Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([N:22]4[CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]4)=[O:21])[CH:14]=3)/[O:7][C:8]2=O)=[CH:4][CH:3]=1.CN(C)C=O.O.[NH2:36][NH2:37]>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([N:22]4[CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]4)=[O:21])[CH:14]=3)=[N:36][NH:37][C:8]2=[O:7])=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC1CCN(C(=O)c2cc(/C=C3\OC(=O)c4cc(Cl)ccc43)ccc2F)CC1
Solvent: O
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4cc(Cl)ccc34)ccc2F)CC1
Temperature: 105 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
(Z)-6-chloro-3-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one (67) (25 mg, 0.06 mmol) was taken up in water (1 mL) and N,N-dimethylformamide (0.5 mL) and treated with Hydrazine monohydrate (20 μL, 0.41 mmol). The resulting mixture was stirred at 105° C. for 1 hour. The reaction mixture was cooled and diluted with water (˜5 mL) and mixture extracted with DCM (2×5 mL). Combined organics were evaporated to dryness to afford the crude product, which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and acetonitrile as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white foam (10 mg, 39% yield); 1H NMR (400.132 MHz, DMSO) δ 1.26-1.35 (1H, m), 1.40-1.49 (1H, m), 1.67-1.74 (1H, m), 1.83-1.90 (1H, m), 2.99-3.06 (1H, m), 3.26 (3H, s), 3.26-3.36 (2H, m), 3.39-3.45 (1H, m), 3.88-3.95 (1H, m), 4.33 (2H, s), 7.22 (1H, t), 7.31 (1H, dd), 7.38-7.42 (1H, m), 7.94 (1H, dd), 8.00 (1H, d), 8.21 (1H, d), 12.72 (1H, s); m/z (LC-MS, ESI+), RT=2.23 (M+H 430.7).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:24][O:25][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][O:19]1)[C:9]3=[O:23].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>CC(=O)CC>[CH3:37][O:36][C:34](=[O:35])[CH2:33][O:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:24][O:25][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][O:19]1)[C:9]3=[O:23]
Reactant: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc(O)ccc12
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)COc1ccc2c(c1)OCC21C(=O)N(C[C@H]2CCCO2)c2ccccc21
Yield: 101.3 %

Procedure:
The mixture of 6-hydroxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.42 g, 1.23 mmol), potassium carbonate (0.22 g, 1.60 mmol) and methyl bromoacetate (0.15 mL, 1.60 mmol) in 2-butanone (10 mL) was refluxed for 15 h. The reaction mixture was concentrated in vacuo to dryness. The residue was purified by flash chromatography with 25% ethyl acetate in hexanes to afford methyl({2′-oxo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-6-yl}oxy)acetate (0.51 g, 87%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.33-7.26 (m, 1H), 7.15-7.00 (m, 3H), 6.64-6.59 (m, 1H), 6.51 (d, J=2.4 Hz, 1H), 6.36 (dd, J=8.4, 2.4 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.72 (d, J=9.0 Hz, 1H), 4.59 (s, 2H), 4.32-4.24 (m, 1H), 3.99-3.66 (m, 7H), 2.07-1.84 (m, 3H), 1.78-1.64 (m, 1H); MS (ES+) m/z 409.9 (M+1), 447.9 (M+39).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][C:24]=1[CH:29]=O>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:29]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1ccncc1C=O
Product: COc1ccncc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Br)cnc2[nH]1
Yield: 43 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and 4-Methoxy-pyridine-3-carbaldehyde (22.3 mg, 0.163) were reacted to produce 29 mg (43%) of the title compound. mp: 160° C., 1H NMR (300 MHz, DMSO-d6): 12.69 (s, 1H), 9.11 (s, 1H), 8.54 (d, J=8 Hz, 1H), 8.07 (s, 1H), 7.74 (s, 1H), 7.27 (d, J=8 Hz, 1H), 7.21 (s, 1H), 7.17 (d, J=9 Hz, 1H), 6.35 (s, 2H), 5.26 (t, J=8 Hz, 1H), 4.02 (s, 3H), 3.38 (q, J=8 Hz, 1H), 3.32 (s, 1H), 2.89 (s, 1H), 2.78 (s, 1H), 2.63 (d, J=8 Hz, 1H), 2.26 (d, J=8 Hz, 1H), 1.40 (d, J=8 Hz, 1H), 1.09 (t, J=8 Hz, 1H). MS: 455, 457 (M+H), HPLC: 1.64 min (G method).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH2:26][CH:27]=[CH2:28])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C1C=CC=CC=1.CC#N.CC#N.Cl[Pd]Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH:26]=[CH:27][CH3:28])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: C=CCc1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: Cl[Pd]Cl
Solvent: CC#N
Solvent: c1ccccc1
Product: CC=Cc1c([N+](=O)[O-])ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Yield: 74 %

Procedure:
To a solution of 10.0 g (24.0 mmole) of (R)-[8-allyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate in 700 mL of benzene was added 1.03 g of bis(acetonitrile)dichloropalladium (II) and the mixture was refluxed under nitrogen for 48 hours. The catalyst was then removed by filtration and the filtrate concentrated in vacuum to a brown oil. Column chromatography on silica gel with methylene chloride as eluant gave 7.2 g of the title compound as a mixture of E and Z isomers. A sample of {(2R)-7-nitro-8[(E)-1-propenyl]-2,3-dihydro-1,4-benzo-dioxin-2-yl}methyl 4-methylbenzenesulfonate was obtained as a yellow solid (m.p. 105-106° C.) by evaporation of a pure E isomer-containing fraction.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])C.[Li]CCCC.[CH3:13][C:14]1C[CH2:17][CH2:16][N:15]=1.C(OC(=O)C)C>C1COCC1>[N:4]1[CH2:1][CH2:3][CH2:7][C:5]=1[CH:6]=[C:14]([NH:15][CH2:16][CH3:17])[CH3:13]
Reactant: CC1=NCCC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNC(C)=CC1=NCCC1
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (22.2 g, 219.3 mmol) in THF (200 mL) was dropwise added n-BuLi (2.89 M, 75.9 mL, 219.3 mmol) at −78° C. under nitrogen. Once all the n-BuLi was added, the temperature was adjusted to −5° C., and the reaction mixture was stirred for 30 min. Then a solution of 2-methyl-1-pyrroline (11.3 g, 135.7 mmol) in THF (15 mL) was added dropwise to the reaction mixture at −5° C., and then stirred. After 30 min, ethylacetate (9.20 g, 104.4 mmol) was added dropwise over 30 min. The reaction mixture was stirred as the temperature was allowed to gradually rise to room temperature, and was continuously stirred at room temperature overnight. THF solvent was removed under reduced pressure, then 80 mL of methanol was added dropwise to the residue. After removing all of the volatile solvent, diethyl ether (100 mL) was added to the residue, and the mixture was filtered. Concentration of the filtrate under reduced pressure, followed by column chromatography, provided the desired product.
Reaction SMILES: [C:1]([CH:5]1[O:9][C:8]([CH2:15][C:16]([OH:18])=[O:17])([CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[C:7](=[O:19])[O:6]1)([CH3:4])([CH3:3])C.[CH2:20](O)[C:21]1C=CC=C[CH:22]=1.[H-].[Na+]>C1COCC1>[CH2:5]([O:6][C:7](=[O:19])[C:8]([OH:9])([CH2:10][CH:11]=[C:12]([CH3:13])[CH3:14])[CH2:15][C:16]([OH:18])=[O:17])[C:1]1[CH:3]=[CH:22][CH:21]=[CH:20][CH:4]=1
Reactant: OCc1ccccc1
Reactant: CC(C)=CCC1(CC(=O)O)OC(C(C)(C)C)OC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCC(O)(CC(=O)O)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
A solution of dioxolanone 74 (120 mg, 0.444 mmol, 1.00 equiv) in THF (4.5 mL) was cooled to 0° C. and benzyl alcohol (69 μL, 0.67 mmol, 1.5 equiv) was added via syringe followed by a 60% dispersion of NaH in mineral oil (45 mg, 1.1 mmol, 2.5 equiv) which resulted in vigorous evolution of gas. The solution was allowed to stir at 0° C. for 30 min, at which time the reaction was quenched with 4.5 mL NaHCO3, removed from the cold bath and allowed to warm to room temperature. The solution was then poured into H2O (4.5 mL), washed with CH2Cl2 6 mL), acidified to pH<5 with 1N HCl, and then extracted with Et2O (4×6 mL). The combined ethereal phases were dried over MgSO4 and solvent removal by rotary evaporation yielded a white solid which was purified by silica gel column chromatography (70:28:2 hex:EtOAc:HOAc) to yield 75 (114 mg, 88%) as a white solid. Rf=0.39 (60:38:2 EtOAc:Hex:HOAc); 1H NMR (500 MHz, CDCl3) δ 7.35 (m, 5H, ArH), 5.20 (s, 2H, PhCH2), 5.07 (m, 1H, vinyl H), 3.00 (d, 1H, J=16.7 Hz, C(O)CH2), 2.76 (d, 1H, J=16.7 Hz, C(O)CH2), 2.41 (m, 2H, CHCH2), 1.67 (d, 3H, J=0.7 Hz, CH3), 1.54 (d, 3H, J=0.7 Hz, CH3); 13C NMR (100 MHz, CDCl3) δ 176.43, 174.60, 136.79, 135.21, 128.71, 128.64, 128.61, 116.45, 75.41, 67.95, 42.69, 38.14, 26.06, 18.09; IR (neat film) 3483 (br m), 2968 (m), 1736 (s), 1498 (w), 1195 (s) cm−1; HRMS (ESI) m/z calcd for C16H20O5Na (M++Na+) 315.1208, observed 315.1214; [α]D=−18° (c 2.98, CHCl3).
Reaction SMILES: [C:1](=[O:14])(OC1C=CC=CC=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22].C(Cl)Cl>CCO>[C:3]([O:2][C:1]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])=[O:14])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)Oc1ccccc1
Reactant: NCCCCCCN
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCCN
Temperature: 78 °C

Procedure:
tert-Butyl phenyl carbonate (25.60 mL, 138.0 mmoles) was added to a stirred solution of 1,6-diaminohexane (15.30 g, 131.7 mmoles) in absolute EtOH (150 mL) in a 250 mL RB flask. The apparatus was fitted with a condenser and heated to 78° C. overnight under a blanket of nitrogen and then allowed to cool to room temperature. The solvent was stripped off the reaction mixture in vacuo (rotary evaporator) yielding a pale pink oily residue. CH2Cl2 (200 mL) was added to the residue and the resultant solution extracted with 3×200 mL portions of de-ionised water. For each extraction the pH of the aqueous phase was monitored and adjusted with HCl (aq, 2M) such that the pH of the aqueous layer was 3<pH<7 [only required for 1st extraction, needing ca. 60-70 mL HCl (aq, 2M)]. The aqueous phases were collected in a Erlenmeyer flask containing aqueous NaOH (aq, 100 mL, 3M). Ensuring that the pH of the collected aqueous extracts was ≧14 the resulting aqueous phase was extracted with CH2Cl2 (3×150 mL). These organic phases were recombined, evaporated to a volume of ca. 200 mL and subjected to the above pH modulated purification protocol for a second time by first extracting with water [3×200 mL, 3<pH<7 modulation with HCl (aq, 2M), again only required for 1st extract needing ca. 45-55 mL HCl (aq, 2M)], basicifying these aqueous extracts with NaOH (100 mL, 3M) and extracting with CH2Cl2 (3×150 mL). The CH2Cl2 extracts were combined, reduced in volume to 200 mL and then dried over anhydrous MgSO4, filtered, and stripped to dryness on a rotary evaporator for a period of 20 minutes to yield 6-(tert-butoxycarbonylamino)hexylamine as a peach oil. This peach oil was then subjected to a short path distillation using a Kugelrohr apparatus with an oven temperature of 180° C. and at a vacuum pressure of 0.160 torr, the receiver bulb was cooled by means of a dry-ice/acetone bath. Yield: 13.1 g (46%, colourless oil). 1H NMR (CDCl3) δ 1.14 (s, 2H, —NH2), 1.26-1.37 (m, 4H, —CH2—), 1.37-1.52 (s+m, 9H+4H, t-Bu+—CH2—), 2.67 (t, 2H, >NCH2—), 3.09 (q, 2H, —C(═O)NCH2—), 4.60 (bs, 1H, —C(═O)NH—).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]([OH:14])=O)[N:10]=1)(=[O:4])=[O:3].P(Cl)(Cl)(Cl)=O.Cl.[NH2:21][CH:22]1[C:47](=[O:48])[N:24]2[C:25]([C:31]([O:33][CH:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[C:26]([CH:29]=[CH2:30])[CH2:27][S:28][C@H:23]12.C[Si](CC(N)=O)(C)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O1CCCC1.O.CN(C)C=O>[CH3:1][S:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]([NH:21][CH:22]2[C:47](=[O:48])[N:24]3[C:25]([C:31]([O:33][CH:34]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:32])=[C:26]([CH:29]=[CH2:30])[CH2:27][S:28][C@H:23]23)=[O:14])[N:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1nc(CC(=O)O)cs1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3csc(NS(C)(=O)=O)n3)[C@H]2SC1
Reaction time: 2 h
Yield: 58.8 %

Procedure:
A mixture of 2-(2-methanesulfonamidothiazol-4-yl)acetic acid (2.6 g), N,N-dimethylformamide (0.88 g) and phosphorus oxychloride (1.85 g) in ethyl acetate (10 ml) and tetrahydrofuran (20 ml) was stirred under ice-cooling for 30 minutes. This solution was added to a solution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (4.3 g) and trimethylsilylacetamide (7.9 g) in ethyl acetate (50 ml) at -20° C. with stirring, and the stirring was continued at -20° to 0° C. for 2 hours. After addition of water, tetrahydrofuran and ethyl acetate, the reaction mixture was adjusted to pH 7 with a saturated aqueous solution of sodium bicarbonate. The precipitated substance was collected by filtration to give benzhydryl 7-[2-(2-methanesulfonamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (3.6 g). After addition of ethyl acetate tetrahydrofuran to the filtrate, the organic layer was separated out, washed with an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate, followed by evaporation to recover the same product (0.9 g). Total yield: 4.5 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]=[C:9]=[O:10])=[CH:3][CH:2]=1.[F:11][C:12]1[C:13](=[O:19])[NH:14][C:15](=[O:18])[NH:16][CH:17]=1>>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]([N:16]2[CH:17]=[C:12]([F:11])[C:13](=[O:19])[NH:14][C:15]2=[O:18])=[O:10])=[CH:3][CH:2]=1
Reactant: O=C=NCc1ccncc1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Product: O=C(NCc1ccncc1)n1cc(F)c(=O)[nH]c1=O
Reaction time: 4 h

Procedure:
To the above solution of 4-pyridylmethyl isocyanate was added 5-fluorouracil (2.60 g.) at 80° C. and stirred for 4 hours at the same temperature. The resultant mixture was evaporated in vacuo. The residue was washed with diethyl ether (3 times) and crystallized. The crystals were filtered and washed with a small amount of ethanol. To the washed crystals a small amount of pyridine was added, and the mixture was warmed to be dissolved and cooled to be recrystallized. The crystals were washed successively with ethyl acetate and diethyl ether to give 1-[N-(4-pyridylmethyl)carbamoyl]-5-fluorouracil (1.75 g.)
Reaction SMILES: [N+]([C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=[O:7])([O-])=O.NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.C(N(CC)CC)C.[F:63]C1C=CC(C(Cl)=O)=CC=1>ClCCl>[F:63][C:32]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][CH:9]([C:11]2[N:16]=[N:15][C:14]([NH:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)=[N:13][CH:12]=2)[CH3:10])=[O:7])=[CH:4][CH:33]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3[N+](=O)[O-])nn2)cc(OC)c1OC
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccc(F)cc3)nn2)cc(OC)c1OC

Procedure:
In a similar manner as described for Intermediate 10, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (0.30 g, 1.0 mmol), triethylamine (0.28 mL, 2.0 mmol) and 4-fluorobenzoyl chloride (0.16 g, 1.0 mmol) in dichloromethane (10 mL) gave 4-fluoro-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (0.32 g) as a white solid. MS m/z 428 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]2[S:13][CH:14]=[CH:15][C:10]2=[CH:9][C:8]=1[CH:16]([N:18]1C(=O)C2C(=CC=CC=2)C1=O)[CH3:17].O.NN>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]2[S:13][CH:14]=[CH:15][C:10]2=[CH:9][C:8]=1[CH:16]([NH2:18])[CH3:17]
Reactant: CC(c1cc2ccsc2nc1-c1ccccn1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(N)c1cc2ccsc2nc1-c1ccccn1
Temperature: 60 °C
Yield: 92.1 %

Procedure:
2-(1-(6-(Pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethyl)isoindoline-1,3-dione (220 mg, 0.57 mmol) was slurried in ethanol (5 mL). To this slurry was added hydrazine hydrate (500 uL, 10.3 mmol, 18 eq). The reaction was heated to 60° C. for 2 h, then cooled to rt and filtered. The filtrate was concentrated and redissolved in ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford 1-(6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)-ethanamine (134 mg, 91.9% yield). 1H NMR (400 MHz, CDCl3) δ 8.69 (ddd, J=4.7, 1.6, 0.8 Hz, 1H), 8.39 (s, 1H), 7.87 (m, 2H), 7.57 (d, J=5.9 Hz, 1H), 7.34 (ddd, J=6.8, 5.1, 2.0, 1H), 7.31 (d, J=5.9 Hz, 1H), 4.63 (q, J=6.7 hz, 1H), 1.44 (d, J=6.7 Hz, 3H) ppm.
Reaction SMILES: [H-].[Na+].[CH2:3]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])P(=O)(OCC)OCC.[NH2:20][C:21]1[C:30]2[N:29]=[CH:28][C:27]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[CH3:41])=[CH:26][C:25]=2[C:24]2[CH:42]=[CH:43][C:44]([CH:46]=O)=[CH:45][C:23]=2[N:22]=1>C1COCC1>[NH2:20][C:21]1[C:30]2[N:29]=[CH:28][C:27]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[CH3:41])=[CH:26][C:25]=2[C:24]2[CH:42]=[CH:43][C:44](/[CH:46]=[CH:3]/[P:12](=[O:19])([O:13][CH2:14][CH3:15])[O:16][CH2:17][CH3:18])=[CH:45][C:23]=2[N:22]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1ccc(CCc2cnc3c(N)nc4cc(C=O)ccc4c3c2)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(/C=C/c1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OC)cc3C)cc12)OCC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of NaH (1.2 equiv.) in THF (0.1 M) cooled at 0° C. was added a solution of tetraethyl methylenediphosphonate (1.3 equiv.) in THF (0.21 M). To the resulting reaction mixture was added a solution of 5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbaldehyde (2-2) (Example 9—Step 1) (1.0 equiv.) in THF (0.08 M). The reaction was stirred at room temperature for 30 minutes, then solvents were removed in vacuo, and the resulting residue was purified by a COMBIFLASH® system (ISCO) using a gradient of 0-5% MeOH/DCM to provide (E)-diethyl 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)vinylphosphonate (3-1) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([F:11])[CH:3]=1.C(Cl)(=O)[C:13](Cl)=[O:14]>C(Cl)CCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:8]=[C:13]=[O:14])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: NC(=O)c1ccc(Cl)cc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccc(Cl)cc1F

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 4-chloro-2-fluorobenzamide (0.200 g, 1.26 mmol), EDC (10 mL) and oxalyl chloride (0.14 mL, 1.15 mmol) to afford 0.200 g of the product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([CH2:15][C:5]2=[C:4]([NH2:17])[C:3]=1[C:18]#[N:19])=[CH:13][CH:12]=[C:11]([OH:16])[CH:10]=3.Br[CH2:21][CH2:22][OH:23].BrCCOCC>>[NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14]([CH2:15][C:5]2=[C:4]([NH2:17])[C:3]=1[C:18]#[N:19])=[CH:13][CH:12]=[C:11]([O:16][CH2:21][CH2:22][OH:23])[CH:10]=3
Reactant: N#Cc1c(N)nc2c(c1N)Cc1ccc(O)cc1O2
Reactant: OCCBr
Agent: CCOCCBr
Product: N#Cc1c(N)nc2c(c1N)Cc1ccc(OCCO)cc1O2

Procedure:
2,4-diamino-8-(2-hydroxyethoxy)-5H-chromeno[2,3-b]pyridine-3-carbonitrile was prepared from 2,4-diamino-8-hydroxy-5H-chromeno[2,3-b]pyridine-3-carbonitrile in the same manner as described in Example 10 using 2-bromoethanol in lieu of 2-bromoethyl-ethylether. The product was isolated as a tan solid (120 mg, 35% yield). 1H NMR (400 MHz, DMSO) δ 7.025 (d, 1H), 6.670 (d, 1H), 6.550 (d, 1H), 3.931 (t, 2H), 3.662 (t, 2H), 3.546 (s, 2H); m/z 413 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12](O)=[O:13])=[C:10]([C:15]([OH:17])=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:18])[CH:8]=2)[N:3]=1.C(OC(=O)C)(=O)C>>[CH3:1][C:2]1[C:11]2[C:12]([O:16][C:15](=[O:17])[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:18])[CH:8]=2)[N:3]=1)=[O:13]
Reactant: Cc1ccc2nc(C)c(C(=O)O)c(C(=O)O)c2c1
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc2nc(C)c3c(c2c1)C(=O)OC3=O

Procedure:
A 2 L round bottom flask fitted with a magnetic stirring bar, reflux condenser, and drying tube was charged with 70 g (0.285 mole) of (i) and 1 L of reagent grade acetic anhydride. The tan suspension was stirred at reflux for 23 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(O)[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)\[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(O)c2ccccc2)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccccc1
Temperature: 0 °C

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-phenylpropan-2-ol (1 g, 2.82 mmol, 1 equiv.) was refluxed with 25% sulfuric acid (7 mL) for 2 h. The reaction mixture was cooled to 5° C. in ice-water bath. KOH (15% aqueous solution) was added dropwise to the reaction mixture until pH 9-10 was achieved. The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with water (10 mL) followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product was purified by silica gel chromatography (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of isomers, which were separated by HPLC. 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 7.66 (m, 2H), 7.60 (m, 1H), 7.40 (m, 3H), 7.25 (d, 1H), 7.18 (d, 1H), 7.08 (s, 1H), 3.60 (m, 2H), 3.40 (m, 2H), 3.0 (m, 2H), 2.85 (m, 3H), 1.90 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([NH:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:22][C:23]([CH2:25]Cl)=[CH2:24]>CN(C)C=O.O>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([N:9]([CH2:25][C:23]([Cl:22])=[CH2:24])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: C=C(Cl)CCl
Reactant: N#CNc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(Cl)CN(C#N)c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Yield: 99.1 %

Procedure:
N-(3-(trifluoromethyl)phenyl)cyanamide (18.6 g) was dissolved in N,N-dimethylformamide (DMF) (93.0 g), to which powdered potassium carbonate (20.7 g) and potassium iodide (1.7 g) were added at room temperature with stirring. Further, 2,3-dichloro-1-propene (13.3 g) was added dropwise at room temperature with stirring. The mixture was heated to 50° C. and stirred at the same temperature for 1 hour. After cooling to room temperature, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water. The solvent was removed by distillation under reduced pressure, which afforded 25.8 g of N-(3-(trifluoromethyl)-phenyl)-N-(2-chloro-2-propenyl)cyanamide as an oil (99% yield in appearance). The percentage areas of gas chromatography and liquid chromatography were 98% and 99%, respectively.