Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH3:19])=[C:9]1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.ClCCl.O.C[N:33](C)C=O>>[NH2:33][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH3:19])=[C:9]1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1
Reactant: COc1ccc(-c2c(C)c3cc(OC)ccc3n2CCCCCCBr)cc1
Reactant: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2c(C)c3cc(OC)ccc3n2CCCCCCN)cc1

Procedure:
8.0 mmol of 1-(6-bromohexyl)-5-methoxy-2-(4-methoxyphenyl)-3-methyl indole and 8.8 mmol of phthalamidepotassium are heated in 100 ml of anhydrous dimethylformamide for 2 hours under reflux. Following cooling the product is shaken with dichloromethane and H2O. The product is then dried over Na2SO4 and the solvent distilled off. The residue is chromatographed on silica gel with dichloromethane. To liberate the amine the so-obtained colorless crystals are taken up in 50 ml of ethanol (99%) and mixed with hydrazine hydrate in 20 ml of ethanol. The mixture is now heated for 2 hours under reflux; after cooling, it is acidified with 40 ml of 2N HCl solution and suctioned off from the precipitate. After distilling off the solvent the mixture is made alkaline with 40 ml of 2N NaOH and extracted three times with ethyl acetate. The mixture is then dried over Na2SO4 and chromatographed on silica gel with dichloromethane/ethyl acetate (10:1, volume/volume). A viscous colorless to yellowish oil is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=1.[H-].[Na+].[C:20]([O:23][C@@H:24]1[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:28]([O:34][C:35](=[O:37])[CH3:36])[C@@H:27]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[O:26][C@@:25]1([O:56][CH3:57])[CH2:43][CH2:44]OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:22])[CH3:21].[O-]C1C=CC=CC=1>CN(C=O)C.CCOC(C)=O>[C:20]([O:23][C@@H:24]1[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:28]([O:34][C:35](=[O:37])[CH3:36])[C@@H:27]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[O:26][C@:25]1([CH2:43][CH2:44][O:17][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)=[C:2]([Cl:1])[CH:3]=1)[O:56][CH3:57])(=[O:22])[CH3:21]
Reactant: CO[C@@]1(CCOS(=O)(=O)c2ccc(C)cc2)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CCc1ccc(Cc2ccc(O)cc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1ccc(Cc2ccc(OCC[C@]3(OC)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc2Cl)cc1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 16.6 %

Procedure:
3-Chloro-4-(4-ethylbenzyl)phenol (15) (55 mg, 0.22 mmol) was dissolved in DMF (0.30 mL) and NaH (9 mg, 0.22 mmol) was added to the solution. After stirring for 5 min, a solution of (2S,3R,4S,5R,6R)-6-(acetoxymethyl)-2-methoxy-2-(2-(tosyloxy)ethyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (17) (102 mg, 0.18 mmol in 200 μL DMF) was added to the phenoxide solution. After 2 h, the reaction was heated to 70° C. and stirred for 18 h. The reaction mixture was then diluted with EtOAc and washed with NaHCO3 (1×). The aqueous layer was back-extracted with EtOAc (2×). The organic layers were combined, dried (Na2SO4), concentrated onto celite and chromatographed over SiO2 (ISCO system, 0-60% EtOAc/hexanes) to provide an oil (19 mg, 17%). 1H NMR (300 MHz, CDCl3) δ ppm: 7.07 (m, 5H), 6.88 (d, J=2.4 Hz, 1H), 6.69 (dd, J=8.9, 2.6 Hz, 1H), 5.47 (t, J=9.6 Hz, 1H), 5.00-5.15 (m, 3H), 3.85-4.17 9 m, 6H), 3.32 (s, 3H), 2.61 (q, J=15, 7.5 Hz, 2H), 2.06 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H), 1.98 (s, 3H), 1.21 (t, J=7.5 Hz, 3H). LC/MS: tR=3.07 min, calcd for C32H39ClO11: 634.22, found 657.4 (M+Na)+.
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([CH3:24])[CH:18]=1)(C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].[OH-].[K+].C(O)C>O>[C:1]([NH:4][CH:5]([C:6]([OH:8])=[O:7])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([CH3:24])[CH:18]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(C)c(C)c1)(NC(C)=O)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)NC(Cc1ccc(C)c(C)c1)C(=O)O
Temperature: 25 °C
Yield: 56 %

Procedure:
Diethyl 2-acetylamino-2-(3,4-dimethylbenzyl)malonate (13.8 g) and potassium hydroxide (2.76 g) were dissolved into a mixed solution of ethanol (138 ml) and water (138 ml) and the solution was stirred under reflux for 8.5 hours. After being cooled to room temperature, the solution was concentrated under reduced pressure and the resulting aqueous solution was adjusted to pH 10 with aqeuous saturated sodium hydrogen carbonate solution. The solution was washed with ethyl acetate and made acidic with diluted hydrochloric acid, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated under reduced pressure to give crystals of N-acetyl-3,4-dimethyl-DL-phenylalanine (5.42 g).
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:27])[C:5]([N:7]([CH3:26])[CH:8]1[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][N:10]2[C:16](=[O:25])[C:17]([OH:24])=[C:18]([C:20]([O:22]C)=O)[N:19]=[C:9]12)=[O:6])[CH3:3].C(N(CC)CC)C.[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>CO>[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH:41][C:20]([C:18]2[N:19]=[C:9]3[CH:8]([N:7]([CH3:26])[C:5](=[O:6])[C:4]([N:2]([CH3:3])[CH3:1])=[O:27])[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][N:10]3[C:16](=[O:25])[C:17]=2[OH:24])=[O:22])=[CH:38][CH:37]=1
Reactant: COC(=O)c1nc2n(c(=O)c1O)CCN(C)CC2N(C)C(=O)C(=O)N(C)C
Reactant: NCc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CN1CCn2c(nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)C(N(C)C(=O)C(=O)N(C)C)C1
Temperature: 25 °C

Procedure:
Methyl 10-[[(dimethylamino)(oxo)acetyl](methyl)amino]-3-hydroxy-8-methyl-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-d][1,4]diazepine-2-carboxylate prepared as described in Step 2 was dissolved in methanol and treated with 1.2 eq. of triethylamine and 1.2 eq. of 4-fluorobenzylamine. The reaction mixture was refluxed overnight, then cooled to room temperature and purified by RP HPLC (C18, 5 μM, H2O/MeCN with 1% of TFA as eluant) affording desired compound (trifluoroacetic salt) as a white solid. 1H NMR (300 MHz, CD3CN) δ 12.4 (bs, 1H), 10.01 (bs, 1H), 7.63 (dd, J=8.6 Hz, J=5.7 Hz, 2H), 7.29 (t, J=8.6 Hz, 2H), 5.53-5.30 (m, 2H), 4.82-4.68 (m, 2H), 4.25-4.13 (m, 3H), 3.95 (bs, 1H), 3.48-3.42 (m, 1H), 3.25 (s, 3H), 3.20 (s, 3H), 3.19 (s, 3H), 3.13 (s, 3H); MS (ES) C22H27FN6O5 requires 474. Found: 475 (M+H+).
Reaction SMILES: [C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17]Cl)[C:10]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:20].[Na+]>CC(C)=O>[C:1]1([CH:7]=[N:8][N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][I:20])[C:10]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [I-]
Reactant: O=C1N(CCCCCl)CCN1N=Cc1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1N(CCCCI)CCN1N=Cc1ccccc1
Reaction time: 1 h
Yield: 65 %

Procedure:
A stirred mixture of 1-phenylmethyleneamino-3-(4-chlorobutyl)-2-imidazolidinone (36.4 g, 0.1301 mole), acetone (700 ml) and sodium iodide (42.9 g, 0.2862 mole) is heated to reflux which is maintained for 24 hours. The mixture is filtered hot, removing the solid. After cooling, the filtrate is poured into H2O (2000 ml) and stirred 1 hour. The solid is collected, washed with H2 O, and air-dried to give 31.4 g, (0.0845 mole) of 1-phenylmethyleneamino-3-(4-iodobutyl)-2-imidazolidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[S:10][C:11]=2[C:12](N(OC)C)=[O:13])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[S:10][C:11]=2[CH:12]=[O:13])=[CH:24][CH:25]=1
Reactant: CON(C)C(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
To a solution of 4-(4-chlorobenzyl)-N-methoxy-N-methyl-2-(pyridin-4-yl)thiazole-5-carboxamide (1.13 g, 3.02 mmol) in THF (36.8 mL) at −50° C. was added 1.0 M diisobutylaluminum hydride in hexane (15.1 mL, 15.1 mmol) and the resulting solution was stirred at −50° C. to −30° C. for 2 hours. The reaction was quenched with saturated ammonium chloride (10 mL) and allowed to warm to room temperature. Water (25 mL) was added and the mixture was extracted with ethyl acetate (2×40 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=0/100→70/30) to give 699 mg of the title compound as a white solid (73% yield). LC/MS (FA) ES+ 315. 1H NMR (300 MHz, CDCl3) δ: 10.16 (s, 1H), 8.78-8.76 (m, 2H), 7.85-7.83 (m, 2H), 7.30-7.25 (m, 4H), 4.47 (s, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[F:12].[CH3:13][OH:14]>C1(C)C=CC=CC=1.[Ag-]=O>[F:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][O:14][CH3:13]
Reactant: CO
Reactant: O=[N+]([O-])c1ccc(F)c(CBr)c1
Agent: O=[Ag-]
Solvent: Cc1ccccc1
Product: COCc1cc([N+](=O)[O-])ccc1F
Temperature: 60 °C

Procedure:
30 g (128 mmol) of the compound from example 26A are dissolved in 1.3 l of anhydrous toluene and admixed with 45 g (192 mmol) of silver(I) oxide and 24.6 g (769 mmol) of anhydrous methanol. The mixture is heated to 60° C. for 16 h. It is then allowed to cool and filtered through silica gel. The product is fractionally eluted with a gradient of cyclohexane and 25:1 cyclohexane/ethyl acetate. The product fractions are concentrated to dryness under reduced pressure and dried under reduced pressure. This affords 17 g (72% of theory) of the desired product.
Reaction SMILES: [CH3:1][N:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[C:12]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:13]3[N:19]=[CH:18][N:17]=[C:16]([N:20]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:22][CH2:23][NH2:24])[C:14]=3[N:15]=2)[CH2:6][CH2:5]1)[CH3:3].[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]([CH:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:11]=[C:12]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[C:13]3[N:19]=[CH:18][N:17]=[C:16]([N:20]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:22][CH2:23][NH:24][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:14]=3[N:15]=2)[CH2:8][CH2:9]1)[CH3:3]
Reactant: CN(C)C1CCN(c2nc(N3CCOCC3)c3ncnc(N(CCCN)Cc4ccccc4)c3n2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C1CCN(c2nc(N3CCOCC3)c3ncnc(N(CCCNC(=O)c4ccccc4)Cc4ccccc4)c3n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.75 g of 2-[4-(N,N-dimethylamino)-piperidino]-8-[N-benzyl-N-(3-aminopropyl)-amino]-4-morpholino-pyrimido[5,4-d]pyrimidine are dissolved in 8 ml of methylene chloride and mixed with 0.24 g of benzoyl chloride and 0.3 g of triethylamine in 2 ml of methylene chloride. The reaction mixture is stirred for 12 hours at ambient temperature and then extracted three times with water. The organic phase is dried over sodium sulphate and concentrated by rotary evaporation. The residue is chromatographed over a silica gel column using methylene chloride/methanol=7:3. Yield: 0.7 g (77% of theory) Oil C34H43N9O2 (609.78)
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([NH:19][C@H:20]([CH2:24][CH3:25])[C:21]([NH2:23])=[O:22])[CH:16]=[N:15][C:14]=2[C:26]#[N:27])=[CH:8][CH:7]=1.[OH-].[Na+].OO.CC(O)=[O:34]>CCO.CS(C)=O>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:14]([C:26]([NH2:27])=[O:34])=[N:15][CH:16]=[C:17]([NH:19][C@H:20]([CH2:24][CH3:25])[C:21]([NH2:23])=[O:22])[N:18]=2)=[CH:8][CH:7]=1
Reactant: CC(=O)O
Reactant: CC[C@@H](Nc1cnc(C#N)c(Nc2ccc(-c3nnco3)cc2)n1)C(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: CC[C@@H](Nc1cnc(C(N)=O)c(Nc2ccc(-c3nnco3)cc2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (R)-2-(6-(4-(1,3,4-oxadiazol-2-yl)phenylamino)-5-cyanopyrazin-2-ylamino)butanamide (57 mg, 0.156 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (3 mg). MS 383.3 (M+H); UV 204.7, 275.5, 329.8 nm; t 0.449 min.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:36]=[CH:35][C:25]([C:26]([NH:28][CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:27])=[CH:24][CH:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:15]1([N:7]2[CH2:8][C:9]([F:14])([F:13])[C:10](=[O:12])[NH:11][C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[O:27])=[CH:35][CH:36]=4)=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Nc1ccc(C(=O)NC2CCOCC2)cc1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: O=C(NC1CCOCC1)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3)cc1
Yield: 84.6 %

Procedure:
A mixture of 0.05 g (0.17 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20), 0.04 g (0.20 mmole) of 4-amino-N-(tetrahydro-pyran-4-yl)-benzamide and 0.05 g (0.25 mmole) of p-toluenesulfonic acid monohydrate in 4.0 mL of 2-propanol was heated at 160 degrees for 2 hours in a microwave reactor. The cooled mixture was then concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane, and the combined organic layers washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was washed with water and dried to give 0.070 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(tetrahydro-pyran-4-yl)-benzamide (I-136).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(NCc3ccccc3)ccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.1 %

Procedure:
To a stirred solution of 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (350 mg, 1.41 mmol) in dichloromethane (15 ml) was added benzaldehyde (143 μl, 1.41 mmol), acetic acid (81 μl, 1.41 mmol) followed by sodium triacetoxyborohydride (418 mg, 1.97 mmol) and the reaction was stirred at room temperature for 16 hrs. The reaction mixture was quenched by cooling in ice batch and neutralising with aqueous sodium hydroxide 2M. The aqueous mixture was extracted using dichloromethane (3×50 ml) and the organics were combined, dried over sodium sulfate and then concentrated in vacuo. The crude residue was purified by column chromatography (1% methanol in dichloromethane) to afford the title compound as cream solid (320 mg, 67% yield). HPLC retention time 4.98 min. Mass spectrum (ES+) m/z 339 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[O:13].C(CN)O>O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:17]2[NH:11][C:12](=[O:13])[NH:14][C:15]2=[O:16])=[CH:5][CH:4]=1
Reactant: O=C1CNC(=O)N1
Reactant: COc1ccc(C=O)cc1
Solvent: NCCO
Solvent: O
Product: COc1ccc(C=C2NC(=O)NC2=O)cc1
Yield: 85.5 %

Procedure:
A mixture of p-methoxybenzaldehyde (2.00 g., 14.7 mmoles) and hydantoin (1.47 g., 1 molar ratio) in water (12 ml) was heated to 70°; monoethanolamine (1.35 g., 1.5 molar ratio) was then added. The mixture was stirred magnetically and heated in an oil bath at 90°-92° for 4 hours. Usual workup furnished the title compound as a pale yellow solid (2.74 g.), m.p. 250°-252°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])[C:12]2[C:13]([CH3:21])=[CH:14][C:15]([C:18](O)=[O:19])=[N:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:31][NH:32][CH3:33].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])[C:12]2[C:13]([CH3:21])=[CH:14][C:15]([C:18]([N:32]([CH3:33])[CH3:31])=[O:19])=[N:16][CH:17]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CNC
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cc(C(=O)N(C)C)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
To a solution of 5-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]-4-methylpyridine-2-carboxylic acid (88 mg, 0.20 mmol) obtained in Example 3 in methylene chloride (2 ml), dimethylamine hydrochloride (18 mg, 0.22 mmol), 1-hydroxybenzotriazole (30 mg, 0.22 mmol), 4-methylmorpholine (0.048 ml, 0.44 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (42 mg, 0.22 mmol) were added at room temperature. After stirring for 6 hours at room temperature, the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of diethyl ether and hexane, and collected by filtration to obtain the title compound (83 mg, 0.18 mmol, 89%) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[NH:7][C:6](=[O:11])[C:5]=1[CH2:12][NH:13][C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH3:26])[C:17]=1[CH3:33])=[O:15].[CH2:34]1[CH2:38]OC[CH2:35]1.CC(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:34]([N:30]1[CH2:29][CH2:28][CH:27]([CH:25]([N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]([C:14]([NH:13][CH2:12][C:5]3[C:6](=[O:11])[NH:7][C:8]([CH3:10])=[CH:9][C:4]=3[O:3][CH3:2])=[O:15])=[C:17]2[CH3:33])[CH3:26])[CH2:32][CH2:31]1)([CH3:38])[CH3:35]
Reactant: C1CCOC1
Reactant: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCNCC2)c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCN(C(C)C)CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 31 %

Procedure:
A 25 mL vial was charged with a magnetic stir bar, (R or S)—N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(piperidin-4-yl)ethyl)-1H-indole-3-carboxamide hydrochloride (Compound 326), THF (2.114 ml, 0.211 mmol), propan-2-one (0.061 g, 1.057 mmol), and sodium triacetoxyborohydride (0.224 g, 1.057 mmol). The reaction was allowed to stir at rt for 12 h. The reaction was inverse quenched onto sat'd aqueous NaHCO3, extracted with ethyl acetate and conc., in vacuo. The resulting material was treated with 10 mL, 7 N ammonia in MeOH and was conc in vacuo to yield material which was purified via silica gel chromatography (10 g) using DCM/MeOH/NH4OH (90:1:0.1) as eluent to afford 33 mg, (0.065 mmol, 31.0% yield) of the title compound as a white solid.). LCMS 479 (M+1)+; 1H NMR (DMSO-d6, 400 MHz) δ 11.59 (s., 1H), 7.64-7.82 (m, 2H), 7.59 (d, 1H), 6.95-7.17 (m, 2H), 6.15 (s, 1H), 4.32 (d, 2H), 4.04-4.24 (m, 1H), 3.84 (σ, 3H), 2.77-2.93 (μ, 2H), 2.68 (δ, 1H), 2.60 (σ, 3H), 2.20 (σ, 3H), 2.08-2.15 (μ, 1H), 1.92 (δ, 1H), 1.83 (βρ. σ., 1H), 1.54 (δ, 3H), 1.27-1.43 (μ, 2H), 0.91 (τ, 6H), 0.71-0.67 (μ, 2H).
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH3:22].O>CN(C)C=O>[CH3:22][C:10]1[N:9]([CH2:8][CH2:7][CH2:6][CH2:5][S:2][CH3:1])[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=1
Reactant: Cc1nc2cnc3ccccc3c2n1CCCCCl
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCCCCn1c(C)nc2cnc3ccccc3c21
Yield: 95.9 %

Procedure:
Sodium thiomethoxide (2.02 g of 95%, 27.40 mmol) was added in a single portion to a solution of 1-(4-chlorobutyl)-2-methyl-1H-imidazo[4,5-c]quinoline (5.0 g, 18.26 mmol) in anhydrous N,N-dimethylformamide (91 mL). After 30 minutes the reaction mixture was poured with rapid stirring into water (500 mL). The resulting solution was extracted with chloroform (2×200 mL). The organic layers were combined, washed with saturated aqueous sodium bicarbonate (100 mL) then with brine (100 mL), dried over sodium sulfate, filtered and then concentrated under reduced pressure to provide 5.0 g 2-methyl-1-[4-(methylthio)butyl]-1H-imidazo[4,5-c]quinoline as a light yellow oil.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:19])[NH:6][C:7]1[N:8]([CH2:16][CH2:17][OH:18])[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[C:30]1[N:34]2[CH:35]=[C:36]([O:39][C@H:40]3[C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[C@@H:43]([NH2:50])[CH2:42][CH2:41]3)[CH:37]=[CH:38][C:33]2=[N:32][N:31]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:50][C@@H:43]2[C:44]3[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=3)[C@H:40]([O:39][C:36]3[CH:37]=[CH:38][C:33]4[N:34]([C:30]([C:24]5[C:23]([Cl:22])=[CH:28][CH:27]=[CH:26][C:25]=5[Cl:29])=[N:31][N:32]=4)[CH:35]=3)[CH2:41][CH2:42]2)=[O:19])[N:8]([CH2:16][CH2:17][OH:18])[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: N[C@H]1CC[C@@H](Oc2ccc3nnc(-c4c(Cl)cccc4Cl)n3c2)c2ccccc21
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCO)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(-c5c(Cl)cccc5Cl)n4c3)c3ccccc32)n(CCO)n1
Temperature: 60 °C
Reaction time: 42 h
Yield: 14.3 %

Procedure:
A mixture of Intermediate 26a (100 mg, 0.279 mmol), Intermediate 26d (108 mg, 0.254 mmol), and DIPEA (73 μL, 0.419 mmol) in dioxane (2.5 mL) was stirred at 60° C. for 42 h and then left standing at RT for 72 h. The volatiles were concentrated in vacuo and the resultant residue was purified by FCC, using 0-10% MeOH in DCM followed by MDAP (Method 7) to afford the title compound (23 mg, 14%) as a white solid. LCMS (Method 5): Rt 4.19 min, m/z 634 [MH+]. 1H NMR (400 MHz, DMSO): 1.21 (9H, s), 1.79-2.16 (4H, m), 3.62-3.70 (2H, m), 3.94 (2H, t, J=6.0 Hz), 4.78-4.88 (1H, m), 4.99 (1H, br s), 5.55 (1H, t, J=4.2 Hz), 6.05 (1H, s), 7.07 (1H, d, J=8.6 Hz), 7.23-7.30 (1H, m), 7.31-7.38 (4H, m), 7.70-7.74 (1H, m), 7.74-7.80 (2H, m), 7.91 (1H, d, J=9.9 Hz), 7.98 (1H, d, J=2.1 Hz), 8.19 (1H, s).