Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[F:12][C:13]1([F:19])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1>>[F:12][C:13]1([F:19])[CH2:18][CH2:17][CH2:16][N:15]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=2)[CH2:14]1
Reactant: FC1(F)CCCNC1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Product: Cc1nc(N2CCCC(F)(F)C2)ccc1[N+](=O)[O-]

Procedure:
Prepared from 6-chloro-2-methyl-3-nitropyridine and 3,3-difluoropiperidine following the method used to prepare Intermediate 51. LCMS (ES+) 258.05 (M+H)+, RT 3.069 minutes (method 1).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][C@@H:16]1[CH2:28][CH:29]=[O:30])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[CH2:8]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH:16]1[CH2:28][C@@H:29]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:30])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: [Li]c1ccccc1
Reactant: O=CC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Solvent: C1CCOC1
Product: O[C@@H](CC1CN(Cc2ccccc2)CCN1Cc1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 4 h
Yield: 75.7 %

Procedure:
Add phenyllithium (11.3 mL, 20.4 mmol, 1.8 M in cyclohexane-ether) dropwise to a −78° C. solution of (S)-(1,4-dibenzyl-piperazin-2-yl)-acetaldehyde (4.2 g, 13.6 mmol) in THF (60 mL). Stir 30 min at −78° C. and 4 h at ambient temperature. Add ice, brine, and extract with ether. Wash the extracts with brine, dry with sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (1%–4%) as the eluent to give 3.98 g (76%) of the title compound: mass spectrum (ion spray): m/z=387 (M+1). HR-MS calculated for C26H31N2O: 387.2436. Found 387.2442.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17](=[O:18])[C:16]3[C@@H:15]4[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]4)[C:11]=3[NH:10]2)=[CH:5][CH:4]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.ClCCl>[CH2:23]([N:10]1[C:11]2[C@@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(-n2[nH]c3c(c2=O)[C@H]2CC[C@]3(C)C2(C)C)cc1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-n2c(=O)c3c(n2Cc2ccccc2)[C@]2(C)CC[C@H]3C2(C)C)cc1
Temperature: 100 °C
Yield: 14 %

Procedure:
A mixture of (4S,7R)-2-(4-methoxy-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 40; 300 mg, 1.0 mmol), tetrabutylammonium iodide (371 mg, 1.0 mmol) and benzyl bromide (478 μL, 4.0 mmol) in dimethylformamide (10 mL) was heated at ˜100° C. overnight. The solvent was evaporated. Dichloromethane (150 mL) was added and the solution was washed with brine (150 mL), saturated aqueous sodium thiosulfate (150 mL; 50% w/v), saturated aqueous sodium hydrogen carbonate (150 mL) and brine (150 mL). The solution was dried (sodium sulfate), filtered, evaporated, and purified using a Biotage 40S system, eluting with 0.5-2% methanol/dichloromethane to give a partially purified product that still contained some tetrabutylammonium iodide (according to 1H NMR). The solid was dissolved in dichloromethane, washed with saturated sodium thiosulfate and brine, and then evaporated to dryness. The solid was passed through a plug of silica, eluting with 0-5% methanol/dichloromethane, to give (4S,7R)-1-Benzyl-2-(4-methoxy-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (54.5 mg, 14%). APCI(+)-MS (M+H) 389.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][C:8]2[S:12][C:11]([NH2:13])=[N:10][N:9]=2)=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:23][C:24]1[O:28][C:27]([CH2:29][CH2:30][C:31](Cl)=[O:32])=[CH:26][CH:25]=1>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[S:12][C:11]([NH:13][C:31](=[O:32])[CH2:30][CH2:29][C:27]3[O:28][C:24]([CH3:23])=[CH:25][CH:26]=3)=[N:10][N:9]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(CCC(=O)Cl)o1
Reactant: COc1ccc(Cc2nnc(N)s2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(Cc2nnc(NC(=O)CCc3ccc(C)o3)s2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (88b, 221 mg, 1.0 mmol), Et3N (0.38 ml) in 1,4-dioxane (8.0 ml) was slowly added 3-(5-methylfuran-2-yl) propanoyl chloride and stirred for further 16.0 hours at room temperature. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4(s), and concentrated under reduced pressure to give N-[5-(4-methoxy-benzyl)-[1,3,4]thiadiazol-2-yl]-3-(5-methyl-furan-2-yl)-propionamide (88): 1H NMR (500 MHz, DMSO) δ7.24(d, 2H), δ6.89(d, 2H), δ5.90(d, 2H), δ4.24(s, 2H), δ3.72(s, 3H), δ2.83 (d, 3H), δ2.71(d, 2H), δ2.17(s, 3H). ESI-MS: 358.0 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15][CH2:16][CH2:17]Br)[CH:11]=2)[CH:6]=1.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>C(O)C>[CH2:19]([N:21]([CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15][CH2:16][CH2:17][N:21]([CH2:22][CH3:23])[CH2:19][CH3:20])[CH:11]=2)[CH:6]=1)[CH3:20]
Reactant: BrCCCc1ccc2cc(CCCBr)ccc2c1
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)CCCc1ccc2cc(CCCN(CC)CC)ccc2c1

Procedure:
To a solution of 132 mg of 2,6-bis(3-bromopropyl)naphthalene in 1 ml of absolute ethanol was added dropwise 368 μl of diethylamine at a room temperature with stirring, and the mixture was refluxed for 2.5 hours and then cooled. The reaction mixture was evaporated under a reduced pressure, and after adding 20 ml of water, extracted with 50 ml of benzene. The extract was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, filtered, and evaporated under a reduced pressure to obtain 78 mg of the title compound as a pale yellow liquid.
Reaction SMILES: COC1C=C(C)C=CC=1C[N:6]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1)C(=O)C(N)=O.[CH3:26][O:27][C:28]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:29]=1[CH2:30][NH:31][C:32](=[O:36])[C:33]([O-:35])=O>[Ni]>[CH3:26][O:27][C:28]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:29]=1[CH2:30][NH:31][C:32](=[O:36])[C:33]([NH:6][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:35]
Reactant: COc1cc(C)ccc1CN(CCc1ccc(C)cn1)C(=O)C(N)=O
Reactant: COc1cc(C)ccc1CNC(=O)C(=O)[O-]
Agent: [Ni]
Product: COc1cc(C)ccc1CNC(=O)C(=O)NCCc1ccc(C)cn1

Procedure:
This method resulted in an improved yield of 85% when compared to the previous example (40%) yield by purification of compound 4 with column chromatography and by using H2/Raney Ni instead of BH3—SMe2. Further, the one-pot preparation of N′-(2-methoxy-4-methylbenzyl)-N2-(2-(5-methylpyridin-2-yl)ethyl) oxalamide shown in the previous example, was divided into two steps in this example. The yield was improved to 44% by purification of 2-(2-methoxy-4-methylbenzylamino)-2-oxoacetate in this example, from 30% yield without any purification of 2-(2-methoxy-4-methylbenzylamino)-2-oxoacetate in the one pot preparation described in the previous example.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].Cl.[CH2:26]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH2:32])[CH3:27].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:26]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH:32][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[S:9](=[O:11])(=[O:10])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:21]([F:22])([F:23])[F:24])[CH:4]=1)[CH3:27]
Reactant: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Reactant: CCOC(=O)CCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 2-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.536 g (10 mmol) of β-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:9][C:6]2=[N:7][CH:8]=1.[H-].[Na+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>CN(C=O)C>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:1][CH2:2][C:3]2[CH:4]=[C:5]3[CH:11]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:9][C:6]3=[N:7][CH:8]=2)=[CH:23][CH:22]=1
Reactant: CN(C)C(=O)c1cc2cc(CO)cnc2o1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COCc2cnc3oc(C(=O)N(C)C)cc3c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
An ice-cold solution of 5-(hydroxymethyl)-N,N-dimethylfuro[2,3-b]pyridine-2-carboxamide (4.2 g, 0.019 mol) in DMF (15 mL) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 1.14 g, 0.0286 mol) in DMF (15 mL) at 0° C. After the resulting mixture was stirred at 0° C. for 15 min, 4-methoxybenzyl chloride (3.89 g, 286 mmol) was added. The reaction mixture was gradually warmed to 23° C., and stirred for 1 h. The excess of sodium hydride was carefully quenched with water (15 mL). The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silcia gel eluting with 35% ethyl acetate in petroleum ether to give the title compound. MS: m/z=341.2 (M+1).
Reaction SMILES: [CH:1]([N:4]1[C:9]2=[N:10][C:11]([C:14]3[C:15]([CH3:31])=[N:16][C:17]([C:20]4[N:24](C5CCCCO5)[CH:23]=[N:22][N:21]=4)=[CH:18][CH:19]=3)=[CH:12][N:13]=[C:8]2[NH:7][CH2:6][C:5]1=[O:32])([CH3:3])[CH3:2].Cl>C(O)C>[CH:1]([N:4]1[C:9]2=[N:10][C:11]([C:14]3[C:15]([CH3:31])=[N:16][C:17]([C:20]4[NH:24][CH:23]=[N:22][N:21]=4)=[CH:18][CH:19]=3)=[CH:12][N:13]=[C:8]2[NH:7][CH2:6][C:5]1=[O:32])([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2nncn2C2CCCCO2)ccc1-c1cnc2c(n1)N(C(C)C)C(=O)CN2
Agent: Cl
Solvent: CCO
Product: Cc1nc(-c2nnc[nH]2)ccc1-c1cnc2c(n1)N(C(C)C)C(=O)CN2
Temperature: 50 °C
Yield: 62 %

Procedure:
To a stirred mixture of 1-isopropyl-7-(2-methyl-6-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.400 g, 0.921 mmol) in ethanol (40 mL) at 50° C. was added hydrogen chloride (4 M in dioxane, 1.381 mL, 5.52 mmol). The resulting mixture was heated at 50° C. under nitrogen for 1 h. The suspension was concentrated under reduced pressure and the resulting solid was taken up in dimethylsulfoxide and purified using silica gel chromatography (0-10% ammonia saturated methanol in dichloromethane) to afford the title compound (0.200 g, 0.571 mmol, 62.0% yield) as a brown-red solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.10 (br. s., 1H), 8.01 (br. s., 2H), 7.92 (s, 1H), 5.26 (quin, J=6.93 Hz, 1H), 4.14 (s, 2H), 3.58 (d, J=5.08 Hz, 3H), 1.47 (d, J=6.64 Hz, 6H); MS (ESI) m/z 351.5 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@@H:9]([C:25]([OH:27])=O)[CH2:10][CH2:11][C@@H:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[F:24])[CH:13]([CH2:15][OH:16])[NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C@@H:9]1[CH2:10][CH2:11][C@@H:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[F:24])[CH:13]([CH2:15][OH:16])[NH:14][C:25]1=[O:27])[C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@@H](c1cccc(F)c1F)C(N)CO)C(=O)O
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1CC[C@@H](c2cccc(F)c2F)C(CO)NC1=O
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a solution (5S)—N2,N2-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-6-(hydroxymethyl)-D-lysine (180 mg, 0.37 mmol) in DCM (5 mL) were added EDC (106 mg, 0.55 mmol) and HOAT (50 mg, 0.37 mmol). After 30 min, NaHCO3 was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered and concentrated and the residue purified by silica gel chromatography (0%→10% MeOH/DCM) to give the title compound (100 mg). MS 471.1 (M+1).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:17])[CH2:15]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][P:21]([O:25]CC)[O:22][CH2:23][CH3:24])[CH3:19].C(Br)C>>[CH2:18]([O:20][P:21]([CH2:15][C:14]([N:9]1[C@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:17])(=[O:25])[O:22][CH2:23][CH3:24])[CH3:19]
Reactant: CCOP(OCC)OCC
Reactant: O=C(CBr)N1C(=O)OC[C@H]1Cc1ccccc1
Solvent: CCBr
Product: CCOP(=O)(CC(=O)N1C(=O)OC[C@H]1Cc1ccccc1)OCC

Procedure:
A solution of 168.0 g (0.56 mol) (R)-4-benzyl-3-(2-bromo-acetyl)-oxazolidin-2-one and 188.6 mL (1.1 mol) of triethylphosphite was stirred for 1.5 h at 60° C., while the ethylbromide formed was distilled off. The reaction mixture was concentrated by evaporation i. vac. and the residue remaining was purified by chromatography on silica gel. The desired product was obtained in the form of a yellowish-brown oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][N:32]=2)[CH2:27][CH2:26]1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:34]5[CH:33]=[N:32][C:31]([N:28]6[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]6)=[CH:36][CH:35]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(N5CCN(C)CC5)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 2-(4-methylpiperazine-1-yl)pyridine-5-boronic acid pinacol ester (Combi-Blocks, San Diego, USA, 40 mg, 0.132 mmol) to give the title compound as a white solid. (HPLC: tR 2.04 min (Method A); M+H=469 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.91 (s, 1H), 8.30-8.24 (m, 1H), 8.14-8.10 (m, 1H), 8.07-8.01 (m, 1H), 7.90-7.83 (m, 1H), 7.62-7.56 (m, 1H), 7.45-7.41 (m, 1H), 6.97-6.90 (m, 1H), 3.92 (s, 3H), 3.55 (s, 7H), 2.41-2.35 (m, 4H), 2.21 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [S:1]([Cl:5])(=O)(=[O:3])[OH:2].[CH3:6][N:7]([CH3:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[CH3:6][N:7]([CH3:14])[C:8]1[CH:9]=[C:10]([S:1]([Cl:5])(=[O:3])=[O:2])[CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(O)Cl
Reactant: CN(C)c1ccccc1
Solvent: ClCCl
Product: CN(C)c1cccc(S(=O)(=O)Cl)c1
Temperature: 0 °C
Yield: 11.3 %

Procedure:
Sulfurochloridic acid (100 g, 862.07 mmol) was cooled to 0° C. and N,N-dimethylbenzenamine (20 g, 165.29 mmol) was added dropwise with stirring, maintaining a temperature of 0° C. The resulting solution was then heated to 120° C. and stirred for 3 hours. After cooling to room temperature, dichloromethane (40 mL) was added and the resulting mixture was added dropwise to 100 mL of ice/salt water. The resulting solution was extracted with dichloromethane (3×500 mL) and the organic layers combined, dried (Na2SO4) and filtered. The filtrate was concentrated and the residue was purified by column chromatography using a 1:100 ethyl acetate/petroleum ether solvent system. The collected fractions were combined and concentrated to give 4.1 g (11%) of 3-(dimethylamino) benzene-1-sulfonyl chloride as a yellow solid. 1H NMR (CDCl3) δ 7.41 (t, 1H), 7.31 (d, 1H), 7.23 (s, 1H), 6.98 (m, 1H), 3.05 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1.[OH-].[Na+]>>[C:25]1([C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Nc1cccc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)c1cc(Nc2cccc(-c3ccccc3)c2)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-aminobiphenyl (65 mg, 0.386 mmol) similar to Example 58. The mixture was basified with aqueous 2N NaOH to pH 10-12. The resulting precipitate was collected by filtration, washed with excess water:ethanol (1:1) and isolated as a light brown solid (64 mg, 85%). 1H NMR (CDCl3): 9.67 (s, 1H), 8.75 (d, J=5.4 Hz, 2H), 7.68 (s, 1H), 7.63-7.37 (m, 10H), 6.98 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)=[O:29])[CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:33]3[CH:32]=[CH:31][C:30]([C:28]([N:25]4[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]4)=[O:29])=[CH:35][CH:34]=3)=[CH:14][C:6]1=2
Reactant: Clc1ccc(Cl)c(CN2CCNc3ncc(I)cc32)c1
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3Cl)CCN4)cc2)CC1
Yield: 49 %

Procedure:
1-(2,5-dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was reacted with (4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4A to give the title compound as a pale yellow foam (49% yield). M.p. (foam), LCMS: m/z=498.07 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.31 (s, 3H), 2.32-2.50 (m, 4H), 3.44-3.51 (m, 2H), 3.45-3.84 (m, 4H), 3.63-3.68 (m, 2H), 4.49 (s, 2H), 5.21 (s, 1H), 6.62 (d, J=1.5 Hz, 1H), 7.18-7.21 (m, 1H), 7.24-7.29 (m, 1H), 7.34 (d, J=8.6 Hz, 1H), 7.39-7.42 (m, 4H), 7.72 (d, J=1.8 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][NH:8][C@@H:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[C@@H:9]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:10]([O:12][CH3:13])=[O:11])=[CH:20][CH:21]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)[C@@H](NCc1ccc(OC)cc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)[C@H](c1ccccc1)N(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a solution of (S)-methyl 2-((4-methoxybenzyl)amino)-2-phenylacetate (1.6 g, 5.61 mmol) in anhydrous dichloroethane (20 mL) was added 4-methoxy benzaldehyde (0.76 g, 5.61 mmol) and few drops of HOAc. After 30 min, the reaction mixture was cooled to 0° C., sodium triacetoxy borohydride (2.38 g, 11.22 mmol) was added and the contents were allowed to stir at ambient temperature. After 2 h, the reaction was quenched with ice cold H2O (10 mL), and the organic contents were extracted with CH2Cl2 (2×25 mL). The combined organic extracts were washed with brine (1×20 mL), dried over Na2SO4, concentrated and the residue thus obtained was purified by flash column chromatography to afford (S)-methyl 2-(bis(4-methoxybenzyl)amino)-2-phenylacetate as pale yellow liquid (1.5 g, 66%). MS: [M+H]+ m/z 406.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:45]1([N:49]2[CH2:55][CH2:54][CH2:53][N:52]([C:56]([N:58]3[CH2:61][CH:60]([NH2:62])[CH2:59]3)=[O:57])[CH2:51][CH2:50]2)[CH2:48][CH2:47][CH2:46]1>CN(C=O)C.C(Cl)Cl>[CH:45]1([N:49]2[CH2:55][CH2:54][CH2:53][N:52]([C:56]([N:58]3[CH2:59][CH:60]([NH:62][C:6]([C:5]4[CH:4]=[N:3][C:2]([CH3:1])=[CH:10][CH:9]=4)=[O:8])[CH2:61]3)=[O:57])[CH2:51][CH2:50]2)[CH2:48][CH2:47][CH2:46]1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: NC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)cn1
Reaction time: 16 h
Yield: 33.6 %

Procedure:
To a stirred solution of 6-methylnicotinic acid (5.5 mg, 40 μmol) in 1:1 DCM:DMF (1 ml) was added HOBt (12 mg, 87 μmol) followed by HBTU (30 mg, 80 μmol) at room temperature. After 15 minutes 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-amine (10 mg, 40 μmol) was added and the reaction was stirred for 16 hours. The reaction was concentrated at reduced pressure and purified directly via preparative HPLC to give the title compound (5 mg, 34%).
Reaction SMILES: [CH2:1]([N:13]([CH2:15][CH2:16][O:17][C:18]1[CH:28]=[CH:27][C:21]2[CH2:22][CH2:23][C:24](=[O:26])[O:25][C:20]=2[CH:19]=1)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:29][OH:30]>>[CH2:1]([N:13]([CH2:15][CH2:16][O:17][C:18]1[CH:28]=[CH:27][C:21]([CH2:22][CH2:23][C:24]([O:30][CH3:29])=[O:26])=[C:20]([OH:25])[CH:19]=1)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CO
Reactant: CCCCCCCCCCCCN(C)CCOc1ccc2c(c1)OC(=O)CC2
Product: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)OC)c(O)c1
Yield: 100 %

Procedure:
A solution of 7-[2-(N-Dodecyl-N-methylamino)ethoxy]-3,4-dihydro-2H-1-benzopyran-2-one (2.0 g, 5.13 mmol) in methanol (30 ml) was stirred at 22° C. for 0.5 h. The solvent was then removed in vacuo at 40° C. to afford the title compound (2.14 g, 100%) as a white solid.
Reaction SMILES: [NH:1]1[C:9](=[O:10])[C:8]2[C:4]([N:5]=[CH:6][N:7]=2)=[N:3][C:2]1=[N:11][NH2:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:25][N:24]=[C:23]([CH2:26][CH2:27][CH:28]=O)[N:22]=2)=[CH:17][CH:16]=1>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[O:25][N:24]=[C:23]([CH2:26][CH2:27][C:28]3[N:1]4[C:9](=[O:10])[C:8]5[NH:7][CH:6]=[N:5][C:4]=5[N:3]([CH2:17][CH2:16][CH2:15][CH2:20][CH3:19])[C:2]4=[N:11][N:12]=3)[N:22]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(-c2nc(CCC=O)no2)cc1
Reactant: NN=C1N=C2N=CN=C2C(=O)N1
Solvent: CCO
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(CCc3noc(-c4ccc(OC)cc4)n3)nnc12
Yield: 95.4 %

Procedure:
A mixture of 1H-purine-2,6-dione 2-hydrazone (680 mg, 2.88 mmol) and 3-[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]propanal (900 mg, 3.88 mmol) in ethanol (20 mL) was refluxed for 4 hours. The reaction mixture was concentrated and the residue was mixed with acetic acid (10 mL). The resulting mixture was refluxed for 3 hours. The reaction mixture was concentrated and then diluted with water and extracted with EtOAc (3×). The combined organic layers was dried over Na2SO4, filtered, concentrated and purified by preparative LCMS to give the desired product (830 mg, 64% yield). LCMS calculated for C22H25N8O3 (M+H): 449.2; found: 449.2.