Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH2:30][NH:31][CH3:32])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:34]1[CH2:36][C@@H:35]1[CH2:37][O:38][C:39]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:40]=1[CH:41]=[CH:42][CH:43]=[N:44]2>C(O)C>[C:14]1([CH2:13][CH2:12][CH2:11][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH2:30][N:31]([CH2:36][C@@H:35]([OH:34])[CH2:37][O:38][C:39]3[CH:48]=[CH:47][CH:46]=[C:45]4[C:40]=3[CH:41]=[CH:42][CH:43]=[N:44]4)[CH3:32])[CH2:25][CH2:24]2)=[O:22])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Reactant: CNCC(=O)N1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Solvent: CCO
Product: CN(CC(=O)N1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1)C[C@@H](O)COc1cccc2ncccc12
Temperature: 25 °C

Procedure:
1-[(N-methyl)-2-aminoacetyl]-piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (63) (223.5 mg; 0.497 mmol]) is dissolved in ethanol (10 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added, then the mixture is refluxed for 17.5 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affording the desired product (110 mg) as a white solid. ESMS:MH+ 651.6.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([C:15]3[NH:19][N:18]=[CH:17][CH:16]=3)[CH3:14])=[CH:12][C:7]=2[S:6][C:5]1=[O:20].CC(C)([O-])C.[Li+].F[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][O:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)=[CH:30][N:29]=1>CN(C)C=O.C1COCC1>[CH3:1][O:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([C:15]3[CH:16]=[CH:17][N:18]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][O:37][CH:38]5[CH2:43][CH2:42][CH2:41][CH2:40][O:39]5)=[CH:30][N:29]=4)[N:19]=3)[CH3:14])=[CH:12][C:7]=2[S:6][C:5]1=[O:20]
Reactant: COCn1c(=O)sc2cc(C(C)c3ccn[nH]3)ccc21
Reactant: Fc1ccc(OCCOC2CCCCO2)cn1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCn1c(=O)sc2cc(C(C)c3ccn(-c4ccc(OCCOC5CCCCO5)cn4)n3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
Dissolve 3-(methoxymethyl)-6-[1-(1H-pyrazol-5-yl)ethyl]-3H-1,3-benzothiazol-2-one (7.7 g, 26.6 mmoles) in dimethylformamide (0.2 M; 133 mL). Add lithium t-butoxide ((1.5 Eq of a 1.00 molar solution in THF), 39.9 mmoles; 39.9 mL)) and stir 15 min. Add 2-fluoro-5-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (2.00 Eq; 53.2 mmoles; 12.8 g). Heat the reaction in an oil bath to 140° C. and purge with N2 to remove THF. Heat the mixture at reflux for 5 hr. Cool the mixture to room temperature and quench with saturated ammonium chloride. Extract into EtOAc (2×200 mL), wash with water (2×100 mL), followed by brine (200 mL). Dry over sodium sulfate, filter and concentrate. Purify by HPLC (silica) eluting with 40% EtOAc/hexanes to give 3-(methoxymethyl)-6-{1-[1-(5-{2-(tetrahydro-2H-pyran-2-yloxy)ethoxy}pyridine-2-yl)-1H-pyrazol-3-yl]ethyl}-3H-1,3-benzothiazol-2-one as a pale yellow oil (10 g; 19.6 mmoles, 74% yield). LCMS (low) rt=2.6, M+1=511.
Reaction SMILES: [CH2:1]([N:7]([CH3:51])[C:8]([CH:10]1[CH:14]([C:15](=[O:32])[NH:16][C:17]2([C:22]([NH:24][S:25]([C:28]3([CH3:31])[CH2:30][CH2:29]3)(=[O:27])=[O:26])=[O:23])[CH2:19][CH:18]2C=C)[CH2:13][CH:12]([O:33][C:34](=[O:50])[NH:35][C:36]2[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=2[C:43]2[S:44][C:45](CC)=[CH:46][N:47]=2)[CH2:11]1)=[O:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH:52]1(S(O)(=O)=O)C[CH2:53]1>>[CH3:51][N:7]1[C:8](=[O:9])[CH:10]2[CH:14]([CH2:13][CH:12]([O:33][C:34](=[O:50])[NH:35][C:36]3[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:37]=3[C:43]3[S:44][CH:45]=[C:46]([CH2:52][CH3:53])[N:47]=3)[CH2:11]2)[C:15](=[O:32])[NH:16][C:17]2([C:22]([NH:24][S:25]([C:28]3([CH3:31])[CH2:30][CH2:29]3)(=[O:26])=[O:27])=[O:23])[CH:19]([CH2:18]2)[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2][CH2:1]1
Reactant: C=CCCCCN(C)C(=O)C1CC(OC(=O)Nc2cc(C)ccc2-c2ncc(CC)s2)CC1C(=O)NC1(C(=O)NS(=O)(=O)C2(C)CC2)CC1C=C
Reactant: O=S(=O)(O)C1CC1
Product: CCc1csc(-c2ccc(C)cc2NC(=O)OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5(C)CC5)CC4C=CCCCCN(C)C(=O)C3C2)n1
Yield: 10 %

Procedure:
The procedure described in Example 18-10 was followed, but using the compound prepared in Example 22 (112) (22 mg, 30 μmol) instead of the corresponding cyclopropanesulphonic acid derivative, which gave the title compound (2.1 mg, 10%). LC/MS (Method I): tr=2.41 min, >95%, m/z (ESI+)=712 (MH+).
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](I)[CH3:20]>CO>[CH2:19]([S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)[CH3:20]
Reactant: CCI
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Solvent: CO
Product: CCSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1

Procedure:
10.3 g of cis-4,5-diphenyl-imidazolidine-2-thione are suspended in a mixture of 25 ml of methanol and 3.8 ml of ethyl iodide and the suspension is refluxed for 1 hour, with stirring. A further 75 ml of methanol are then added and the mixture is refluxed for 16 hours. The clear reaction solution is evaporated to dryness and the residue is taken up in a mixture of 150 ml of water and 250 ml of ethyl acetate. In order to liberate the base, the mixture is rendered alkaline iwth concentrated aqueous ammonia solution and shaken thoroughly and the organic phase is separated off, dried over sodium sulfate and evaporated. Recrystallisation of the residue from isopropanol/petroleum ether yields cis-2-ethylthio-4,5-diphenyl-imidazoline with a melting point of 95°-96°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:32])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:23]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(C1C=CC(NC(=O)C2C=CC(N3CCNCC3)=NC=2)=CC=1)(C)(C)C>>[C:28]([C:24]1[CH:23]=[C:22]([NH:21][C:20](=[O:32])[C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][CH:16]=2)[CH:27]=[CH:26][CH:25]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cn2)CC1
Agent: CC(C)(C)c1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)nc2)c1

Procedure:
N-(3-tert-Butyl-phenyl)-6-piperazin-1-yl-nicotinamide was prepared from 4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester in a manner similar to the one described in the synthesis of N-(4-tert-butyl-phenyl)-6-piperazin-1-yl-nicotinamide above. HRMS m/z calcd for C20H26N4O [M+H]+: 339.2179. Found: 339.2180.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1)#[CH:2].[F:11][C:12]1[CH:21]=[CH:20][C:19](I)=[CH:18][C:13]=1[C:14]([NH:16][CH3:17])=[O:15].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:11][C:12]1[CH:21]=[CH:20][C:19]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=2)=[CH:18][C:13]=1[C:14]([NH:16][CH3:17])=[O:15]
Reactant: C#Cc1cncc(OC)c1
Reactant: CNC(=O)c1cc(I)ccc1F
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CNC(=O)c1cc(C#Cc2cncc(OC)c2)ccc1F
Temperature: 60 °C
Yield: 72.2 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (64 mg, 0.091 mmol), copper (I) iodide (35 mg, 0.19 mmol), and 3-ethynyl-5-methoxypyridine, (prepared as described in PREPARATION 10), (250 mg, 1.9 mmol) to a solution of 2-fluoro-5-iodo-N-methylbenzamide, (prepared as described in PREPARATION 39), (0.63 g, 2.3 mmol) in triethylamine (3.8 mL, 27.3 mmol) and heat at 60° C. for 16 h. Cool to room temperature and concentrate. Purify by silica gel chromatography, eluting with 100:0 to 10:90 dichloromethane:ethyl acetate, followed by a second silica gel chromatography eluting with 50:50 to 75:25 ethyl acetate:hexanes, to give the title compound as a white solid (390 mg, 73%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16])[C:6](O)=[O:7].CN(C)C=O.C(Cl)(=O)C([Cl:27])=O>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16])[C:6]([Cl:27])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C(CCCCl)c1ccccc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)C(CCCCl)c1ccccc1C(F)(F)F
Reaction time: 1.5 h

Procedure:
5-Chloro-2-(2-trifluoromethylphenyl)valeric acid obtained in Preparation Example 2-3 (500 mg) was dissolved in tetrahydrofuran (9 mL). Dimethylformamide (0.1 ml) and oxalyl chloride (184 μL) were added at 0° C. and the reaction was initiated at room temperature. After 1.5 hours, concentration under reduced pressure gave an oil (532 mg), which was used directly for the next reaction as a crude product.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[C:11]([CH3:15])=[N:12][N:13]([CH3:14])[C:9]=2[C:8](=[O:16])[NH:7][C:6]2[N:17]=[CH:18][CH:19]=[CH:20][C:5]1=2)=[O:3].[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:33][CH2:34][NH2:35])[CH2:24][CH3:25])[CH3:22]>C(#N)C>[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:33][CH2:34][NH:35][C:2]([N:4]1[C:10]2[C:11]([CH3:15])=[N:12][N:13]([CH3:14])[C:9]=2[C:8](=[O:16])[NH:7][C:6]2[N:17]=[CH:18][CH:19]=[CH:20][C:5]1=2)=[O:3])[CH2:24][CH3:25])[CH3:22]
Reactant: Cc1nn(C)c2c1N(C(=O)Cl)c1cccnc1NC2=O
Reactant: CCN(CC)CC1CCCCN1CCN
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CCNC(=O)N1c2cccnc2NC(=O)c2c1c(C)nn2C
Yield: 17 %

Procedure:
Prepared analogously to Example 2 from 4-(chlorocarbonyl)-1,3-dimethyl-1,4,9,10-tetrahydro-pyrazolo[4,3-e]pyrido[2,3-b][1,4]diazepin-10-one and 2-[2-[(diethylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 17% of theory. Colourless crystals, m.p. 138°-139° C. (acetonitrile).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:12])[CH:9]([OH:11])[CH3:10])=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:12])[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: C=C(c1ccc(C)cc1)C(C)O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C=C(C(C)=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.91 g of alcohol 39 is dissolved in 300 ml of methylene chloride, and 43.5 g of manganese dioxide is added under nitrogen. It is stirred overnight at room temperature, filtered on Celite, and the residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 850 mg of title compound 40 in addition to 1.06 g of the starting material are obtained as colorless oils.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[CH:13][N:14]([CH3:16])C)[C:7](=[O:12])[NH:8][CH2:9]2)=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23]C(N)=[CH:21][CH:20]=1>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[CH:13][NH:14][C:16]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[C:7](=[O:12])[NH:8][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(N)cc1
Reactant: CN(C)C=C1C(=O)NCc2cc(Br)ccc21
Solvent: CN(C)C=O
Product: COc1ccc(NC=C2C(=O)NCc3cc(Br)ccc32)cc1
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 22.2 %

Procedure:
To a suspension of crude 7-bromo-4-dimethylaminomethylene-1,4-dihydro-2H-isoquinolin-3-one (400 mg, 1.43 mmol) in N,N-dimethylformamide (250 mL) is added 4-anisidine (193 mg, 1.57 mmol). The reaction mixture is shaken at 115° C. for 1.5 hours. The reaction mixture is filtered and the filtrate is purified by Prep. HPLC. The pure fractions were combined and concentrated to yield 114 mg of 7-Bromo-4-[(4-methoxy-phenylamino)-methylene]-1,4-dihydro-2H-isoquinolin-3-one.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[CH2:29]([N:31]1[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=2)[C:32]1=[O:49])[CH3:30]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:36]3[CH:37]=[C:38]4[C:33](=[CH:34][CH:35]=3)[C:32](=[O:49])[N:31]([CH2:29][CH3:30])[CH2:39]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CCN1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Reactant: COc1cc(OC)c(Cl)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Product: CCN1Cc2cc(-c3n[nH]c4cc(-c5c(F)c(OC)cc(OC)c5Cl)ncc34)ccc2C1=O

Procedure:
This compound was prepared using procedures analogous to those described in Example 52, Step 8 starting from 6-(2-chloro-6-fluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=466.1.
Reaction SMILES: [C:1]([O:20]C)(=O)[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][CH3:18].[NH2:22][CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26].CC(C)([O-])C.[K+]>>[CH3:27][C:24]([CH3:28])([CH2:25][OH:26])[CH2:23][NH:22][C:1](=[O:20])[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][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC
Reactant: CC(C)(CN)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCCCCCCCCCCCCCCC(=O)NCC(C)(C)CO
Temperature: 190 °C

Procedure:
In a 500 ml, three-neck, round-bottom flask equipped with a thermometer, stirrer and a Stark and Dean trap with condenser were placed 119.4 g of methyl stearate, 41 g of 3-amino-2,2-dimethylpropanol and 3 g of potassium tert-butoxide. The mixture was heated to 190° C., and the methanol distilled off. The reaction mixture was dissolved in hot isopropanol and filtered. On cooling, the product crystallized, and after filtration and drying it melted at 44° C. IR showed an ester carbonyl. The pure product was obtained by washing with hot hexane. The pure product melted at 68°-69° C.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH:8]=[CH2:9])([OH:7])[CH2:5][CH2:4][NH:3]1.[F:10][C:11]1[C:18]([CH3:19])=[C:17](F)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14].C(=O)([O-])[O-].[Li+].[Li+]>>[F:10][C:11]1[C:18]([CH3:19])=[C:17]([N:3]2[CH2:4][CH2:5][C@@:6]([OH:7])([CH:8]=[CH2:9])[C@@H:2]2[CH3:1])[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cc1c(F)ccc(C#N)c1F
Reactant: C=C[C@]1(O)CCN[C@H]1C
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C=C[C@]1(O)CCN(c2ccc(C#N)c(F)c2C)[C@H]1C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3R)-2-methyl-3-vinylpyrrolidin-3-ol (556 mg), 2,4-difluoro-3-methylbenzonitrile (350 mg) and lithium carbonate (350 mg), the title compound was obtained as a colorless solid (yield: 84.6 mg, yield: 23%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:25]=[C:26]([N:31]([CH3:54])[CH:32]([C:34]2[CH:35]=[C:36]([C:51](O)=[O:52])[CH:37]=[C:38]3[C:43]=2[O:42][C:41]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[CH:40][C:39]3=[O:50])[CH3:33])[CH:27]=[C:28]([F:30])[CH:29]=1.C(N(C(C)C)C(C)C)C.[CH3:64][NH:65][CH2:66][CH2:67][OH:68]>CN(C=O)C>[F:30][C:28]1[CH:27]=[C:26]([N:31]([CH3:54])[CH:32]([C:34]2[CH:35]=[C:36]([C:51]([N:65]([CH2:66][CH2:67][OH:68])[CH3:64])=[O:52])[CH:37]=[C:38]3[C:43]=2[O:42][C:41]([N:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)=[CH:40][C:39]3=[O:50])[CH3:33])[CH:25]=[C:24]([F:23])[CH:29]=1
Reactant: CC(c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1
Reactant: CNCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1cc(C(=O)N(C)CCO)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
TBTU (108 mg, 0.34 mmol) was added in one portion to a stirred solution of 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (125 mg, 0.28 mmol), N-ethyl-N-isopropylpropan-2-amine (0.103 mL, 0.59 mmol) and 2-(methylamino)ethanol (0.027 mL, 0.34 mmol) in DMF (1 mL). The resulting solution was stirred at RT for 2 hrs. The reaction mixture was filtered and purified by preparative HPLC using a reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 mL/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-N-(2-hydroxyethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (90 mg, 64%) as a off-white solid. Mass Spectrum: M+H+ 502. NMR Spectrum (DMSOd6 at 323° K): 1.58 (d, 3H), 2.65 (s, 3H), 3.01 (s, 3H), 3.23-3.40 (m, 5H), 3.4-3.71 (m, 7H), 4.74 (bs, 1H), 5.52 (s, 1H), 5.57 (q, 1H), 6.38 (t, 1H), 6.53 (d, 2H), 7.74 (bs, 1H), 7.93 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:12]([Si](C)(C)C)#[CH:13]>>[C:12]([C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)#[CH:13]
Reactant: Brc1cncc2cccnc12
Reactant: C#C[Si](C)(C)C
Product: C#Cc1cncc2cccnc12

Procedure:
The title compound can be synthesized from 8-ethynyl-1,6-naphthyridine and N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 1. 8-ethynyl-1,6-naphthyridine is prepared from 8-bromo-1,6-naphthyridine and ethynyltrimethylsilane according to the 2 steps procedure described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17](O)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:37][CH:38]=3)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)C(CCOC)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1

Procedure:
1.50 g (3.98 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate), 658 mg (3.98 mmol) of ethyl 4-aminobenzoate, 566 mg (3.98 mmol) of Oxima and 620 μl (3.98 mmol) of DIC in 39 ml of dimethylformamide were reacted according to General Method 5B. Filtration gave the title compound. Yield: 1.87 g (85% of theory)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[C:23]3[C:18](=[N:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]([CH2:25][CH3:26])[C:16](=[O:27])[C:15]=2[CH2:28][CH2:29][C:30]([OH:32])=O)[CH:11]=[CH:12][CH:13]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.Cl>CN(C=O)C.C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[C:23]3[C:18](=[N:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]([CH2:25][CH3:26])[C:16](=[O:27])[C:15]=2[CH2:28][CH2:29][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH:11]=[CH:12][CH:13]=1
Reactant: CCn1c(=O)c(CCC(=O)O)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Reactant: C1COCCN1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCn1c(=O)c(CCC(=O)N2CCOCC2)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 0.3 ml portion of oxalyl chloride and one drop of DMF were added to a 20 ml THF solution containing 1.00 g of 3-[4-(3-chlorophenyl)-l-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoic acid, followed by stirring at room temperature for further 30 minutes. The reaction mixture was added dropwise to an ice-cooled 10 ml THF solution containing 1.0 ml of morpholine, followed by stirring for 30 minutes. To the reaction mixture was added 1M hydrochloric acid and the whole was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography (chloroform-methanol) and then recrystallized from diisopropyl ether-ethyl acetate to obtain 780 mg of 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-[3-(morpholin-4-yl)-3-oxopropyl]-1,8-naphthyridin-2(1H)-one as colorless crystals.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=2)[C:29](O)=[O:30])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:57]1[CH2:61][CH2:60][CH2:59][CH:58]1[C:62]([O:64][CH3:65])=[O:63]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=2)[C:29]([N:57]2[CH2:61][CH2:60][CH2:59][CH:58]2[C:62]([O:64][CH3:65])=[O:63])=[O:30])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Reactant: COC(=O)C1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)C1CCCN1C(=O)c1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Reaction time: 0.17 h
Yield: 59.3 %

Procedure:
To a stirred solution of 5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinic acid (80.0 mg, 0.190 mmol) (prepared as in Example 12) in DMF (2 mL), were added DMAP (35.0 mg, 0.285 mmol) and HATU (108 mg, 0.285 mmol) and the reaction mixture was stirred for 10 minutes. Methyl pyrrolidine-2-carboxylate (12.0 g, 0.0950 mmol) was added and the reaction mixture was stirred at room temperature for 14 h. The reaction mixture concentrated under reduced pressure to remove DMF and to the resulting residue water (10 mL) was added. The aqueous mixture was extracted with CH2Cl2 (15×2 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (Condition B-68 as described in general methods) to obtain methyl 1-(5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinoyl)pyrrolidine-2-carboxylate (30.0 mg, 59.3%). LCMS Condition B-14: retention time 2.31 min, [M−1]=531.2. HPLC Condition B-63: retention time 16.30 min, Purity 99.70%. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.87-1.98/2.30-2.35 (m, 4H), 3.44/3.70 (s, 3H), 3.55/3.67 (dd, J=6.0 Hz, J=6.8 Hz, 2H), 4.47-4.49/4.56-4.58 (m, 1H), 4.54/4.82 (d, J=5.6 Hz, 2H), 6.71/6.76 (t, J=5.6 Hz, 1H), 6.82 (d, J=2.8 Hz, 1H), 7.23-7.56 (m, 10H), 7.91/7.94 (d, J=2.8 Hz, 1H), 8.44/8.58 (t, J=2.0 Hz, 1H), 8.65/8.81 (d, J=2.0 Hz, 1H), 9.39/9.44 (d, J=2.0 Hz, 1H). Molecule exists as two rotomers with ratio 70/30.