Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=O)=[C:6]([OH:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.[CH2:13]1CCN2C(=NCCC2)C[CH2:14]1.[Br-].C(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=C>C(#N)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[C:7]=1[CH:8]=[CH:13][CH2:14][O:10]2
Reactant: COc1ccc(F)c(C=O)c1O
Reactant: C1CCC2=NCCCN2CC1
Agent: C=C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Solvent: O
Product: COc1ccc(F)c2c1OCC=C2
Yield: 35.1 %

Procedure:
6-Fluoro-2-hydroxy-3-methoxy-benzaldehyde (3.32 g, 19 mmol) was dissolved in acetonitrile (20 ml) and DBU (2.97 ml, 19 mmol) was-added followed by vinyltriphenylphosphine bromide (7.2 g, 19 mmol). The reaction mixture was heated under reflux for 48 h, diluted with water and extracted with ether (3×50 ml). The organic phase was washed with water, 10% sodium hydroxide, water and brine and evaporated in vacuo. The residue was submitted to column chromatography (silica gel, EA:Hex, 1:20) yielding 1.2 g of 5-fluoro-8-methoxy-2H-chromene (34%).
Reaction SMILES: O[C:2]([C:10]1([CH3:13])[CH2:12][CH2:11]1)=[CH:3][C:4](=[O:9])[CH:5]=[CH:6][O:7]C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[CH3:13][C:10]1([C:2]2[O:7][CH:6]=[CH:5][C:4](=[O:9])[CH:3]=2)[CH2:11][CH2:12]1
Reactant: COC=CC(=O)C=C(O)C1(C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC1(c2cc(=O)cco2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 49.9 %

Procedure:
A mixture of 1-hydroxy-5-methoxy-1-(1-methyl-cyclopropyl)-penta-1,4-dien-3-one (Step 40.7) (1.07 g, 5.9 mmol) and TFA (0.9 mL, 11.7 mmol, 2 eq) in toluene (50 mL) is stirred for 14 h at rt and concentrated. Purification of the residue by silica gel column chromatography (Hex/EtOAc, 1:0→3:7) provides 442 mg of the title compound as a red solid: ESI-MS: 151.1 [M+H]+; tR=2.89 min (System 1); TLC: Rf=0.19 (Hex/EtOAc, 1:1).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[CH:21][N:22]([CH3:24])[CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[CH:28](=O)[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[CH:21][N:22]([CH3:24])[CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cn1cnc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)c1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-c2nc3c(N4CCN(Cc5cn(C)cn5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-4-(4-((1-methyl-1H-imidazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.035 g, 0.088 mmol, 1 eq), EtOH (2 mL) and DMF (0.3 mL), p-anisaldehyde (0.013 g, 0.097 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.26 mL, 0.26 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 94:6). The title compound was obtained as a solid after trituration with diethyl ether (0.011 g, 26%); 1H-NMR (500 Mz, DMSO-d6): δ 2.59-2.68 (m, 4H, piperazine N(CH2)2), 3.43 (s, 2H, NCH2), 3.60-3.66 (m, 7H, piperazine N(CH2)2 and imidazole Me), 3.84 (s, 3H, OMe), 7.00 (d, J=1.0 Hz, 1H, imidazole 5-H), 7.10 (d, J=9.0 Hz, 2H, ArH, C6H4), 7.47 (d, J=1.0 Hz, 1H, imidazole 2-H), 8.13 (d, J=9.0 Hz, 2H, ArH, C6H4), 8.19 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.34 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=2.87 min—482/484 [(M+H+), Br isotopic pattern, 100%]; ESI-HRMS: Found: 482.1300, calculated for C22H25BrN7O (M+H)+: 482.1304.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:14][N:15]([CH3:17])[CH3:16])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][C:22]=1[NH:31][C:32]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[O:33])[CH3:19]>>[CH3:17][N:15]([CH3:16])[CH2:14][C@H:2]([NH:1][S:27]([C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:18][CH3:19])=[C:22]([NH:31][C:32]([N:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)=[O:33])[CH:23]=1)(=[O:28])=[O:29])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1NC(=O)N1CCOCC1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Product: CCOc1ccc(S(=O)(=O)N[C@H](CC(=O)OCc2ccccc2)CN(C)C)cc1NC(=O)N1CCOCC1
Yield: 68 %

Procedure:
According to the method described in example S72a, (R)-benzyl 3-amino-4-(dimethylamino)butanoate (30 mg, 0.086 mmol) was reacted with 4-ethoxy-3-(morpholine-4-carboxamido)benzene-1-sulfonyl chloride to yield the title compound as a white solid (32 mg, 68%). MS ESI 549.3 [M+H]+, calcd for [C26H36N4O7S+H]+ 549.23
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].Cl[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:16]=1.O>C1COCC1>[O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: OC1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 35.4 %

Procedure:
Oxan-4-ol (0.302 g, 2.96 mmol) was dissolved in THF (5 mL) and cooled to 0 C under nitrogen. Potassium tert-butoxide (0.332 g, 2.96 mmol) was added and the mixture stirred for 5 min. Ethyl 6-chloronicotinate (0.500 g, 2.69 mmol) was added, the mixture was warmed to room temperature and stirred for 3 h. Water (5 mL) was added and the mixture extracted with EtOAc (2×10 mL). The organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with a gradient of 5-20% EtOAc in heptane to afford the title compound as a colourless oil (0.239 g, 35%). 1H NMR (250 MHZ, CDCl3) δ ppm 8.80 (1H, dd), 8.14 (1H, m), 6.73 (1H, dd), 5.25 (1H, m), 4.39 (2H, dq), 3.96 (2H, m), 3.60 (2H, m), 2.05 (2H, m), 1.81 (2H, m) and 1.40 (3H, dt).
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1OC)[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[OH:26][CH2:27][CH2:28][CH2:29][NH2:30]>CO>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([NH:30][CH2:29][CH2:28][CH2:27][OH:26])=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: NCCCO
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Solvent: CO
Product: COC12C(CO)C3=C(C(=O)C(C)=C(NCCCO)C3=O)N1CC1NC12
Product: NC(=O)O
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of 60 mg mitomycin A (0.17 mmol) in 5 ml of anhydrous methanol was added with stirring 0.5 ml of 3-hydroxypropylamine. The progress of the reaction was checked by TLC and the reaction appeared to be complete in two hours. The solvent was removed by evaporation under reduced pressure. The residue was dissolved in 100 ml of ethyl acetate and the organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was removed by evaporating under reduced pressure. The residue was then chromatographed using silica-gel as adsorbent. The fraction obtained by eluting the column with a mixture of ethyl acetate and acetone (9:1 by volume) was evaporated to dryness under reduced pressure. Recrystallization from acetone gave 60.7 mg (91% yield) of the desired product as purple crystals having a melting point of >250° (decomposing and providing the following analysis:
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]([CH3:29])([CH3:28])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:23]([O:25]CC)=[O:24])([CH3:22])[CH3:21])[S:15][CH2:14][CH2:13][CH2:12][S:11]1)C.[OH-].[K+].Cl>C(O)C.O>[C:23]([C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][CH2:16][C:10]1([CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:29])([CH3:28])[C:4]([OH:30])=[O:3])[S:15][CH2:14][CH2:13][CH2:12][S:11]1)([OH:25])=[O:24]
Reactant: CCOC(=O)C(C)(C)CCCCC1(CCCCC(C)(C)C(=O)OCC)SCCCS1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCCC1(CCCCC(C)(C)C(=O)O)SCCCS1)C(=O)O
Yield: 95.5 %

Procedure:
A solution of 6-[2-(5-ethoxycarbonyl-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-hexanoic acid ethyl ester (870 mg, 1.89 mmol) and potassium hydroxide (85%, 750 mg, 11.33 mmol) in ethanol (16 mL) and water (4 mL) was heated under reflux for 3 h. The reaction mixture was diluted with water (100 mL) and acidified to pH 4 with 1 N HCl (8 mL). The emulsion was extracted with dichloromethane (3 75 mL). The combined organic phases were washed with water (50 mL), dried over MgSO4, concentrated in vacuo, and dried in high vacuo to furnish 6-[2-(5-carboxy-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-hexanoic acid (730 mg, 95%) as a viscous, yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): (ppm): 2.80 (m, 4H), 1.94 (m, 2H), 1.85 (m, 4H), 1.56 (m, 4H), 1.41 (m, 4H), 1.30 (m, 4H), 1.19 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): (ppm): 185.08, 53.36, 42.28, 40.52, 38.27, 26.18, 25.69, 25.23, 25.11, 24.73. HRMS (LSIMS, nba): Calcd. for C20H37O4S2 (MH+): 405.2133. found: 405.2115.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[CH:9]=[CH:10][C:3]=12
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1ccnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (2 g, 10.15 mmol) in DMF (50 mL) stirred at 0° C. was added sodium hydride (0.487 g, 12.18 mmol). After stirring for 30 min at 0° C., benzenesulfonyl chloride (1.570 mL, 12.18 mmol) was added to the mixture and stirred at 0° C. for 1.5 hour. The reaction was quenched with addition of saturated NH4Cl aq. solution and the mixture was poured into saturated aq. NH4Cl (100 mL). The mixture was extracted with ethyl acetate (20 mL×3). The organic layers were combined, washed with brine (100 mL), dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by chromatography on silica, eluting with a gradient of 0-25% ethyl acetate in cyclohexane to give the title compound (3.39 g). LCMS (A): m/z (M+H)+ 337/339, C13H9BrN2O2S requires 336/338 (acidic).
Reaction SMILES: [N:1]1([C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])[CH2:5][CH:4]=[CH:3][CH2:2]1.[OH2:12].C[N+]1([O-])CC[O:17]CC1.Cl>CC(C)=O.O.O=[Os](=O)(=O)=O>[OH:12][C@H:3]1[C@@H:4]([OH:17])[CH2:5][N:1]([C:6](=[O:11])[C:7]([F:9])([F:10])[F:8])[CH2:2]1
Reactant: O=C(N1CC=CC1)C(F)(F)F
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: Cl
Solvent: CC(C)=O
Product: O=C(N1C[C@@H](O)[C@@H](O)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.3 %

Procedure:
Compound 320 (22.0 mmol) and N-methylmorpholine N-oxide monohydrate (35.0 mmol) were dissolved in a mixture of acetone and H2O (1:1, v/v; 60 mL). OsO4 (0.4 mmol, 2 mol %) was added and the resulting pale yellow solution was stirred at room temperature for 16 h. Na2S2O5 (3.9 mmol) was then added and the solution was stirred for an additional 1 h. The solution was acidified to pH=2 with 6 M HCl and extracted with CH2Cl2 (4×70 mL). The organic phase was washed with saturated NaHCO3 (50 mL), brine (50 mL), dried over MgSO4, concentrated and purified by column chromatography (0–5% MeOH in CH2Cl2) to give 1-(cis-3,4-Dihydroxy-pyrrolidin-1-yl)-2,2,2-trifluoro-ethanone (321) (17 mmol, 78% yield) as a colorless oil. 1H NMR (400 MHz, CD3OD) δ=3.95 ppm (dd, 1H, J=4, 13 Hz), 3.59 (dd, 1 H, J=6, 12 Hz), 3.65 (dd, 1H, J=6, 13 Hz), 3.84 (dd, 1H, J=5, 12 Hz), 4.19–4.27 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: C[O-]
Reactant: Cc1cc(C)c(C#N)c(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(C)cc(C)c1C#N
Reaction time: 10 h
Yield: 99 %

Procedure:
2-chloro-4,6-dimethyl-nicotinonitrile (2.5 g, 15.01 mmol) was dissolved in anhydrous methanol(70 mL), added with sodium methoxide (4.27 g, 75.03 mmol) at 0° C. and stirred for about 10 hours at nitrogen atmosphere. The above mixture was concentrated under reduced pressure and then neutrailized with a saturated solution of ammonium chloride and then extracted twice with 150 mL of methylenechloride. The resulting organic layer was dried using anhydrous sodium sulfate, filtered and concentrated. A silica gel column chromatography (20% EtOAc/Hexanes) was performed on the resulting residue and 2.41 g (99%) of 2-methoxy-4,6-dimethyl-nicotinonitrile was obtained in white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9](OC)=O)[C:5]1=[O:13].[Cl:14][C:15]1[CH:22]=[CH:21][C:18](CCl)=[CH:17][CH:16]=1>C1C=CC=CC=1>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:9][CH:6]2[CH2:7][CH2:8][CH:4]([CH3:3])[C:5]2=[O:13])=[CH:17][CH:16]=1
Reactant: COC(=O)C1CCC(C)C1=O
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC1CCC(Cc2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into 126 ml of anhydrous benzene, 3.04 g of sodium hydride (prepared by washing 60% oily sodium hydride with anhydrous benzene) were added, and then 18 g of methyl 3-methyl-2-oxocyclopentanecarboxylate were added to the thus formed mixture. After stirring the whole mixture for one hour at room temperature, 21.5 g of 4-chlorobenzyl chloride were added to the mixture and the thus obtained mixture was refluxed for 6 hours in an oil bath at 90° C.
Reaction SMILES: C(S[C:4]1N=C[C:7]([C:10]([Cl:12])=[O:11])=[C:6]([Cl:13])[N:5]=1)C.C(SC1NC(=O)C(C(O)=O)=CN=1)C.P(Cl)(Cl)(Cl)=O.OC1C(C(O)=O)=NC2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1.S(Cl)(Cl)=O>CN(C)C=O>[Cl:13][C:6]1[C:7]([C:10]([Cl:12])=[O:11])=[N:34][C:35]2[C:4](=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:5]=1
Reactant: O=C(O)c1nc2ccccc2nc1O
Reactant: CCSc1ncc(C(=O)Cl)c(Cl)n1
Agent: CCSc1ncc(C(=O)O)c(=O)[nH]1
Solvent: O=S(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1nc2ccccc2nc1Cl

Procedure:
o-Halogeno-(hetero-)aryl-carboxylic acid halides which can be employed in the process according to the invention, and processes for their preparation, are known. Thus, for example, J. Am. Chem. Soc. 40,233 (1908) describes the preparation of 2-ethylmercapto-6-chloropyrimidine-5-carboxylic acid chloride by reacting 2-ethylmercapto-4-oxo-3,4-dihydropyrimidine-5-carboxylic acid with phosphorus oxychloride. The reaction of 2-hydroxy-quinoxaline-3-carboxylic acid with thionyl chloride in the presence of a catalytic amount of dimethylformamide to give 2-chloroquinoxaline-3-carboxylic acid chloride is described in Arch. Pharm. 306, 401 (1973). The reaction 4-chloronicotinic acid with thionyl chloride under reflex to give 4-chloronicotinic acid chloride is described in J. Chem. Soc. (C), 1966, 1816.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[CH2:6]([O:13][S:14](C1CC1)(=[O:16])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI>C1COCC1>[CH3:2][C:3]1([S:14]([O:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)(=[O:15])=[O:16])[CH2:5][CH2:4]1
Reactant: [Li]CCCC
Reactant: O=S(=O)(OCc1ccccc1)C1CC1
Solvent: CI
Solvent: C1CCOC1
Product: CC1(S(=O)(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
n-BuLi (0.78 g, 12.25 mmol) was added drop-wise at −78° C. to a solution of Benzylcyclopropane sulfonate (2.0 g, 11.2 mmol) in THF (20 mL) and continued stirring at the same temperature for 10 min. CH3I (3.98 g, 28.0 mmol) was added at −78° C., allowed the reaction to warm to 0° C. with stirring for 30 min. The reaction mixture was quenched with ice cold water, diluted with ethylacetate (100 mL), organic layer collected was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude. The crude was purified by column chromatography (using silica gel and 4% ethyl acetate in Hexane as eluent) to afford benzyl 1-methylcyclopropane-1-sulfonate (Int-25). 1H NMR (300 MHz, CD3OD) δ ppm 4.2-4.1 (2H, t), 1.7-1.6 (2H, m), 1.4 (3H, s), 1.5-1.3 (2H, m), 1.3-1.2 (2H, m), 1.0-0.9 (2H, m), 0.9 (3H, t).
Reaction SMILES: O[C:2]1C(=O)C=C(CNS(C2C=CC(C)=CC=2)(=O)=O)OC=1CO.[CH2:23]([O:30][C:31]1[C:32](=[O:50])[CH:33]=[C:34]([CH2:39][NH:40][S:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)(=[O:43])=[O:42])[O:35][C:36]=1[CH2:37][OH:38])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][C:31]1[C:32](=[O:50])[CH:33]=[C:34]([CH2:39][NH:40][S:41]([C:44]2[CH:45]=[CH:46][CH:47]=[C:48]([CH3:2])[CH:49]=2)(=[O:43])=[O:42])[O:35][C:36]=1[CH2:37][OH:38])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(O)c(CO)o2)cc1
Product: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(CO)o2)c1
Yield: 41.35 %

Procedure:
N-(5-Benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-3-methyl-benzenesulfonamide (10-06) (3.7 g, 41.35%) was synthesized as a white solid from N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-4-methyl-benzenesulfonamide (9-06) (7.0 g, 21.54 mmol) following the procedure described for N-(5-benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (10-01).
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)[CH3:2].[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Cl:38])[C:14]=1[NH:15][C:16]1[C:25]2[C:20](=[C:21]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:22]([O:26][CH3:27])=[CH:23][CH:24]=2)[O:19][C:18](=[O:37])[CH:17]=1.CO>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Cl:38])[C:14]=1[NH:15][C:16]1[C:25]2[C:20](=[C:21]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:2])=[O:35])[C:22]([O:26][CH3:27])=[CH:23][CH:24]=2)[O:19][C:18](=[O:37])[CH:17]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCC(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12
Reaction time: 0.17 h

Procedure:
A solution of TMSCHN2 (0.75 mL, 2M Et2O, 1.5 mmol) was added to a solution of 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)hexanoic acid (115 mg, 0.25 mmol, Example 44), methanol (1 mL), and toluene (8 mL). After 10 min, the reaction was concentrated and purified by silica gel chromatography (4:1→1:4; hexanes:ethyl acetate) to give methyl 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)hexanoate: 1H NMR (400 MHz, DMSO-d6): δ 9.50 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.20 (d, 1H), 4.63 (s, 1H), 3.97 (t, 2H), 3.91 (s, 3H), 3.56 (s, 3H), 2.31 (t, 2H), 1.67 (m, 2H), 1.57 (m, 2H), 1.46 (m, 2H); MS (ESI): 480.9.
Reaction SMILES: Br[C:2]1[CH:16]=[N:15][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([CH2:13][OH:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1.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>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:25]=[CH:26][C:27]([C:2]3[CH:16]=[N:15][C:5]4[NH:6][C:7]5[CH:12]=[N:11][C:10]([CH2:13][OH:14])=[CH:9][C:8]=5[C:4]=4[CH:3]=3)=[CH:28][CH:29]=2)[CH2:20][CH2:19]1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: OCc1cc2c(cn1)[nH]c1ncc(Br)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(-c3cnc4[nH]c5cnc(CO)cc5c4c3)cc2)CC1
Temperature: 150 °C

Procedure:
A suspension of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-methanol (40.7 mg, 0.146 mmol), 4-(4-methylpiperazin-1-yl)phenylboronic acid pinacol ester (46.4 mg, 0.154 mmol) and bis(triphenylphosphine)palladium(II) dichloride (5.1 mg, 7.3 mmol) in acetonitrile (0.73 mL) and 2N aqueous sodium carbonate solution (0.73 mL) was heated at 150° C. under microwave irradiation for 20 minutes. The cooled reaction mixture was diluted with THF, the solid removed by filtration, and washed with THF and DCM. The combined filtrate was concentrated in vacuo and the resultant residue purified by flash chromatography (silica, 1-15% (2N ammonia methanol) in DCM) to afford the title compound. 1H NMR (DMSO-D6, 400 MHz): 12.46 (s, 1H), 9.76 (s, 1H), 9.07 (d, J=1.8 Hz, 1H), 8.97 (d, J=1.8 Hz, 1H), 8.50 (s, 1H), 7.76 (d, J=8.7 Hz, 2H), 7.17 (d, J=8.7 Hz, 2H), 4.13 (s, 2H), 3.38-3.30 (m, 8H), 2.89 (s, 3H). LCMS (Method D): RT=5.24 min, M+H+=374.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][NH2:19]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:19][CH2:18][C:17]3[CH:20]=[CH:21][CH:22]=[C:15]([Br:14])[CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: NCc1cccc(Br)c1
Product: Nc1cc2ncnc(NCc3cccc(Br)c3)c2cn1
Yield: 51.7 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (228 mg, 1.19 mmol) (described in a previous experimental) and 3-bromobenzylamine (0.84 g, 4.52 mmol) is stirred under N2 at 1400C for 1 h. The resulting product is chromatographed on silica gel (2-10% EtOH/EtOAc) to give 7-amino-4-[(3-bromophenyl)methylamino]pyrido[4,3-d]pyrimidine (203 mg, 52%) as a light brown solid. 1H NMR (DMSO) δ 9.09 (1H, s), 8.86 (1H, t, J=5.8 Hz), 8.26 (1H, s), 7.54 (1H, s), 7.44 (1H, d, J=7.8 Hz,), 7.36 (1H, d, J=7.6 Hz), 7.29 (1H, t, J=7.7 Hz), 6.48 (2H, s), 6.37 (1H, s), 4.73 (2H, d, J=5.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[C:5]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:4]=1.[CH2:30]([N:32](CC)CC)C.CN.O>CN(C)C=O.C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([S:15]([NH:32][CH3:30])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[C:5]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:4]=1
Reactant: COc1ccc(CCNc2cc(-c3cccc(S(=O)(=O)Cl)c3)nc(OC)n2)cc1
Reactant: CCN(CC)CC
Agent: CN
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CNS(=O)(=O)c1cccc(-c2cc(NCCc3ccc(OC)cc3)nc(OC)n2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzenesulfonylchloride [0.05 g, Intermediate (10)] and triethylamine (0.064 mL) in dimethylformamide (5 mL) is cooled to 0° C. and the treated with a solution of methylamine in THF (5 mL, 2 M). The mixture is allowed to reach room temperature overnight, poured into water (100 mL). This mixture is extracted twice with EtOAc (100 mL). The combined extracts are washed with water, dried over sodium sulfate, filtered and evaporated. The residue is subjected to chromatography on silica gel eluting with EtOAc to give 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-N-methyl-benzenesulfonamide [21.5 mg, Example 4(a)]. MS: 429 (M+H), 1H NMR [(CD3)2SO]: δ 8.4 (1H, s); 8.2 (1H, m); 7.85 (1H, d, J=3 Hz); 7.75-7.8 (1H, m); 7.5-7.6 (2H, m); 7.2 (2H, d, J=7 Hz); 6.95 (2H, d, J=7 Hz); 6.6 (1H, s); 3.9 (3H, s); 3.7 (3H, s); 3.5-3.6 (2H, m); 2.8 (2H, t); 2.45 (3H, d, J=2 Hz).