]2[CH:21]=[CH:22][C:16]([C:14]#[CH:15])=[CH:17][CH:18]=2)[C:6]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cccc(C=O)c1O
Reactant: C#Cc1ccc(N)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: C#Cc1ccc(N=Cc2cccc(C(C)(C)C)c2O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 43 %

Procedure:
3-tert-butyl salicylaldehyde (1) (0.70 g/3.93 mmol) and 4-ethynyl aniline (0.49 g/4.2 mmol) were dissolved in 100 ml of ethanol. Molecular sieves (3 Å, 15 g) and a few drops of glacial acetic acid were added and the mixture was stirred at room temperature for three days. After filtration over sodium sulphate and removal of the solvent, the residue was extracted several times with n-pentane. The solution was filtered again over sodium sulphate, and the solvent was removed. The title compound was obtained as a yellow powder. Yield: 43%.