Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([NH:25][C:26]2[N:27]=[C:28]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[S:29][CH:30]=2)=[O:24])[N:17]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>CO>[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:16]1[N:17]=[C:18]([NH:22][C:23]([NH:25][C:26]2[N:27]=[C:28]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[S:29][CH:30]=2)=[O:24])[CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CNc1cccc(NC(=O)Nc2csc(-c3ccncc3)n2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(Nc1cccc(NCC2CCCCN2)n1)Nc1csc(-c2ccncc2)n1
Temperature: 50 °C

Procedure:
2-({6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-ylamino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (52 mg, 0.102 mmol) in MeOH (10 mL) was treated with TFA (0.1 mL, 1.3 mmol). The resulting mixture was heated at 50° C. for 24 h. The reaction mixture was cooled to RT and neutralized to pH between 8–9. Solvent was removed. The residue was partitioned between H2O and CHCl3.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.[CH3:19][C:20]1([CH3:27])[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:19][C:20]1([CH3:27])[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=2)[CH2:22][CH2:21]1
Reactant: CC1(C)CCC(N)CC1
Reactant: O=[N+]([O-])c1cccc2c(Cl)nc(C(F)(F)F)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)CCC(Nc2nc(C(F)(F)F)nc3c([N+](=O)[O-])cccc23)CC1
Yield: 45.2 %

Procedure:
A suspension of 4-chloro-8-nitro-2-(trifluoromethyl)quinazoline (200 mg, 0.72 mmol), 4,4-dimethylcyclohexanamine (109 mg, 0.86 mmol), K2CO3 (398 mg, 2.89 mmol) in CH3CN (2 mL) was heated at reflux for 8 h. Then the reaction mixture was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 120 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.91-8.89 (d, J=7.2 Hz, 1H), 8.69-8.66 (d, J=7.8 Hz, 1H), 8.39-8.37 (d, J=7.8 Hz, 1H), 7.84-7.79 (t, J=8.1 Hz, 1H), 4.12 (m, 1H), 1.76-1.64 (m, 4H), 1.46-1.28 (m, 4H), 0.98 (s, 3H), 0.95 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:9][CH:8]=[N:7][CH:6]=1)=[O:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:20]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.CCOC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[O:9][C:8]([Cl:20])=[N:7][CH:6]=1)=[O:4]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: COC(=O)c1cnco1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cnc(Cl)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of oxazole-5-carboxylic acid methyl ester (1.4 g, 11 mmol) in anhydrous THF (50 mL) at −40° C. under an argon atmosphere was slowly added a solution of LiHMDS (13.3 mL, 1 M in THF). After 1 h at −40° C., solid hexachloroethane (3.91 g, 16.5 mmol) was added. The mixture was then allowed to slowly warm to room temperature and stir for 16 h. The reaction was diluted with AcOEt/H2O (30 mL/10 mL). The organic layer was washed with brine, dried with MgSO4 and filtered. After removal of solvent the residue was silica gel column chromatographed (CH2Cl2/Cyclohexane: 1/1) to give 1.1 g of 2-chloro-oxazole-5-carboxylic acid methyl ester (62%) as a white solid. m.p.=35-50° C.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([OH:33])(=[O:32])[CH3:31].C(O)C>O>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([O-:33])(=[O:32])[CH3:31]
Reactant: CC(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CCO
Solvent: O
Product: CC(=O)[O-]
Temperature: 60 °C

Procedure:
A solution of Sunitinib acetate was prepared in the following way: 10 g Sunitinib Base (1 eq) was suspended in 50 ml of water, then 1.58 g (1.05 eq) of acetic acid was added under stirring obtaining a solution. This solution was heated to 60° C. Then 160 ml of ethanol were added at this temperature.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:26])[C@H:5]([CH2:7][C:8]1[CH:15]=[C:13]([I:14])[C:12]([O:16][C:17]2[CH:24]=[C:22]([I:23])[C:21]([OH:25])=[C:19]([I:20])[CH:18]=2)=[C:10]([I:11])[CH:9]=1)[NH2:6].C(N(CC)CC)C.[CH3:34][N:35]1[CH2:41][C:40](=[O:42])[O:39][C:37](=[O:38])[CH2:36]1>CN(C)C=O.O1CCCC1>[CH3:2][O:3][C:4](=[O:26])[C@H:5]([CH2:7][C:8]1[CH:9]=[C:10]([I:11])[C:12]([O:16][C:17]2[CH:18]=[C:19]([I:20])[C:21]([OH:25])=[C:22]([I:23])[CH:24]=2)=[C:13]([I:14])[CH:15]=1)[NH:6][C:40](=[O:42])[CH2:41][N:35]([CH3:34])[CH2:36][C:37]([OH:39])=[O:38]
Reactant: COC(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Reactant: CN1CC(=O)OC(=O)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)CN(C)CC(=O)O
Reaction time: 0.17 h
Yield: 103.4 %

Procedure:
In 15 ml of dimethylformamide (DMF), 2 g of thyroxine methyl ester hydrochloride was dissolved and 500 μl of triethylamine was added to the resulting solution. After 10 minutes passed, a solution of 0.55 g of N-methyliminodiacetic acid anhydride in 5 ml of tetrahydrofuran (THF) was added to the mixture. After completion of the reacton, the reaction mixture was condensed using a rotary evaporator and the residue was dissolved in 50 ml of THF. Further, 150 ml of ethyl acetate was added to the solution. After stirring the mixture by shaking, the ethyl acetate layer was taken out and washed three times with distilled water and then once with a saturated aqueous sodium chloride solution. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the supernatant was condensed using a rotary evaporator. To the residue, 20 ml of THF was added and then a small quantity of n-hexane was added to form precipitates. The precipitates were subjected to suction filtration to obtain white crystals. The crystals were dried in a dessicator under reduced pressure to obtain 2.3 g of white crystals. The yield was 69%.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.C(N(CC)CC)C.[Cl:25][C:26]1[N:31]=[C:30]([NH2:32])[CH:29]=[CH:28][C:27]=1[CH2:33][CH3:34]>ClCCl>[Cl:25][C:26]1[N:31]=[C:30]([NH:32][C:14]([C:11]2([C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:17])([F:1])[O:3][C:4]=4[CH:10]=3)[CH2:13][CH2:12]2)=[O:15])[CH:29]=[CH:28][C:27]=1[CH2:33][CH3:34]
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: CCc1ccc(N)nc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reaction time: 16 h
Yield: 69 %

Procedure:
1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (1.08 g, 4.15 mmol) was placed in an oven-dried flask which was allowed to cool under nitrogen. Dichloromethane (10 mL), triethylamine (1.75 mL, 12.5 mmol), and 6-chloro-5-ethylpyridin-2-amine (4.15 mmol) were added and the reaction mixture was stirred for 16 hours. The reaction mixture was then washed with a saturated aqueous solution of sodium chloride, evaporated to near dryness, and then purified on 40 g of silica gel utilizing a gradient of 0-30% ethyl acetate in hexanes to yield N-(6-chloro-5-ethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (1.09 g, 69%). ESI-MS m/z calc. 380.1, found; 381.0 (M+1)+Retention time 2.24 minutes.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.CCN(CC)CC.O=C(Cl)[O:32][C:33](Cl)(Cl)Cl.[CH2:38]([NH2:41])[CH2:39][CH3:40]>C(Cl)Cl>[CH2:38]([NH:41][C:33]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:32])[CH2:39][CH3:40]
Reactant: CCCN
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Reaction time: 0.17 h
Yield: 4.6 %

Procedure:
To a mixture of 13.7 mg (0.06 mmol) 2-(4-Trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one and 24.2 mg (0.24 mmol) NEt3 in 2 mL CH2Cl2 at 0° C. was added 13 mg (0.066 mmol) diphosgene and stirred for 10 min. After addition of 10.6 mg (0.18 mmol) propylamine the mixture was stirred for 16 h at room temperature, evaporated to dryness and purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 1.1 mg (5%) the title compound. MS (ESI): 400.3 (MH+).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7](O)=[O:8].C(Cl)(C(Cl)=O)=O.[NH2:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:21](=[O:34])[N:22]2[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[CH:28]=1>C(#N)C.CN(C=O)C.C(Cl)Cl>[NH2:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:21](=[O:34])[N:22]2[C:27]1[CH:28]=[C:29]([NH:33][C:7](=[O:8])/[CH:6]=[CH:5]/[CH2:4][N:3]([CH3:10])[CH3:2])[CH:30]=[CH:31][CH:32]=1
Reactant: Nc1cccc(-n2c(=O)n(-c3ccc(Cl)cc3)c3c(N)ncnc32)c1
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN(C)C/C=C/C(=O)Nc1cccc(-n2c(=O)n(-c3ccc(Cl)cc3)c3c(N)ncnc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.2 %

Procedure:
To a suspension of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride salt (94 mg, 0.57 mmol) in dry acetonitrile (5 mL) was added 1 drop of DMF before introducing (COCl)2 (0.5 mL, 5.3 mmol). Resulting mixture was stirred at room temperature for 1 hour. Concentrated and dissolved in dry DCM (2 mL) before introducing a solution of 6-amino-9-(3-aminophenyl)-7-(4-chlorophenyl)-7H-purin-8(9H)-one (13) (100 mg, 0.28 mmol) in DCM (2 mL). Resulting solution was stirred at room temperature for 2 hours before quenched the reaction with MeOH (2 mL). Solvent was removed and the residue was pre-purified by column chromatography (silica gel, 0 to 10% methanol in methylene chloride (0.3% Et3N)) followed by preparative HPLC (RP, C18, 10 to 95% acetonitrile in water (0.2% NH3.H2O)) to give (E)-N-(3-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)but-2-enamide (14) (25 mg, 19.1%) as a white solid. LC-MS (ESI): m/z (M/M+2) 464/466. 1H NMR (400 MHz, DMSO) δ 10.57 (s, 1H), 9.82 (s, 1H), 8.11 (s, 1H), 7.99 (s, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.62 (d, J=8.7 Hz, 2H), 7.56-7.45 (m, 3H), 7.35 (d, J=8.8 Hz, 1H), 6.82-6.65 (m, 1H), 6.46 (d, J=15.3 Hz, 1H), 5.98 (s, 2H), 4.01-3.87 (m, 2H), 2.79 (s, 3H), 2.78 (s, 3H).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([N:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=[O:21])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH2:22].[OH:23]O>>[C:6]([NH:14][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]([O:21][OH:23])=[O:22])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1CCCCCN1C(=O)c1ccccc1
Reactant: OO
Reactant: O
Agent: O=S(=O)(O)O
Product: O=C(CCCCCNC(=O)c1ccccc1)OO
Temperature: 80 °C
Reaction time: 1 h

Procedure:
140 g of sulfuric acid are added dropwise in the course of half an hour to a liquid mixture of N-benzoyl-caprolactam (21.7 g, 100 mmol) and water (8.0 g, 440 mmol) at 68° C. The internal temperature increases in the course of this to 80° C., and the mixture is further stirred for 1 hour at this temperature. After the reaction solution is cooled to 20° C., 42 ml of 50% strength aqueous hydrogen peroxide solution are added dropwise. The internal temperature is kept between 25° and 30° C. during this by ice cooling. After one hour, the reaction batch is admixed with 500 ml of ice water, and the resulting colorless precipitate is filtered off by suction and washed to neutrality with water. Yield 22.2 g (88%), active oxygen content 6.2 % (98%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([OH:22])=O)[CH2:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([Cl:25])=[O:22])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)nc2)C1
Product: O=C(Cl)C1=NN(c2ccccc2Cl)C(c2ccc(Br)nc2)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
5-(6-Bromo-pyridin-3-yl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid (450.0 mg, 1.2 mmol) prepared in Step 3 was added to thionyl chloride (5.0 mL). The reaction mixture was stirred at 100° C. for 2 hours and then concentrated under reduced pressure. The resulting residue was concentrated under reduced pressure three times, along with using toluene, to give 5-(6-bromo-pyridin-3-yl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carbonyl chloride as a dark brown liquid.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]=[C:7]2[C:11]3([O:13][CH2:12]3)[C:10]([CH3:15])([CH3:14])[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]=[C:7]2[CH:8]=[CH:9][C:10]([CH3:15])([CH3:14])[C:11]2([CH2:12][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[OH:13])=[CH:4][CH:3]=1
Reactant: CC1(C)C=CC(=Cc2ccc(F)cc2)C12CO2
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C=CC(=Cc2ccc(F)cc2)C1(O)Cn1ccnc1

Procedure:
A mixture of 7-(4-fluorobenzylidene)-4,4-dimethyl-1-oxaspiro[2.4]hept-5-ene (5.5 g), produced according to the previous example, with imidazole (2 g) and potassium carbonate (6.6 g) is heated in N,N-dimethyl-formamide (50 cc) for 4 hours. The mixture is poured into water and extracted with ethyl acetate. The organic phase is washed, dried and recrystallized to obtain the product indicated, m.p. 172° C., compound no. 32
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[C:14]([CH2:20][CH3:21])[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:20]([C:14]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]2[C:4]3[CH:3]=[C:2]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=1)[CH3:21]
Reactant: OB(O)c1ccccc1
Reactant: CCc1nc2c(N)nc3ccc(Br)cc3c2n1CC(C)C
Product: CCc1nc2c(N)nc3ccc(-c4ccccc4)cc3c2n1CC(C)C

Procedure:
8-Bromo-2-ethyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and benzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Chromatography on silica gel (5%–7% methanol in CH2Cl2 gradient) afforded 2-ethyl-1-isobutyl-8-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 233–235° C.
Reaction SMILES: Cl.[CH:2](N)=[NH:3].[NH2:5][C:6]1[NH:7][C:8]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[N:24]=[C:23]([Cl:26])[CH:22]=[CH:21]3)=[CH:9][C:10]=1[C:11]([O:13]CC)=O>CC(O)C>[ClH:26].[Cl:26][C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[C:16]([C:8]3[NH:7][C:6]4[N:5]=[CH:2][NH:3][C:11](=[O:13])[C:10]=4[CH:9]=3)[CH:17]=[CH:18][CH:19]=2)[N:24]=1
Reactant: CCOC(=O)c1cc(-c2cccc3ccc(Cl)nc23)[nH]c1N
Reactant: N=CN
Agent: Cl
Solvent: CC(C)O
Product: O=c1[nH]cnc2[nH]c(-c3cccc4ccc(Cl)nc34)cc12
Temperature: 100 °C
Yield: 178 %

Procedure:
Formamidine hydrochloride (0.296 g, 3.67 mmol) and ethyl 2-amino-5-(2-chloroquinolin-8-yl)-1H-pyrrole-3-carboxylate (0.232 g, 0.735 mmol) were combined in 3 mL IPA, sealed, and heated to 100° C. overnight. An additional 1 mL IPA was added, and the reaction resealed and heated to 110° C. for 24 additional hours. The reaction was cooled, diluted with IPA, and filtered, rinsing 2×IPA. The solid was collected and dried in vacuo to give 6-(2-chloroquinolin-8-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one hydrochloride (0.218 g, 0.654 mmol, 89% yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 12.34 (1H, br. s.), 8.53 (1H, d, J=8.6 Hz), 8.23-8.30 (1H, m), 8.00 (1H, dd, J=7.9, 1.1 Hz), 7.92 (1H, s), 7.66-7.77 (2H, m), 7.49 (1H, s), 7.01-7.26 (2H, m). m/z (ESI, +ve) 296.9 (M+H)+.
Reaction SMILES: [C:1]1([C:11](Cl)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:22]([CH2:32][CH:33]=[CH2:34])[CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:18]=[CH:19][C:20]=1[Cl:21].[CH2:35]([N:37](CC)CC)C>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:22]([CH2:32][CH:33]=[CH2:34])[CH2:23][N:24]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[C:3]([C:35]#[N:37])[CH:2]=2)=[O:12])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: C=CCC(CNCCCCC(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CCN(CC)CC
Product: C=CCC(CN(CCCCC(=O)O)C(=O)c1cc(C#N)cc2ccccc12)c1ccc(Cl)c(Cl)c1

Procedure:
1-Naphthoyl chloride (0.97 g) was combined with [2-(3,4-dichlorophenyl)]-N-[(2-carboxyethyl)ethyl]-4-pentenamine (1.49 g) and triethyl amine under standard acylation conditions to afford N-[2-(3,4-dichlorophenyl)-4-pentenyl]-N-[(2-carboxyethyl)ethyl]-3-cyano-1-naphthamide (0.56 g) as a solid after purification by chromatography (5:4:1 Hexane:DCM:EtOAc); MS: m/z 509 (M+); 1H NMR (CDCl3) δ 8.25-8.10 (m), 7.95-7.05 (m), 6.98-6.80 (m), 6.78-6.62 (m), 6.60-6.41 (m), 5.77-5.58 (m), 5.35-4.72 (m), 4.30-1.90 (m), 1.40-1.15 (m).
Reaction SMILES: C([Li])CCC.CCCCCC.[Br:12][C:13]1[CH:17]=[C:16](Br)[N:15]([CH3:19])[N:14]=1.Cl[C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>O1CCCC1.[Cu](I)I.O>[Br:12][C:13]1[CH:17]=[C:16]([C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:15]([CH3:19])[N:14]=1
Reactant: Cn1nc(Br)cc1Br
Reactant: CCOC(=O)C(=O)Cl
Agent: I[Cu]I
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=O)c1cc(Br)nn1C
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 62.5 %

Procedure:
Under nitrogen atmosphere, n-butyllithium 1.6M in hexane (6.5 mL, 10.42 mmol) was added dropwise to a solution of 3,5-dibromo-1-methyl-1H-pyrazole (11d) (2.00 g, 8.34 mmol) in anhydrous tetrahydrofuran (40 mL) at −78° C. After 30 minutes stirring at the same temperature, copper iodide (5.56 g, 29.18 mmol) was added. The temperature was allowed to reach 0° C. for 40 minutes, then cooled to −78° C. Ethyl chlorooxoacetate (2.80 mL, 25.01 mmol) was dropwise added. The mixture was stirred at room temperature for 2 hours. Water (20 mL) was added and the mixture was extracted with ethyl acetate (2×30 mL). The organic layer was washed with a saturated solution of sodium hydrogenocarbonate (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 100/0 to 80/20) to provide ethyl 2-(3-bromo-1-methyl-1H-pyrazol-5-yl)-2-oxoacetate (11e) (1.36 g, 5.21 mmol, 62%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][CH3:14])[CH:8]=2)[N:3]=1.[NH3:15].O>CO.C(Cl)(Cl)Cl>[NH2:15][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][CH3:14])[CH:8]=2)[N:3]=[C:2]([Cl:1])[N:11]=1
Reactant: N
Reactant: CCc1ccc2nc(Cl)nc(Cl)c2c1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCc1ccc2nc(Cl)nc(N)c2c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of 2,4-dichloro-6-ethylquinazoline (10.8 g) in methanol and chloroform (70 ml) was cooled with ice-water. Ammonia was passed through the reaction mixture for 20 minutes and the mixture was allowed to stand for 18 hours at ambient temperature. The resultant mixture was concentrated under reduced pressure to give a residue, to which was added water and heated to 50°-60° C. with stirring. The precipitates was separated by filtration, washed with hot water and recrystallized from dioxane to give crystalline 4-amino-2-chloro-6-ethylquinazoline (8.3 g). Crystals (0.7 g) of the same compound were obtained by treating the mother liquor in substantially the same manner as mentioned above.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C:5]1[CH:6]=[CH:7][C:8]([I:15])=[C:9]([CH2:11][C:12](Cl)=[O:13])[CH:10]=1.CCOC(C)=O>CCOCC>[CH3:1][N:2]([CH3:3])[C:12](=[O:13])[CH2:11][C:9]1[CH:10]=[C:5]([CH3:4])[CH:6]=[CH:7][C:8]=1[I:15]
Reactant: CNC
Reactant: Cc1ccc(I)c(CC(=O)Cl)c1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1ccc(I)c(CC(=O)N(C)C)c1

Procedure:
Dimethylamine (200 ml of 2 M solution in THF) is added dropwise to a solution of 5-methyl-2-iodophenylacetyl chloride in Et2O (500 ml) which is cooled in an ice bath. After the addition is complete, EtOAc (350 ml) is added and the solution is washed with water (350 ml), brine (250 ml) and dried (MgSO4). Evaporation on a rotovap and trituration with 1:1 Et2O/hexanes gives N,N-dimethyl-5-methyl-2-iodophenylacetamide as a light tan solid, m.p. 47-49°.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:6][C@H:5]([OH:7])[CH2:4]1.[N:8]1[CH:9]=[CH:10][N:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[C:12]=12.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[N:8]1[CH:9]=[CH:10][N:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:2][C@@H:3]3[CH2:6][C@H:5]([OH:7])[CH2:4]3)[C:12]=12
Reactant: O=Cc1cccn2ccnc12
Reactant: N[C@H]1C[C@@H](O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: O[C@H]1C[C@@H](NCc2cccn3ccnc23)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 104.3 %

Procedure:
To an emulsion of cis-3-aminocyclobutanol hydrochloride (1.254 g, 10.15 mmol) in DCM (15 mL) was added MeOH (60 mL), imidazo[1,2-a]pyridine-8-carbaldehyde (1.5 g, 10.26 mmol) and DIPEA (2 mL, 11.45 mmol) and the reaction mixture stirred at room temperature under nitrogen for 10 minutes. Sodium triacetoxyborohydride (5.4 g, 25.5 mmol) was then added and the reaction mixture stirred under nitrogen for 18 hours and then concentrated in vacuo. The residue was dissolved in DCM (200 mL), aqueous sodium hydroxide (2M, 200 mL) was added and the mixture was stirred at room temperature for 1 hour. The layers were separated and to the aqueous phase was added sodium hydroxide pellets (ca. 5 g) which was then extracted with 3:1 chloroform:isopropanol (2×500 mL). The combined organic extracts were dried using a hydrophobic frit, evaporated in vacuo and the residue was dissolved in DCM and purified on a silica cartridge (100 g) using a 0-25% methanol-DCM gradient over 60 min. The product containing fractions were combined and evaporated in vacuo to give the title compound as an orange oil (2.3 g).
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[CH:7]=[C:6]([CH:17]([CH3:19])[CH3:18])[C:5]=1[N:20]1[CH2:24][CH2:23][N:22]=[C:21]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=O.[K+].CO>C(#N)C.ClCCl>[CH:1]([C:4]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[CH:7]=[C:6]([CH:17]([CH3:19])[CH3:18])[C:5]=1[N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1cc2oc3ccccc3c2c(C(C)C)c1N1CCN=C1c1ccccc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1cc2oc3ccccc3c2c(C(C)C)c1-n1ccnc1-c1ccccc1
Reaction time: 1 h
Yield: 44.2 %

Procedure:
1-(1,3-diisopropyldibenzo[b,d]furan-2-yl)-2-phenyl-4,5-dihydro-1H-imidazole (4.78 g, 12.05 mmol) in 70 mL of acetonitrile and 70 mL of dichloromethane were added to a 1 L round bottom flask. Potassium permanganate (3.81 g, 24.11 mmol) was ground in a mortar and pestle. Monmorilonite K was added and was ground together finely with the potassium permanganate. This mixture was added to the solution in portions over 0.5 hours. Reaction was done 1 h after first addition. 100 mL of methanol was added and stirred for 1 h. The solid was filtered through Celite. The material was purified using a 200 g Varian column eluting with 20% ethyl acetate/hexanes. 2.1 g (44% yield) of product was obtained after column.