Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[N:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=4)=[CH:20][N:19]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:31](O)(=[O:38])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[N:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][C:27]([O:30][C:31](=[O:38])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:26][CH:25]=4)=[CH:20][N:19]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC1Cc2ccc(-c3ncc(-c4ccc(O)cc4)cn3)cc2C1
Reactant: CCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCC1Cc2ccc(-c3ncc(-c4ccc(OC(=O)CCCCCC)cc4)cn3)cc2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.9 %

Procedure:
0.15 g (0.37 mM) of 2-octyl-5-[5-(4-hydroxyphenyl)pyrimidine-2-yl]indan, 0.05 g (0.38 mM) of heptanoic acid, 0.08 g (0.39 mM) of DCC, 0.01 g of 4-dimethylaminopyridine and 3 ml of methylene chloride were mixed and stirred for 5 hours at room temperature. The resultant N,N'-dichlorhexylurea was recovered by filtration, washed with dichloromethane, and added to the filtrate. The resultant dichloromethane solution was subjected to distillation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=100/1) and recrystallized from a mixture solvent (toluene/methanol) to obtain 0.14 g of 2-octyl-5-[5-(4-heptanoyloxyphenyl)pyrimidine-2-yl]indan (Yield: 72.9%). ##STR143##
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH:10]([CH3:15])[C:9](=[O:16])[C:8]=2[CH:17]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH:10]([CH3:15])[C:9](=[O:16])[C:8]=2[CH:17]=1
Reactant: CC1C(=O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Agent: [Pd]
Solvent: CO
Product: CC1C(=O)c2cc(N)ccc2OC1(C)C
Reaction time: 5 h
Yield: 102.3 %

Procedure:
A mixture of of 6-nitro-2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one (23.5 g, 0.1 mol) and 10% palladium on carbon (2 g) in methanol was stirred under an atmosphere of hydrogen at 40°-50° C. for five hours at atmospheric pressure. The solution was then filtered, and the solvent removed from the filtrate under reduced pressure to give 21 g of 6-amino-2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one as an oil. B. To a mixture of water (293 ml) and concentrated hydrochloric acid (25.7 ml) at 0° C. was added a solution of 6-amino-2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one (20.5 g, 0.1 mol) in ethanol (140 ml). A solution of sodium nitrite (7.6 g, 0.11 mol) in water (90 ml) was then added, such that the temperature did not rise above 0° C. After fifteen minutes at 0° C., the reaction mixture was poured into a solution containing potassium cyanide (58.6 g, 0.90 mol) and cuprous cyanide (80.61 g, 0.90 mol) in water at 90° C., whilst maintaining the temperature of the reaction above 70° C. The resulting mixture was heated at 90° C. for one hour and then cooled to 20° C., extracted with ethyl acetate and the extract washed with water. The organic layer was separated and the solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluting with dichloromethane/acetone (99/1) to give 16.58 g of 6-cyano-2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one, 1H NMR (CDCl3): δ 1.2 (d, 3H), 1.30 (s, 3H), 1.5 (s, 3H), 2.8 (q, 1H), 7.0 (d, 1H), 7.70 (d, 1H), 8.1 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23]3[CH:28]=[C:27](/[CH:29]=[CH:30]\[C:31]([O:33]C(C)(C)C)=[O:32])[CH:26]=[CH:25][N:24]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23]3[CH:28]=[C:27](/[CH:29]=[CH:30]\[C:31]([OH:33])=[O:32])[CH:26]=[CH:25][N:24]=3)[CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)/C=C\c1ccnc(N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3Nc3cc(/C=C\C(=O)O)ccn3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a round bottom flask was aded (Z)-tert-butyl 3-(2-(((1R,2R)-2-(((S)-1-(4-cyanophenyl)piperidin-3-yl)amino)cyclohexyl)amino)pyridin-4-yl)acrylate (30 mg, 0.060 mmol), TFA (1 mL) and CH2Cl2 (1 mL). The reaction was stirred at rt overnight. The reaction was concentrated and dried to give (Z)-3-(2-(((1R,2R)-2-(((S)-1-(4-cyanophenyl)piperidin-3-yl)amino)cyclohexyl)amino)pyridin-4-yl)acrylic acid (29 mg, 0.049 mmol, 82% yield) as a beige solid. Anal. Calcd. for C26H31N5O2 m/z 445.5, found: 446.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[O:17]C2CCCCO2)[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH2:4][CH2:3]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[CH3:1][C:2]1([CH3:24])[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[OH:17])[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(OC2CCCCO2)c(C2=CCCC2(C)C)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC(=O)c1ccc(O)c(C2=CCCC2(C)C)c1
Temperature: 50 °C
Reaction time: 19 h
Yield: 90 %

Procedure:
To a stirred solution of 66.6G (19.0 g, 57.6 mmol) in MeOH (150 mL) was added PPTS (1.46 g, 5.80 mmol). The mixture was heated to 50° C. and monitored with TLC. After 19 hours, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-15% EtOAc in hexanes) to yield 66.6H as a white solid (yield 90%). 1H NMR (400 MHz) (CDCl3) δ ppm 7.89 (1H, dd, J=8.6, 2.0 Hz), 7.79 (1H, d, J=2.3 Hz), 6.97 (1H, d, J=8.6 Hz), 5.87 (1H, s), 5.81 (1H, t, J=2.3 Hz), 3.89 (3H, s), 2.51 (2H, td, J=7.1, 2.5 Hz), 1.94 (2H, t, J=7.0 Hz), 1.12 (6H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1)([O-])=O.[H][H]>CCOC(C)=O.CO.[Ni]>[N:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:11]=1[NH:10][C:5]1[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccccc1Nc1ncccn1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccccc1Nc1ncccn1
Yield: 72.2 %

Procedure:
To a solution of (2-nitrophenyl)-pyrimidin-2-yl-amine (13.2 g, 61.1 mmol) in a mixture of EtOAc (450 mL) and CH3OH (350 mL) was added Raney Nickle (16 g (water wet)) and the reaction mixture hydrogenated under 1 atm hydrogen at ambient temperature for 3 h. The catalyst was separated by filtration and the filtrate concentrated in vacuo to a red-brown solid which upon trituration with cold CH3OH (250 mL) gave the title compound (8.21 g, 44.1 mmol) as a grey solid: 1H NMR (CDCl3, 400 MHz): 8.38 (d, 2H, J=4.9 Hz), 7.37 (d, 1H, J=7.9 Hz), 7.08 (t, 1H), 7.00 (br s, 1H), 6.83 (m, 2H), 6.67 (t, 1H), 3.60 (br s, 2H); TLC (EtOAc/Hexanes(2:1)): Rf =0.33.
Reaction SMILES: C[N:2]([CH3:19])[C:3]([C:5]1[N:14]([CH:15]2[CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:20]([O:24][C:25]([N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH2:29][N:30]([C:35]([C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[CH:41][CH:42]=1)=[O:36])[CH2:31]2)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH:28]2[CH2:34][CH2:33][CH:32]1[CH2:31][N:30]([C:35]([C:37]1[CH:38]=[N:39][C:40]([NH:43][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[NH:2][CH3:19])[N:14]([CH:15]5[CH2:16][CH2:17][CH2:18]5)[C:8]=4[N:9]=3)=[CH:41][CH:42]=1)=[O:36])[CH2:29]2)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCC1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nc1)C2
Product: CNC(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCC1
Yield: 54.2 %

Procedure:
Following general N—C coupling procedure 1, 2-Chloro-7-cyclobutyl-7H-pyrrolo[2, 3-d]pyrimidine-6-carboxylic acid dimethylamide (200 mg, 0.718 mmol, 1.0 eq) was combined with 3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (262 mg, 0.789 mmol, 1.1 eq) to give 3-[6-(7-Cyclobutyl-6-methylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (218 mg, 50% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 9H) 1.62 (br. s., 1H) 1.67 (br. s., 1H) 1.77-2.07 (m, 6H) 2.41-2.58 (m, 2H) 3.17 (s, 6H) 3.19-3.29 (m, 2H) 3.64 (br. s., 1H) 4.28 (br. s., 2H) 4.54 (br. s., 1H) 5.01 (dq, J=8.84, 8.67 Hz, 1H) 6.50 (s, 1H) 7.83 (dd, J=8.84, 2.27 Hz, 1H) 8.42 (d, J=2.02 Hz, 2H) 8.67 (d, J=9.09 Hz, 1H) 8.78 (s, 1H); MS m/z 574.9 (M+H)+.
Reaction SMILES: [Na][Na].[N:3]([C:15]1[CH:16]=[C:17]([OH:24])[C:18](=[CH:22][CH:23]=1)[C:19]([O-:21])=[O:20])=[N:4][C:5]1[CH:13]=[C:9]([C:10]([O-:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1.C(O)(=O)C>O>[N:3]([C:15]1[CH:16]=[C:17]([OH:24])[C:18](=[CH:22][CH:23]=1)[C:19]([OH:21])=[O:20])=[N:4][C:5]1[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1
Reactant: O=C([O-])c1ccc(N=Nc2ccc(O)c(C(=O)[O-])c2)cc1O
Agent: [Na][Na]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(N=Nc2ccc(O)c(C(=O)O)c2)cc1O

Procedure:
1 g of disodium-4,5'-azo-bis-salicylate was dissolved in 20 ml of boiling water, whereupon the solution was acidified with acetic acid down to pH 4. After cooling, the product was filtered off, washed with water and dried. Yield: 0.8 g.
Reaction SMILES: C([O:8][CH:9]1[CH2:12][CH:11]([C:13]2[C:18]([O:19][CH2:20][C:21]3[N:22]([CH3:26])[N:23]=[CH:24][N:25]=3)=[N:17][N:16]3[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[F:36])=[N:28][N:29]=[C:15]3[CH:14]=2)[CH2:10]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)=O>[F:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:27]1[N:16]2[N:17]=[C:18]([O:19][CH2:20][C:21]3[N:22]([CH3:26])[N:23]=[CH:24][N:25]=3)[C:13]([CH:11]3[CH2:12][CH:9]([OH:8])[CH2:10]3)=[CH:14][C:15]2=[N:29][N:28]=1
Reactant: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1C1CC(OCc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O=CO
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1C1CC(O)C1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of 7-(3-benzyloxycyclobutyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine (0.04 g, 0.082 mmol), excess ammonium formate (1.0 g), formic acid (1 ml) and 10% palladium on carbon (0.10 g) was stirred at 60° C. under nitrogen for 18 h, then cooled and concentrated. The residue was diluted with dichloromethane (20 ml) and washed with brine (20 ml). The organic layer was dried (Na2SO4), filtered and concentrated. Preparative thin layer chromatogaphy on silica gel, eluting with 10% methanol-dichloromethane, gave recovered 7-(3-benzyloxycyclobutyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine (0.016 g, 40%) and 3-(2-fluorophenyl)-7-(3-hydroxycyclobutyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine (0.009 g, 28%) as a white solid, a 3:1 mixture of trans:cis isomers; 1H NMR (360 MHz, CDCl3) δ 2.08-2.18, 2.36-2.56 and 2.70-2.84 (4H, m), 3.00-3.08 and 3.70-3.78 (1H, m), 3.82 (3H, s), 4.36-4.40 and 4.44-4.58 (1H, m), 5.47 (2H, s), 7.24-7.32 (1H, m), 7.43-7.40 (1H, m), 7.54-7.60 (1H, m), 7.82-7.96 (3H, m); MS (ES+) m/e 396 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:15]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]([CH3:25])[CH2:16]2)C(=O)C(F)(F)F)=[CH:4][CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.[Na].[O:36]1CC[CH2:38][CH2:37]1.C(OC(=O)C)(=O)C.[Cl-].[NH4+]>O1CCCC1>[C:37]([N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][N:20]=2)[C@H:15]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:16][C@@H:17]1[CH3:25])(=[O:36])[CH3:38]
Reactant: C1CCOC1
Reactant: CC1CC(N(C(=O)C(F)(F)F)c2ccc(Cl)cc2)c2cccnc2N1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1c2ncccc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
[Step 8] 70 mg of the N-(4-chlorophenyl)-2,2,2-trifluoro-N-[2-methyl-1,2,3,4-tetrahydro-1,8-naphthyridin-4-yl]acetoamide were dissolved in 0.3 mL of tetrahydrofuran followed by the addition of a 1.9 M sodium hexamethyldisilazane/tetrahydrofuran solution at −15° C. After stirring for 30 minutes at −15° C., 45 μL of acetic anhydride were added, and the solution was gradually returned to room temperature followed by stirring for 2 hours. Following completion of the reaction, the solution was neutralized with a saturated aqueous solution of ammonium chloride followed by extracting three times with ethyl acetate. After washing with saturated brine and dehydrating with anhydrous sodium sulfate, the solution was concentrated under reduced pressure and the resulting residue was purified using silica gel chromatography (ethyl acetate:hexane=2:1) to obtain 1.5 mg of the target compound in the form of a pale yellow oil (2.5%).
Reaction SMILES: [ClH:1].[C:2]1([N:8]2[CH2:13][CH2:12][N:11](CCCCN3C(=O)C4C=CC=C5C=4C(=CC=C5)C3=O)[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][N:39]1[C:48](=[O:49])[C:47]2[CH:50]=[CH:51][CH:52]=[C:45]3[C:46]=2[C:41](=[CH:42][CH:43]=[CH:44]3)[C:40]1=[O:53].BrCCCCN1C(=O)C2C=CC=C3C=2C(=CC=C3)C1=O>>[ClH:1].[C:2]1([N:8]2[CH2:13][CH2:12][N:11]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][N:39]3[C:48](=[O:49])[C:47]4[CH:50]=[CH:51][CH:52]=[C:45]5[C:46]=4[C:41](=[CH:42][CH:43]=[CH:44]5)[C:40]3=[O:53])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCN(c2ccccc2)CC1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCBr
Agent: Cl
Agent: O=C1c2cccc3cccc(c23)C(=O)N1CCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCN1CCN(c2ccccc2)CC1

Procedure:
Following the procedure of part (b) of example 34 but substituting 2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione for the 2-(4-bromobutyl)-1H-benz[de]isoquinoline-1,3(2H)-dione, one obtains 2-[5-(4-phenyl-1-piperazinyl)pentyl]-1H-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[H-].[Na+].Cl[C:16]1[N:24]=[C:23]2[C:19]([N:20]=[C:21]([CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([C:33]([OH:36])([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[N:22]2[CH3:25])=[C:18]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[N:17]=1>CN(C=O)C.O>[CH3:1][O:2][CH2:3][C:4]1[N:5]([C:16]2[N:24]=[C:23]3[C:19]([N:20]=[C:21]([CH2:26][N:27]4[CH2:32][CH2:31][CH:30]([C:33]([OH:36])([CH3:35])[CH3:34])[CH2:29][CH2:28]4)[N:22]3[CH3:25])=[C:18]([N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)[N:17]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COCc1cc2ccccc2[nH]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1cc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Temperature: 180 °C
Yield: 18.9 %

Procedure:
To a solution of 2-(methoxymethyl)-1H-indole (57 mg, 0.35 mmol) in DMF (2 mL) was added sodium hydride (60% dispersion, 15 mg, 0.38 mmol) at 0° C. The mixture was stirred at 0° C. for 10 minutes before the addition of 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (120 mg, 0.29 mmol). The mixture was then heated in the microwave at 180° C. for 15 minutes. The reaction mixture was then diluted with water. The mixture was extracted with three times with EtOAc. The combined extracts were washed with water, dried over Na2SO4, filtered and concentrated. The crude product was then purified by flash chromatography (0-100% gradient EtOAc-heptane) followed by RP-HPLC to give 127 (29.2 mg, 19%). LCMS: M+H+=534.3. 1H-NMR (400 MHz, DMSO-d6): δ 8.18 (d, 1H), 7.57 (d, 1H), 7.20 (t, 1H), 7.12 (t, 1H), 6.66 (s, 1H), 4.98 (s, 2H), 4.25 (s, br, 4H), 4.02 (s, 1H), 3.81 (s, 3H), 3.77 (m, 4H), 3.72 (s, 2H), 2.90 (d, 2H), 1.99 (m, 2H), 1.67 (m, 2H), 1.21 (m, 3H), 1.02 (s, 6H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[CH:11]=[C:12]([OH:16])C=C[CH:15]=1.FC1C=C(O)C=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:12](=[O:16])[CH2:11][CH:10]([CH3:15])[O:8]2)=[CH:6][CH:7]=1
Reactant: Oc1cccc(Br)c1
Reactant: Oc1cccc(Cl)c1
Agent: Oc1cccc(F)c1
Product: CC1CC(=O)c2ccc(Br)cc2O1
Yield: 30 %

Procedure:
By the method of Preparations L1 and L2, and 3-bromophenol, 3-chlorophenol and 3-fluorophenol were converted, respectively, to 7-bromo-2-methylchroman-4-one (30% yield; oil); 7-chloro-2-methylchroman-4-one (35% yield; oil;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13]C(=O)C(F)(F)F)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>C1COCC1>[NH2:13][C@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)C(F)(F)F)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (S)-1-(tert-butoxycarbonyl)-3-(trifluoro-acetamido)pyrrolidine, as described above in Step A, (2.80 g, 9.5 mmol) in THF (80 mL) and H2O (10 mL) was added 1.0 N aqueous lithium hydroxide (10.5 mL, 10.5 mmol) and the resulting mixture was stirred at ambient temperature for 18 hours, then adjusted to pH 7 with 1.0 N aqueous HCl and concentrated to dryness in vacuo to give the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:23](O)[CH2:24][OH:25].C([O-])(O)=O.[Na+]>C1C=CC=CC=1.CCO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:25][CH2:24][CH2:23][O:7]2)=[C:4]([F:10])[CH:3]=1
Reactant: OCCO
Reactant: O=Cc1ccc(Br)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: CCO
Product: Fc1cc(Br)ccc1C1OCCO1
Temperature: 0 °C
Yield: 99 %

Procedure:
A mixture of 4-bromo-2-fluorobenzaldehyde (5.00 g, 24.6 mmol), p-toluenesulfonic acid monohydrate (190 mg, 1.00 mmol) and ethylene glycol (10 mL) were refluxed in benzene (50 mL) and EtOH (10 mL) under a Dean-Stark trap for 3 h. The reaction mixture was cooled and poured into a mixture of 5% aqueous NaHCO3 (100 mL) and ice (100 mL). The mixture was extracted with ether (3×150 mL), and the combined ethereal extracts were washed with brine (200 mL) and dried (MgSO4). Concentration under reduced pressure afforded 6.02 g (99%) of 88 that was used without further purification. 1H NMR (400 MHz, CDCl3): δ 4.01-4.14 (m, 4H), 6.02 (s, 1H), 7.24-7.31 (m, 2H), 7.41 (t, J=7.9 Hz, 1H).
Reaction SMILES: [CH:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:6]2[C:7](=[O:10])[O:8][CH2:9][C:5]=2[CH:4]=1)=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[CH3:13][C:12]1[C:3]([CH:1]2[CH2:2][O:22]2)=[CH:4][C:5]2[CH2:9][O:8][C:7](=[O:10])[C:6]=2[CH:11]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1cc2c(cc1C)C(=O)OC2
Solvent: ClCCl
Product: Cc1cc2c(cc1C1CO1)COC2=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-ethenyl-6-methyl-2-benzofuran-1(3H)-one (1.00 g, 5.75 mmol) in 50 mL of DCM was slowly added mCPBA (3.50 g, 17.4 mmol) in 50 mL of DCM at 0° C. The mixture was warmed to room temperature, and stirred for 2 days. The mixture was washed with aqueous Na2SO3 until KI indicator paper didn't change color. The organic layer was washed with brine and then concentrated. The residue was purified via silica column to give the title compound. LC-MS M+1 (calc. 191. found 191).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([NH2:20])[CH:14]=1>>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][C:15]=2[NH2:20])=[O:9])=[CH:10][CH:11]=1
Reactant: Cc1ccc(N)c(N)c1
Reactant: N#Cc1ccc(C(=O)O)cc1
Product: Cc1ccc(NC(=O)c2ccc(CN)cc2)c(N)c1
Yield: 33.9 %

Procedure:
The title compound (173 mg, 68% yield) was prepared as a grey solid from 4-cyano-benzoic acid (294 mg, 2 mmol) and 4-methyl-o-phenylenediamine (293 mg, 2.4 mmol) by an analogous procedure to that described in example 8. LC-MS (m/z) 256 (M+1).
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.C(N(CC)CC)C.Cl[C:19]1[N:24]=[C:23]([Cl:25])[CH:22]=[C:21]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:28]=2[CH3:34])[N:20]=1>COCCOC.O>[Cl:25][C:23]1[CH:22]=[C:21]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:28]=2[CH3:34])[N:20]=[C:19]([NH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:24]=1
Reactant: Cc1cccc(Nc2cc(Cl)nc(Cl)n2)c1C
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)CNc1nc(Cl)cc(Nc2cccc(C)c2C)n1

Procedure:
A suspensione of 100% sodium hydride (27 mg) in anhydrous 1,2-dimethoxyethane (1.5 ml) is treated with small amounts of NH2CH2CO2C2H5.HCl (156 mg). Triethylamine (0.16 ml) and 2,4-dichloro-6-(2,3-xylidino)-pyrimidine (300 mg) are added, and the mixture is refluxed for 18 hours. Triethylamine (0.16 ml) is added again, heating under reflux for 24 hours more. Finally, after cooling, the reaction mixture is diluted with water and extracted with methylene chloride. The organic phase is washed to neutrality and dried over Na2SO4. By evaporation of the solvent and crystallization from ethyl acetate 300 mg of ethyl ester of N-[4-chloro-6-(2,3xylidino)-2-pyrimidinyl]-aminoacetic acid (I, 2) are obtained.
Reaction SMILES: CS[C:3]1[NH:4][CH:5]=[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[C:7](=[O:9])[N:8]=1.[Cl:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>C(O)C>[Cl:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH:31][C:3]3[NH:4][CH:5]=[C:6]([CH2:10][C:11]4[CH:12]=[N:13][CH:14]=[N:15][CH:16]=4)[C:7](=[O:9])[N:8]=3)=[CH:25][CH:24]=2)=[CH:20][CH:19]=1
Reactant: NCCc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CSc1nc(=O)c(Cc2cncnc2)c[nH]1
Solvent: CCO
Product: O=c1nc(NCCc2ccc(Oc3ccc(Cl)cc3)cc2)[nH]cc1Cc1cncnc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
2-Methylsulfanyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (30 mg, 0.128 mmol, 1 eq) and 2-[4-(4-Chloro-phenoxy)-phenyl]-ethylamine (47.5 mg, 0.192 mmol, 1.5 eq) were dissolved in dry ethanol (300 μl) and stirred at 130° C. for overnight. Reaction mixture was evaporated and crude residue was purified via Biotage SP-1 Snap Si 10 g; 15 ml/min; UV Wavelength (Collection: 254 nm; Monitor: 290 nm) in the gradient of MeOH in DCM: 0% for 1 CV, 0-8% for 15 CV. The appropriate fractions were combined and product was triturated with cyclohexane to give 2-{2-[4-(4-Chloro-phenoxy)-phenyl]-ethylamino}-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (0.077 mmol; yield: 60.2%, HPLC-MS/UV: [M+H]+=434.90; rt: 10.52 min; purity: 95%). 1H NMR (300 MHz; DMSO-d6) δ/ppm 2.77 (t, J=7.12 Hz, 2H), 3.40-3.50 (m, 2H), 3.52 (s, 2H), 6.34 (br.s., 1H), 6.90-7.03 (m, 4H), 7.25 (d, J=7.63, 2H), 7.40 (d, J=8.65, 2H), 7.68 (s, 1H), 8.66 (s, 2H), 8.97 (s, 1H), 10.85 (br.s., 1H)