Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.CCCCCC.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C@@H:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C@@H:23]([CH:32]=[CH2:33])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>CO>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C@@H:24]([CH2:27][CH2:28][C:29]([O:31][CH3:1])=[O:30])[C@@H:23]([CH:32]=[CH2:33])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=C[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1CCC(=O)O
Solvent: CO
Solvent: CCCCCC
Product: C=C[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1CCC(=O)OC
Temperature: 22 °C
Reaction time: 3 h

Procedure:
50 cm3 of a solution of 2M trimethylsilyldiazomethane/hexane are added, at a temperature in the region of 15° C., under an argon atmosphere, to 5 g (17.64 mmol) of (3R,4R)-1-tert-butyloxycarbonyl-4-(2-carboxyethyl)-3-vinylpiperidine in solution in 50 cm3 of methanol. After stirring for 3 hours at a temperature in the region of 22° C., the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give 5.3 g of (3R,4R)-1-tert-butyloxycarbonyl-4-(2-methoxycarbonylethyl)-3-vinylpiperidine in the form of an orange oil.
Reaction SMILES: [S:1](OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].C(OC=C)(=O)C.[CH3:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1C=CC(O)=[CH:32][CH:33]=1>O>[CH2:32]([SH:1])[CH2:33][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: CCCCCCCCCc1ccc(O)cc1
Agent: [NH4+]
Solvent: O
Solvent: C=COC(C)=O
Product: CCCCCCCCCCCCS

Procedure:
As soon as the mixture has reached 80° C., a solution of 2 g of ammonium persulfate in 10 cm3 of water is added thereto. A mixture containing 1,251 g of vinyl acetate and 450 g of "Versatate VEOVA 10", and a solution containing 100 g of deionized water, 2 g of ammonium persulfate and 82.5 g of a 22% strength aqueous solution of polyoxyethyleneated nonylphenol (30 units of ethylene oxide), are then introduced simultaneously at a constant rate over 3 hours.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[CH:14][N:15]2[C:20]=1[C:19](=[O:21])[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]([CH:29]([NH:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:30][CH3:31])=[N:16]2)=[O:11].[CH3:44][C:45]1[CH:53]=[CH:52][C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=1>C(Cl)Cl>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[CH:14][N:15]2[C:20]=1[C:19](=[O:21])[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]([CH:29]([N:32]([CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[C:49](=[O:50])[C:48]1[CH:52]=[CH:53][C:45]([CH3:44])=[CH:46][CH:47]=1)[CH2:30][CH3:31])=[N:16]2)=[O:11]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCC(NCCCNC(=O)OC(C)(C)C)c1nn2ccc(C(=O)OC)c2c(=O)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(c1nn2ccc(C(=O)OC)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
Triethylamine (0.011 mL, 0.079 mmol) was added to a solution of 3-benzyl-2-[1-(3-tert-butoxycarbonylamino-propylamino)-propyl]-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid methyl ester (0.013 g, 0.026 mmol) and 4-methyl-benzoyl chloride (0.01 mL, 0.079 mmol) in CH2Cl2 (0.50 mL) at 0 C. The reaction mixture was stirred at 0° C. for 4 h, quenched with saturated NaHCO3 (3 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 8/1 to 1/1 hexane/EtOAc to afford the title compound (0.015 g, 94%) as a solid: 1H NMR (CDCl3) δ 7.02–7.32 (m, 11H), 5.95 (m, 3H), 4.85 (m, 1H), 3.86 (s, 3H), 3.25 (m, 2H), 2.65 (m, 2H), 2.32 (s, 3H), 2.00 (m, 1H), 1.80 (m, 1H), 1.60 (m, 1H), 1.32 (s, 9H), 0.85 (m, 1H), 0.65 (m, 3H); MS (ESI+) 616 (M++H); HRMS (ESI+) calculated: 616.3135 (M++H). found: 616.3110 (M++H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][CH2:12][O:13][CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]#[CH:23])[CH:19]=[CH:20][CH:21]=1>CO>[C:22]([C:18]1[CH:17]=[C:16]([NH:15][C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH2:11][CH2:12][O:13][CH3:14])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:21]=[CH:20][CH:19]=1)#[CH:23]
Reactant: COCCn1ccc2c(Cl)ncnc21
Reactant: C#Cc1cccc(N)c1
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3c2ccn3CCOC)c1
Yield: 81 %

Procedure:
Following a procedure analogous to that described in Example 11, the title product was prepared in 81% yield from 4-chloro7-(2-methoxy-ethyl)-7H-pyrrolo[2,3-d]pyrimidine (1.0 eq) and m-aminophenyl acetylene (1.2 eq) in methanol: MP: 240-241° C.; LC-MS: 292 (MH+); anal. RP18-HPLC RT: 4.16 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4](Cl)[N:3]=1.Cl.[NH2:26][C@@H:27]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:28]([O:30][CH3:31])=[O:29].C(N(C)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:26][C@H:27]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[N:3]=1
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: COc1ccc(CN2Cc3c(F)c(Cl)nc(Cl)c3C2=O)c(OC)c1
Agent: CC(C)N(C)C(C)C
Agent: Cl
Solvent: CC#N
Product: COC(=O)[C@@H](CC(C)C)Nc1nc(Cl)c2c(c1F)CN(Cc1ccc(OC)cc1OC)C2=O
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (3 g, 8.08 mmol), (5)-methyl 2-amino-4-methylpentanoate hydrochloride (2.94 g, 16.16 mmol), and N-isopropyl-N-methylpropan-2-amine (3.76 mL, 24.25 mmol) in ACN (50 mL) was stirred at 100° C. for 3 d. The solvent was removed and the resulting residue was used in the next step without further purification. [M+H] calc'd for C23H27ClFN3O5, 480. found, 480.
Reaction SMILES: FC(F)(F)C([O-])=[O:4].[F:8][C:9]([F:27])([F:26])[C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[C:28]([S:32](Cl)=[O:33])([CH3:31])([CH3:30])[CH3:29].C(N(CC)CC)C.ClC1C=CC=C(C(OO)=O)C=1>C(OCC)C.O1CCCC1>[F:27][C:9]([F:8])([F:26])[C:10]1[CH:11]=[CH:12][C:13]([S:16]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([S:32]([C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:33])=[O:4])[CH2:22][CH2:21]2)(=[O:18])=[O:17])=[CH:14][CH:15]=1
Reactant: O=S(=O)(OC1CCNCC1)c1ccc(C(F)(F)F)cc1
Reactant: O=C([O-])C(F)(F)F
Reactant: CC(C)(C)S(=O)Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)S(=O)(=O)N1CCC(OS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a tetrahydrofuran (20 mL) solution of the trifluoroacetate salt of piperidin-4-yl 4-(trifluoromethyl)benzenesulfonate (800 mg, 1.97 mmol) at −78° C. was added tert-butylsulfinyl chloride (209 μL, 2.20 mmol). The reaction mixture was stirred for 10 minutes at −78° C. before triethylamine (1.10 mL, 7.88 mmol) was added. It was then stirred for another 2 hours at −78° C. Diethyl ether (50 mL) was added to the reaction mixture, and the combined organic layers were washed with 1 M hydrochloric acid (30 mL), water (30 mL), brine (30 mL), dried (sodium sulfate), filtered and concentrated in vacuo. The resulting oil was dissolved in dichloromethane (20 mL), cooled to 0° C., and m-chloroperbenzoic acid (374 mg, 2.17 mmol) was added to the solution. The ice-bath was removed, and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was washed with saturated sodium bicarbonate (40 mL), water (40 mL), brine (40 mL), dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography over silica gel, eluting with hexanes/ethyl acetate, afforded the title compound.
Reaction SMILES: [CH2:1]([S:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)([Cl:27])=O>CN(C)C=O>[CH2:1]([S:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([Cl:27])=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCS(=O)(=O)c1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCS(=O)(=O)c1ccc(C(=O)Cl)cc1
Temperature: 60 °C

Procedure:
4-Dodecylsulfonylbenzoic acid (25.45 g, 71.8 mMole) was added to thionyl chloride (100 mL) together with 2 drops of dirnethylformarnide. The resulting mixture was heated to 60° C. for 3 hours. The solution was then cooled, concentrated under reduced pressure and co-evaporated with ethyl acetate (2×50 mL). The residual solid, assuming a quantitative yield, was taken on to the next step.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([CH2:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)=O)[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(C(=O)Cc2ccc(N)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(CCc2ccc(N)cc2)CC1

Procedure:
4-(4-Methylpiperazin-1-yl)carbonylmethylaniline (596 mg, 2.55 mmol) was treated in anhydrous THF (20 mL) under nitrogen with lithium aluminium hydride (291 mg, 2.67 mmol) overnight. The reaction was quenched with water (3×0.29 mL), 15% sodium hydroxide (3×0.29 mL) and again water (3×0.29 mL). The resulting precipitate was removed by filtration. Evaporation of the filtrate afforded the title compound as an orange oil. LC:2.5 min; Rt 0.21(m/z 220, M+H+) 90%, 1HNMR: (400MHz, CDCl3); 2.30 (3H, s), 2.40-2.73 (2H +8H, m), 2.69 (2H, m); 6.62 (2H, d, J 8.31), 6.99 (2H, d, J 8.31).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>>[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][C:3](=[O:11])[NH:4][C:5]=2[CH:10]=1)=[O:18]
Reactant: O=C(Cl)CCCCCl
Reactant: O=C1COc2ccccc2N1
Product: O=C1COc2ccc(C(=O)CCCCCl)cc2N1
Yield: 66.9 %

Procedure:
Using 2H-1,4-benzoxazin-3(4H)-one (10.0 g) and 5-chlorovaleryl chloride (12.5 g) according to the same method as that of Reference Example 1, the title compound (12.0 g) was obtained as colorless crystals.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[PH2:6]([O-:8])=[O:7].[CH:9]([NH3+:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH:9]([NH:22][CH:1]([P:6]([OH:8])[OH:7])[CH:2]([CH3:4])[CH3:3])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)C=O
Reactant: O=[PH2][O-]
Reactant: [NH3+]C(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CC(C)C(NC(c1ccccc1)c1ccccc1)P(O)O

Procedure:
19.8 parts of isobutyraldehyde and 62.2 parts of benzhydrylammonium hypophosphite were dissolved in 75 parts of ethanol and the mixture was heated at reflux for 3 hours. After cooling the mixture was filtered to give DL-1-benzhydrylamino-2-methyl-propanephosphonous acid of melting point 189°-192°.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4](Cl)[N:3]=1.C(O)CCC.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][S:13][CH2:12]2)=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1
Reactant: Nc1ccccc1
Reactant: Clc1nc(Cl)c2ncn(C3CCSC3)c2n1
Solvent: CCCCO
Solvent: CC(C)O
Product: Clc1nc(Nc2ccccc2)c2ncn(C3CCSC3)c2n1
Reaction time: 20 h

Procedure:
The operation is carried out as in Stage 2 of Example 5 starting from 160 mg of the product obtained in Stage 1 of Example 5, 3 ml of butanol and using 0.055 ml of aniline in place of the benzylamine and the reaction medium is taken to a temperature of approximately 80 to 85° C. for 20 hours, left to return to ambient temperature, diluted with 5 ml of isopropanol, placed for approximately one hour at a temperature of approximately 0° C., followed by separating, washing with 5 ml of isopropanol and drying under vacuum to a temperature of approximately 50° C. After purification on silica eluting with methylene chloride/ethyl acetate in a proportion of 90/10, 173 mg of expected product is thus obtained in the form of white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4](=[O:13])[CH:3]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH2:31][CH2:32][NH:33][C:34](=[O:36])[CH3:35])=[CH:23]1>>[OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4](=[O:13])[C:3]=1[CH:20]([C:16]1[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=1)[C:23]1[NH:22][C:30]2[C:25]([C:24]=1[CH2:31][CH2:32][NH:33][C:34](=[O:36])[CH3:35])=[CH:26][CH:27]=[CH:28][CH:29]=2
Reactant: O=C1C=C(O)C(c2ccccc2)C1
Reactant: CC(=O)NCCc1c[nH]c2ccccc12
Reactant: O=Cc1cccnc1
Product: CC(=O)NCCc1c(C(C2=C(O)C(c3ccccc3)CC2=O)c2cccnc2)[nH]c2ccccc12

Procedure:
Using general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) was reacted with pyridine-3-carbaldehyde and N-[2-(1H-indol-3-yl)-ethyl]-acetamide to give the title compound as pale brown solid. MS: 466.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CCN(C(C)C)C(C)C.[F:34][C:35]([F:50])([F:49])[C:36]([NH:38][CH:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42][NH:41][CH2:40]1)=[O:37]>CN(C=O)C.CCOC(C)=O>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([N:41]2[CH2:40][CH:39]([NH:38][C:36](=[O:37])[C:35]([F:50])([F:34])[F:49])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42]2)=[O:13])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Reactant: O=C(NC1CNCc2ccccc21)C(F)(F)F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(CNc1cc(Cl)cc(Cl)c1)N1Cc2ccccc2C(NC(=O)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
To a solution of 2-(3,5-dichlorophenylamino)acetic acid (0.332 g, 1.5 mmol) in DMF (10 mL) was added HOBt (0.30 g, 2.2 mmol) EDCI: HCl (0.434 g, 2.2 mmol), DIEA (0.39 g, 3.0 mmol) and 2,2,2-trifluoro-N-(1,2,3,4-tetrahydroisoquinolin-4-yl)acetamide (370 mg, 1.5 mmol) at 0° C. The reaction mixture was warmed to rt and stirred overnight. After the reaction was shown to be complete as indicated by TLC the reaction mixture was diluted with EtOAc (50 mL), and washed with water (20 mL×3). The EtOAc layer was concentrated in vacuo to give crude reaction mixture which was purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to give (0.45 g, 74%) of the titled intermediate. 1H NMR (DMSO-d6, 400 MHz): δ 7.56 (s, 1H), 7.37-7.21 (m, 4H), 6.74 (d, J=11.6 Hz, 2H), 6.61 (s, 1H), 6.4-6.2 (m, 1H), 5.20-5.06 (m, 1H), 4.85 (t, J=16.4 Hz, 1H), 4.60 (d, J=16.8 Hz, 1H), 4.58 (d, J=17.6, 1 H), 4.12-4.03 (m, 1H), 3.9-3.8 (m, 1H), 3.58-3.39 (m, 1H). LCMS: M/z: (M+1):446
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][CH:10]=[O:11].O1CCOCC1.[Br:18]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Br:18][CH:9]([C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH:10]=[O:11]
Reactant: Cc1cccc(C)c1CC=O
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cccc(C)c1C(Br)C=O
Reaction time: 0.17 h
Yield: 103.8 %

Procedure:
2-(2,6-dimethylphenyl)-acetaldehyde (4.4 g, 29.7 mmol) was dissolved in DCM (30 mL) and dioxane (50 mL) and a solution of bromine (1.7 mL, 32.7 mmol) in DCM (30 mL) was added dropwise at room temperature. Completion of reaction was determined by GC/MS. Upon completion, sodium thiosulfate aqueous solution was added and stirred for 10 minutes. The layers were separated, and washed twice with DCM (100 mL) and combined organics with 10% aqueous LiCl solution (100 mL). The organic layers were dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to give 7 g (93%) of 2-bromo-2-(2,6-dimethylphenyl)acetaldehyde as an orange oil. NMR confirmed the product, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[CH2:29]Br.CCN(C(C)C)C(C)C>CC#N>[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[CH2:29][N:9]([CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:8][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1cccnc1CNCc1ncccc1C
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1C)Cc1ncccc1C

Procedure:
Using General Procedure A: Reaction of bis-(3-methyl-pyridin-2-ylmethyl)-amine, 2-bromomethyl-5-cyano-benzoic acid methyl ester and DIPEA in CH3CN gave 2-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-5-cyano-benzoic acid methyl ester as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1([CH:19]([NH:22][C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][CH:29]=[CH:28]3)=[O:24])[CH2:20][CH3:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:30]2[C:31]3[C:27](=[CH:26][C:25]([C:23]([NH:22][CH:19]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:20][CH3:21])=[O:24])=[CH:33][CH:32]=3)[CH:28]=[CH:29]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CCC(NC(=O)c1ccc2[nH]ccc2c1)c1ccccc1
Product: CCC(NC(=O)c1ccc2c(ccn2C(=O)c2ccc([N+](=O)[O-])cc2)c1)c1ccccc1

Procedure:
The title compound was prepared following the same general protocol as described in Example 25, using 4-nitrobenzoylchloride and N-(1-phenylpropyl)-1H-indole-5-carboxamide. LC-MS 428 (M+H)
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.OC1C=CC(C(OC)=O)=CC=1.[CH3:31][O:32][C:33]1[CH:34]=C(CCO)C=C[CH:38]=1>>[CH3:31][O:32][C:33]1[CH:38]=[C:1]([CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:18][CH:19]=2)[CH:3]=[CH:2][CH:34]=1
Reactant: COc1cccc(CCO)c1
Reactant: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Agent: COC(=O)c1ccc(O)cc1
Product: COc1cccc(CCOc2ccc(C(=O)NCC(=O)O)cc2)c1
Yield: 92 %

Procedure:
The same reactions as in Example 9 (9a) and (9b) were conducted using methyl 4-hydroxybenzoate (4.26 g, 28.0 mmol) and 2-(3-methoxyphenyl)ethanol (4.32 mL, 31.0 mmol) to give 8.54 g of the title compound (colorless crystal, yield: 92%).
Reaction SMILES: [CH3:1][N:2]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[CH2:20][CH2:21]S(C)(=O)=O)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16].I.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[C:50]([CH:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)=[O:51]>>[CH3:1][N:2]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[CH2:20][CH2:21][N:55]1[CH2:56][CH2:57][CH:52]([C:50]([C:42]2[N:41]([CH2:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=3)[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[N:43]=2)=[O:51])[CH2:53][CH2:54]1)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16]
Reactant: COc1ccc(C2C=NN=N2)cc1C(=O)N(C)CC(CCS(C)(=O)=O)c1ccc(F)cc1
Reactant: O=C(c1nc2ccccc2n1Cc1ccccn1)C1CCNCC1
Agent: I
Product: COc1ccc(C2C=NN=N2)cc1C(=O)N(C)CC(CCN1CCC(C(=O)c2nc3ccccc3n2Cc2ccccn2)CC1)c1ccc(F)cc1

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-(4-fluorophenyl)-4-methanesulfonylbutyl)-2-methoxy-5-(4H-triazol-4-yl)benzamide and 4-(1-(pyrid-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine hydriodic acid salt to give the title compound.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:7][CH2:8][CH2:9][O:10][C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)[CH2:4][CH2:5][CH3:6]>CC(C)=O>[I-:2].[CH2:3]([O:7][CH2:8][CH2:9][O:10][C:11]1[C:15]([C:16]2[CH:17]=[N+:18]([CH3:1])[CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CI
Reactant: CCCCOCCOc1nsnc1-c1cccnc1
Solvent: CC(C)=O
Product: CCCCOCCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.5 ml, 9 mmol) and 3-(3-(2-butoxyethoxy)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) in acetone (4 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 1.07 g (85%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1)[NH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O1C[CH2:25][CH:24]([NH:27][C:28]2[N:29]=[CH:30][C:31]3[CH2:37][CH2:36][NH:35][CH2:34][C:32]=3[N:33]=2)[CH2:23]C1.Cl.ClC1C=C(C(C2[O:53][CH:52]=NC=2)N)C=CC=1Cl>>[Si:1]([O:8][CH2:9][CH2:10][CH:11]([NH:12][C:52]([N:35]1[CH2:36][CH2:37][C:31]2[CH:30]=[N:29][C:28]([NH:27][CH:24]([CH3:23])[CH3:25])=[N:33][C:32]=2[CH2:34]1)=[O:53])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: c1nc(NC2CCOCC2)nc2c1CCNC2
Reactant: NC(c1ccc(Cl)c(Cl)c1)c1cnco1
Reactant: CC(C)(C)[Si](C)(C)OCCC(N)c1ccc(F)c(F)c1
Agent: Cl
Product: CC(C)Nc1ncc2c(n1)CN(C(=O)NC(CCO[Si](C)(C)C(C)(C)C)c1ccc(F)c(F)c1)CC2
Yield: 31.9 %

Procedure:
Condensation of 306 and 72 was carried out in accord with the procedure described in step 6 of example 1 except 72 was used in place of 28 and 306 was used in place of 22. The crude product was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (500:5 to 500:8) to afford 0.11 g (31.9%) of N-(3-(tert-butyldimethylsilyloxy)-1-(3,4-difluorophenyl)propyl)-2-(isopropylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxamide (308). The silyl group was removed with TBAF in accord with the procedure described in step 5 of example 42. The product was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (500:15-500:25) to afford 0.010 g (12.8%) of I-77: MS m/z (APCI-pos) M+1=406.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([O:11][CH3:12])[CH:5]=1)([O-:3])=[O:2].Br[N:14]1[C:18](=O)[CH2:17][CH2:16][C:15]1=O.N1CCCC1>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:6]([O:11][CH3:12])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc([N+](=O)[O-])ccc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCNC1
Product: COc1cc([N+](=O)[O-])ccc1CN1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A mixture of 4-nitro-2-methoxytoluene (5 g, 30 mmol), N-bromosuccinimide (5.3 g, 30 mmol), azobisisobutyronitrile (AIBN, 10 mg) and CCl4 was refluxed for 60 h. The reaction mixture was cooled to 0° C., filtered through diatomaceous earth and concentrated under vacuum. The resulting oil was redissolved in THF (50 mL) and added portionwise to a cold (0° C.) stirred solution of pyrrolidine (10.65 g, 150 mmol). Afterwards, the cooling bath was removed and the reaction was stirred at ambient temperature for 1 h. It was then concentrated to an oil, diluted with 100 mL saturated aqueous NaHCO3 and 50 mL brine. Following extraction three times with 125 mL EtOAc, the combined organic layer was dried over MgSO4 and concentrated to 6.5 g of an oil. Purification by chromatography (SiO2 ; 30% EtOAc in hexanes) yielded 5.7 g (24 mmol, 80%) of the desired compound as an oil.