Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([Cl:18])[N:3]=1.N[CH2:20][CH2:21][OH:22]>C1COCC1>[Cl:18][C:4]1[C:5]([C:16]#[N:17])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([C:8]#[N:9])=[C:2]([NH:1][CH2:20][CH2:21][OH:22])[N:3]=1
Reactant: NCCO
Reactant: N#Cc1c(N)nc(Cl)c(C#N)c1-c1ccccc1
Solvent: C1CCOC1
Product: N#Cc1c(Cl)nc(NCCO)c(C#N)c1-c1ccccc1

Procedure:
1 g (3.65 mmol) of 2,6-dichloro-4-phenyl-3,5-pyridinedicarbonitrile [Quintela et al., Heterocycles 38, 1299-1305 (1994)] is, together with 0.33 g (5.47 mmol) of 2-aminoethanol, dissolved in 3 ml of THF, and the mixture is heated under reflux for 8 h. The reaction mixture is purified by preparative HPLC on reversed-phase silica gel (gradient: water+0.1% formic acid/acetonitrile 90:105:95 in 35 minutes).
Reaction SMILES: Cl.[NH:2]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH:15]([CH2:21][C:22]([OH:24])=O)[C:16](=[O:20])[NH:17]2)=[CH:12][CH:11]=1)[C:3]([NH2:5])=[NH:4].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1.Cl.CN(C)CCCN=C=NCC.CN(C1C=CC=CN=1)C>CN(C=O)C>[CH3:35][C:25]1[CH:26]=[CH:27][C:28]([S:31]([NH:34][C:22](=[O:24])[CH2:21][CH:15]2[CH2:14][C:13]3[C:18](=[CH:19][C:10]([O:9][CH2:8][CH2:7][CH2:6][NH:2][C:3]([NH2:5])=[NH:4])=[CH:11][CH:12]=3)[NH:17][C:16]2=[O:20])(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: N=C(N)NCCCOc1ccc2c(c1)NC(=O)C(CC(=O)O)C2
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC(=O)CC2Cc3ccc(OCCCNC(=N)N)cc3NC2=O)cc1
Temperature: 25 °C
Reaction time: 504 h
Yield: 6.1 %

Procedure:
To [7-(3-guanidino-propoxy)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid hydrochloride (0.90 g) was added para-toluenesulfonamide (0.65 g), 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.73 g), dimethylaminopyridine (0.05 g), and DMF (40 mL) and the resulting slurry formed a solution as it was stirred under N2 at room temperature for 21 days. The DMF was removed by vacuum distillation. The golden oil was triturated with CH2Cl2 (25 mL) followed by EtOAc (25 mL). The resulting oil was dissolved in 10 mL of 25% CH3CN/H2O and chromatographed on a C18 reverse phase column, eluting with a gradient of 10% CH3CN/H2O to 40% CH3CN/H2O to afford the title compound (73 mg) as an ivory solid after lyophilization.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])[CH:5]=[C:4]([Cl:14])[N:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:11][CH2:10][C:9]([NH:8][C:6]1[CH:5]=[C:4]([Cl:14])[N:3]=[C:2]([Cl:1])[N:7]=1)([CH3:12])[CH3:13])(=[O:25])=[O:24]
Reactant: CC(C)(CO)Nc1cc(Cl)nc(Cl)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(COS(C)(=O)=O)Nc1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-((2,6-dichloropyrimidin-4-yl)amino)-2-methylpropan-1-ol (6.67 g, 28.3 mmol) and triethylamine (11.59 mL, 85 mmol) in dichloromethane (DCM) (100 mL) was added dropwise MsCl (4.40 mL, 56.5 mmol) at 0° C. The reaction mixture was stirred at rt for 2 h, diluted with DCM (100 mL), washed with water (50 mL×3) then brine (50 mL×2), dried over Na2SO4, filtered and concentrated to give the residue as a yellow solid, which was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([S:22](Cl)(=[O:24])=[O:23])[CH:13]=1>CN(C1C=CN=CC=1)C>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:22]([C:14]2[CH:13]=[N:12][C:21]3[C:16]([CH:15]=2)=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:23])=[O:24])[CH:7]=[CH:8][CH:9]=1
Reactant: O=S(=O)(Cl)c1cnc2ccccc2c1
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1cnc2ccccc2c1
Yield: 20.9 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (57 mg, 0.40 mmol), quinoline-3-sulfonyl chloride (10 mg, 0.44 mmol) and DMAP (cat.) gave the title compound (28 mg, 21%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:12]O.P(Br)(Br)[Br:15]>C(OCC)C.O>[Br:15][CH2:12][C:3]1[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: CS(=O)(=O)c1ccc(CO)c(Cl)c1
Solvent: O
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Temperature: 0 °C

Procedure:
A cooled (0° C.), stirred suspension of (2-chloro-4-methanesulfonyl-phenyl)-methanol (19.1 g, 0.087 mol) in diethyl ether (250 ml) under an inert atmosphere, is treated with phosphorus tribromide (5.2 ml, 0.029 mol) and allowed to stir and warm to room temperature overnight. The resulting mixture is diluted with water (100 ml) and the organic portion is separated and dried over NaOH pellets for 5 minutes. The solvent is removed in vacuo and the resulting crude residue is loaded on a pre-packed Isolute™ silica column and eluted with iso-hexane/ethyl acetate (4:1) to yield the titled compound as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:7]2[CH2:8][CH:3]1[C:4](=C)[CH2:5][C:6]2=[O:9].[O:12]=[O+][O-].CSC>CO>[CH3:11][C:2]1([CH3:1])[CH:3]2[CH2:8][CH:7]1[C:6](=[O:9])[CH2:5][C:4]2=[O:12]
Reactant: C=C1CC(=O)C2CC1C2(C)C
Reactant: O=[O+][O-]
Solvent: CO
Solvent: CSC
Product: CC1(C)C2CC1C(=O)CC2=O
Reaction time: 8 h

Procedure:
A solution of 6,6-dimethyl-4-methylene-bicyclo[3.1.1]heptan-2-one (2(10)pinen-4-one, 6.8 g, 45.3 mmol) in dry methanol (300 mL) under a nitrogen atmosphere was cooled to −78° C. in a dry ice/acetone bath. The stirred reaction was treated with ozone for 20 minutes, during which time the solution turned a light blue color, indicating accumulation of ozone and completion of the reaction. The reaction was purged with oxygen (5 minutes), followed by nitrogen (10 minutes) at −78° C., and then dimethyl sulfide (5.0 ml, 68.2 mmole) was added dropwise via a syringe. The resulting reaction mixture was stirred overnight, during which time it came up to room temperature. Methanol was removed on a rotary evaporator, and the residue was partitioned between ethyl acetate (300 mL) and water (300 mL). The aqueous layer was extracted with two additional portions of ethyl acetate (300 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by column chromatography on silica gel (20% ethyl acetate/hexane) to gave the desired product as a white solid (5.7 g; 83% yield), mp=80–81° C.; MS (−) ESI m/z=151 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:20][C:21]([F:34])([F:33])[O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:29]([C:26]2[CH:25]=[CH:24][C:23]([O:22][C:21]([F:20])([F:33])[F:34])=[CH:28][CH:27]=2)(=[O:31])=[O:30])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1)c1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 4-trifluoromethoxybenzene-1-sulfonyl chloride.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][C@@H:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:39])([F:38])[F:37])[CH3:29])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][C@@H:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:37])([F:38])[F:39])[CH3:29])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1
Reactant: C[C@@H](Oc1cc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](Oc1cc(-n2cnc3cc(CO)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example 51, 370 mg of 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide and 166 mg of tetra-n-butylammonium fluoride (˜75% in H20) in 6 ml THF yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[CH3:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](O)=O.C>C(O)C>[CH2:16]([C:15]1[NH:11][C:10]2[CH:9]=[C:8]3[NH:7][C:6](=[O:12])[C:5]([CH3:14])([CH3:13])[C:4]3=[CH:3][C:2]=2[N:1]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCC(=O)O
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Solvent: CCO
Product: CCCCCCc1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C

Procedure:
Analogously to Example 11, from 0.48 g. 5,6-diamino-3,3-dimethylindolin-2-one and 0.36 g. oenanthic acid, after heating with 4.5 g. polyphosphoric acid for 30 minutes at a bath temperature of 200° C., there is obtained 0.7 g. of crude product which is dissolved in 35 ml. ethanol, treated with active charcoal, filtered and the clear filtrate evaporated in a vacuum. The evaporation residue, after trituration with diethyl ether, gives 0.37 g. of the title compound in the form of the monohydrate; m.p. 233°-234° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccccc1-c1csc(N)n1
Solvent: c1ccncc1
Product: COc1ccccc1-c1csc(NC(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(2-Methoxy-phenyl)-thiazol-2-ylamine (41.3 mg, 0.200 mmol) and benzoyl chloride (28.1 mg, 0.200 mmol) were dissolved in 1 mL of pyridine. The reaction mixture was stirred at room temperature overnight and then purified by reverse-phase preparative liquid chromatography (11.4 mg, 0.0367 mmol, 18.4%). ESI-MS m/z calc. 310.1, found 311.2 (M+1)+ Retention time 3.55 minutes.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12].[N:17]1[C:22]2[NH:23][CH:24]=[CH:25][C:21]=2[CH:20]=[N:19][CH:18]=1.[OH-].[K+].O>CO>[F:1][C:2]1[C:7]([CH:8]([OH:9])[C:25]2[C:21]3[CH:20]=[N:19][CH:18]=[N:17][C:22]=3[NH:23][CH:24]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12]
Reactant: CCCS(=O)(=O)Nc1cccc(C=O)c1F
Reactant: c1ncc2cc[nH]c2n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCS(=O)(=O)Nc1cccc(C(O)c2c[nH]c3ncncc23)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.8 %

Procedure:
To propane-1-sulfonic acid (2-fluoro-3-formyl-phenyl)-amide (18.75 mg, 0.30 mmol) in 0.6 mL of methanol, 7H-pyrrolo[2,3-d]pyrimidine (6, 73 mg, 0.61 mmol) and potassium hydroxide (51 mg, 0.92 mmol) were added under an atmosphere of nitrogen. The reaction was stirred at room temperature for 24 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and purified by silica gel column chromatography eluting with 5% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a solid (P-0005, 85 mg, 76%). MS(ESI) [M+H+]+=365.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].O.[C:13](OCC)(=[O:15])C>>[N+:8]([C:4]1[C:3]2[O:11][C:13](=[O:15])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: CCOC(C)=O
Reactant: Nc1cccc([N+](=O)[O-])c1O
Solvent: O
Product: O=c1[nH]c2cccc([N+](=O)[O-])c2o1
Reaction time: 3 h
Yield: 73 %

Procedure:
2.27 g of N,N′-carbonyldiimidazole (14 mmol, 1.4 eq) in a homogeneous suspension in 6 ml of ethyl acetate were added to 1.54 g of 2-amino-6-nitrophenol (10 mmol, 1 eq) in solution in 10 ml of ethyl acetate. The reaction medium was vigorously stirred for 3 hours, and then 10 ml of water were added. The stirring was continued for 15 minutes, before evaporating off approximately ¾ of the ethyl acetate. The reaction medium was brought to 0° C. and then 2 ml of 37% hydrochloric acid were added. The stirring was again continued for 15 minutes. The reaction medium was filtered. The solid obtained was washed with a 1 N hydrochloric acid solution, with water and with a water-ethanol (4:1) mixture, and then oven-dried. 1.3 g of product were obtained in the form of a pale yellow solid. Yield=73%.
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6].[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18].S(=O)(=O)(O)O>>[CH2:16]([NH:20][C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6])[CH:17]([CH3:19])[CH3:18]
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1F
Reactant: CC(C)CN
Agent: O=S(=O)(O)O
Product: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1NCC(C)C
Temperature: 25 °C
Reaction time: 192 h

Procedure:
2.0 g (9 mmol) of 3-fluoro-2-methyl-4-(methylsulfonyl)benzoic acid were dissolved in 26.5 ml (267 mmol) of isobutylamine. The mixture was heated at reflux with stirring for 8 days, cooled to RT, acidified with 10% strength sulfuric acid and extracted twice with ethyl acetate. The combined organic phases were dried over MgSO4, and the solvent was removed under reduced pressure. This gave 2.4 g of a colorless solid of a purity of 98%.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[NH:14]1[CH2:15][CH2:16][CH:11]([CH2:10][N:9]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:13]1
Reactant: O=Cc1ccccc1
Reactant: NCC1CCNCC1
Solvent: Cc1ccccc1
Product: C(=NCC1CCNCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Benzaldehyde (28.0 g; 0.264 mol) was added, dropwise, to a solution of 4-aminomethylpiperidine (30.2 g; 0.264 mol) in toluene (100 ml). The solution thus obtained was kept stirred at room temperature. After 3 h, the solvent was removed by evaporation at reduced pressure and the residue was taken up twice in toluene. 53.4 g of N-hexahydro-4-pyridinylmethyl-N-phenylmethylidenamine was thus obtained, and was used in subsequent reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[CH2:20][CH2:21]OS(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[CH2:20][CH2:21][O:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn2cccc(O)c2n1
Reactant: CS(=O)(=O)OCCc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn2cccc(OCCc3c(Cl)cccc3Cl)c2n1
Temperature: 70 °C
Reaction time: 6 h
Yield: 23.4 %

Procedure:
A mixture of 8-hydroxy-2-methylimidazo[1,2-a]pyridine (296 mg), 1,3-dichloro-2-(2-mesyloxyethyl)benzene (645 mg) and potassium carbonate (828 mg) in N,N-dimethylformamide (12 ml) was stirred for 6 hours at 70° C. The mixture was treated according to a similar manner to that of Preparation 16 to give 8-[2-(2,6-dichlorophenyl)ethyloxy]-2-methylimidazo[1,2-a]pyridine (150 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[N:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])=[C:6]2[OH:26])#[CH:2].C(O)(C(F)(F)F)=O>>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[N:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[C:7]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])=[C:6]2[OH:26])#[CH:2]
Reactant: C#Cc1cnc2c(c1)c(O)c(C(=O)NCC(=O)OC(C)(C)C)c(=O)n2C
Solvent: O=C(O)C(F)(F)F
Product: C#Cc1cnc2c(c1)c(O)c(C(=O)NCC(=O)O)c(=O)n2C

Procedure:
The title compound was prepared similarly to the procedure described for Example 1 (g) by treatment of tert-butyl 2-(6-ethynyl-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamido)acetate (Example 79 (b)) with TFA. MS (ESI, pos. ion) m/z: 302 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.39 (t, J=5.3 Hz, 1 H), 8.91 (d, J=2.2 Hz, 1 H), 8.44 (d, J=2.3 Hz, 1 H), 4.51 (s, 1 H), 4.15 (d, J=5.7 Hz, 2 H), 3.68 (s, 3 H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].C(OC([N:38]1[CH2:43][CH2:42][CH:41]([C:44]2[CH:49]=[CH:48][C:47]([C:50](O)=O)=[CH:46][CH:45]=2)[CH2:40][CH2:39]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:50][C:47]1[CH:46]=[CH:45][C:44]([CH:41]2[CH2:40][CH2:39][NH:38][CH2:43][CH2:42]2)=[CH:49][CH:48]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: CCNc1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(C2CCNCC2)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 36.2 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (50 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (100 mg) according to an analogous synthetic method to Example 209, the title compound (22 mg) was obtained.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]3[CH:23]=[CH:22][CH2:21][N:20]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]5[O:32][CH2:33][O:34][C:28]=5[CH:27]=4)[C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])C.Cl.O>C(O)C>[C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]3[CH:23]=[CH:22][CH2:21][N:20]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]5[O:32][CH2:33][O:34][C:28]=5[CH:27]=4)[C:18]=3[N:19]=2)[CH2:10][CH2:9]1)([OH:7])=[O:5]
Reactant: CCOC(=O)C1CCN(c2ncc3c(n2)N(NCc2ccc4c(c2)OCO4)CC=C3)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCN(c2ncc3c(n2)N(NCc2ccc4c(c2)OCO4)CC=C3)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.1 %

Procedure:
1.56 ml of 1N sodium hydroxide was added to a solution of 170 mg of 2-(4-ethoxycarbonylpiperidino)-8(3,4-methylenedioxybenzyl)aminopyrido[2,3-d]pyrimidine in 10 ml of ethanol. The obtained mixture was stirred at room temperature for 6 hours and neutralized by the addition of 1N hydrochloric acid and water. The crystals thus precipitated were recovered by filtration, whereby 121 mg of the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][N:12](C=O)C>C(Cl)Cl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:11]#[N:12])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Solvent: ClCCl
Product: N#Cc1ccc([N+](=O)[O-])cn1
Reaction time: 0.33 h

Procedure:
A mixture comprising 2-bromo-5-nitropyridine (5.6 g, 27.7 mmol), cuprous cyanide (2.5 g, 27.4 mmol) and DMF (5 mL) was heated at 105° C. for 2.5 hours, cooled and diluted with methylene chloride (200 mL). The mixture was stirred 20 minutes, filtered and concentrated under reduced pressure. The residue was dissolved in methylene chloride and the solution was washed sequentially with 2N sodium hydroxide (150 mL), 7M ammonium hydroxide (150 mL) and water (150 mL), dried (MgSO4), filtered and concentrated under reduced pressure to provide 5-nitropyridine-2-carbonitrile (3.14 g, 21 mmol) as a yellow oil. 1H-NMR (300 Mhz, DMSO-d6): 8.4 (d, 1H), 8.8 (d, 1H), 9.5 (s, 1H); MS (EI); Calculated for C6H3N3O2, 149.1, Found (MH+): 149.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[C:19]([C:21]1([OH:28])[CH2:25][CH2:24][N:23]([CH3:26])[C:22]1=[O:27])#[CH:20]>>[OH:28][C:21]1([C:19]#[C:20][C:2]2[CH:18]=[CH:17][C:5]3[O:6][CH2:7][CH2:8][C:9]4[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=4[C:4]=3[CH:3]=2)[CH2:25][CH2:24][N:23]([CH3:26])[C:22]1=[O:27]
Reactant: C#CC1(O)CCN(C)C1=O
Reactant: NC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: CN1CCC(O)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)sc2CCO3)C1=O
Yield: 48 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide) was reacted with 3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (WO2009/158011 A1) to give the titled compound as a brown solid (56.1 mg, 48%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[NH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:17]=1)[CH:7]=[CH:6]2.Cl.N1C=CC=CC=1>Cl>[C:18]1([C:15]2[NH:14][C:13]([C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]4)=[CH:17][CH:16]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc2cc(-c3ccc(-c4ccccc4)[nH]3)ccc2c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2cc(-c3ccc(-c4ccccc4)[nH]3)ccc2c1
Temperature: 200 °C
Yield: 94.9 %

Procedure:
A mixture of 2-(6-methoxy-2-naphthyl)-5-phenyl-1H-pyrrole (0.72 g, 2.4 mmol), prepared in the previous step, and pyridine hydrochloride (7.2 g) was heated at 200° C. under a nitrogen atmosphere for 1 hour. The mixture was cooled to ambient temperature and the solids were dissolved in 1N HCl (150 mL). The mixture was extracted three times with methylene chloride. The combined extracts were washed one time with water, dried (MgSO4), filtered and the solvent removed under reduced pressure to give 6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthol as a grayish solid (0.65 g, 95%), mp 209.5–210.5 Elemental Analysis for C20H15NO Calc'd: C, 84.19; H, 5.30; N, 4.91. Found: C, 83.38; H, 5.38; N, 4.67.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:28][CH2:29][NH:30]C(OC(C)(C)C)=O)[C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])(C)(C)C.Cl>O1CCOCC1>[NH2:30][CH2:29][CH2:28][N:21]([CH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:9]2[C:8]([C:6]([OH:7])=[O:5])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:19][CH:18]=1)[C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCC(=O)N(CCNC(=O)OC(C)(C)C)Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCC(=O)N(CCN)Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
4′-[(2-t-Butoxycarbonylaminoethyl)pentanoylamino]methylbiphenyl-2-carboxylic acid t-butyl ester (3b) and 4′[(2-aminoethyl)pentanoylamino]methylbiphenyl-2-carboxylic acid (3c): Valeryl chloride (4.6 mL, 38.7 mmol) was added to a solution of crude intermediate (3a) (15 g, 35.2 mmol) in toluene (100 mL) at 0° C. followed by the addition of DIPEA (18.4 mL, 105 mmol). The mixture was stirred at room temperature for 3 hours. 1M aqueous NaOH (10 mL) was added and the mixture was concentrated in vacuo. The concentrate was extracted with EtOAc (3×150 mL) and water (80 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford crude intermediate (3b). A solution of crude intermediate (3b), 1,4-dioxane (50 mL) and 4M HCl in 1,4-dioxane (50 mL) was stirred for 40 minutes at room temperature. The precipitate was filtered and purified by reverse phase HPLC to afford intermediate (3c).