Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[C:17](=O)(O)[O-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:5]([O:7][CH3:17])=[O:6]
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C)c(O)c(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3,5-dimethyl-4-hydroxybenzoic acid (2 g, 0.012 mol) in anhydrous methanol (60 mL) was cooled in an ice-bath and thionyl chloride (5 mL) was added drop wise to this solution. The reaction was stirred in the ice-bath for one hour and was then warmed to room temperature and stirred for 16 hours. Solid sodium bicarbonate was then added to neutralize the acid and then the mixture was evaporated to dryness by rotary evaporation. The residue was partitioned between ethyl acetate and water (100 mL each). The ethyl acetate layer was separated and washed once with brine. It was then dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. Yield=2.146 g, white powder.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=1.N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:45]I>CC#N.O>[I:45][CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=1
Reactant: II
Reactant: CC(C)(C)OC(=O)n1cc(CCCO)c2ccccc21
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)n1cc(CCCI)c2ccccc21
Reaction time: 3 h

Procedure:
To a stirring solution of tert-butyl 3-(3-hydroxypropyl)-1H-indole-1-carboxylate in MeCN were added imidazole (44 mg), PPh3 (129 mg) and iodine (124 mg) at ambient temperature. After 3 hours, water was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=15:1) to give tert-butyl 3-(3-iodopropyl)-1H-indole-1-carboxylate (63 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br[CH2:10][CH2:11][OH:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1
Reactant: OCCBr
Reactant: Nc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: OCCNc1cccc(Br)c1
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixture of 3-bromo-aniline (0.037 mol), 2-bromo-ethanol (0.074 mol) and triethylamine (0.0555 mol) in toluene (35 ml) was stirred under reflux for 12 hours. The reaction was cooled down to room temperature and the precipitate was filtered off. The solvent of the filtrate was evaporated until dryness. The residue (22 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 98/2/0.1; 20-45 μm). The pure fractions were collected and the solvent was evaporated, yielding 4.8 g of 2-(3-bromo-phenylamino)-ethanol (60%).
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Br.[Cl:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH2:14])=[CH:9][CH:8]=1.C(N(CC)CC)C>CN1CCCC1=O>[Cl:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:14][CH2:3][CH:2]([F:5])[F:1])=[CH:9][CH:8]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: FC(F)CBr
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: FC(F)CNCc1ccc(Cl)nc1
Temperature: 100 °C
Yield: 83.1 %

Procedure:
19.9 g (0.135 mol) of 2,2-difluoro-1-bromoethane, 10 g (0.067 mol) of 1-(6-chloropyridin-3-yl)methanamine and 8.2 g of triethylamine are initially charged with 31 g of N-methylpyrrolidone. The mixture is heated to 100° C. for 2 hours and then cooled again to 80° C. The N-methylpyrrolidone is distilled off at 80° C. under reduced pressure and the reaction mixture is poured onto 50 ml of water. 2 ml of 45% sodium hydroxide solution are used to adjust the pH to 12, and the mixture is then extracted twice with 30 ml of toluene. The product is subsequently finely distilled under reduced pressure. This gives 11.5 g of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethanamine (corresponds to 83.1% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:29])=[C:6]([C:8]2[N:13]=[C:12]([S:14][CH3:15])[N:11]=[C:10]3[N:16]([C:21]4[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=4[F:28])[C:17](=[O:20])[NH:18][CH2:19][C:9]=23)[CH:7]=1.[S:30]1[CH:34]=[CH:33][C:32]([C:35](O)=[O:36])=[CH:31]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[F:27][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([F:28])[C:21]=1[N:16]1[C:10]2[N:11]=[C:12]([S:14][CH3:15])[N:13]=[C:8]([C:6]3[CH:7]=[C:2]([NH:1][C:35]([C:32]4[CH:33]=[CH:34][S:30][CH:31]=4)=[O:36])[CH:3]=[CH:4][C:5]=3[CH3:29])[C:9]=2[CH2:19][NH:18][C:17]1=[O:20]
Reactant: CSc1nc(-c2cc(N)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: O=C(O)c1ccsc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CSc1nc(-c2cc(NC(=O)c3ccsc3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The compounds 5-(5-amino-2-methylphenyl)-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.205 g, 0.5 mmol), 3-thiophenecarboxylic acid (0.0647 g, 0.5 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.107 g, 0.55 mmol), 4-(dimethylamino)pyridine (0.002 g, 0.016 mmol), and triethylamine (0.14 mL, 1 mmol), were dissolved in chloroform (10 mL) and stirred under argon at room temperature for 16 h. The reaction was not complete. An additional 3-thiophenecarboxylic acid (0.13 g, 1.0 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.107 g, 0.55 mmol) were dded and heated to 40° C. for 17 h. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water (3×), brine (1×), dried over anhydrous Na2SO4, filtered and evaporated. The crude product was flash chromatographed on silica gel (10 g) eluted with 0-5% MeOH/CH2Cl2 to give the title compound as a solid. LC-MS m/z 524 (M+H)+, 2.2 min (ret. time).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][C:13]=1[Cl:20].N>>[Cl:20][C:13]1[CH:14]=[C:15]([C:18]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[N:8][CH:9]=3)[CH:19]=2)[CH:16]=[CH:17][C:12]=1[Cl:11]
Reactant: ON=C(Cl)c1cncnc1
Reactant: C#Cc1ccc(Cl)c(Cl)c1
Agent: N
Product: Clc1ccc(-c2cc(-c3cncnc3)no2)cc1Cl

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 1,2-dichloro-4-ethynylbenzene (Aldrich, 86 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.86-7.96 (m, 3H), 8.20 (d, J=1.7 Hz, 1H), 9.31 (s, 2H), 9.36 (s, 1H) ppm; MS (DCI/NH3) m/z 294 (M+H)+, 292 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN1CCCC1=O>[C:13]1([CH:12]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[O:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClC(Cl)c1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Brc1ccc(OC(Oc2ccc(Br)cc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
Inside a nitrogen purged glove box, to a solution of 4-bromophenol (12.0 grams, 69.4 millimoles, 2.5 equivalents) dissolved in anhydrous 1-methyl-2-pyrrolidinone (100 milliliters), was added 95% sodium hydride (1.82 grams, 72.1 millimoles, 2.6 equivalents) in small portions over a 30 minute period. The reaction was stirred for an additional 90 minutes at room temperature. α,α-dichlorotoluene (4.13 milliliters, 27.7 millimoles, 1.0 equivalent) was added and the reaction was heated to 70° C. overnight. The reaction was quenched addition to water (200 milliliters). The aqueous phase was extracted with a 1:1 mixture of diethyl ether and ethyl acetate (3×120 mL). The combined organic phases were then washed with de-ionized water (5×100 milliliters), brine (1×100 milliliters) and dried over magnesium sulfate. After filtration and concentration on the rotary evaporator, the residue was taken up in diethyl ether (60 milliliters) and filtered through a plug of basic alumina. The product was fully eluted with additional diethyl ether (700 milliliters) and concentrated on the rotary evaporator. Further drying under high vacuum for several days yielded the product quantitatively in form of a yellow oil that crystallizes over time to give an off-white solid (12.0 grams, 27.7 millimoles, 100%). m.p.: 50.8; 1H-NMR (400 MHz, CDCl3) δ 7.59-7.51 (m, 2H), 7.44-7.37 (m, 3H), 7.37-7.29 (m, 4H), 6.93-6.82 (m, 4H), 6.59 (s, 1H); 13C-NMR (101 MHz, CDCl3) δ 155.07, 136.58, 132.59, 129.65, 128.86, 126.78, 119.60, 115.42, 100.77; FTIR: 605, 658, 674, 694, 741, 792, 816, 848, 886, 928, 984, 1031, 1060, 1100, 1115, 1167, 1178, 1210, 1242, 1280, 1304, 1363, 1449, 1483, 1584, 1689, 3033, 3065 cm−1; UV/Vis 223 (shoulder), 237, 278 nm; GC/MS/EI+: 432, 434, 436 [M+] (2×Br isotope pattern); 261, 263 [Br—C6H4—O—CHPh]+ (1×Br isotope pattern); 182 [C6H4—O—CHPh]+; HRMS (ESL): calc. for C19H13Br2O2− [M+Na]+ 430.9288, found 430.9287.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([Br:20])=[CH:13]3)[C:5]([NH2:21])=[N:4][CH:3]=1.[N:22]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:20][C:14]1[CH:15]=[N:16][C:17]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH2:9][N:8]1[C:6]3=[N:7][C:2]([Br:1])=[CH:3][N:4]=[C:5]3[N:21]=[N:22]1)=[CH:19][CH:18]=2
Reactant: O=N[O-]
Reactant: Nc1ncc(Br)nc1NCc1ccc2ncc(Br)cc2c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1cnc2ccc(Cn3nnc4ncc(Br)nc43)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a solution of 6-bromo-N2-((3-bromoquinolin-6-yl)methyl)pyrazine-2,3-diamine (300 mg, 0.73 mmol) in 5 mL of acetic acid was added dropwise a solution of NaNO2 (150 mg, 2.17 mmol) in 0.5 mL of water at 20° C. The mixture was stirred at rt overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with DCM/methanol gradient to afford the title compound (130 mg, 42%). 1H-NMR (400 MHz, CDCl3) δ ppm 8.84 (s, 1H), 8.71 (s, 1H), 8.24 (s, 1H), 8.01 (d, 1H), 7.74 (s, 2H), 5.99 (s, 2H). LCMS (method E): [MH]+=421, tR=5.50 min.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([N:28]=[C:29]=[O:30])=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1>>[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([NH:28][C:29](=[O:30])[O:17][C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]4)=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1
Reactant: O=C=Nc1ccc2c(c1)OCCO2
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Product: O=C(Nc1ccc2c(c1)OCCO2)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (30.0 mg, 0.133 mmol) using the same procedure employed for Example 2 (2), but with 2,3-dihydro-1,4-benzodioxin-6-ylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a solid (29.1 mg, 50%) having the following characteristics.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]1=2.C(N(CC)CC)C.ClC(OCC)=O.[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30].Cl>CN(C)C=O>[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH:30][C:11]([C:4]1[C:3]2[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=2[NH:6][CH:5]=1)=[O:13]
Reactant: Nc1ccccc1F
Reactant: O=C(O)c1c[nH]c2c1C(=O)CCC2
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1F)c1c[nH]c2c1C(=O)CCC2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 64.9 %

Procedure:
To a solution of 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (538 mg, 3 mmol) and triethylamine (0.88 mL, 6.3 mmol) in N,N-dimethylformamide (15 mL) at 0° C. was added ethyl chloroformate (0.57 mL, 6 mmol). After stirring at 0° C. for 45 minutes, 2-fluoroaniline (0.58 mL, 6 mmol) wad added. The mixture was stirred for an additional 45 minutes, then allowed to stir at ambient temperature for 14 hours. The mixture was poured into aqueous 1.2 N hydrochloric acid and extracted 2× with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. To the residue was added aqueous 1N sodium hydroxide (10 mL) and ethyl alcohol (2 mL) and the mixture heated at reflux for 4.5 hours. After cooling in an ice water bath, the mixture was acidified with aqueous hydrochloric acid, the precipitate collected, rinsed with water and dried. Recrystallization from ethyl alcohol afforded N-(2-fluorophenyl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 46) (530 mg). mp 238-240° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH2:17][C:18](F)(F)F)[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:22])[CH:4]=1.[CH:25](=O)CC>>[F:1][C:2]([F:24])([F:23])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH3:25])[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:22])[CH:4]=1
Reactant: O=c1cc(C(F)(F)F)c2cc3c(cc2[nH]1)CCCN3CC(F)(F)F
Reactant: CCC=O
Product: CCCN1CCCc2cc3[nH]c(=O)cc(C(F)(F)F)c3cc21

Procedure:
This compound was prepared in a similar fashion as that described in Example 84 from Compound 192 (Structure 33 of Scheme VI, where R1═H, n=1) and propionaldehyde. 1H NMR (400 MHz, CDCl3) 11.23 (br. s, 1H), 7.07 (s, 1H), 6.99 (s, 1H), 6.78 (s, 1H), 3.34 (t, 2H, J=5.6), 3.26 (t, 2H, J=7.4), 2.88 (t, 2H, J=6.3), 1.97 (m, 2H), 1.65 (m, 2H), 0.97 (t, 3H, J=7.4).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][CH2:21][CH2:22][C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: N#Cc1ccc(CCN)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NCCc2ccc(C#N)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 130 °C
Yield: 16.4 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.175 g, 0.58 mmol), 4-(2-aminoethyl)benzonitrile (0.101 g, 0.69 mmol) and TEA (0.23 g, 2.31 mmol) was dissolved in dry DMF (3 ml) and heated in a microwave reactor at 130° C. for 30 mins. The reaction mixture was purified by preparative HPLC to yield the title compound (0.039 g, 16%). 1H NMR (500 MHz, CDCl3): δ 7.53-7.43 (m, 7H), 6.88-6.84 (m, 2H), 5.39-5.33 (m, 1H), 3.17-3.10 (m, 2H), 2.65-2.60 (m, 2H), 1.71 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 159.7, 143.2, 134.7, 132.7, 131.8, 130.1, 129.5, 129.1, 125.2, 118.8, 111.1, 108.1, 61.9, 44.5, 41.2, 36.2, 27.8; Mass Spectrum: M−H+ 410.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:21][CH:22]=1)#[N:25]
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: N#Cc1ccc(N)cc1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Nc2ncnc3ccc4nc(C#N)sc4c23)cc1
Yield: 36 %

Procedure:
Prepared from VII and 4-aminobenzonitrile. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 36%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3293, 2225, 2218, 1722, 1628, 1590, 1562, 1495, 1461, 1387, 1261, 1228, 1132, 966, 847, 814; 1H NMR (300 MHz, DMSO-d6) δ 8.54 (d, 1H, J=9.0 Hz), 8.28 (s, 1H), 7.77 (m, 3H), 7.40 (d, 2H, J=9.0 Hz); HRMS calcd for C17H9N6S (M+H+): 329.0609, found 329.0612.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].[OH-].[Na+]>FC(F)(F)C(O)=O.O.O=[Pt]=O>[NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24]
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COCCc1nc2c(N)nc3c(c2n1CCOCCN)CCCC3
Reaction time: 96 h
Yield: 56.8 %

Procedure:
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (10.0 g, 27.3 mmol) was dissolved in 50 mL of trifluoroacetic acid and treated with PtO2 (1.0 g). The reaction mixture was shaken under H2 (3 Kg/cm2). After 4 d, an additional 0.5 g of PtO2 was added and hydrogenation was continued for an additional 3 d. The reaction was then filtered through Celite and concentrated under reduced pressure to give a brown oil. The yellow oil was dissolved in 200 mL of H2O then made basic (pH˜11) by addition of 10% NaOH solution. This was then extracted with CHCl3 (5×75 mL) and the combined organic layers were dried over Na2SO4 and concentrated to give 5.17 g of 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as a tan solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[N:16][C:17]=4[NH2:19])[N:12]([CH3:20])[N:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](O)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]4[C:18]5[C:13](=[N:14][CH:15]=[N:16][C:17]=5[NH2:19])[N:12]([CH3:20])[N:11]=4)=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(F)cc(F)c2)c2c(N)ncnc21
Yield: 72.1 %

Procedure:
A solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.495 mmol), (3,5-difluorophenyl)acetic acid (85 mg, 0.495 mmol), HATU (188 mg, 0.495 mmol), DIEA (0.346 mL, 1.982 mmol) was stirred at room temperature over the weekend. At this time, LCMS analysis indicated complete conversion, so the reaction mixture was poured into water (10 mL), whereupon a beige precipitate formed. The precipitate was filtered, suspended in DCM-methanol and dry-loaded onto silica, then purified by flash chromatography (0-10% methanol in DCM) to afford 3-{1-[(3,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.357 mmol, 72.0% yield) as a white solid. LC-MS (ES) m/z=421 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.27 (m, 2H), 3.94 (s, 3H), 3.97 (s, 2H), 4.18-4.32 (m, 2H), 7.02-7.09 (m, 2H), 7.11-7.20 (m, 1H), 7.41-7.47 (m, 1H), 7.50-7.55 (m, 1H), 8.12-8.22 (m, 1H), 8.25 (s, 1H). Note: NH's are not observed as individual peaks.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][N:10]2[CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH:13]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[N:3]1[C:23]([O:25][CH2:26][CH3:27])=[O:24].C1C(=O)N([Br:35])C(=O)C1>CN(C=O)C.O>[Br:35][C:6]1[CH:7]=[C:8]2[CH:13]3[CH2:14][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17][CH:12]3[N:10]3[CH2:11][CH:2]([CH3:1])[N:3]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:4]([CH:5]=1)=[C:9]23
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)N1CCC2C(C1)c1cccc3c1N2CC(C)N3C(=O)OCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCC2C(C1)c1cc(Br)cc3c1N2CC(C)N3C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a solution of diethyl 2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (40 mg, 0.1 mmol) in DMF (10 mL) at 0° C. was added NBS (20 mg, 0.11 mmol) and stirred at 0° C. for 2 hours. The solution was diluted with water (10 mL), and extracted with EtOAc (2×20 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford diethyl 5-bromo-2-methyl-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (40 mg, 88%) as a clear oil. MS [M+H]+454.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[N:16][C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:14]2[OH:26].CCOCC>N1C=CC=CC=1>[OH:26][C:14]1[C:13]2[C:18](=[CH:19][CH:20]=[C:11]([NH:10][S:2]([CH3:1])(=[O:5])=[O:3])[CH:12]=2)[N:17]=[N:16][C:15]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CCOC(=O)c1nnc2ccc(N)cc2c1O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)c1nnc2ccc(NS(C)(=O)=O)cc2c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulphonic anhydride (1.392 g.) was added to a solution of ethyl 6-amino-4-hydroxycinnolin-3-yl carboxylate (0.932 g.) in dry pyridine (20 ml.), and the mixture was stirred at room temperature overnight. The resulting solution was poured into ether (500 ml.) and the amorphous solid which precipitated was filtered off and applied to a silica column (100 g. Kieselgel 60). Elution with a mixture of 15% v/v ethanol and 85% v/v chloroform, and evaporation of the appropriate fractions gave ethyl 4-hydroxy-6-(methanesulphonylamino)cinnolin-3-yl carboxylate, m.p. 274°-5° C.
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH2:19][OH:20])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2].CS(C)=O.[CH3:25][C:26](OC(C)=O)=[O:27]>O>[CH2:1]([C:3]1([CH2:18][CH2:19][O:20][C:26](=[O:27])[CH3:25])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CCO)OCC3
Solvent: O
Solvent: CS(C)=O
Product: CCc1cccc2c3c([nH]c12)C(CC)(CCOC(C)=O)OCC3
Yield: 78 %

Procedure:
A solution of compound 1 (273 mg, 1.0 mmol), dry DMSO (3 mL), dry Ac2O (2 mL), and dry TEA (1 mL) was stirred overnight at room temperature. The reaction mixture was then diluted with water and extracted three times with EtOAc. The combined organic phases were washed with saturated NaHCO3 and brine, dried with Na2SO4, concentrated, and purified by column chromatography using 10:90:EtOAc:Hexane to give a yellow solid (245 mg, 78%): mp 126-127° C. 1HNMR (CDCl3, δ TMS): 0.91 (t, 3H), 1.38 (t, 3H), 1.88 (s, 3H), 1.90 (m, 2H), 2.21 (t, 2H), 2.78 (m, 2H), 2.87 (q, 2H), 4.01 (t, 2H), 4.14 (m, 2H), 7.02-7.37 (m, 3H, Ar—H), 7.71 (br, 1H, NH). MS−: m/z 350 (MCl−), 314 ([M−H]−). Anal. (C19H25NO3): C, H, N.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:5]([CH2:6][CH2:7][O:8][CH3:9])[CH2:4][CH2:3][O:2][CH3:1])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: COCCNCCOC
Product: COCCN(CCOC)S(=O)(=O)c1ccc(Br)cc1
Yield: 99 %

Procedure:
Starting materials: bis(2-methoxyethyl)amine and 4-bromobenzenesulfonyl chloride. Yield: 99% as a yellow oil: 1H NMR (CDCl3) δ 7.69 (d, J=9 Hz, 2H), δ 7.62 (d, J=9 Hz, 2H), 3.49 (m, 4H), 3.39 (m, 4H), 3.27 (s, 6H); MS (ESP) m/z 352, 354 (M++1).