Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]([C@@H:7]2[O:20][CH2:19][C@@H:14]([O:15]C(=O)C)[C@@H:9]([O:10]C(=O)C)[CH2:8]2)[C:5]2[CH:21]=[C:22]([Cl:26])[C:23]([Cl:25])=[CH:24][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CCCCCC>O>[Br:1][C:2]1[N:6]([C@@H:7]2[O:20][CH2:19][C@@H:14]([OH:15])[C@@H:9]([OH:10])[CH2:8]2)[C:5]2[CH:21]=[C:22]([Cl:26])[C:23]([Cl:25])=[CH:24][C:4]=2[N:3]=1
Reactant: CC(=O)O[C@H]1C[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)OC[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: O[C@@H]1CO[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
An ethanolic solution of 2-bromo-5,6-dichloro-1-(3,4-di-O-acetyl-2-deoxy-beta-D-erythro-pentopyranosyl)-1H-benzimidazole (0.13 g, 0.28 mmol) was deprotected in a modification of General Procedure VI with 0.077 g (0.73 mmol) of sodium carbonate in 1 ml of water. After stirring overnight at ambient temperature, the mixture was treated as described in General Procedure VI. The crude product was triturated in dichloromethane and hexane to give 0.06 g (0.16 mmol, 56% yield) of 2-bromo-5,6-dichloro-1-(2-deoxy-beta-D-erythro-pentopyranosyl)-1H-benzimidazole. 1H NMR (DMSO-d6) δ8.01 (s, 1H), 7.92 (s, 1H), 5.96-5.94 (d, 1H), 5.02 (s, 1H), 4.90-4.89 (d, 1H), 4.01 (s, 1H), 3.94-3.86 (m, 1H), 3.74-3.72 (d, 2H), 2.42-2.39 (m, 1H—partially underneath residual DMSO signal), 1.90-1.87 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([Cl:18])[C:3]=1[NH:19][C:20](=[O:30])[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1.[BH4-].[Na+].N>CO.C(OCC)(=O)C.O.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]([NH:19][C:3]2[C:4]([Cl:18])=[CH:5][C:6]([C:8]([F:17])([C:13]([F:14])([F:15])[F:16])[C:9]([F:10])([F:11])[F:12])=[CH:7][C:2]=2[Cl:1])=[O:30])=[CH:26][CH:25]=1
Reactant: O=C(Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Ni]Cl
Agent: N
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Nc1ccc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
N-[2,6-Dichloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)phenyl]-4-nitro-benzamide (3.2 g) and nickel (II) chloride hexahydrate (3.33 g) were dissolved in methanol (30 ml). To the reaction solution, NaBH4 (0.80 g) was added slowly under ice cooling, and the mixture was stirred for 1 hour while increasing the temperature to room temperature. Aqueous ammonia (about 5 ml) was added to the reaction solution under stirring, and then diluted with ethyl acetate and water. The organic phase was separated and the aqueous layer was extracted with ethyl acetate. The organic phases were combined, and then dried over magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude product, which was then separated and purified by column chromatography to give 4-amino-N-[2,6-dichloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)phenyl]-benzamide (2.89 g, yield 96%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH:11](Br)[CH2:12][CH2:13][CH3:14])[CH:5]=1.[C:18]([NH2:21])(=[O:20])[CH3:19]>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:21]=[C:18]([CH3:19])[O:20][C:11]=2[CH2:12][CH2:13][CH3:14])[CH:5]=1
Reactant: CCCC(Br)C(=O)c1cccc(C(=O)OC)c1
Reactant: CC(N)=O
Product: CCCc1oc(C)nc1-c1cccc(C(=O)OC)c1
Yield: 36.1 %

Procedure:
A sample of rac-3-(2-bromo-pentanoyl)-benzoic acid methyl ester (1.50 g) and acetamide (0.89 g) were heated together to 130° C. for 15 h. The mixture was partitioned between AcOEt and brine, the organic layer was dried and evaporated and the residual oil was chromatographed on silica gel using AcOEt/hexane (1:3) as eluent to give 3-(2-methyl-5-propyl-oxazol-4-yl)-benzoic acid methyl ester (0.47 g) as a light-yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:27]=[C:26]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:25]=[CH:24][C:16]=2[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:10][CH:9]=1>ClCCl>[C:8]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:27]=[C:26]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:25]=[CH:24][C:16]=2[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1Nc1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(CCc2ccccc2)cc1Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
Trifluoroacetic acid 2.0 mL was added to dichloromethane 2.0 mL solution of tert-butyl 2-((biphenyl-4-yl)amino)-4-phenethylbenzoate 50 mg, and it was stirred at room temperature for 4 hours and 30 minutes. The solvent was removed under reduced pressure,diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 2-((biphenyl-4-yl)amino)-4-phenethylbenzoic acid 27 mg of a yellow solid.
Reaction SMILES: C([O:8][CH2:9][CH:10]([CH2:24][O:25]CC1C=CC=CC=1)[CH2:11][CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][C:16]([NH2:23])=[N:17][C:18]=2Cl)C1C=CC=CC=1.C(O)=[O:34]>[Pd]>[OH:8][CH2:9][CH:10]([CH2:24][OH:25])[CH2:11][CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:18](=[O:34])[NH:17][C:16]([NH2:23])=[N:15][C:14]1=2
Reactant: O=CO
Reactant: Nc1nc(Cl)c2ncn(CCC(COCc3ccccc3)COCc3ccccc3)c2n1
Agent: [Pd]
Product: Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Reaction time: 0.75 h
Yield: 45 %

Procedure:
A solution of 4-(2-amino-6-chloropurin-9-yl)-2-benzyloxymethylbutyl benzyl ether (0.904 g, 2 mmol) in 25 ml of 80% aqueous formic acid was kept at 100° C. for 1h, palladium catalyst (10% on carbon, 0.40 g) was added, and the mixture was hydrogenated at room temperature and atmospheric pressure with efficient stirring for 45 min. After evaporation in vacuum to dryness the residue was heated to boiling with 50 ml of water, 1 ml of concentrated aqueous ammonia was added, the solution was boiled gently for a short while and then evaporated to dryness. Recrystallization from water afforded 0.23 g (45%) of 9-[4-hydroxy-3-(hydroxymethyl)butyl]guanine. M.p. 252°-262° C. (decomposition, slow heating) or 264°-265° (fast immersion of the capillary).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:12][CH2:13][CH2:14][CH2:15][C:16](O)=[O:17].B(F)(F)F.CCOCC>O>[Cl:12][CH2:13][CH2:14][CH2:15][C:16]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[OH:11])=[O:17]
Reactant: Oc1cccc2ccccc12
Reactant: O=C(O)CCCCl
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Product: O=C(CCCCl)c1ccc2ccccc2c1O
Reaction time: 0.5 h
Yield: 38.2 %

Procedure:
A mixture of 1-naphthol (15.14 g, 0.105 mole), 4-chlorobutyric acid (9.90 mL, 0.100 mole), and boron trifluoride etherate (75 mL) was heated on a steam bath for 4 hours. The mixture was then treated slowly with 100 mL of water, and heating continued for 30 minutes. The mixture was poured into water, stirred, and the solution decanted. The residue was triturated with water, then crystallized from ethanol to provide the title compound (9.50 g, 38%) as a pale green solid, mp 73°-79°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])[CH2:23][CH2:22]2)[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18]([OH:20])=[O:19])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:36](OCC)C.C[Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO.CCCCCC>[C:1]([O:5][C:6]([NH:8][C@@:9]1([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])[CH2:23][CH2:22]2)[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18]([O:20][CH3:36])=[O:19])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N[C@]1(C2CCN(C(=O)OCC[Si](C)(C)C)CC2)C[C@@H]2SC[C@@H](C(=O)O)N2C1=O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CS[C@H]2C[C@](NC(=O)OC(C)(C)C)(C3CCN(C(=O)OCC[Si](C)(C)C)CC3)C(=O)N21
Reaction time: 2 h

Procedure:
223 mg of (3R,6S,7aS)-6-tert-butoxycarbonylamino-5-oxo-6-[1-(2-trimethylsilanylethoxycarbonyl)piperidin-4-yl]hexahydropyrrolo[2,1-b]thiazole-3-carboxylic acid were dissolved in 10 ml of methanol and 10 ml of diethyl ether and cooled to 0° C. 400 μl portions of a 1 N solution of trimethylsilyldiazomethane in hexane were added dropwise twice at an interval of 1.5 h. The mixture was stirred for 2 h and then 1 ml of acetic acid was added dropwise. After 1 h, the solvents were removed in vacuo and the residue was purified by chromatogrpahy on silica gel.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9](I)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]([C:16]1[CH:17]=[C:18]([CH:26]([OH:29])[C:27]#[CH:28])[CH:19]=[C:20]([Cl:25])[C:21]=1[N:22]([CH3:24])[CH3:23])([CH3:15])([CH3:14])[CH3:13]>[Cu](I)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>[C:12]([C:16]1[CH:17]=[C:18]([CH:26]([OH:29])[C:27]#[C:28][C:9]2[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([OH:1])[CH:10]=2)[CH:19]=[C:20]([Cl:25])[C:21]=1[N:22]([CH3:23])[CH3:24])([CH3:15])([CH3:14])[CH3:13]
Reactant: C#CC(O)c1cc(Cl)c(N(C)C)c(C(C)(C)C)c1
Reactant: O=C(O)c1ccc(I)cc1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CN(C)c1c(Cl)cc(C(O)C#Cc2ccc(C(=O)O)c(O)c2)cc1C(C)(C)C
Yield: 42 %

Procedure:
In a manner analogous to example 1 f, the process is carried out by a reaction of 220 mg (0.83 mmol) of 2-hydroxy-4-iodobenzoic acid with 320 mg (1.2 mmol) of 1-(3-tert-butyl-5-chloro-4-dimethylaminophenyl)prop-2-yn-1-ol in the presence of 9 mg (0.05 mmol) of copper iodide and 17 mg (0.025 mmol) of bis(triphenyl-phosphine)palladium chloride. 140 mg of 4-[3-(3-tert-butyl-5-chloro-4-dimethylaminophenyl)-3-hydroxyprop-1-ynyl]-2-hydroxybenzoic acid are obtained in the form of a yellowish oil (Mp=175° C., yield=42%).
Reaction SMILES: [C:1]1(=[O:15])[C:10]2[C:5]3[C:6](=[CH:11][CH:12]=[CH:13][C:4]=3[C:3](=[O:14])[NH:2]1)[CH:7]=[CH:8][CH:9]=2.[Br:16][CH2:17][CH:18](Br)[CH2:19][CH2:20][CH3:21]>>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:2]1[C:3](=[O:14])[C:4]2[CH:13]=[CH:12][CH:11]=[C:6]3[C:5]=2[C:10](=[CH:9][CH:8]=[CH:7]3)[C:1]1=[O:15]
Reactant: O=C1NC(=O)c2cccc3cccc1c23
Reactant: CCCC(Br)CBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCBr

Procedure:
This compound was prepared according to GP-1 using benzo[de]isoquinoline-1,3-dione (1) and 1,2 dibromopentane (2c) The crude product was purified by flash column chromatography using EtOAc-hexane to give 3c. 1H NMR (500 MHz, CDCl3) δ 8.63 (d, J=7.5 Hz 2H), 8.24 (d, J=8.0 Hz, 2H), 7.78 (t, J=7.5 Hz, 2H), 4.22 (t, J=7.0, 2H), 3.45 (t, J=7.0 Hz, 2H), 2.01-1.94 (m, 2H), 1.84-1.78 (m, 2H), 1.64-1.57 (m, 2H), MS (ES+) m/z 368 (M+Na)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[O:15]1[C:19]2=[CH:20][CH:21]=[CH:22][C:23]([C:24](O)=[O:25])=[C:18]2[CH:17]=[CH:16]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.CC(=O)OCC.CCCCCCC>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([NH:1][C:24]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]3[O:15][CH:16]=[CH:17][C:18]=23)=[O:25])[CH2:3]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: O=C(O)c1cccc2occc12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)c2cccc3occc23)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.1 %

Procedure:
A mixture of (R)-3-amino-1-N-Boc-piperidine (1 g), benzofuran-4-carboxylic acid (809 mg), PyBOP (2.6 g), DIEA (1.96 mL) in dry DMF (10 mL) was stirred at RT under nitrogen for 20 h. The reaction mixture was diluted with EA, washed with water. The aqueous phase was extracted twice with EA, the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to yield a crude light brown oil. FC (EA/n-heptane: 1/1 to EA) gave 1.41 g (82%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH2:21][O:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=2)=[N:6][CH:7]=1.Cl.[CH2:33]([NH2:35])[CH3:34].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH2:21][O:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([NH:35][CH2:33][CH3:34])=[O:29])=[CH:25][CH:24]=2)=[N:6][CH:7]=1
Reactant: CCN
Reactant: O=C(O)c1ccc(OCc2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(OCc2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-({5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methoxy)benzoic acid (0.48 g, 1.05 mmol), ethylamine hydrochloride (0.09 g, 1.05 mmol) and DIPEA (0.55 ml, 3.15 mmol) in 9 mL of DMF was added BOP (0.56 g, 1.26 mmol). It was stirred at room temperature for 2 h. Water was added and extracted with EA. The organic layers were combined and washed with 3M LiCl (3×), dried over Na2SO4, filtered and concentrated. The reaction was purified by flash chromatography (silica, 30-70% EtOAc/hexanes) to give 4-({5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methoxy)-N-ethylbenzamide: 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J=2.5 Hz, 1H), 8.08 (m, 2H), 7.66 (d, J=8.7 Hz, 2H), 7.48 (dd, J=8.4, 2.6 Hz, 1H), 7.15 (m, 2H), 6.96 (m, 3H), 5.95 (s, 1H), 5.15 (s, 2H), 3.45 (m, 2H), 1,22 (t, J=7.3 Hz, 3H); HRMS exact mass calc for C24H19ClFN3O3S [M+H]+: 484.0892; observed: 484.0900.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.CO[C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][C:37]=1N1CCNCC1>>[CH2:2]1[C:37]2[C:36](=[CH:42][CH:41]=[C:39]([NH:40][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:38]=2)[CH2:5][CH2:4][NH:3]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: COc1ccc(N)cc1N1CCNCC1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 4-(methyloxy)-3-(1-piperazinyl)aniline in a manner analogous to Example 64. 1H NMR (400 MHz, DMSO-d6) δ 2.90 (s, 8H), 3.72 (s, 3H), 6.43 (d, 1H, J=5.3 Hz), 6.80 (d, 1H, J=8.8 Hz), 7.09 (t, 1H, J=6.5 Hz), 7.22 (d, 2H, J=8.1 Hz), 7.25 (d, 1H, J=3.9 Hz), 7.32 (t, 2H, J=8.3 Hz), 7.45 (q, 2H, J=7.9 Hz), 7.58 (quintet, 1H, J=8.3 Hz), 7.79 (d, 1H, J=8.2 Hz), 7.99 (s, 1H), 8.18 (d, 2H, J=5.7 Hz), 8.43 (bd, 1H, J=8.3 Hz), 8.81 (d, 1H, J=6.8 Hz), 9.26 (s, 1H), 10.92 (s, 1H); ESIMS (M+H)+=633.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]#[N:11].Br[CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:13]([N:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:10]#[N:11])[C:5]1=[O:9])[CH2:14][CH2:15][CH3:16]
Reactant: COc1cc[nH]c(=O)c1C#N
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCn1ccc(OC)c(C#N)c1=O
Temperature: 110 °C
Yield: 99.9 %

Procedure:
To a solution of 4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (20 g, 133 mmol) in acetonitrile (800 ml) were added 1-bromobutane (15.8 ml, 146 mmol) and potassium carbonate (36.7 g, 266 mmol) and the mixture was heated at 110° C. for 24 hours. The mixture was cooled to room temperature and the solid was filtered off. The filtrate was evaporated till dryness and the resulting crude residue was then triturated with diethylether to yield pure intermediate 2 (27.39 g, >99%) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:9]=[O:10])=[CH:11][C:12]=1[N+:18]([O-:20])=[O:19])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C=O)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(C)Cc1ccc(C=O)cc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
4-Isobutyl benzaldehyde (7 g, 0.0431 mol) is added drop wise to a mixture of concentrated sulfuric acid & nitric acid (68-72%) (9:1, 60 mL) at 0-5° C. Reaction mixture is allowed to stir at this temperature for 2 hrs, then poured into crushed ice. It is then extracted with ethyl acetate (3×40 mL). Combined organic layer is dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography (silica gel, 230-400 mesh, ethyl acetate:n-hexane 1:19) to yield 4-isobutyl-3-nitrobenzaldehyde.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[CH3:15][C:16]1[CH:25]=[C:24]([CH2:26][O:27][C:28]2[CH:52]=[CH:51][C:31]([C:32]([NH:34][CH2:35][C:36]3([CH:45]4[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]4)[C:41](=[O:42])[NH:40][C:39](=[O:43])[NH:38][C:37]3=[O:44])=[O:33])=[CH:30][CH:29]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.[N:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH:59]=O)[CH:54]=1>>[CH3:15][C:16]1[CH:25]=[C:24]([CH2:26][O:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:34][CH2:35][C:36]3([CH:45]4[CH2:50][CH2:49][N:48]([CH2:59][C:55]5[CH:54]=[N:53][CH:58]=[CH:57][CH:56]=5)[CH2:47][CH2:46]4)[C:37](=[O:44])[NH:38][C:39](=[O:43])[NH:40][C:41]3=[O:42])=[O:33])=[CH:51][CH:52]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: Cc1cc(COc2ccc(C(=O)NCC3(C4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Reactant: O=Cc1cccnc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C(=O)NCC3(C4CCN(Cc5cccnc5)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 45 %

Procedure:
Following procedures analogous to that used in reaction (9), the compound from Example 29 was reacted with 3-pyridinecarboxaldehyde for 2 days to provide the title compound (7.3 mg, 45%). MS found: (M−H)−=605.5.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[OH-].[Na+].[C@H:27]1([OH:33])[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28]1.Cl>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.COCCOC>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:2]([O:32][C@H:29]4[CH2:30][CH2:31][C@H:27]([OH:33])[CH2:28]4)=[N:7][CH:6]=[N:5][C:4]=3[O:8][C:9]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][CH:13]=1
Reactant: O[C@H]1CC[C@H](O)C1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: COCCOC
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@H]4CC[C@H](O)C4)c23)cc1

Procedure:
Add 1,2-dimethoxyethane to 10 g (29.7 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine in 150 ml of toluene at 70° C. until a homogeneous solution forms. Then add 23.75 g (296.9 mmol) of 50% sodium hydroxide solution and 2.5 ml of water, and, with vigorous stirring, 1.0 g (2.97 mmol) of tetra-n-butylammonium hydrogen sulphate and 4.55 g (44.54 mmol) of (+/−)-cis/trans-1,3-cyclopentanediol, and stir the reaction mixture at 70° C. for 4 h. After cooling, add the mixture to water and neutralize with conc. hydrochloric acid. Extract three times with dichloromethane, wash the combined organic phases with satd. sodium chloride solution, dry over magnesium sulphate and concentrate under reduced pressure. From the residue, chromatography on silica gel (eluent: cyclohexane/ethyl acetate 4:1→2:1) affords contaminated product. Crystallize this crude product by stirring with methanol. Filter off and dry the resulting crystals (Yield: 690 mg). Concentrate the mother liquor under reduced pressure and purify by preparative RP-HPLC. In this way, a further 1230 mg of the target product are obtained. In total, 1920 mg of the target compound are obtained (16.1% of theory).
Reaction SMILES: Cl.Cl[C:3]1C=CC(NN)=CC=1.C(Br)C#C.ClC1C=CC(N(CC#C)N)=CC=1.C(OC(OCC)CCCNC)C.[Cl:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[N:45]([CH2:49][C:50]#[CH:51])[CH:44]=[C:43]2[CH2:52][CH2:53][NH:54][CH3:55].C=O.C(O)(C(F)(F)F)=O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[Cl:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[N:45]([CH2:49][C:50]#[CH:51])[C:44]1[CH2:55][N:54]([CH3:3])[CH2:53][CH2:52][C:43]2=1
Reactant: C#CCn1cc(CCNC)c2cc(Cl)ccc21
Reactant: NNc1ccc(Cl)cc1
Agent: C#CCBr
Agent: C#CCN(N)c1ccc(Cl)cc1
Agent: C=O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: C#CCn1c2c(c3cc(Cl)ccc31)CCN(C)C2

Procedure:
The title compound was prepared by following General Methods 2, 3 and 4 using 4-chlorophenylhydrazine hydrochloride, propargyl bromide, and tetra-n-butylammonium chloride (General Method 2), 1-(4-chlorophenyl)-1-(prop-2-ynyl)hydrazine (Example 8) and 4,4-diethoxy-N-methylbutan-1-amine (General Method 3) and 2-(5-chloro-1-(prop-2-ynyl)-1H-indol-3-yl)-N-methylethanamine (Example 17), formaldehyde and TFA in acetonitrile (General Method 4).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:2]1.Cl.[NH2:20][C:21]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:25]([O:24][C:22](=[O:23])[C:21]([NH:20][C:12]([C:10]1[CH:9]=[CH:8][C:7]([C:15]([F:18])([F:17])[F:16])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH2:29][CH3:30])[CH2:27][CH3:28])[CH3:26]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CC2)n1
Reactant: CCOC(=O)C(N)(CC)CC
Agent: Cl
Product: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 293, 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113 d) and ethyl 2-amino-2-ethylbutanoate hydrochloride (CAN 1135219-29-2) were condensed to the title product. MS (EI): m/e=403.4 [M+H]+.