Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]([NH:12][C:13]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Li+].[OH-]>CO.C1COCC1.O>[C:6]1([CH2:5][CH:4]([NH:12][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:14])[C:3]([OH:21])=[O:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NC(Cc1ccccc1)C(=O)O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a solution of 3-phenyl-2-[(pyridine-3-carbonyl)-amino]-propionic acid methylester (1.2 g, 4.2 mmol) in methanol (10 mL), THF (30 mL) was added LiOH (0.885 g, 21.1 mmol) dissolved in water (10 mL). The mixture was allowed to stir at room temperature (25° C.) over a period of 2 hrs. THF was evaporated from reaction mixture, acidified with 1.5N HCl then extracted with ethylacetate (200 mL) and concentrated to obtain product as yellow color solid (1.0 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:43](COCC[Si](C)(C)C)[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([CH2:24][NH:25]C(=O)OCC4C5C=CC=CC=5C5C4=CC=CC=5)=[N:22][CH:23]=3)[C:15]=2[CH:14]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(N)CN>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:43][C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([CH2:24][NH2:25])=[N:22][CH:23]=3)[C:15]=2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(CNC(=O)OCC5c6ccccc6-c6ccccc65)n43)n1COCC[Si](C)(C)C)cn2C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(CN)n43)[nH]1)cn2C
Temperature: 85 °C

Procedure:
To a round bottom flask was added (9H-fluoren-9-yl)methyl (7-(5-methoxy-1-methyl-1H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)methylcarbamate (0.300 g, 0.429 mmol, prepared using J.1 from Preparation #I.1 with 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)acetic acid and L.1 with mercury(II) trifluoroacetate), DMF (10 mL), TBAF (1.0 M in THF, 1.72 mL, 1.72 mmol) and ethylenediamine (0.870 mL, 12.9 mmol). The mixture was heated to about 85° C. for about 6 h. The mixture was cooled to rt and concentrated in vacuo. The crude material was purified by flash chromatography (120 g silica gel column, DCM/MeOH 1:0 to 10:1). The solid was purified by reverse phase preparatory HPLC (Table 2, Method e) to give fractions with the title compound. The fractions were combined and concentrated in vacuo until a precipitate formed. The solid was collected by vacuum filtration and then dried under reduced pressure at about 60° C. for about 16 h to give (7-(5-methoxy-1-methyl-1H-indol-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)methanamine (0.021 g, 14%): LC/MS (Table 2, Method a) Rt=1.53 min; MS m/z 347 (M+H)+. Syk IC50=B.
Reaction SMILES: [CH:1]1([S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=5)=[CH:25][C:23]=4[CH:24]=3)=[O:17])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:44])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH:1]1([S:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=5)=[CH:25][C:23]=4[CH:24]=3)=[O:17])=[CH:13][CH:14]=2)=[O:44])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSC4CCCCC4)cc2)CCO3)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)C4CCCCC4)cc2)CCO3)cc1
Reaction time: 0.17 h
Yield: 24.5 %

Procedure:
To a solution of N-(4-(cyclohexylthiomethyl)phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.19 g) in dichloromethane (5 ml) was added 70% m-chloroperbenzoic acid (0.097 g) under ice-cooling, and the mixture was stirred for 10 minutes. To the mixture was added sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (methanol/dichloromethane) to give crude crystals, which were recrystallized from ethanol to give N-(4-(cyclohexylsulfinylmethyl)phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 106) (0.048 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4/[CH:27]=[CH:28]\[C:29]([O:31]C)=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4/[CH:27]=[CH:28]\[C:29]([OH:31])=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: COC(=O)/C=C\c1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(/C=C\C(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 60 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
To a solution of methyl (2Z)-3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]-2-propenoate (D63) (30 mg) in THF (5 mL) was added aqueous NaOH (2 M, 1 mL). The reaction was stirred at 60° C. for 4 h. The mixture was cooled to room temperature and acidified with aqueous HCl (2 M) to pH 4-5, partitioned between ethyl acetate (25 mL) and water (25 mL). The organic phase was washed with water (25 mL), dried over anhydrous sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford (2Z)-3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]-2-propenoic acid (E38) (25 mg). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 3.75 (3H, s), 4.89 (1H, m), 5.77 (1H, d), 7.34 (2H, m), 7.45 (1H, d), 7.52 (1H, dd), 8.07 (1H, dd), 8.14 (1H, dd), 8.21 (1H, d), 8.70 (1H, s), 12.02 (1H, br s). MS (ES): C23H20ClN3O4 requires 437; found 438.2 (M+H+).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[N:8]=[CH:9][N:10]2[CH:14]=[CH:13][S:12][C:11]=12)(=[O:4])=[O:3].C([Li])CCC.CCCCCC.[CH2:26]([Sn:30](Cl)([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH3:29].P([O-])([O-])([O-])=O>CN(P(N(C)C)(N(C)C)=O)C.C1COCC1>[CH3:1][S:2]([NH:5][CH2:6][C:7]1[N:8]=[CH:9][N:10]2[CH:14]=[C:13]([Sn:30]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:26][CH2:27][CH2:28][CH3:29])[S:12][C:11]=12)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)NCc1ncn2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(CNS(C)(=O)=O)c2s1
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
A solution of 231 mg of 7-(methanesulfonylaminomethyl)imidazo[5,1-b]thiazole dissolved in a mixed solution composed of 10 ml of dry THF and 1 ml of dry HMPA was cooled to −5° C. with stirring. A 1.6 N n-butyllithium/n-hexane solution (2.0 ml) was added dropwise to the mixed solution in an argon atmosphere at −51 to −49° C. over a period of 15 min . The mixture was stirred at the same temperature for 15 min. Further, 0.34 ml of tri-n-butylstannyl chloride was added dropwise thereto at −50 to −48° C. over a period of 10 min. The mixture was stirred at −50 to −40° C. for 140 min. Tri-n-butylstannyl chloride (0.07 ml) was additionally added to the reaction solution at −42° C. The mixture was stirred for 30 min. 0.38 M phosphate buffer (pH 6.0) (15 ml) was added thereto. The mixed solution was extracted with 30 ml of ethyl acetate. The organic layer was washed with 0.38 M phosphate buffer (pH 6.0) and saturated brine in that order, and then dried over anhydrous sodium sulfate. The anhydrous magnesium sulfate was removed by filtration. The solvent was removed by distillation. The brown oil thus obtained was purified by column chromatography on silica gel (eluting with dichloromethane:ethyl acetate=1:1 and then with ethyl acetate only) to give 160 mg of the title compound as a yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH:13]=[O:14])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:15][C:11]1[CH:10]=[C:9]([CH:13]=[O:14])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1cccn1-c1ncccc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)cn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a solution of 1.5 g of 3-chloro-2-(2-formyl-1H-pyrrol-1-yl)pyridine in 20 ml of N,N-dimethylformamide, 1.3 g of N-bromosuccinimide was added. The mixture was stirred at room temperature for 3 hours. Water was poured into the reaction mixture, and a deposited precipitate was collected by filtration to obtain 1.9 g of 4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)=[CH:5][CH:4]=[N:3]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:44][CH2:45][CH:46]([OH:58])[CH2:47][N:48]1[CH2:57][CH2:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:49]1>C(Cl)Cl.O>[CH2:49]1[C:50]2[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:56][CH2:57][N:48]1[CH2:47][CH:46]([OH:58])[CH2:45][NH:44][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: Cn1nccc1-c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1nccc1-c1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24 %

Procedure:
To a solution of 3-(1-methyl-1H-pyrazol-5-yl)benzoic acid (130 mg, 0.64 mmol) in DCM (6 mL) was added EDCI (245 mg, 1.28 mmol), HOBt (173 mg, 1.28 mmol), Et3N (195 mg, 1.93 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (132 mg, 0.64 mmol). The mixture was stirred at room temperature for 16 h until completion of the reaction was indicated by which TLC. The reaction solution was then diluted with water (10 mL) and extracted with DCM (2×10 mL) then the combined organic layers were concentrated. The residue was purified by prep-HPLC to give the desired product (60 mg, Yield 25%). 1H NMR (400 MHz, MeOD): 7.55 (s, 1H), 7.52 (s, 1H), 7.24-7.15 (m, 3H), 6.85-6.73 (m, 4H), 6.03 (s, 1H), 4.22 (br.s, 1H), 4.03-3.99 (m, 1H), 3.45 (s, 3H), 3.17-2.73 (m, 7H). LCMS (m/z): 391.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([NH:5][C:6]1[CH:7]=[C:8]([NH:12]/[C:13](=[C:20]2\[C:21](=[O:29])[NH:22][C:23]3[C:28]\2=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=1)=[O:4].[C:32](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:31][C:2]([F:1])([F:30])[C:3]([N:5]([C:6]1[CH:7]=[C:8]([NH:12]/[C:13](=[C:20]2\[C:21](=[O:29])[NH:22][C:23]3[C:28]\2=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=1)[CH3:32])=[O:4]
Reactant: O=C1Nc2ccccc2/C1=C(/Nc1cccc(NC(=O)C(F)(F)F)c1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN(C(=O)C(F)(F)F)c1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
636 mg (1.5 mmol) of (Z)-3-[1-(3-trifluoroacetylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone are dissolved in 20 ml of acetone and after the addition of 423 mg (3 mmol) of potassium carbonate and 0.25 g (3 mmol) of methyl iodide stirred for 18 hours at ambient temperature. The reaction solution is freed from the solvent in vacuo after the insoluble matter has been filtered off. The residue is divided between dichloromethane/water, the organic phase is dried and concentrated by evaporation. The residue is triturated with ether, suction filtered and dried.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:7]2=[O:25])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:40]=[N:41][C:42]([NH2:45])=[CH:43][CH:44]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1(C)C=CC=CC=1>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:40]=[N:41][C:42]([NH:45][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:7](=[O:25])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:43][CH:44]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: COCCOCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: Cc1ccccc1
Product: COCCOCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Yield: 8.4 %

Procedure:
8-Cyclopentyl-2-methanesulfinyl-6-(2-methoxy-ethoxymethyl)-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.86 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.10 g, 3.95 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The reaction mixture was cooled to room temperature and purified by silica gel chromatography to give 4-{6-[8-cyclopentyl-6-(2-methoxy-ethoxymethyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (0.140 g, 14.7%). 1H NMR δ (400 MHz, CDCl3) 8.60 (s, 1H), 8.34 (m, 1H), 7.95 (s, 1H), 7.69 (t, J=1.4 Hz, 1H), 7.42 (m, 1H), 5.91 (m, 1H), 4.53 (d, J=1.2 Hz, 1H), 3.78 (m, 1H), 3.63 (m, 6H), 3.43 (s, 3H), 3.11 (m, 4H), 2.35 (m, 2H), 2.08 (m, 2H), 1.88 (m, 2H), 1.69 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.O.[NH2:16][NH2:17]>C(O)C>[Cl:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][NH2:17])[C:11]([O:12][CH3:13])=[N:10]2
Reactant: NN
Reactant: COc1nc2cc(Cl)ccc2nc1Cl
Solvent: CCO
Solvent: O
Product: COc1nc2cc(Cl)ccc2nc1NN

Procedure:
A mixture of 4.9 g. (0.02 mole) of 2,6-dichloro-3-methoxyquinoxaline and 2.7 g. (0.053 mole) of hydrazine hydrate (2.6 ml.) in 75 ml. of ethanol was stirred at room temperature overnight (i.e., at ca. 20° C. for approximately 16 hours). Upon completion of this step, the resulting mixture was filtered and the recovered precipitate was washed with ethanol to ultimately afford 4.4 g. (98%) of pure 6-chloro-2-hydrazino-3-methoyquinoxaline, m.p. 175°-179° C. (decomp.). Mass Spectrum: m/e, 224 (P); m/e, 226 (P+2).
Reaction SMILES: I.[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][C:32](O)=[O:33].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([C:32](=[O:33])[CH2:31][CH2:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)CCc1ccccn1
Reactant: Cc1onc2c1c(=O)n(C1CCCNC1)c1cccc(Cl)c21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1onc2c1c(=O)n(C1CCCN(C(=O)CCc3ccccn3)C1)c1cccc(Cl)c21
Yield: 77.6 %

Procedure:
Add 9-chloro-3-methyl-5-piperidin-3-yl-5H-isoxazolo[4,3-c]quinolin-4-one hydroiodide (50 mg, 0.11 mmol), 2-pyridine propionic acid (20 mg, 0.13 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.13 mmol), 1-hydroxy-7-azabenzotriazole (18 mg, 0.13 mmol), 4-dimethylamino-pyridine (1 mg, 0.01 mmol), and dimethylformamide (3 mL) to a dry roundbottom flask. Stir the reaction under nitrogen, and add triethylamine (30 μL, 0.22 mmol) dropwise. Stir the solution under nitrogen at room temperature overnight. Concentrate the solution and dissolve in 20% isopropanol/chloroform; wash with saturated aqueous sodium bicarbonate solution and brine; dry over magnesium sulfate; and concentrate. Purify by flash chromatography on silica gel (eluting with 0–2% methanol/chloroform) to give 38.5 mg of the title compound as a white solid, 76% yield. 1H NMR: consistent with structure. MS (ion spray) 451 (M+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][CH:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2.O.[OH-].[Li+]>O1CCCC1.O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][CH:7]([C:14]([F:17])([F:15])[F:16])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(I)c(OC)cc2OC1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(cc1I)C=C(C(=O)O)C(C(F)(F)F)O2
Yield: 89.3 %

Procedure:
To the solution of 3.0 g (7.0 mmol) of ethyl 6-iodo-7-methoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 50 mL of tetrahydrofuran was added a solution of 1.2 g (28 mmol) of lithium hydroxide hydrate in 55 mL of water. The resulting solution was heated to reflux for four hr. The volatiles were removed. The residue was diluted with water. The resulting solution was acidified at 0° .C with dilute hydrochloric acid to pH=1.5. The product was extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concd to afford 2.5 g (81%) of a light yellow solid: 1H NMR (CDCl3/400 MHz) 7.56(s, 1H), 7.52(s, 1H), 6.42(s, 1H), 5.60(q, J=6.8 Hz, 1H), 3.81 (s, 3H). MS (ESI+) 400.9 (M+1, 100). MS(ES−) 398.9(M−H, 100). HRMS (ES−) m/z calcd for (C12H7F3O4) M−H: 398.9336, found 398.9359.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([Cl:15])[NH:10][C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[N:35]([C:36]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:34]=[N:33][N:32]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([Cl:15])[N:10]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35]([C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:34]=[N:33][N:32]=3)=[CH:23][CH:24]=2)[C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=c1cc(Cl)[nH]c(=O)n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.1 %

Procedure:
A mixture of 3-benzyl-6-chloropyrimidine-2,4(1H,3H)-dione (0.5 g), 4-bromomethyl-2'-(N-trityltetrazol-5-yl)biphenyl (1.24 g) and potassium carbonate (0.36 g) in DMF (20 ml) was stirred at room temperature for 24 hours. The reaction mixture was concentrated to dryness in vacuo and then the residue was dissolved in methylene chloride. The insoluble material was removed from the reaction mixture by filtration and the filtrate was concentrated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless amorphous powders (0.8 g, 53%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10](OS(C)(=O)=O)[C@@H:9]([NH:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])[C@H:8]([O:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH:7]=1)=[O:5])[CH3:2].[N-:32]=[N+:33]=[N-:34].[Na+]>CCO.CS(C)=O.CCOC(C)=O.CC1CCCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@H:10]([N:32]=[N+:33]=[N-:34])[C@@H:9]([NH:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])[C@H:8]([O:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH:7]=1)=[O:5])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NP(=O)(OCC)OCC)[C@H](OS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CCO
Solvent: CC1CCCCC1
Solvent: CS(C)=O
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NP(=O)(OCC)OCC)[C@@H](N=[N+]=[N-])C1
Temperature: 87.5 °C
Reaction time: 20 h
Yield: 15.1 %

Procedure:
To a solution of 104 mg of 18 in 0.50 mL of EtOH and 0.50 mL of DMSO in a 5.0 mL round-bottom flask equipped with a magnetic stirrer, a reflux condenser and an inert gas supply was added 28 mg sodium azide and the reaction mixture was stirred at 85-90° C. for 20 h. The brown reaction mixture was cooled to RT diluted with 1.0 mL of EtOAc and extracted with 1.0 mL of aqueous 1 M NaHCO3. The separated organic phase was dried (Na2SO4), filtered and evaporated at 40° C./120-10 mbar to obtain 40 mg of the crude product as brown crystals. The crude product was dissolved in 0.40 mL methylcyclohexane, stirred for 5 h at RT. The white crystals which formed were filtered and washed with 0.15 mL of methylcyclohexane, dried at 40° C./10 mbar for 2 h to afford 14 mg of 26 as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=[O:23])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[CH:20][C:21]#[N:22])[CH:14]=1.[H-].[Na+].S(OC)(O[CH3:30])(=O)=O>CN(C)P(N(C)C)(N(C)C)=O>[CH3:30][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=[O:23])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[CH:20][C:21]#[N:22])[CH:14]=1
Reactant: Cc1cc(O)c(C(=O)C=Cc2cccc(C=CC#N)c2)c(=O)o1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc(C)oc(=O)c1C(=O)C=Cc1cccc(C=CC#N)c1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 30.6 %

Procedure:
To a mixture of 20 ml of hexamethylphosphoramide and 3.50 g of 4-hydroxy-3-[3-[3-(2-cyanoethenyl)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one was added 0.46 g of sodium hydride (60% oily) at about 0° C., and a temperature was raised to 50° C., followed by stirring for 1 hour and 10 minutes. Then, 3.22 g of dimethyl sulfate was added thereto, and the mixture was stirred at 50° C. for 4 hours. Thereafter, the reaction mixture was added to ice water, and the mixture was extracted with ethyl acetate. The organic layer washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 1.12 g of 4-methoxy-3-[3-[3-(2-cyanoethenyl)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (2a)] as a pale yellow crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[NH:7])=[CH:4][CH:3]=1.C([Li])CCC.Cl[P:23]([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25]>>[CH:24]([P:23]([CH:27]([CH3:29])[CH3:28])[N:7]=[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:16][CH:15]=1)([CH3:26])[CH3:25]
Reactant: Cc1ccc(C(=N)Nc2ccccc2)cc1
Reactant: CC(C)P(Cl)C(C)C
Agent: [Li]CCCC
Product: Cc1ccc(C(=NP(C(C)C)C(C)C)Nc2ccccc2)cc1

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.05 g of 4-methyl-N1-phenylbenzamidine (Amidine IX, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.80 mL chlorodiisopropylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, a yellow oil was isolated (1.62 g, 99%).