Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[H-].[Na+].F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>CN(C)C=O>[O:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][O:1][C:15]2[CH:14]=[CH:13][CH:20]=[CH:19][C:16]=2[CH:17]=[O:18])[CH2:5][CH2:6]1
Reactant: OCCN1CCOCC1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
To dried dimethylformamide (20 ml) solution in which 4-(2-hydroxyethyl)morpholine (1 g, 7.62 mmol) was dissolved, sodium hydride (201.2 mg, 8.38 mmol) was slowly added under nitrogen at room temperature. The mixture was stirred for 30 minutes at room temperature, and 4-fluorobenzaldehyde (1.1 g, 8.86 mmol) in dried dimethylformamide (5 ml) was added over 10 minutes. The reaction mixture was stirred at room temperature for 18 hours until the initial reaction product disappeared. Subsequently, 20 ml of ice water was added to the resulting mixture, and the mixture was extracted with ethyl acetate and water. The organic layer was washed with water several times, dried over anhydrous magnesium sulfate, filtered and solvent-evaporated. The residual oil was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to afford the intermediate compound 4-(2-(morpholinoethoxy)benzaldehyde (1.42 g, 79%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.O>C(#N)C>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: ClCCN1CCOCC1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1CCN1CCOCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (0.100 g, 0.303 mmol), cesium carbonate (0.296 g, 0.909 mmol), and 4-(2-chloroethyl)morpholine (0.059 g, 0.394 mmol) were suspended in acetonitrile (4 mL). The reaction was stirred at 60° C. overnight. H2O (25 mL) was added and the resulting precipitate was collected by filtration. The solid was subjected to chromatography (silica gel, ethyl acetate with 10% methanol) afforded an off-white solid (0.040 g, 30%). 1H NMR (400 MHz, CDCl3) δ 7.55 (app q, J=7.92 Hz, 1H), 6.93 (app t, J=8.39 Hz, 1H), 6.84 (app t, J=9.40 Hz, 1H), 5.95 (s, 1H), 5.18 (s, 2H), 4.16 (app t, J=6.78 Hz, 2H), 3.68 (s, 4H), 2.65 (app t, J=6.38 Hz, 2H), 2.54 (s, 4H), 2.43 (s, 3H). ES-HRMS m/z 443.0743 (M+H C19H21BrF2N2O3 requires 443.0776).
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.[O:18]=[C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][N:20]1[CH:34]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:14]([NH:13][C:11](=[O:12])[NH:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([F:17])[C:2]([C:23]3[CH:22]=[CH:21][N:20]([CH:34]4[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[CH2:35]4)[C:19](=[O:18])[CH:24]=3)=[CH:16][C:6]=2[N:7]=1)[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc(B3OC(C)(C)C(C)(C)O3)cc2=O)C1
Reactant: CCNC(=O)Nc1nc2cc(Br)c(F)cc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3ccn(C4CCN(C(=O)OC(C)(C)C)C4)c(=O)c3)c(F)cc2s1
Temperature: 80 °C
Yield: 36 %

Procedure:
A solution of 1-(5-bromo-6-fluoro-benzothiazol-2-yl)-3-ethyl-urea (0.07 g, 0.31 mmol), tert-butyl 3-(2-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl)pyrrolidine-1-carboxylate (0.24 g, 0.62 mmol) and K3PO4 (0.13 g, 0.62 mmol) in DMF-H2O (5.0 mL, 3:2) was degassed by flushing with nitrogen for 15 min. Dichlorobis(triphenylphosphine)-palladium(II) (0.022 g, 0.03 mmol) was then added to the reaction mixture followed by degassing with nitrogen for another 15 min. The resulting reaction mixture was then heated to 80° C. for 2 h. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to room temperature and poured onto ice-cold water followed by extraction with EtOAc (3×50 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude was then purified over silica gel (100-200 M, 1.50% MeOH-DCM) to obtain the desired product (0.056 g, 36%). MS: 502.20 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7][OH:8].[CH:13](I)([CH3:15])[CH3:14]>>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH:13]([CH3:15])[CH3:14])=[CH:9][C:6]=1[CH2:7][OH:8])([O-:12])=[O:11]
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1ccc(O)cc1CO
Product: CC(C)Oc1ccc([N+](=O)[O-])c(CO)c1

Procedure:
10 g (60 mmol) of 5-hydroxy-2-nitrobenzyl alcohol were reacted with 7.0 ml (70 mmol) of isopropyl iodide analogously to Example 4a); after purification over silica gel with n-heptane/ethyl acetate (3:2), 10.3 g of oily crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][S:18]([NH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([S:32](Cl)(=[O:34])=[O:33])[CH:30]=2)[C:25]([N:36]=[N:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]#[N:45])=[CH:24][CH:23]=1)(=[O:20])=[O:19].Cl>O.CC(C)=O>[CH3:17][S:18]([NH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([S:32](=[O:34])(=[O:33])[NH:1][C:2]3[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][CH:3]=3)[CH:30]=2)[C:25]([N:36]=[N:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]#[N:45])=[CH:24][CH:23]=1)(=[O:20])=[O:19]
Reactant: Nc1ccc(S(=O)O)cc1
Reactant: CS(=O)(=O)Nc1ccc(N=Nc2ccccc2C#N)c2ccc(S(=O)(=O)Cl)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CS(=O)(=O)Nc1ccc(N=Nc2ccccc2C#N)c2ccc(S(=O)(=O)Nc3ccc(S(=O)O)cc3)cc12
Reaction time: 1 h

Procedure:
To a solution of 52.5 g of p-aminobenzene sulphinic acid and 96 g of potassium carbonate in 850 ml of water first 1 l of acetone was added and then portionwise 157 g of compound P with stirring. Thereupon, the mixture was stirred for 1 h, poured into 2.5 l of water and acidified with 100 ml of concentrated hydrochloric acid. The precipitate formed was sucked off, washed with methanol and dried. Yield: 160 g.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[C:3]=1[N+:11]([O-])=O.O.O.[C:16](O)(=[O:20])[C:17](O)=[O:18]>C(O)C.Cl>[OH:18][C:17]1[C:16]([OH:20])=[N:1][C:2]2[CH:10]=[CH:9][C:5]3[S:6][CH:7]=[CH:8][C:4]=3[C:3]=2[N:11]=1
Reactant: Nc1ccc2sccc2c1[N+](=O)[O-]
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: CCO
Solvent: O
Product: Oc1nc2ccc3sccc3c2nc1O
Yield: 38.8 %

Procedure:
A solution of 5-amino-4-nitrobenzo[b]thiophene (0.50 g, 2.6 mmol) in 50 ml of 96% ethanol was hydrogenated at room temperature and atm. pressure in the presence of 5% palladium-on-carbon until the theoretical amount of hydrogen was absorbed. The catalyst was filtered off, and the filtrate was acidified with 1N hydrochloric acid and evaporated to dryness. The residue was refluxed with oxalic acid dihydrate (0.40 g, 3.1 mmol) in 25 ml of 4M hydrochloric acid for 2 h. The mixture was cooled, and the precipitated solid was isolated by filtration, washed with water, ethanol and ether, and dried. The crude product was dissolved in a minimum amount of 2N sodium hydroxide, treated with decolourising charcoal, and filtered. The filtrate was acidified with 4M hydrochloric acid and the resulting precipitate was collected by filtration, washed with water, ethanol and ether to give 0.22 g (39%) of the thienoquinoxaline; m.p. 186.6° C.; IR (KBr): 1680 cm-1 ; H-NMR (DMSO-d6 ) 7.13 (d,J=9 Hz, 1H, ArH), 7.62 (D,J=9 Hz, 1H, ArH), 7.72 (d,J=5 Hz, 1H, ArH), 7.95 (d,J=5 Hz, 1H, ArH); MS m/z: 218 (M+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[C:11](=[C:12]([CH3:26])[N:13]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:14]=2)[C:10](=O)[CH2:9]1.[C:28]([NH:31][NH2:32])([NH2:30])=[NH:29].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[C:11](=[C:12]([CH3:26])[N:13]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:14]=2)[C:10](=[N:32][NH:31][C:28]([NH2:30])=[NH:29])[CH2:9]1
Reactant: Cc1c2c(nn1CCCc1ccccc1)CC(c1ccccc1Cl)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1c2c(nn1CCCc1ccccc1)CC(c1ccccc1Cl)CC2=NNC(=N)N
Yield: 154.3 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-methyl-2-(3-phenylpropyl)-4,5,6,7-tetrahydroindazol-4-one (0.25 g), aminoguanidine hydrochloride (0.11 g), concentrated hydrochloric acid (0.16 ml), water (0.16 ml) and ethanol (15 ml) was refluxed for 8 hours. Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethanol-water to give 6-(2-chlorophenyl)-4-guanidinoimino-3-methyl-2-(3-phenylpropyl)-4,5,6,7-tetrahydroindazole hydrochloride (Compound 154) (0.24 g) as colorless crystals.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][C:5]1[CH:6]=[C:7]([C:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)[CH2:8]Cl>O.C(O)C>[CH3:4][C:5]1[CH:6]=[C:7]([CH2:8][C:1]#[N:2])[C:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(Sc2ccccc2)c(CCl)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(Sc2ccccc2)c(CC#N)c1

Procedure:
570.7 g of 3-methyl-6-(phenylthio)-benzyl alcohol are dissolved in 1.5 litres of benzene and heated under reflux. There are added dropwise thereto within 45 minutes 352 ml of thionyl chloride and the mixture is boiled for a further 90 minutes. Then the mixture is concentrated under reduced pressure and there is obtained 3-methyl-6-(phenylthio)-benzyl chloride as a red-brown oil. 194 g of potassium cyanide in 250 ml of water are heated under reflux for 17 hours under an argon atmosphere with 616.9 g of 3-methyl-6-(phenylthio)-benzyl chloride in 900 ml of ethanol. Then the ethanol is distilled off under reduced pressure, the residue then diluted with water and extracted with ether. The extracts are washed with water, dried over sodium sulphate and evaporated. There is obtained 3-methyl-6-(phenylthio)-phenylacetonitrile as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)(=[O:16])=[O:15])[CH:6]=[CH:5][C:4]1=2.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1.O>[F:23][C:19]1[CH:18]=[C:17]([S:14]([NH:13][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]([CH2:2][NH:1][C:24](=[O:26])[CH3:25])[CH2:12][CH2:11][CH2:10]3)(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=1
Reactant: NCC1CCCc2cc(NS(=O)(=O)c3cccc(F)c3)ccc21
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NCC1CCCc2cc(NS(=O)(=O)c3cccc(F)c3)ccc21
Temperature: 23 °C
Reaction time: 4 h

Procedure:
To a solution of 0.18 grams (0.538 mmoles) N-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-fluoro-benzenesulfonamide in 25 mL pyridine was added 0.052 grams (0.511 mmole) acetic anhydride. The reaction mixture was stirred at 23° C. for 4 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with 0.5M hydrochloric acid, water, and saturated aqueous sodium chloride. The organic phase was dried (magnesium sulfate) and concentrated under reduced pressure. N-[6-(3-Fluoro-benzenesulfonylamino)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-acetamide was obtained as a crystalline solid from ethyl acetate/ethyl ether, 0.18 grams (89%), m.p. 136-137° C., M+H=377.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:29])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]([OH:27])[C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([O:18]C)=O)[N:15]=[C:7]3[C:6]=2[CH:28]=1.C[O-].[Na+].C([NH2:35])=O>>[Br:1][C:2]1[C:3]([F:29])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]([OH:27])[C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([NH2:35])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:28]=1
Reactant: COC(=O)c1nc2n(c1C(O)c1ccnn1C)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Product: Cn1nccc1C(O)c1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Yield: 90 %

Procedure:
10-bromo-9-fluoro-3-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly to as described in General Procedure L. Methyl 10-bromo-9-fluoro-3-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with sodium methoxide and formamide to afford 131 mg (90% yield) of the title compound.
Reaction SMILES: [CH3:1][Mg+].[Br-].[CH3:4][O:5][C:6](=[O:29])[C:7]1[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[C:10]([NH:16][CH:17]=[O:18])=[C:9]([F:19])[C:8]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=1[F:28]>CCOCC.C1COCC1>[CH3:4][O:5][C:6](=[O:29])[C:7]1[CH:12]=[C:11]([C:13]([OH:15])([CH3:1])[CH3:14])[C:10]([NH:16][CH:17]=[O:18])=[C:9]([F:19])[C:8]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=1[F:28]
Reactant: COC(=O)c1cc(C(C)=O)c(NC=O)c(F)c1Nc1ccc(Br)cc1F
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1cc(C(C)(C)O)c(NC=O)c(F)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of MeMgBr (3.20 equiv., 3.0 M solution in diethyl ether) in ether is added a solution of 5-acetyl-2-(4-bromo-2-fluorophenylamino)-3-fluoro-4-formylamino-benzoic acid methyl ester (1.00 equiv.) in THF at 0° C. The reaction mixture is warmed to room temperature and stirred for 16 hours. The reaction is quenched with saturated aqueous NH4Cl and diluted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that is used directly without further purification.
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]2[C:15](=[O:16])[O:14][C:12](=O)[C:11]2=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH2:28])=O>O>[NH:1]([C:8]1[CH:9]=[C:10]2[C:15](=[O:16])[NH:28][C:12](=[O:14])[C:11]2=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC=O
Reactant: O=C1OC(=O)c2cc(Nc3ccccc3)c(Nc3ccccc3)cc21
Solvent: O
Product: O=C1NC(=O)c2cc(Nc3ccccc3)c(Nc3ccccc3)cc21

Procedure:
A suspension of 21.9 g (66.3 mmol) of 4,5-bis(anilino)phthalic anhydride in60 ml of formamide under argon atmosphere is heated at 125°-130° for 5 hours. The reaction mixture is cooled to 70°, and 250 ml of water are slowly added. This mixture is cooled to 0° for 30 minutes, and the reddish crystals are filtered off, washed with water and dried. Recrystallization from DMF/water yields the title compound in the form of orange crystals, m.p. 205°-207° C., FAB-MS: 330 [M+ +H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[O:17][CH2:18][C:19]2([N:41]=1)[C:28]1([CH2:31][O:30][CH2:29]1)[CH2:27][O:26][C:25]1[C:20]2=[CH:21][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:24]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:43]1[CH:44]=[N:45][CH:46]=[C:47]([C:49]#[C:50][CH2:51][O:52][CH3:53])[CH:48]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:53][O:52][CH2:51][C:50]#[C:49][C:47]1[CH:48]=[C:43]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[O:26][CH2:27][C:28]2([CH2:31][O:30][CH2:29]2)[C:19]23[CH2:18][O:17][C:16]([N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])=[N:41]2)[CH:44]=[N:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(B3OC(C)(C)C(C)(C)O3)ccc1OCC21COC1
Reactant: COCC#Cc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COCC#Cc1cncc(-c2ccc3c(c2)C2(COC(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=N2)C2(COC2)CO3)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
Under argon atmosphere, a mixture of di-tert-butyl[6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]imidodicarbonate (213 mg, 0.372 mmol), 3-bromo-5-(3-methoxyprop-1-yn-1-yl)pyridine (252 mg, 1.12 mmol), Na2CO3 (158 mg, 1.49 mmol), tetrakis(triphenylphosphine)palladium(0) (21.5 mg, 0.019 mmol), dioxane (3.4 mL) and water (0.85 mL) was stirred for 3 hours at 110° C. The reaction mixture was cooled down to ambient temperature, and water was added to the mixture. The mixture was extracted with MeOH—CHCl3 (1:9), and the organic layer was dried over Na2SO4 prior to filtration. The filtrate was concentrated at reduced pressure to give crude di-tert-butyl {6′-[5-(3-methoxyprop-1-yn-1-yl)pyridin-3-yl]dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl}imidodicarbonate, which was used for the next reaction without further purification.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:9][C:10]([NH:12]C(=O)C2C=CC=CC=2)=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-].[Na+]>CCO>[NH2:2][C:1]1[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][C:4]=2[NH:9][C:10](=[O:11])[N:12]=1
Reactant: N#Cc1cccnc1NC(=O)NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(=O)[nH]c2ncccc12
Temperature: 25 °C
Yield: 54.8 %

Procedure:
A solution of N-(3-cyanopyridin-2-ylcarbamoyl)benzamide (example 53a) (360 mg, 1.35 mmol) and NaOH (2 N, 1.85 mL) in EtOH (5 mL) was stirred at 100° C. under nitrogen for half an hour. After cooling to room temperature, the clear reaction solution was filtered and the filtrate was carefully neutralized with 10% AcOH with vigorous stirring at 0° C. The resultant precipitate was collected by filtration, and washed with warm 20% EtOH in water to give the final product 4-aminopyrido[2,3-d]pyrimidin-2(1H)-one (120 mg, 55%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.22 (dd, J=4.4 Hz, 4.8 Hz, 1H), 7.29 (dd, j=4.8 Hz, 1H), 8.24 (dd, J=2 Hz, 1.6 Hz, 1H), 8.59 (dd, J=2 Hz, 1.6 Hz, 1H), 8.66-8.71 (m, 2H), 8.70 (d, J=1.2 Hz, 1H). MS 162 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-])=O.[NH2:14][C:15](N)=[S:16].O>S1(CCCC1)(=O)=O>[NH2:14][C:15]1[S:16][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N:1]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NC(N)=S
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: Nc1nc2cc([N+](=O)[O-])ccc2s1
Reaction time: 12 h

Procedure:
A suspension of 10.13 g of 2,4-dinitrochlorobenzene and 15.2 g of thiourea in 50 ml of sulpholane (tetrahydrothiophene 1,1-dioxide) is stirred at 110° to 120° C. for 12 hours. After cooling, the mixture is thoroughly stirred with 800 ml of water, and the solid is filtered off with suction and washed with water. After drying, 11.2 g of a yellow powder which, according to HPLC analysis (high pressure liquid chromatography), contains 69.5% of 2-amino-5-nitrobenzothiazole (corresponding to 80% of theory) are obtained. Recrystallisation from dimethylformamide raises the melting point to 307° C. (decomposition) (Zhur. Obschei Khim. 30, 1363-6 (1960) reports melting point 308°-309° C., decomposition).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[CH3:23][O-:24].[Na+].Cl.S(=O)(=O)(O)O>CO.O>[CH3:23][O:24][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccc(OCCCCBr)cc2)cc1
Reactant: C[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCCCCOc1ccc(-c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of methyl 4-[4-(4-bromobutoxy)phenyl]benzoate (1.40 g) in methanol (14 ml) was treated with 28% sodium methoxide in methanol (14 ml) and the solution was reluxed for 5 hours. After cooling to room temperature, the reaction mixture was poured into cold 1N-hydrochloric acid (110 ml) and the resulting precipitate was collected by filtration, washed thoroughly with water and dried to give a white solid. To a mixture of this solid in methanol (20 ml) was added concentrated sulfuric acid (0.5 ml) and refluxed for 4 hours. After cooling to room temperature, the reaction mixture was poured into cold water and the resulting precipitate was collected by filtration, washed thoroughly with water and dried to give methyl 4-[4-(4-methoxybutoxy)phenyl]benzoate (1.16 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[C:10][C:11]([C:13]2[N:17]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:21][C:16]3=[N:15][CH:14]=2)=O)[C:4]=1[NH:27]C(=O)OC(C)(C)C.[I-:35].[Na+]>C(O)(=O)C.C(O)=O>[I:35][C:9]1[C:5]2[C:4](=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][CH:6]=2)[N:27]=[C:11]([C:13]2[N:17]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:21][C:16]3=[N:15][CH:14]=2)[CH:10]=1
Reactant: COCCOc1ccn2c(C(=O)C#Cc3cccc(OC)c3NC(=O)OC(C)(C)C)cnc2c1
Reactant: [I-]
Agent: [Na+]
Solvent: O=CO
Solvent: CC(=O)O
Product: COCCOc1ccn2c(-c3cc(I)c4cccc(OC)c4n3)cnc2c1
Temperature: 60 °C
Yield: 92 %

Procedure:
To tert-butyl 2-methoxy-6-(3-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)-3-oxoprop-1-ynyl)phenylcarbamate (2.51 g, 5.39 mmol) and sodium iodide (16.2 g, 108 mmol) was added acetic acid/formic acid (5 mL/5 mL). The reaction vessel was purged with N2 and heated to 60° C. for 3 hours. The reaction was then cooled to ambient temperature and diluted with H2O/DCM (50 mL/100 mL), followed by extraction with DCM. The combined organics were washed with saturated NaHCO3, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/MeOH 10:1) provided the desired product (92%).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)C)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[CH3:1][NH:8][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CN(CCN1CCCCC1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CNCCN1CCCCC1

Procedure:
A solution of the title compound of Step 11 (1.85 g, 7.96mmol) and 20% Pd(OH)2 on carbon in EtOH (50 mL) was placed under a hydrogen atmosphere (60 psi) at room temperature for 17 hours. The mixture was filtered and concentrated to give the title compound as a clear, yellow liquid (1.02 g, 90% crude yield). The proton spectral data were consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6].[NH3:16]>>[NH2:16][C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6]
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1Cl
Reactant: N
Product: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1N
Temperature: 180 °C

Procedure:
A mixture of 79.0 g (grams)(320 mmol (millimole)) of 3-chloro-2-methyl-4-methylsulfonylbenzoic acid, 1.0 g (12.6 mmol) of cupric oxide, and 500 mL (milliliter) of concentrated aqueous ammonia was heated at 180° C. for 17 hours in a stirred Parr reactor. The resulting dark mixture was concentrated by evaporation under reduced pressure. The residue was acidified with 2N aqueous hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The extract was filtered and concentrated by evaporation under reduced pressure. The solid residue was mixed with hexane, recovered by filtration, and dried to obtain 50.0 g (68 percent of theory) of the title acid compound as a light tan powder melting at 197-198° C.