Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:8][CH:7]=2.[N:31]1([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(#N)C>[N:31]1([CH:37]2[CH2:42][CH2:41][N:40]([CH2:2][C:3]3[C:4]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)=[N:5][C:6]4[C:11]([C:12]=3[C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:8][CH:7]=4)[CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Solvent: CC#N
Product: COC(=O)c1c(CN2CCC(N3CCCCC3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Reaction time: 3 h
Yield: 145.4 %

Procedure:
A suspension of methyl 3-(bromomethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.45 g, 2.88 mmol) and 1,4′-bipiperidine (0.630 g, 3.74 mmol) in acetonitrile (10 mL) was stirred for 3 hours. The solvent was removed under reduced pressure. The residue was dissolved in DMSO and was purified via HPLC (Biotage, 0-50% MeCN/H2O with 0.1% TFA). Fractions containing the product were neutralized with saturated aqueous NaHCO3 and extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford methyl 3-(1,4′-bipiperidin-1′-ylmethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.47 g, 87% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J=1.76 Hz, 1H), 8.37 (d, J=8.78 Hz, 1H), 8.27-8.33 (m, 1H), 8.00 (s, 1H), 7.89-7.96 (m, 2H), 7.76-7.82 (m, 1H), 4.04 (s, 3H), 3.66 (s, 2H), 3.39 (s, 3H), 2.54-2.71 (m, 3H), 2.31-2.47 (m, 4H), 1.82 (br. s., 2H), 1.53 (d, J=10.04 Hz, 2H), 1.45 (br. s., 4H), 1.21-1.40 (m, 4H); MS (m/z) 590.2 (M+H+).
Reaction SMILES: Cl.Cl.[N:3]1([NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][CH:17]=2)=[O:11])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Br[CH2:25][C:26]#[N:27].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[C:26]([CH2:25][N:6]1[CH2:5][CH2:4][N:3]([NH:9][C:10]([C:12]2[CH:17]=[N:16][C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][CH:13]=2)=[O:11])[CH2:8][CH2:7]1)#[N:27]
Reactant: O=C(NN1CCNCC1)c1cnc(-c2ccccc2)nc1
Reactant: N#CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCN1CCN(NC(=O)c2cnc(-c3ccccc3)nc2)CC1
Yield: 40.6 %

Procedure:
A solution of 2-phenyl-pyrimidine-5-carboxylic acid piperazin-1-ylamide dihydrochloride (0.29 mmol), bromoacetonitrile (0.29 mmol) and Na2CO3 (1.46 mmol) in wet THF (8 mL) is stirred at rt overnight. The reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 1-2% methanol in DCM to afford 2-phenyl-pyrimidine-5-carboxylic acid (4-cyanomethyl-piperazin-1-yl)-amide (38 mg, 40%) as a solid. MS: 323 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.60-3.30 (m, 8H), 3.55 (s, 2H), 6.63 (br, 0.5 N—H), 7.14 (br, 0.5 N—H), 7.52 (s, 3H), 8.53 (d, 2H), 9.06-9.38 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:3]=1[CH3:19].[Br:20][C:21]1[CH:22]=[CH:23][C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[C:25]([NH2:27])[CH:26]=1.Cl.O1CCOCC1>CN1C(=O)CCC1>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[C:25]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:3]=2[CH3:19])[CH:26]=1
Reactant: Nc1cc(Br)ccc1N1CCOCC1
Reactant: Cc1c(-c2ccccc2F)nc2ccccc2c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(Br)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 2 using 4-chloro-2-(2-fluorophenyl)-3-methylquinoline (230 mg, 848 μmol), 5-bromo-2-morpholinobenzenamine (109 mg, 424 μmol) and 4N hydrochloric acid solution in dioxane (0.011 mL, 42 μmol) in NMP (0.50 mL) to afford a colorless solid upon purification by chromatography on silica gel, eluting with EtOAc gradient in hexane. Mass Spectrum (ESI) m/e=492.1 & 494.1 (M+1).
Reaction SMILES: [Cl:1]Cl.[CH:3](=[N:10][OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:3](=[N:10][OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClCl
Reactant: ON=Cc1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: ON=C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
A solution of chlorine (1.5 g) in carbon tetrachloride (42 ml) was added in portions to a stirred partial solution of benzaldehyde oxime [2.5 g; 1H NMR: δ8.18(1H,s), 9.40(1H,brs) ppm] in carbon tetrachloride (20 ml) at room temperature. Following the addition, the reaction mixture was stirred at room temperature for 3 hours then poured into water. The organic layer was separated, dried and concentrated to give almost pure α-chlorobenzaldehyde oxime (3.2 g) as a yellow liquid. A solution of sodium methanethiolate (0.68 g) in methanol (15 ml) was added dropwise to an ice-cooled and stirred solution of part of this α-chlorobenzaldehyde oxime (1.5 g) in methanol (15 ml). Following the addition, the reaction mixture was stirred for 2 hours with continued cooling in iced-water. The methanol was removed under reduced pressure and the residue was chromatographed using dichloromethane as eluant to give a single stereoisomer of α-methylthiobenzaldehyde oxime (0.670 g, 42% yield) as a white crystalline solid, m.p. 76°-78° C., 1H NMR: δ2.08(3H,s), 9.12(1H,s) ppm.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[OH:18][CH2:17][CH:13]1[CH2:14][CH2:15][CH2:16][N:12]1[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: OCC1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2CCCC2CO)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
20 g of 5-fluoro-2-nitrotoluene, 14.3 g of 2-pyrrolidine methanol and 20 g of potassium carbonate were added to 100 ml of dimethylformamide. They were stirred at 100° C. for 2 h. After leaving to cool, the reaction mixture was poured into water. After extraction with ethyl acetate, the extract was washed with water, concentrated and recrystallized from acetonitrile to obtain 26 g of 2-hydroxymethyl-N-(3-methyl-4-nitrophenyl)pyrrolidine (d) as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:8]1[CH2:12][C:11](=O)[N:10]=[C-:9]1>[O-2].[O-2].[Ti+4]>[C:2]1([N:1]2[CH2:12][CH2:11][NH:10][C:9]2=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CO[C-]=N1
Reactant: Nc1ccccc1
Agent: [Ti+4]
Agent: [O-2]
Product: O=C1NCCN1c1ccccc1
Temperature: 0 °C
Yield: 47 %

Procedure:
Aniline (15.40 g; 0.165 mole) and 2-oxazolidone (9.60 g; 0.110 mole) were refluxed for 6.5 hours with 1.00 g (0.0125 mole) of titanium dioxide (Harshaw Ti 0720 which had been calcined at 300° C. for 4 hours). The reaction mass was cooled to 0° C. and the crystals which had formed were filtered off. The crystals were recrystallized from ethanol to give N-phenylimidazolidone in 47% yield. The conversion based on 2-oxazolidone was 99%.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=O)[N:9]3CC[C@H:10]3[C:11]3[N:12](C=NC=3/C=C\Cl)[C:6]=2[CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[OH2:33]>CN(C)C=O>[N:12]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]2[C:6]=1[C:5](=[O:33])[CH:4]=[CH:3][CH:2]=2
Reactant: O
Reactant: O=C1c2c(Cl)cccc2-n2cnc(/C=C\Cl)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=c1cccc2cnccnc1-2

Procedure:
2.21 g (6.9 mmol) of (S)-8-chloro-1-[(Z)-2-chlorovinyl]-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one was heated to boiling under reflux for 4 hours together with 1.23 ml (8.3 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 30 ml of N,N-dimethylformamide. The reaction mixture was subsequently poured into 300 ml of water and extracted five times with methylene chloride. The organic extracts were washed four times with water, dried over magnesium sulphate and evaporated. After chromatography on silica gel while eluting with ethyl acetate and subsequent recrystallization from ethyl acetate there was obtained (S)-8-chloro-1-ethynyl-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4benzodiazepin-9-one of melting point 249°-250°.
Reaction SMILES: [CH3:1][NH2:2].O1CCCC1.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:17]=2)[CH:12]=[CH:11][N:10]=1>>[CH3:1][NH:2][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CN
Reactant: CCOC(=O)c1ccc2ccnc(Cl)c2c1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2ccnc(NC)c2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A solution of methylamine in tetrahydrofuran (30 mL, 60 mmol, 2 M) was added to ethyl 1-chloroisoquinoline-7-carboxylate (formed in Step 3 of Intermediate 27) (705 mg, 2.99 mmol) in a sealed tube. The reaction was heated to 60° C. and stirred overnight. LCMS indicated the reaction was not complete. Additional methylamine (10 mL, 20 mmol, 2 M in THF) was added and the reaction was heated to 60° C. for another 18 hours. The reaction was cooled to room temperature and concentrated. The residue was partitioned between water and dichloromethane. The organic layer was dried over magnesium sulphate, filtered, and concentrated. Purification by flash column chromatography (25-65% ethyl acetate/heptanes) gave the title compound (584 mg, 85%) as a yellow oil that solidified upon standing. +ESI (M+H) 231.1; 1H NMR (400 MHz, DMSO-d6, δ): 8.83-8.94 (m, 1H), 8.07 (dd, J=8.58, 1.56 Hz, 1H), 7.99 (d, J=5.85 Hz, 1H), 7.89 (d, J=4.49 Hz, 1H), 7.77 (d, J=8.58 Hz, 1H), 6.92 (d, J=5.07 Hz, 1H), 4.38 (q, J=7.02 Hz, 2H), 2.97 (d, J=4.49 Hz, 3H), 1.38 (t, J=7.12 Hz, 3H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([CH2:11][C:12]([OH:14])=[O:13])#[N:10].C(O)(=O)C.C([O-])(=O)C.[NH4+]>C(O)C>[C:9]([C:11](=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:12]([OH:14])=[O:13])#[N:10]
Reactant: O=Cc1ccccc1
Reactant: N#CCC(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CC(=O)O
Product: N#CC(=Cc1ccccc1)C(=O)O
Yield: 81.2 %

Procedure:
Benzaldehyde (200 g), cyanoacetic acid (176 g), acetic acid (30 ml) and ammonium acetate (14.5 g) were refluxed for 4 hours in ethyl alcohol (800 ml) with heating. After the reaction, the mixture was concentrated to 400 ml by removing ethyl alcohol under a reduced pressure, followed by pouring into 1 liter of ice water to separate crystals. The resulting crystals were recrystallized from 250 ml of acetonitrile to obtain 265 g of 2-cyano-3-phenylacrylic acid which melted at 184° to 188° C. The resulting compound (150 g) and thionyl chloride (176 g) were dissolved in acetonitrile (100 ml) with heating for 1 hour. After the reaction, the acetonitrile and the thionyl chloride were distilled off under a reduced pressure, and the resulting solid was added to a solution consisting of hydroxyethyl methacrylate (124 g), pyridine (75 g) and acetonitrile (1 l). The reaction was carried out for 2 hours while keeping the reaction temperature below 40° C. After the reaction, the reaction solution was poured into ice water to separate crystals, and the resulting crystals were recrystallized form ethyl alcohol (1 l) to obtain 205 g of the desired compound which melted at 68° to 70° C.
Reaction SMILES: [C:1]([O:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25](S(C)(=O)=O)[N:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].NCCC[N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C1COCC1.CN(C)C(=O)C>[C:1]([O:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([CH2:9][CH2:8][CH2:7][NH:6][N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)[N:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)ONc1ccccc1NC(=O)c1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1
Reactant: NCCCN1CCOCC1
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)ONc1ccccc1NC(=O)c1ccc(-c2ccnc(CCCNN3CCOCC3)n2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 193.7 %

Procedure:
N-(2-t-Butoxyaminophenyl)-4-(2-methylsulfonyl-pyrimidin-6-yl)benzamide (Method 21, 62.5 mg, 0.133 mmol) was dissolved in a mixture of THF (2 ml) and N,N-dimethylacetamide (2 ml) and N-(3-aminopropyl)morpholine (60 μl 0.411 mmol) added. The reaction mixture was heated to 50° C. and stirred for 2 hours. The reaction mixture was then cooled and solvents removed under reduced pressure. The resultant oil was purified by elution through silica with a 5% methanol in dichloromethane, to yield the title compound as a colourless solid (65 mg, 92%); NMR Spectrum: (DMSO-d6) 1.45 (s, 9H), 1.74 (m, 2H), 2.37 (m, 6H), 3.40 (br, 2H), 3.59 (m, 4H), 7.20 (m, 2H), 7.23 (d, 1H), 7.34 (t, 1H), 7.57 (d, 1H), 8.08 (d, 2H), 8.26 (d, 2H), 8.40 (m, 1H), 8.72 (s, 1H), 9.94 (s, 1H); Mass Spectrum: M+H+ 534.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH:20][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH:24]3[NH2:31])[CH2:22]1)[CH2:28]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]([CH3:19])([CH3:18])[C:15]([NH:31][CH:24]2[CH:23]3[CH2:29][CH:27]4[CH2:28][C:21]([OH:20])([CH2:30][CH:25]2[CH2:26]4)[CH2:22]3)=[O:17])(=[O:11])=[O:12])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Reactant: CC(=O)c1ccc(S(=O)(=O)NC(C)(C)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(S(=O)(=O)NC(C)(C)C(=O)NC2C3CC4CC2CC(O)(C4)C3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
2-(4-acetylphenylsulfonamido)-2-methylpropionic acid (109 mg, 0.38 mmol), 5-hydroxy-2-adamantanamine (127 mg, 0.76 mmol), and BOP (168 mg, 0.38 mmol) were charged, and CH2Cl2 (5 ml) was added thereto, followed by stirring for 30 minutes at room temperature. DIPEA (0.18 ml, 1.14 mmol) was added thereto, followed by stirring at room temperature for 12 hours. After the reaction was completed, the organic layer was separated using CH2Cl2 and H2O, dried with MgSO4, and filtered. Then, through vacuum distillation, the solvent was removed, and the resultant product was purified with column chromatography to obtain 2-(4-acetylphenylsulfonamido)-N-(5-hydroxyadamantane-2-yl)-2-methylpropanamide (110 mg, 0.25 mmol, 69%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:11])[CH:5]=[C:6]2[CH:10]=[N:9][NH:8][C:7]=12.[CH3:12][Al](C)C.[NH4+].[Cl-]>C1COCC1.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>[CH3:11][C:4]1[CH:5]=[C:6]2[CH:10]=[N:9][NH:8][C:7]2=[C:2]([CH3:12])[N:3]=1
Reactant: Cc1cc2cn[nH]c2c(Br)n1
Reactant: C[Al](C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc2cn[nH]c2c(C)n1
Temperature: 65 °C
Reaction time: 60 h

Procedure:
To a vigorously stirred solution of 7-bromo-5-methyl-1H-pyrazolo[3,4-c]pyridine (3.65 g, 14.6 mmol) and Pd(PPh3)4 (845 mg, 0.73 mmol) in THF (65 mL) was added trimethylaluminum (14.6 mL, 29.3 mmol; 2 M sol. in toluene) under argon. The reaction mixture was stirred at 65° C. for 60 h, and then was cooled to RT and poured into a sat. aq. NH4Cl solution. The resulting suspension was filtered, the solid was washed with water and discarded. The filtrate and the combined washings were extracted with EtOAc (3×). The combined organics were washed with brine, then dried (Phase separator) and concentrated under reduced pressure to give 5,7-dimethyl-1H-pyrazolo[3,4-c]pyridine as a solid. MS (LC-MS): 148 [M+H]+, tR (HPLC conditions k): 0.50 min.
Reaction SMILES: [NH:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3.CC(C)([O-])C.[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O.O>[CH2:26]([N:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1COc2cccc3nc4c(c(c23)N1)CCCC4
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COc2cccc3nc4c(c(c23)N1Cc1ccccc1)CCCC4
Reaction time: 0.08 h
Yield: 41 %

Procedure:
To a suspension of 1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.30 g) in dry dimethylformamide (50 ml) was added potassium tert-butoxide (2.1 g). To the solution was added benzyl bromide (2.22 ml), and stirring was continued for five mins. The reaction mixture was diluted with water (150 ml) and extracted with diethyl ether. The organic phase was washed with water, brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. Trituration of the residue with pentane followed by recrystallization from methanol gave 2.42 g (41%) of product, mp 166°-167.5° C.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.Cl[CH2:18][CH:19]=O>CS(C)=O>[CH2:2]1[C@H:1]([N:9]2[C:10](=[O:11])[N:12]3[C:13](=[N:14][CH:18]=[CH:19]3)[CH:15]=[CH:16]2)[O:8][C@H:5]([CH2:6][OH:7])[C@H:3]1[OH:4]
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Reactant: O=CCCl
Solvent: CS(C)=O
Product: O=c1n([C@H]2C[C@H](O)[C@@H](CO)O2)ccc2nccn12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
3,N4 -Ethenodeoxycytidine is synthesized according to the published procedure of Eberle et al. (Carcinogenesis 10:2751-2756, 1989). To 2'-deoxycytidine (8 mg, available from Sigma Chemical Company) in 0.4 mL of DMSO is added 0.04 mL of a 45% aqueous solution of chloroacetaldehyde and the reaction mixture is stirred for 1 hour at 70° C. The reaction mixture is then evaporated to dryness and the resulting residue purified by reverse-phase HPLC on a Nucleosil C18 column (Altech) to yield 3,N4 -ethenodeoxycytidine.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[CH2:18]([NH2:20])[CH3:19].Cl>C1COCC1>[CH2:18]([NH:20][S:12]([C:8]1[CH:9]=[C:10]([F:11])[C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:14])=[O:13])[CH3:19]
Reactant: CCN
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1cc(F)c(F)c(C(=O)O)c1
Yield: 82 %

Procedure:
To a 5 ml Biotage microwave reaction tube was added 2,3-difluoro-5-(chlorosulfonyl)benzoic acid (100 mg, 0.390 mmol). To this was added 2 ml of THF followed with (0.08 ml, 0.818 mmol) 10M aqueous NaOH. To the resulting stirred mixture was added ethanamine (0.195 ml, 0.390 mmol) as a 2M solution in THF. The reaction mixture was heated with stirring to 110° C. for 1.1 minutes using a Biotage Initiator 8 microwave set for high absorbance. After reaction cooled to room temperature 6M aqueous HCl (0.150 ml, 0.896 mmol) was added with stirring. The water was removed from the mixture by adding excess anhydrous Na2SO4 and subsequent filtration. The filtered salts were washed with acetonitrile and DMF (19:1, 10 ml, 2×). The combined filtrates were concentrated with rotary evaporation, yielding a DMF solution of 5-[(ethylamino)sulfonyl]-2,3-difluorobenzoic acid (82% pure by LCMS, % purity used as stoichiometry for next step), which was carried forward without purification.
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][C:2]21[CH:14]1[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]1)[CH2:10]2.C([O-])(=O)C.[Na+].[Br:22]Br.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Br:22][C:8]1[CH:9]=[C:4]2[CH2:3][C:2]3([CH:14]4[CH2:13][CH2:12][N:11]([CH2:16][CH2:15]4)[CH2:10]3)[O:1][C:5]2=[N:6][CH:7]=1
Reactant: BrBr
Reactant: c1cnc2c(c1)CC1(CN3CCC1CC3)O2
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1cnc2c(c1)CC1(CN3CCC1CC3)O2
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A solution of spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (100 mg 0.462 mmol) and sodium acetate (410 mg, 5 mmol) in 50% aqueous acetic acid (4 ml) was heated to 60° C. Bromine (0.100 ml, 1.94 mmol) was added via a syringe over 10 minutes, and the solution was then heated under reflux for 1 hour. The mixture was allowed to cool to ambient temperature, basified to pH>10 with sodium carbonate, and extracted with chloroform (3×15 ml). The combined extracts were dried (MgSO4), filtered, and evaporated under reduced pressure to give the title compound (110 mg, 0.37 mmol, 81%) as an off-white solid: electrospray MS 295 ([MH]+, with 79Br, 100), 297 ([MH]+, with 81Br, 98).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([O:10]C)=O)=[C:6]([OH:12])[C:5]2[S:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=3[C:4]=2[S:3]1(=[O:22])=[O:21].[NH2:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1>>[CH3:1][N:2]1[C:7]([C:8]([NH:23][C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)=[O:10])=[C:6]([OH:12])[C:5]2[S:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=3[C:4]=2[S:3]1(=[O:22])=[O:21]
Reactant: Nc1cnccn1
Reactant: COC(=O)C1=C(O)c2sc3cc(C)ccc3c2S(=O)(=O)N1C
Product: Cc1ccc2c3c(sc2c1)C(O)=C(C(=O)Nc1cnccn1)N(C)S3(=O)=O
Yield: 39 %

Procedure:
Prepared analogous to Example 1 from methyl 2,7-dimethyl-4-hydroxy-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and amino-pyrazine with a yield of 39% of theory.
Reaction SMILES: CO[C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[NH:27]([CH2:31][CH2:32][OH:33])[CH2:28][CH2:29][OH:30]>CO.O1CCCC1>[OH:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][OH:33])[C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1
Reactant: OCCNCCO
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(C(=O)N(CCO)CCO)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Yield: 30.6 %

Procedure:
A solution of 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in methanol (40 mL) and tetrahydrofuran (10 mL) was treated with diethanolamine (0. 162 g) and the mixture was refluxed for 18 hours. The solvents were removed by evaporation and the residue was crystallized from acetone to give 0.185 g of N,N-bis(2-hydroxyethyl)-4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetamide as a colorless solid, mp 128°-133° C.