Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[N:11]=[C:12]2Cl)=[CH:7][C:6]=1[O:23][CH3:24])=[O:4]>C(O)(C)C>[CH3:1][N:2]([CH3:25])[C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([NH:16][C:17]3[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=3)[N:11]=[C:12]2[O:23][CH:6]([CH3:7])[CH3:5])=[CH:7][C:6]=1[O:23][CH3:24])=[O:4]
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1C(=O)N(C)C
Solvent: CC(C)O
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC(C)C)c2cc1C(=O)N(C)C

Procedure:
Similar procedure as described in example 400 was used, starting from isopropyl alcohol and 1-Chloro-6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-7-carboxylic acid dimethylamide (example 9G) to give 1-Isopropoxy-6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-7-carboxylic acid dimethylamide. LC-MS: m/e 384(MH+).
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:26](O)(=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>>[C:26]([O:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])(=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCC(O)CC(=O)OC(C)(C)C
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)OC(C)(C)C
Yield: 96.5 %

Procedure:
tert-Butyl 3-hydroxyoctadecanoate (1.068 g) was acylated by the acid chloride derived from hexadecanoic acid (3.84 g) according to similar manner to that of Preparation 1-(2) to give an oil of tert-butyl 3-hexadecanoyloxyoctadecanoate (1.72 g).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]([OH:13])=[O:12])([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: [H][H]
Reactant: O=C(O)CNCCCc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1CCCNCC(=O)O
Yield: 77 %

Procedure:
To a solution of 13.0 g. (5.46 × 10-2 moles) of N-(o-nitrobenzyl)ethyl glycine in 200 ml. of absolute ethyl alcohol was added slowly 0.76 g. (5% by weight) of 10% Pd/C catalyst and the mixture placed on a Paar hydrogenator. The mixture was shaken until theoretical hydrogen (16.4 × 10-2 moles) had been absorbed, removed from the Paar and the mixture filtered under suction. The catalyst was washed with ethyl alcohol and the solvent removed in vacuo affording a yellow oil. Purification of the oil was effected by distillation yielding 8.8 g. (77% yield) of a colorless oil; b.p. 124°-126°C. (0.03 mm).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:3]1>C(OCC)(=O)C.[Pd]>[O:1]=[C:2]1[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C@@H:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:3]1
Reactant: CCOC(=O)CC1=C(c2ccccc2)CC(=O)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H]1CCC(=O)C[C@@H]1c1ccccc1
Yield: 87.9 %

Procedure:
A stirred solution of the ethylene ketal of ethyl (4-keto-2-phenylcyclohex-1-enyl)-acetate (7.0 g.) in ethyl acetate (70 ml.) was hydrogenated at atmospheric pressure over a 5% w/w palladium-on-charcoal catalyst (0.7 g.) for 16 hours. The mixture was filtered through diatomaceous earth and the filtrate was evaporated. The residue was purified by flash chromatography on silica, eluting with ether/hexane (4:6 v/v), to give the ethylene ketal of ethyl (4-keto-2-phenyl-cis-cyclohexyl)acetate (6.2 g.), as a colourless solid, m.p. 83°-86° C.; NMR (CDCl3): 3.29 (1H, d of t, Jaa=13 Hz, Jae=3 Hz, Jae=3 Hz, cis-Ph.CH); mass spectrum: m/e 304.
Reaction SMILES: O[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][C:7]1[C:2]2[O:19][C:17](=[O:18])[CH2:16][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1cccc(Oc2ccccc2Cl)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C1Cc2cccc(Oc3ccccc3Cl)c2O1
Yield: 67.5 %

Procedure:
A mixture of 2-[2-hydroxy-3-(2-chlorophenoxy)phenyl]acetic acid (1.9 g) and p-toluenesulfonic acid (0.5 g) in benzene 50 ml was treated in a similar manner to that of Example 1-(6), and the residue was recrystallized from a mixture of diethyl ether and n-hexane to give 7-(2-chlorophenoxy)-2,3-dihydrobenzofuran-2-one (1.2 g). mp 118°-120° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH3:7].S([O-])([O-])(=O)=S.[Na+].[Na+].[Br:21]Br>C(Cl)Cl>[Br:21][C:5]1[O:1][C:2]([CH:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH3:7])=[CH:3][CH:4]=1
Reactant: CC(c1ccco1)N1CCOCC1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(c1ccc(Br)o1)N1CCOCC1
Temperature: 0 °C
Yield: 42 %

Procedure:
4-(1-furan-2-yl-ethyl)-morpholine (1.1 mmol) was taken up in DCM (5 ml) and stirred at 0° C. Nitrogen was passed through the reaction vessel and bubbled out through a Dreschel bottle containing a saturated aqueous solution of sodium thiosulphate, whilst bromine (1.54 mmol in 2 ml DCM) was added dropwise. After addition the reaction was stirred at room temperature for 2 h, then diluted with more DCM, washed twice with 2M Na2CO3 solution, dried over Na2SO4 and concentrated in-vacuo. After purification by flash chromatography (silica, 5 to 10% EtOAc in hexane), 4-[1-(5-bromo-furan-2-yl)-ethyl]-morpholine was obtained as a golden oil: m/z in MS ES+=260, 262 [M+H]+, 0.46 mmol, 42% yield.
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:8]2=[N:9][C:10]([CH:22]=[O:23])=[C:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]([OH:13])=[C:7]2[CH:6]=[N:5]1)[CH3:3].[OH:24]O>C(O)(=O)C>[CH2:2]([N:4]1[C:8]2=[N:9][C:10]([C:22]([OH:24])=[O:23])=[C:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:12]([OH:13])=[C:7]2[CH:6]=[N:5]1)[CH3:3]
Reactant: CCn1ncc2c(O)c(CCc3ccccc3)c(C=O)nc21
Reactant: OO
Agent: Cl
Solvent: CC(=O)O
Product: CCn1ncc2c(O)c(CCc3ccccc3)c(C(=O)O)nc21
Reaction time: 20 h

Procedure:
16.5 g. of 1-ethyl-4-hydroxy-5-(2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxaldehyde, hydrochloride (1:1) (0.05 mol.) are dissolved in 150 ml. of boiling glacial acetic acid. To the filtered solution, cooled to about 30°, 10 g. of H2O2 (35%) (0.1 mol.) are added in two portions and the mixture is allowed to stand for 20 hours at room temperature. The crystallized 1-ethyl-4-hydroxy-5-(2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid is filtered off, washed with acetic acid and ether, yield: 10.1 g. (65%); m.p. 250°-251° (ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH2:22][OH:23])=[N:12][C:11]=2[CH:24]([CH3:26])[CH3:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])N.[C:31]([N:46]=[C:47]=[O:48])(=[O:45])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>>[C:31]([NH:46][C:47](=[O:48])[O:23][CH2:22][C:13]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:24]([CH3:26])[CH3:25])[N:12]=1)(=[O:45])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CC(C)c1nc(CO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CCCCCCCCCCCCCC(=O)N=C=O
Agent: NC(=O)[O-]
Product: CCCCCCCCCCCCCC(=O)NC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1Cc1ccncc1
Yield: 46 %

Procedure:
The compound 89 (245 mg, 0.6 mmol) was converted to the carbamate with myristoyl isocyanate (5 eq.) in the same manner as the example 66 to give the compound 94 (182 mg, 46%) as oil. Rf 0.41 (EtOAc).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:10](OCC)(=[O:16])[C:11](OCC)=[O:12].Cl>C(O)(=O)C>[CH3:1][S:2][C:3]1[CH:9]=[C:8]2[C:6](=[CH:5][CH:4]=1)[NH:7][C:11](=[O:12])[C:10]2=[O:16]
Reactant: CSc1ccc(N)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Product: CSc1ccc2c(c1)C(=O)C(=O)N2
Temperature: 90 °C
Reaction time: 8 h
Yield: 9.8 %

Procedure:
A mixture of 4-(methylthio)aniline (13.92 g, 100 mmol) and diethyl ethanedioate (17.42 g, 100 mmol) in acetic acid (50 mL) was stirred at 90° C. for 8 h. The mixture was cooled to room temperature and allowed to stand overnight, at which time the product had crystallized. The crystals were collected by filtration and washed with minimal acetic acid. The crystals were dissolved in 5% sodium hydroxide (150 mL), and the solution was heated to 90° C. Air was bubbled through the solution continuously, forming a yellow solution. After 8 hours, the solution was cooled and acidified with concentrated HCl. The precipitate was collected by filtration and was washed with water and dried to afford 5-(methylthio)-1H-indole-2,3-dione (1.9 g, 10% yield). MS (m/z) 194.0 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])[CH2:4][CH2:3]1.Cl[C:16]1[N:34]=[C:19]2[C:20]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[CH:21][CH:22]=[CH:23][N:18]2[N:17]=1>>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][NH:24][C:20]2[C:19]3[N:18]([N:17]=[C:16]([NH:11][C:10]4[CH:12]=[CH:13][CH:14]=[C:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)[CH:9]=4)[N:34]=3)[CH:23]=[CH:22][CH:21]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc(CNc2cccn3nc(Cl)nc23)cc1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Product: COc1ccc(CNc2cccn3nc(Nc4cccc(N5CCN(C)CC5)c4)nc23)cc1

Procedure:
N(8)-(4-Methoxy-benzyl)-N(2)-[3-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from 3-(4-Methylpiperazin-1-yl)aniline (74.2 mg, 0.388 mmol) and (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(4-methoxy-benzyl)-amine (99.9 mg, 0.346 mmol) in a manner analogous to Example 2d. Product isolated as a red foam (9.16 mg, 6%). 1H NMR (400 MHz, CD3OD, δ, ppm): 7.85 (d, J=5.9 Hz, 1H), 7.33 (m, 3H), 7.19-7.08 (m, 2H), 6.90 (d, J=8.0 Hz, 2H), 6.76 (t, J=14.4, 7.5 Hz, 1H), 6.57 (d, J=8.2 Hz, 1H), 6.44 (d, J=7.4 Hz, 1H), 4.42 (s, 2H), 3.78 (s, 3H), 3.23 (s, 4H), 2.64 (s, 4H), 2.37 (s, 3H). MS=444 (MH)+.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:4]=1[O:5][C:6]1[CH:7]=[CH:8][C:9]([F:19])=[C:10]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:11]=1)#[N:2]>CO.[C].[Pd]>[NH2:24][C:22]1[CH:21]=[CH:20][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]([F:19])=[C:10]([NH:12][C:13](=[O:18])[C:14]([F:15])([F:16])[F:17])[CH:11]=2)=[C:3]([C:1]#[N:2])[CH:23]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Oc1ccc(F)c(NC(=O)C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: N#Cc1cc(N)ccc1Oc1ccc(F)c(NC(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a solution of N-[5-(2-cyano-4-nitrophenoxy)-2-fluorophenyl]-2,2,2-trifluoroacetamide (6.00 g, 16.3 mmol) in methanol (160 mL) was added 10% palladium-carbon (600 mg), and the mixture was stirred at room temperature for 2 hr under a hydrogen atmosphere (1 atm). Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (5.44 g, 99%) as a gray oil.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].N.[Li].[Cl-].[NH4+]>O1CCCC1.C(O)C>[CH3:8][C:2]([C:9]1[CH2:10][CH:11]=[C:12]([CH3:15])[CH2:13][CH:14]=1)([CH3:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: Cc1ccc(C(C)(C)CCC(=O)O)cc1
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1=CCC(C(C)(C)CCC(=O)O)=CC1
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
To a refluxing solution of 4-methyl-4-p-tolylpentanoic acid (51.5 g, 0.25 mol) in tetrahydrofuran (500 ml) and liquid ammonia (1500 ml) was added, portionwise, lithium metal (26.0 g, 3.75 gram atom). After the reaction mixture was stirred for 15 minutes, ethanol (150 ml) was added over 40 minutes. The reaction mixture was stirred an additional hour until the dark blue solution became colorless. Ammonium chloride (50 g) was added and the ammonia allowed to evaporate. The residue was acidified with HCl (pH ca. 3), extracted with ethylene dichloride, washed with water, concentrated and distilled to yield 49.6 g (80.8%) of the 4-methyl-4-(4-methyl-1,4-cyclohexadien-1-yl)pentanoic acid: bp 128° -130° C (1 mm); nD20 1.4955; λmax 211 nm; δTMSCDCl3 11.21 (s,1), 5.43-5.50 (broad band, 2) 2.62 (s,4), 1.66 (s,3) 1.03 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1.[Al]>>[CH3:1][CH:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]1=[O:10]
Reactant: CC1=CCCC(C)(C)C1=O
Agent: [Al]
Product: CC1C=CCC(C)(C)C1=O
Reaction time: 60 h
Yield: 92 %

Procedure:
150 g of 2,6,6-trimethyl-cyclohex-2-en-1-one and 15 g of aluminium isopropylate were heated at 160° under argon atmosphere until obtention of a clear solution, in a reaction vessel fitted with a fractioning device. The clear mixture was then progressively heated to 190° and kept at this temperature for 60 hours, under vigorous stirring, the formed 2,6,6-trimethyl-cyclohex-3-en-1-one being directly distilled from the reaction mixture. During this period, a further amount of 300 g of starting ketone was added to the reaction mixture. 285 g of a distillate containing 40% of the desired product and 60% of unreacted starting material were thus obtained. After further distillation of the above 285 g there were finally isolated 105 g of the desired ketone having b.p. 62°/15 Torr (yield: 92%-conversion rate of 25%).
Reaction SMILES: [H-].[Na+].[F:3][CH2:4][CH2:5][OH:6].[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Br.[Cl-].[NH4+]>C1COCC1>[Br:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:10]([CH2:11][O:6][CH2:5][CH2:4][F:3])[CH:9]=1
Reactant: BrCc1cccc(Br)c1
Reactant: OCCF
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: FCCOCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 58 %

Procedure:
A mixture of sodium hydride [60% in oil] (343, mg, 8.6 mmol) and THF at −5° C. was treated via a syringe with a solution of 2-fluoroethanol in THF over a 1 min. period, stirred for 2 min., warmed to room temperature, stirred for 15 min. at room temperature, treated with 3-bromobenzylbromide (2.5 g, 11.7 mmol), stirred for 1 h, poured into saturated ammonium chloride and extracted with ether. The extracts were combined, washed sequentially with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, 20:1 hexane/ ethyl acetate as eluent, to afford 1-bromo-3-(2-fluoroethoxymethyl)benzene as a yellow oil, 1 g (58% yield), 1H NMR (DMSO-d6) δ 3.6 (dxt, 2H); 4.5 (dxt, 2H); 4.4 (s, 2 H); 7.3 (m, 2H); 7.5 (m, 2H); MS [(+)ESI] m/z 219 [M−H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([OH:12])=[CH:7]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][O:33][CH2:34][CH2:35]O.C1COCC1.CCOC(/N=N/C(OCC)=O)=O>CO.ClCCl.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12][CH2:35][CH2:34][O:33][CH3:32])=[CH:7]2
Reactant: COCCO
Reactant: Oc1cnc2c(Cl)ccnc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COCCOc1cnc2c(Cl)ccnc2c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 55.6 %

Procedure:
A round bottom flask under nitrogen environment was charged with 8-chloro-1,5-naphthyridin-3-ol (1.05 g, 5.8 mmol), 22.8 g of PS-Triphenylphosphine (loading: 2.2 mmol/g), 2-methoxyethanol (2.2 mL, 27.9 mmol), and THF (29.1 ml, 5814 μmol)/DCM (58.1 mL). Mixture cooled to 0° C. and to this was added DEAD (1.84 mL) dropwise via syringe. Reaction mixture allowed to stir at room temperature for 16 hours. Diluted with 50 mL of 10% MeOH/dichloromethane and resin bound reagent filtered. Filtrate concentrated under reduced pressure and purified by ISCO silica gel chromatography (10-30% EtOAc/Hexanes) to afford 8-chloro-3-(2-methoxyethoxy)-1,5-naphthyridine (770 mg, 55% yield) as white solid. MS [M+H]=238.9. Calc'd for C11H11ClN2O2=238.67.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]OS(C)(=O)=O)[CH:5]=[N:6][CH:7]=1.[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C=O)C.O>[N:14]([CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCc1cncc(Br)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1cncc(Br)c1
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a solution of crude methanesulfonic acid 5-bromo-pyridin-3-ylmethyl ester (4.20 g) in DMF (60 mL) was added NaN3 (10.0 g, 153.8 mmol). The mixture was stirred under N2 overnight then diluted with water. The mixture was extracted with EtOAc (2×300 mL) and the combined organic layers washed with water before drying over Na2SO4. The solution was concentrated in vacuo to afford crude 3-azidomethyl-5-bromo-pyridine (2.04 g) as a dark brown oil. This crude material was used directly in the next step.
Reaction SMILES: C[C:2]1[CH:7]=[C:6](C)[CH:5]=[C:4]([CH3:9])[C:3]=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22].C(Cl)(=O)C1C=CC=CC=1>N1C=CC=CC=1>[Br:21][C:18]1[CH:19]=[CH:20][N:15]2[N:14]=[C:9]([C:4]3[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=3)[N:22]=[C:16]2[CH:17]=1
Reactant: Nc1cc(Br)cc[n+]1N
Reactant: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: c1ccncc1
Solvent: O=C(Cl)c1ccccc1
Product: Brc1ccn2nc(-c3ccccc3)nc2c1
Reaction time: 2 h
Yield: 61.5 %

Procedure:
1,2-Diamino-4-bromopyridinium 2,4,6-trimethylbenzenesulfonate (15.6 g, 40.2 mmole) in pyridine (106 ml) is heated overnight at 100° C. with benzoyl chloride (9.4 ml, 80 mmole) giving a redbrown solution and after 2 hrs a brown suspension. The reaction mixture is concentrated in vacuo and the residue is triturated for 2.5 hr in sat. aqueous ammonium chloride solution (300 ml), while neutralizing to pH 6-7 with sat. aqueous sodium bicarbonate solution. The solid is collected by filtration, washed with water (40 ml) and dried affording 7-bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (6.78 g, 61.6%) as an off-white solid. mp.: 189-191° C. MS: m/z=276.1, 274.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:17])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[C:6]=1[C:7]#[N:8].[CH3:18][C:19]([CH3:21])=O.Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1.[OH-].[Na+]>[CH3:17][C:4]1[S:3][C:2]2[N:1]=[C:19]([CH3:21])[CH:18]=[C:7]([NH2:8])[C:6]=2[C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1
Reactant: COc1cccc(-c2c(C)sc(N)c2C#N)c1
Reactant: CC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cccc(-c2c(C)sc3nc(C)cc(N)c23)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.2 %

Procedure:
To a solution of 2-amino-5-methyl-4-[3-(methyloxy)phenyl]-3-thiophenecarbonitrile (Description 3) (260 mg, 1.064 mmol) in toluene (2.5 mL), were added at RT, acetone (0.094 mL, 1.277 mmol) and SnCl4 (0.150 mL, 1.277 mmol), the reaction mixture was stirred for 5 min at RT then for 15 min at 150° C. in a microwave. The reaction mixture was cooled to RT then diluted with aqueous NaOH (1M) until the solution turned basic. The aqueous layer was then extracted with DCM (3×30 mL), the combined organic extracts were dried over a phase separating column and concentrated. Purification by chromatography on silica gel, eluting with a gradient of 0-30% ethyl acetate in cyclohexane, afforded the title compound (167 mg). LCMS (A) m/z: 285 [M+1]+, Rt 1.20 min (basic).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][CH3:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:18](Br)[C:19]#[CH:20]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][N:7]([CH2:20][C:19]#[CH:18])[CH3:8])=[CH:4][CH:3]=1
Reactant: CNCc1ccc(Cl)cc1
Reactant: C#CCBr
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C#CCN(C)Cc1ccc(Cl)cc1

Procedure:
To a solution of 31.1 g (0.2 mole) N-(4-chlorobenzyl)-methylamine and 30.3 g (0.3 mole) triethylamine in 150 ml dry benzene are added in portions at room temperature while stirring 23.8 g (0.2 mole) propargyl bromide. The solution is heated for 17 hours with reflux. After filtering off the solid phase, the the solvent is distilled under vacuum and the remaining residue fractionally distilled under reduced pressure. One thus obtains 30.9 g N-(4-chlorobenzyl)-N-methyl-2-propinylamine (79% of the theory as colorless liquid of the boiling point 86°-106° C./2 Torr.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][CH2:22][O:23][CH3:24])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:25]C(=O)OCC)[C:9]=3[C:8]2=[O:31])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21][CH2:22][O:23][CH3:24])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([OH:25])[C:9]=3[C:8]2=[O:31])=[CH:32][CH:33]=1
Reactant: CCOC(=O)Oc1c2c(c(OCOC)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1c2c(c(O)c3cccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To the ethyl carbonate methoxymethyl ether 5 (70.9 mg, 0.156 mmol) in THF (7.6 mL) at room temperature was added a solution (5 mL) of K2CO3 (215 mg, 1.56 mmol) in water and 4-dimethylaminopyridine (3.8 mg, 0.03 mmol). The yellow solution was stirred at room temperature under nitrogen atmosphere overnight. Most of THF was removed under reduced pressure at 30-40° C. and the remaining solution was diluted with dichloromethane, washed with 1N HCl and brine, dried (MgSO4) and concentrated to give solid crude product (51 mg, 85%), which is triturated in diethylether/hexane to afford the product, 7-(4-fluoro-benzyl)-5-hydroxy-9-methoxymethoxy-pyrrolo [3,4-g]quinoline-6,8-dione 6 as a yellow solid (34 mg). 1H NMR (CDCl3) δ 9.1 (dd, 1H), 8.7 (dd, 1H), 7.6 (dd, 1H), 7.4 (dd, 2H), 7.0 (t, 2H), 5.8 (s, 2H), 4.8 (s, 2H), 3.7 (s, 1H). MS: 383 (M+1); 381 (M-1).
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:10]2[N:14]=[C:13]([NH:15]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:12][N:11]=2)[C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[NH2:15][C:13]1[S:12][N:11]=[C:10]([C:6](=[N:5][O:4][CH:1]2[CH2:3][CH2:2]2)[C:7]([OH:9])=[O:8])[N:14]=1
Reactant: O=C(O)C(=NOC1CC1)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1nc(C(=NOC2CC2)C(=O)O)ns1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-cyclopropyloxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer)(1 g) in anisole (2 ml) was added trifluoroacetic acid (8 ml) under ice-cooling. After stirring for 2 hours at ambient temperature, the mixture was concentrated in vacuo. The residue was poured into ice-water (50 ml). The mixture was adjusted to pH 7 with saturated aqueous solution of sodium bicarbonate and an insoluble material was filtered off. After washing with a mixture of ethyl acetate and tetrahydrofuran, the filtrate was adjusted to pH 2 with 6N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, concentrated in vacuo, and triturated with diisopropyl ether to give 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(cyclopropyloxyimino)acetic acid (syn isomer) as a crystal. The physical data of this compound were identical to those of the compound prepared in Preparation 48.