Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]1([C:7]2[CH:16]=[C:15]3[C:10]([NH:11][C:12](=[O:21])[C:13](=[O:20])[N:14]3[CH2:17][CH2:18][CH3:19])=[CH:9][CH:8]=2)[CH:6]=[CH:5][N:4]=[CH:3]1.[N+:22]([O-])([O-:24])=[O:23].[K+]>S(=O)(=O)(O)O>[ClH:1].[N:2]1([C:7]2[CH:16]=[C:15]3[C:10]([NH:11][C:12](=[O:21])[C:13](=[O:20])[N:14]3[CH2:17][CH2:18][CH3:19])=[CH:9][C:8]=2[N+:22]([O-:24])=[O:23])[CH:6]=[CH:5][N:4]=[CH:3]1
Reactant: CCCn1c(=O)c(=O)[nH]c2ccc(-n3ccnc3)cc21
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccnc3)cc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of 1 g of 7-(1-imidazolyl)-1-n-propylquinoxaline-2,3-(1H,4H)-dione hydrochloride in 8 ml of sulfuric acid was added 0.4 g of potassium nitrate, and the mixture was stirred overnight. The reaction mixture was poured in ice-water and adjusted to pH 7. The resulting crystals were recrystallized from 1N-hydrochloric acid to provide 0.9 g of 7-(1-imidazolyl)-6-nitro-1-n-propylquinoxaline-2,3-(1H,4H)-dione hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH2:18][CH3:19])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)COc1ccc(Cl)cc1
Reaction time: 96 h
Yield: 93 %

Procedure:
A solution of 4-chlorophenoxyacetic acid (Aldrich) (18.62 g, 99.8 mmoles) and concentrated sulfuric acid (Fisher) (2.5 mL) in ethanol (170 mL) was refluxed with stirring under a Drierite tube for 96 hours. The reaction solution was cooled in an ice-bath, and the volatiles were removed by spin evaporation in vacuo to a volume of about 100 mL. The liquid was dissolved in dichloromethane (225 mL) and washed with a solution of 5% aqueous sodium bicarbonate (4×100 mL) and finally with brine (1×50 mL). The solution was dried over sodium sulfate and spin evaporated in vacuo to give 19.97 g (93% yield) of ethyl 4-chlorophenoxyacetate as an amber liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]([C:10]2[CH:15]=[C:14]([C:16]3[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:13]=[C:12]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:11]=2[O:28][CH3:29])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1.CCOC(C)=O>[C:24]([C:12]1[C:11]([O:28][CH3:29])=[C:10]([N:8]([CH3:9])[C:6](=[O:7])[C:5]2[CH:30]=[CH:31][C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:3][CH:4]=2)[CH:15]=[C:14]([C:16]2[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:13]=1)([CH3:25])([CH3:26])[CH3:27]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ncccc1-c1cc(N(C)C(=O)c2ccc(N)cc2)c(OC)c(C(C)(C)C)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ncccc1-c1cc(N(C)C(=O)c2ccc(NS(C)(=O)=O)cc2)c(OC)c(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
step 3—To a solution of 140 (0.15 g, 0.36 mmol) in pyridine (3 mL) cooled to 0° C. was added methanesulfonyl chloride (0.053 g, 0.46 mmol) and the resulting solution stirred at 0° C. for 2 h, followed by 2 h at RT. The reaction mixture was diluted with EtOAc, washed sequentially with aqueous CuSO4 and 2N HCl, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient to afford 0.17 g (97%) of N-[3-tert-butyl-2-methoxy-5-(2-methoxypyridin-3-yl)phenyl]-4-methanesulfonylamino-N-methylbenzamide (142) as a white foam (0.17 g, 94%
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH3:8])([OH:7])[CH2:5][CH2:4][NH:3]1.[F:9][C:10]1[CH:17]=[C:16](F)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13].C(=O)([O-])[O-].[Li+].[Li+].O>CS(C)=O>[F:9][C:10]1[CH:17]=[C:16]([N:3]2[CH2:4][CH2:5][C@@:6]([OH:7])([CH3:8])[C@@H:2]2[CH3:1])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccc(F)cc1F
Reactant: C[C@@H]1NCC[C@]1(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@@H]1N(c2ccc(C#N)c(F)c2)CC[C@]1(C)O
Yield: 40.5 %

Procedure:
A solution (2 mL) of (2S,3S)-2,3-dimethylpyrrolidin-3-ol 0.5 oxalate (228 mg), 2,4-difluorobenzonitrile (292 mg) and lithium carbonate (206 mg) in DMSO was stirred at 80° C. for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) and recrystallized from hexane-isopropyl ether to give the title compound as a colorless solid (yield: 188 mg, yield: 57%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[C:4](I)[CH:3]=1.N#N.[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19]>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[C:4](/[CH:19]=[CH:18]/[C:17]([O:21][CH3:22])=[O:20])[CH:3]=1
Reactant: Fc1cc(-n2cnnn2)c(I)cc1Cl
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: CC#N
Product: COC(=O)/C=C/c1cc(Cl)c(F)cc1-n1cnnn1
Temperature: 85 °C

Procedure:
A solution of Intermediate 5B (100 g, 324.4 mmol) in ACN (1000 mL) was degassed with N2. TEA (64 mL) and methyl acrylate (60 mL) were added and the reaction was further degassed. Pd(OAc)2 (8 g, 11.8 mmol) was added and the reaction was heated to 85° C. for 18 h. The reaction was concentrated and the residue was diluted with H2O. The aqueous layer was extracted with EtOAc and the combined organics were washed with brine. Purification by silica gel chromatography gave 25 g of Intermediate 5C. MS (ESI) m/z: 283.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:39])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]5[CH:29]=[CH:28][C:27]([O:30][CH2:31][C@@H:32]6[CH2:36][O:35]C(C)(C)[O:33]6)=[CH:26][CH:25]=5)[N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.CC1C=CC(S(O)(=O)=O)=CC=1>CO.O>[F:39][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]5[CH:29]=[CH:28][C:27]([O:30][CH2:31][C@@H:32]([OH:33])[CH2:36][OH:35])=[CH:26][CH:25]=5)[N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(OC[C@@H]2COC(C)(C)O2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(OC[C@@H](O)CO)cc1
Temperature: 80 °C
Yield: 82.3 %

Procedure:
To a solution of (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-5-methylpyridin-2-yl)cyclopropane-carboxamide (160 mg, 0.30 mmol) in methanol (3 mL) and water (0.3 mL) was added 4-methylbenzenesulfonic acid (11 mg, 0.060 mmol). The mixture was heated at 80° C. for 1 hour. The reaction mixture was partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with sat. NaHCO3 and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography to yield (S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(4-(2,3-dihydroxypropoxy)phenyl)-5-methylpyridin-2-yl)cyclopropane-carboxamide (123 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=8.4 Hz, 1H), 7.62 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.29 (d, J=8.7 Hz, 2H), 7.14 (td, J=9.1, 1.7 Hz, 2H), 7.00 (d, J=8.2 Hz, 1H), 6.87 (d, J=8.7 Hz, 2H), 4.02-3.94 (m, 3H), 3.75 (dd, J=11.4, 3.7 Hz, 1H), 3.66 (dd, J=11.4, 5.2 Hz, 1H), 2.19 (s, 3H), 1.67 (q, J=3.6 Hz, 2H), 1.08 (q, J=3.6 Hz, 2H). MS (ESI) m/e (M+H+) 499.3.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[C@H:21]([CH:22]=O)[C@@H:20]2[CH2:24][C@H:17]1[CH2:18][CH2:19]2)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[C@H:21]([CH2:22][NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:20]2[CH2:24][C@H:17]1[CH2:18][CH2:19]2)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1C=O
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1CNCc1ccccc1
Reaction time: 0.33 h

Procedure:
Benzylamine (49.7 mmol) is added to a solution of (1R,35,45)-3-formyl-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (49.7 mmol) in DCM (200 mL). The mixture is treated with sodium triacetoxyborohydride (69.6 mmol), stirred for additional 20 min, poured into water (200 mL) and stirred vigorously for 10 min. The layers are separated and the aq. layer is extracted twice with DCM (2×100 mL). The combined organic layers are washed with sat. NaHCO3 solution (100 mL), water (100 mL) and brine (150 mL), dried over MgSO4 and treated with activated charcoal (5 g). The mixture is filtered through celite and the filtrate is concentrated in vacuo to give the desired benzylamine which is used without further purification. LC-MS (basic): tR=1.00 min; [M+H]+=317.3.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[N:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.[H-].[Na+].[CH2:24](I)[CH:25]([CH3:27])[CH3:26].O>CN(C)C=O>[CH2:24]([O:15][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]2[N:4]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:3]=[C:2]([CH3:1])[C:14]=12)[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)CI
Reactant: Cc1nn(-c2ccccn2)c2[nH]c3ccccc3c(=O)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccn2)c2nc3ccccc3c(OCC(C)C)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
To an ice-cold solution of 3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one (1.93 g, 7.0 mmol) in N,N-dimethylformamide (30 mL), sodium hydride (oiliness, content 60%, 0.42 g, 10.5 mmol) was added and the mixture was stirred at room temperature for 1 hour. Subsequently, isobutyl iodide (2.0 mL, 17.4 mmol) was added to the mixture, and the mixture was stirred at room temperature for 16 hours, and heated under reflux at 70° C. for 8 hours. The reaction solution was allowed to cool and iced water was added to the mixture, and the organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (hexane:ethyl acetate:chloroform=3:1:1) to give the title compound (0.54 g, 23% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([O:17][C:18]1[C:19]2[N:20]([CH:24]=[C:25]([CH2:27][CH2:28][C:29]#[CH:30])[N:26]=2)[CH:21]=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[C:19]2[N:20]([CH:24]=[C:25]([CH2:27][CH2:28][C:29]#[C:30][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)[N:26]=2)[CH:21]=[CH:22][CH:23]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCc1cn2cccc(OCc3ccccc3)c2n1
Product: FCc1cccc(C#CCCc2cn3cccc(OCc4ccccc4)c3n2)n1
Yield: 6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 190(F), from 2-bromo-6-(fluoromethyl)pyridine (82 mg, 0.43 mmol) and 8-(benzyloxy)-2-(but-3-ynyl)-imidazo[1,2-a]pyridine (119 mg, 0.43 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: from 100/0 to 60/40 as eluent) to afford 10 mg of 8-(benzyloxy)-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 6%) beige solid (Mp=92-94° C.)
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=[O:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[O-:18][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCn1c2ccccc2c2cc(C(=O)O)ccc21
Yield: 75.6 %

Procedure:
To a solution of 9-Ethyl-9H-carbazole-3-carbaldehyde (Aldrich, 5.0 g, 22.39 mmol) in acetone (100 ml) at 70° C. under nitrogen was added dropwise a solution of KMnO4 (4.74 g, 30.00 mmol) in H2O (100 ml) slowly over 1 hour. When the reaction was complete the reaction mixture was filtered through celite, the celite pad washed with H2O/acetone, and the filtrate washed with ether. The aqueous layer was then acidified to pH 2 with aqueous HCl, and the white precipitate filtered and dried under vacuum to afford the desired product (4.05 g, 76% yield). MS m/z @ 240 (m+1).
Reaction SMILES: [OH-:1].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.OO>O.C(O)C>[N:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]([NH2:20])=[O:1])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: N#Cc1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of sodium hydroxide (1.0 g) in water (5 ml) was added to a solution of the product of (i) above (1.0 g) in ethanol (10 ml), followed by 30% hydrogen peroxide solution (2.5 ml). The mixture was stirred at 50° C. for 1.5 hours, at room temperature for 1 hour and then evaporated. The residue was triturated with water, the mixture was filtered and the solid was crystallised from n-propanol/water to give the title compound (0.28 g), m.p. 327°-330° C. Found: C,68.31; H,6.59; N,19.78. C16H18N4O requires: C,68.09; H,6.43; N,19.85%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=2[F:30])=[N:10]1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH:32]1[C:37]([OH:39])=[O:38]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=2[F:30])[NH:12][C:13]([CH2:20][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH:32]2[C:37]([OH:39])=[O:38])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2c(F)cc(F)cc2F)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)C1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2c(F)cc(F)cc2F)=NC1c1ccc(F)cc1Br
Yield: 33.3 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(2,4,6-trifluorophenyl)-1,4-dihydropyrimidine-5-carboxylate (1.21 g, 2.2 mmol) was reacted with morpholine-3-carboxylic acid (0.29 g, 2.2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.44 g, 33%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Yield: 96 %

Procedure:
Dissolve 4-bromo-2-fluoro-benzoic acid (15 g, 68.5 mmol) in methanol (70 mL). Add concentrated sulfuric acid (500 μl) to the solution and heat the mixture to reflux for 20 h under a nitrogen atmosphere. Cool the mixture to room temperature and concentrate in vacuo. Dissolve the residue in EtOAc (200 mL) and wash successively with saturated aqueous NaHCO3 (50 mL) and water (2×50 mL). Dry the organic layer over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate (15.4 g, 96%). GC-MS m/z: 232 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])=[O:12])[C:5]2[CH:10]=[N:9][NH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:32].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])=[O:12])[C:5]2[CH:10]=[N:9][N:8]([CH:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:32])[C:6]=2[N:7]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3[nH]ncc23)c(=O)[nH]1
Reactant: CC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)c2ccccc2)c(=O)[nH]1
Yield: 82 %

Procedure:
6-Bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.25 g, 0.66 mmol) was dissolved in DMF (3 mL) and K2CO3 (0.17 g, 0.79 mmol) and (1-bromoethyl)benzene (0.148 g, 0.799 mmol) was added to it. The reaction mixture was refluxed for overnight. On completion, water was added to it. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate (0.26 g, 92.8%).
Reaction SMILES: C1(C[O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]#[N:20])=[N:11][CH:10]=2)C=CC=CC=1.[ClH:21].[H][H]>CO.[Pd]>[ClH:21].[ClH:21].[NH2:20][CH2:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([OH:8])=[CH:10][N:11]=1
Reactant: [H][H]
Reactant: N#Cc1ncc(OCc2ccccc2)c2ccccc12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1ncc(O)c2ccccc12

Procedure:
A mixture of the product from step 2 (2 g) and 10% Pd on carbon (800 mg) in 50 ml of methanol containing 4 ml of conc. HCl is hydrogenated with a balloon of hydrogen for about half an hour. The mixture is filtered through CELITE and concentrated under vacuum to a solid. Recrystallization from EtOAc and methanol yields the title compound (1.3 g) as a white solid, m.p. 214-216° C (dec).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].Cl[CH2:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14].[H-].[Na+]>C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][N:5]1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1=[O:14]
Reactant: COC(CN)OC
Reactant: O=C(Cl)CCCCCl
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(CN1CCCCC1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a stirred mixture of aminoacetaldehyde dimethylacetal (0.74 g, 7 mmole) in ethyl acetate (20 mL) and 2M sodium carbonate (20 mL) was added 5-chlorovaleryl chloride (1.55 g, 10 mmole). The reaction mixture was stirred at ambient temperature for 1 hour. The aqueous layer was separated and extracted with ethyl acetate. The combined organic phase was washed with 1% hydrochloric acid and water, dried (magnesium sulfate), and concentrated. The oily residue was dissolved in tetrahydrofuran, and sodium hydride (60% in oil) (0.3 g, 7.5 mmole) was added. The reaction mixture was heated under reflux for 1.5 hours and filtered. The filtrate was concentrated to give 1-(2,2-dimethoxyethyl)-piperidin-2-one (1.06 g) as a pale yellow oil.
Reaction SMILES: Cl.[S:2]1[CH2:6][C@@H:5]([C:7]([NH2:9])=[O:8])[NH:4][CH2:3]1.CCN(CC)CC.[Cl:17][CH2:18][C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH2:18][C:19]([N:4]1[C@H:5]([C:7]([NH2:9])=[O:8])[CH2:6][S:2][CH2:3]1)=[O:20]
Reactant: O=C(Cl)CCl
Reactant: NC(=O)[C@@H]1CSCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)[C@@H]1CSCN1C(=O)CCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a stirred suspension of the hydrochloride salt obtained in step III (16.5 g, 0.1 mol) in dichloromethane (200 mL) cooled to 0° C. were added Et3N (41 mL, 0.3 mol) and chloroacetyl chloride (8.8 mL, 0.11 mol). The reaction mixture was slowly warmed to room temperature and stirred for 1 h. The reaction mass was filtered through a sintered funnel, the salt bed was washed with ether, and the filtrate was evaporated under vacuum to obtain the crude product (4R)-3-(chloroacetyl)-1,3-thiazolidine-4-carboxamide (20.8 g) as viscous liquid, which was used in the next step without further purification. m/z (M+1) 209; IR cm−1 3418, 2925, 1736, 1667, 1416, 1219, 771; 1H NMR (CDCl3) 300 MHz δ 6.60-6.30 (s (br), ½H), 6.0-5.65 (s (br), ½H), 5.02 (dd, J=3.6, 6.9 Hz, 0.8H), 4.88-4.75 (m, 0.4H), 4.70 (d, J=8.8 Hz, 0.8H), 4.62 (d, J=8.8 Hz, 0.8H), 4.51 (d, J=10.0 Hz, 0.2H), 4.16 (s, 1.6H), 4.11 (s, 0.4H), 3.56 (dd, J=3.4, 11.8 Hz, 0.8H), 3.44 (dd, J=4.7, 8.0 Hz, 0.4H), 3.15 (dd, J=7.1, 11.8 Hz, 0.8H), 1.28 (s, 1.6H), 1.25 (s, 7.4H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:12][C:13]([OH:15])=O)=[CH:3]1.C1(=O)O[C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.C([O-])(=O)C.[Na+]>O>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:12]=[C:13]2\[O:15][C:19](=[O:20])[C:18]3[C:22]\2=[CH:23][CH:24]=[CH:25][CH:17]=3)=[CH:3]1
Reactant: Cc1cccc2c1c(CC(=O)O)cn2C
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc2c1c(/C=C1\OC(=O)c3ccccc31)cn2C
Temperature: 200 °C

Procedure:
A reaction flask equipped with a nitrogen line and a stir bar is charged with (1,4-Dimethyl-1H-indol-3-yl)-acetic acid (0.5 g, 2.4 mmol), 0.3 g (2.4 mmol) of phthalic anhydride followed by 1.2 g (15.2 mmol) of anhydrous sodium acetate. The flask is heated to 200° C. under a stream of nitrogen for 2 h. Water formed is azeotropically evaporated using toluene. The resulting brown melt (98%) is taken immediately to the next step LC/MS (M++1): 290.3.
Reaction SMILES: C(O)C.[C-:4]#[N:5].[Na+].CS(O[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[N:18]([CH3:20])[CH3:19])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>Cl.C(Cl)Cl>[CH3:19][N:18]([CH3:20])[CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[C:4]#[N:5]
Reactant: [C-]#N
Reactant: CN(C)C1CCCCC1OS(C)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CN(C)C1CCCCC1C#N

Procedure:
To 200 mL of 80% aqueous ethanol add 10 g (0.2 mol) of sodium cyanide and 22.1 (0.1 mol) of 2-(dimethylamino)-cyclohexanol methanesulfonate. Reflux the reaction and monitor by thin-layer chromatography. Upon completion add in HCl until gas evolution ceases. Remove solvent in vacuo and add saturated aqueous sodium carbonate (ph=11) and 100 mL of methylene chloride. Separate the layers and dry the organic phase over Na2SO4. Filter the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:4]=1[OH:5].[CH3:11][OH:12]>>[OH:5][C:4]1[C:3]([O:2][CH3:1])=[CH:9][C:8]2[O:10][C:11](=[O:12])[C:6]([CH2:4][CH2:3][OH:2])=[C:7]([CH3:8])[C:7]=2[CH:6]=1
Reactant: CO
Reactant: COc1cc(O)ccc1O
Product: COc1cc2oc(=O)c(CCO)c(C)c2cc1O
Yield: 54 %

Procedure:
Process F; starting material: methoxyhydroquinone; yield 54%; m.p. 229°-235° C. (from methanol).
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=O.Cl.[NH2:17][OH:18]>C(O)(C)C.O>[Br:1][C:2]1[C:3]([S:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[N:17][OH:18]
Reactant: NO
Reactant: CC(C)(C)Sc1c(Br)cc(F)cc1C=O
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)Sc1c(Br)cc(F)cc1C=NO
Temperature: 90 °C

Procedure:
A mixture of 3-bromo-2-tert-butylsulfanyl-5-fluorobenzaldehyde (4 g, 13.7 mmol) and hydroxylamine hydrochloride in isopropanol (160 mL) and water (33 mL) was heated to 90° C. for 16 h. The reaction mixture was cooled and 2-propanol was removed in vacuo. Water was added to residue, followed by saturated aqueous sodium bicarbonate until the pH was ˜8. The mixture was extracted with dichloromethane (2×30 mL). The combined organic fractions were dried sodium sulfate, filtered, and concentrated to afford 3.8 g of the crude title compound, which was used without further purification.