Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:6]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:26]([OH:28])=O)[C:7](=[O:22])[C:8]([Cl:21])=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[N:10]=1)[CH:2]=[CH2:3].ClC(OCC(C)C)=O.CN1CCOCC1.[CH2:48]([NH2:51])[CH:49]=[CH2:50]>CN(C)C(=O)C>[CH2:48]([NH:51][C:26](=[O:28])[C:25]1[CH:29]=[CH:30][C:31]([CH3:32])=[C:23]([N:6]2[C:7](=[O:22])[C:8]([Cl:21])=[C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:10]=[C:5]2[NH:4][CH2:1][CH:2]=[CH2:3])[CH:24]=1)[CH:49]=[CH2:50]
Reactant: C=CCN
Reactant: C=CCNc1nc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(C(=O)O)ccc1C
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: C=CCNC(=O)c1ccc(C)c(-n2c(NCC=C)nc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a cooled (0° C.) solution of 3-[2-(allylamino)-5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (from Step 3) (0.37 g, 0.80 mmol) in N,N-dimethylacetamide (2 mL) was added isobutyl chloroformate (0.12 mL, 0.96 mmol) and 4-methylmorpholine (0.11 mL, 1.04 mmol). Stirred at 0° C. for 5 min, ambient temperature for 30 min. Added allyl amine (0.09 mL, 1.20 mmol). Stirred at ambient temperature for 2 h. Purified by preparatory HPLC using a 10-90% CH3CN/H2O (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z=494) were combined, freeze-dried, and lyophilized. Washed with 5% NaHCO3 (20 mL) and extracted with DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as a white solid (0.24 g, 60%). 1H NMR (CD3OD/400 MHz) δ7.93 (m, 1H), 7.67 (s, 1H), 7.55 (q, 2H, J=8.0 Hz), 7.00 (t, 2H, J=8.8 Hz), 5.90 (m, 1H), 5.80 (m, 1H), 5.51 (m, 2H), 5.21 (m, 1H), 5.09 (m, 3H), 3.95 (m, 4H), 2.14 (s, 3H). ESHRMS m/z 501.1520 (M+H calculated for C25H24ClF2N4O3 requires 501.1500).
Reaction SMILES: [CH3:1][C:2]([OH:20])([CH3:19])[CH2:3][NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:10]=1.C(N(CC)CC)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH3:19][C:2]1([CH3:1])[O:20][C:29](=[O:31])[N:4]([C:5]2[N:6]=[N:7][C:8]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH2:3]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(O)CNc1ccc(C#Cc2ccccc2)nn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)CN(c2ccc(C#Cc3ccccc3)nn2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
A solution of 2-methyl-1-(6-(phenylethynyl)pyridazin-3-ylamino)propan-2-ol (Example 152, step 1) (90 mg, 337 μmol) and triethylamine (102 mg, 141 μl, 1.01 mmol, 3 equiv.) in 4 ml of THF was cooled to 0-5° C. and then triphosgene (99.9 mg, 337 μmol, 1 equiv.) was added and the reaction was stirred for 1 hour at 0-5° C. The mixture was quenched with 5 ml of 5% sodium bicarbonate solution and worked up with ethyl acetate/water. The crude material was adsorbed onto silicagel and purified by flash chromatography over a heptane to 50% ethyl acetate in heptane gradient to yield the title compound (51 mg, 52% yield) as a crystalline light yellow solid, MS: m/e=294.2 (M+H+).
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16])=[CH:4][NH:3][CH2:2]1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:21]([N:3]1[CH2:2][CH2:1][C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16])=[CH:4]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCOC(=O)C1=CNCCc2c1[nH]c1ccccc21
Reactant: O=C(Cl)c1ccccc1
Product: CCCOC(=O)C1=CN(C(=O)c2ccccc2)CCc2c1[nH]c1ccccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using n-propyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (compound of step A) and benzoyl chloride; 1H-NMR (CDCl3): δ 10.55 (1H, br s), 8.07 (1H, s), 7.52-7.58 (4H, m), 7.47 (2H, m), 7.33 (1H, d), 7.21 (1H, m), 7.12 (1H, m), 4.23 (2H, t), 4.13 (2H, m), 3.28 (2H, m), 1.56 (2H, m), 1.40 (3H, t); MS (ES): 375 (MH+).
Reaction SMILES: CS(O[C@@H:6]([CH3:32])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:20](=[O:21])[C:19]2[NH:18][C:17]([CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:16][C:15]=2[N:14]([CH3:31])[C:12]1=[O:13])(=O)=O.[C-:33]#[N:34].[K+]>CS(C)=O>[C:33]([C@H:6]([CH3:32])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:20](=[O:21])[C:19]2[NH:18][C:17]([CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:16][C:15]=2[N:14]([CH3:31])[C:12]1=[O:13])#[N:34]
Reactant: C[C@@H](CCCCn1c(=O)c2[nH]c(CNC(=O)OC(C)(C)C)nc2n(C)c1=O)OS(C)(=O)=O
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H](C#N)CCCCn1c(=O)c2[nH]c(CNC(=O)OC(C)(C)C)nc2n(C)c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
A suspension of (S)-1-(5-methanesulfonyloxyhexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.47 g, 1.0 mmol) and potassium cyanide (0.39 g, 6.0 mmol) in dimethylsulfoxide (8.0 ml) was stirred at 60° C. overnight. The reaction was quenched by addition of water (30 ml) and extracted with ethyl acetate (3×15 ml). The combined extracts were washed with water (2×15 ml), saturated aqueous sodium chloride solution (15 ml), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 15% methanol-ethyl acetate to give (R)-1-(5-cyanohexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.25 g, 62% yield) as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[CH3:26])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:35]([O:37][CH3:38])=[O:36]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]([CH3:26])=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:35]([O:37][CH3:38])=[O:36])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:24]=1
Reactant: COC(=O)Cl
Reactant: Cc1ccc(Cl)cc1[C@H](OCCN)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCCO[C@@H](c1cc(Cl)ccc1C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 21 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(5-chloro-2-methylphenyl)methyl)piperidine-1-carboxylate (6.2 g, 16.2 mmol) and DMAP (0.2 g, 1.62 mmol) in dry CH2Cl2 (70 mL), Et3N (8 g, 81 mmol) was added. The resulting mixture was cooled to 0-5° C. in ice-water bath, a solution of methyl chloroformate (3.1 g, 32.4 mmol) in dry CH2Cl2 (30 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 hr at 0-5° C. The reaction was quenched with water. The aqueous layer was extracted with CH2Cl2 (3×30 mL), the combined organic layers were washed with brine, then dried over Na2SO4, filtered and concentrated to give the crude product, which was firstly purified by column chromatography and then by preparative HPLC to give (R)-tert-butyl 3-((R)-(5-chloro-2-methylphenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (1.5 g). 1H NMR (CD3OD, 400 MHz) δ 7.30 (s, 1H), 7.20-7.10 (d, 2H), 4.81 (s, 1H), 4.46-4.30 (d, 1H), 4.29-4.15 (d, 1H), 3.95-3.83 (d, 1H), 3.62 (s, 3H), 3.30 (s, 4H), 2.90-2.65 (dd, 2H), 2.30 (s, 3H), 1.70 (s, 1H), 1.59 (s, 1H), 1.41 (s, 9H), 1.35-1.20 (m, 3H).
Reaction SMILES: [CH2:1]([C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[S:21]1[CH2:27][C:25](=[O:26])[NH:24][C:22]1=[S:23]>C(O)(=O)C.C([O-])(=O)C.[Na+]>[CH2:1]([C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:12]=[C:13]([CH:14]=[C:27]3[S:21][C:22](=[S:23])[NH:24][C:25]3=[O:26])[CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C1CSC(=S)N1
Reactant: CCCCCc1ccc(Oc2cccc(C=O)c2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCCc1ccc(Oc2cccc(C=C3SC(=S)NC3=O)c2)cc1
Yield: 61.9 %

Procedure:
The 3-(4-n-pentylphenoxy)benzaldehyde was coupled with rhodanine in acetic acid and sodium acetate essentially as described previously to yield 1.3 grams (61.9%) of the title product.
Reaction SMILES: [CH2:1]([CH:3]1[C@H:8]2[C@H:9]3[C@H:20]([CH2:21][CH2:22][C@:6]2([CH3:7])[C:5](=[O:24])[CH2:4]1)[C@:17]1([CH2:18][OH:19])[C:12](=[CH:13][C:14](=O)[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[CH2:25]([Li])CCC.O>O1CCCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([CH:3]1[C@H:8]2[C@H:9]3[C@H:20]([CH2:21][CH2:22][C@:6]2([CH3:7])[C:5](=[O:24])[CH2:4]1)[C@:17]1([CH2:18][OH:19])[C:12](=[CH:13][C:14](=[CH2:25])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CCC1CC(=O)[C@@]2(C)CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@H]12
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C=C1C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC(CC)[C@@H]34)[C@@]2(CO)CC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
2.7 g of 15-alpha-ethyl-19-hydroxy-4-androstene-3,17-dione in 25 ml of tetrahydrofuran is instilled in a suspension of 28.6 of methyl triphenylphosphonium bromide in 200 ml of tetrahydrofuran, which was stirred with 200 ml of butyllithium solution (1.6 m in ether) for 1.5 hours at 20° C., and stirred for one hour at 20° C. Then it is mixed with water, extracted three times with ethyl acetate, washed neutral, dried on sodium sulfate and is freed from the solvent in a vacuum. After chromatographic purification on silica gel with hexane/ethyl acetate, 1.95 g of pure 15-alpha-ethyl-3-methylene-19-hydroxy-4-androsten-17-one is obtained as foam.
Reaction SMILES: [O:1]1[CH2:28][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27].[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30]>CN(C=O)C>[CH2:29]([N:31]([CH2:28][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27])[CH2:32][CH3:33])[CH3:30]
Reactant: CCNCC
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CO1
Solvent: CN(C)C=O
Product: CCN(CC)CC(O)COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3)c2cc1OC
Temperature: 70 °C
Yield: 45.2 %

Procedure:
A mixture of 7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg, 0.27 mmol), (prepared as described for the starting material in Example 162), and diethylamine (100 μl, 0.8 mmol) in DMF (4 ml) was heated at 70° C. for 24 hours. The solvent was removed by evaporation and the residue was purified by silica column chromatography eluting with dichloromethane/methanol/0.880 aqueous ammonia (100/8/1). The relevant fractions were evaporated to dryness then the residue treated with a little dichloromethane and dried under high vacuum to give 7-(3-(N,N-diethylamino)-2-hydroxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (55 mg, 46%) as a white foam.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[Li]CCCC.C([O:26][B:27](OC(C)C)[O:28]C(C)C)(C)C>C1COCC1>[CH2:1]([C:5]1[S:9][C:8]([S:10]([NH:13][C:14]([CH3:15])([CH3:17])[CH3:16])(=[O:12])=[O:11])=[C:7]([B:27]([OH:28])[OH:26])[CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)Cc1ccc(S(=O)(=O)NC(C)(C)C)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Cc1cc(B(O)O)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: -20 °C
Reaction time: 4 h

Procedure:
5-iso-Butyl-N-tert-butylthiophene-2-sulfonamide (10.6 g, 0.039 mol, see step (b) above) was dissolved in THF (165 mL) under N2 and then cooled to −78° C. n-BuLi (1.6 M, 60.19 mL, 0.096 mol) was added via a syringe. The reaction mixture was stirred at −20° C. for 4 h. The tri-iso-propylborate (13.3 mL, 0.058 mol) was then added via a syringe and the reaction mixture was stirred overnight at room temperature. The reaction was quenched with 2 M HCl (20 mL). The organic phase was separated and the water phase was extracted with EtOAc (3×100 mL). The combined organic phase was washed with brine, dried and concentrated in vacuo. The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21].C(N(CC)CC)C>C(Cl)Cl>[NH2:13][C:14]1[C:15]([CH3:21])=[CH:16][CH:17]=[CH:18][C:19]=1[O:20][S:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])(=[O:11])=[O:10]
Reactant: Cc1cccc(O)c1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(OS(=O)(=O)c2ccc(Cl)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 2,4-dichlorobenzenesulfonyl chloride (20.2 g, 82.3 mmol) and 2-amino-m-cresol (11 g, 89.4 mmol) in 200 mL of methylene chloride, triethylamine (8.5 g, 83.4 mmol) was added dropwise at 5° C. The mixture was stirred at ambient temperature for 16 hours.
Reaction SMILES: [CH2:1]1O[C:4]([N:8]2[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][C:12](=[O:17])[CH2:13]3)[CH2:9]2)([O:5]CC)[O:3][CH2:2]1>OS(O)(=O)=O>[O:17]=[C:12]1[CH2:11][CH:10]2[CH2:16][CH:14]([CH2:15][N:8]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:9]2)[CH2:13]1
Reactant: CCOC1(N2CC3CC(=O)CC(C3)C2)OCCO1
Agent: O=S(=O)(O)O
Product: CCOC(=O)N1CC2CC(=O)CC(C2)C1
Reaction time: 4 h
Yield: 88.1 %

Procedure:
Ethyl 7-oxo-3-azabicyclo[3.3.1]nonane-3-carboxylate ethylene ketal (4.40 g, 17.2 mmol) was combined with 2% aqueous H2SO4(50 ml) and stirred for 4 h. Then the reaction mixture was extracted with ethyl acetate (4×30 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation to yield a light yellow oil (3.20 g, 88.1%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([F:11])[CH:4]=1.[CH2:12]([N:18](CCCCCC)CCCCCC)CCCCC.[C-]#N.[Na+]>O>[F:11][C:5]1[CH:4]=[C:3]([CH2:2][C:12]#[N:18])[CH:8]=[CH:7][C:6]=1[O:9][CH3:10]
Reactant: CCCCCCN(CCCCCC)CCCCCC
Reactant: COc1ccc(CBr)cc1F
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: COc1ccc(CC#N)cc1F

Procedure:
A mixture of 4-(bromomethyl)-2-fluoroanisole (45.8 g, 0.21 mol), trihexylamine (1.4 g) and sodium cyanide (20.5 g, 0.42 mol) in water (50 ml) is heated at 60°-65° C. for 18 hours. The mixture is cooled and extracted in its ether, washed with water, saturated sodium chloride solution and dried (CNa2SO4). Evaporation of the solvent gives a solid, (33.2 g): m.p. 42°-46° C.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].CN(C)[CH:15]=[O:16]>>[O:16]1[CH:15]=[CH:1][CH:2]=[C:10]1[CH2:9][CH2:8][CH2:7][CH2:3][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN(C)C=O
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1CCCCc1ccco1
Temperature: 0 °C

Procedure:
2[1-(4-bromobutyl)]furan (406 mg) and potassium phthalimide (370 mg) were stirred together at room temperature in dry dimethylformamide overnight. The solution was poured into ice-water and the resulting white solid filtered, dried and recrystallised from chloroform/petroleum ether (b.p. 60°-80°) to give 2-[4-(2-Furanyl)butyl]-1H-isoindole-1,3(2H)-dione as white microcrystals (430 mg) m.p. 61°-63°.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][CH:10]=[CH:11][C:12](=O)[N:13]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=2)[N:13]=1
Reactant: O=c1cc[nH]c(-c2cccc(I)c2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccnc(-c2cccc(I)c2)n1

Procedure:
A 32.9 g portion of 2-(3-iodophenyl)-4(1H)-pyrimidinone was stirred and refluxed in 123 ml. of phosphorus oxychloride for 2 hours, then cooled overnight and the solvent evaporated at 55° C. The residue was suspended in 400 ml of chloroform, then evaporated. This residue was taken up in 300 ml of chloroform, filtered and washed twice with 75 ml of chloroform. The combined filtrate and washes were evaporated giving 4-chloro-2-(3-iodophenyl)pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[C:17](N(OC)C)=[O:18])[CH:5]=[CH:6][CH:7]=1.[CH3:23][Mg]Br>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[C:17](=[O:18])[CH3:23])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cc2ccccc2n1-c1cccc(F)c1
Solvent: C1CCOC1
Product: CC(=O)c1cc2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-(3-fluorophenyl)-N-methoxy-N-methyl-1H-indole-2-carboxamide (0.30 g, 1.0 mmol) in tetrahydrofuran (6 mL) was added 1.4 M methylmagnesium bromide in tetrahydrofuran (1.1 mL, 1.5 mmol). The reaction was stirred at room temperature for 2 hours, then quenched with saturated NH4Cl solution, extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to give the desired product (0.27 g). The crude product was used directly in next step. LCMS calculated for C16H13FNO(M+H)+: m/z=254.1. Found: 254.1.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:16])[N:6]=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=2)[N:3]=1.[F-:17].[K+].C1OCCOCCOCCOCCOCCOC1>CN1CCCC1=O>[F:17][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:16])[N:6]=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=2)[N:3]=1
Reactant: [F-]
Reactant: Nc1nc2ccccc2c2ccc(Cl)nc12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Nc1nc2ccccc2c2ccc(F)nc12
Temperature: 25 °C

Procedure:
A solution of 3-chlorobenzo[f][1,7]naphthyridin-5-amine (Example 20) (1.0 eq.), potassium fluoride (3.0 eq.), and 18-crown-6 (0.2 eq.) in N-methylpyrrolidone (NMP) (0.4 M) was heated in a microwave reactor at 210° C. for 80 minutes. After cooling to room temperature, the crude reaction mixture was purified by HPLC using 10-50% acetonitrile in water to give 3-fluorobenzo[f][1,7]naphthyridin-5-amine. 1H NMR (acetone d-6): δ 11.40 (br, 2H), 9.38-9.42 (dd, 1H), 8.60 (d, 1H), 7.89-7.92 (dd, 1H), 7.81-7.83 (m, 2H), 7.59-7.66 (m, 1H). LRMS [M+H]=214.1
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Br:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[NH2:12].CO>ClCCl>[Br:8][C:9]1[CH:10]=[C:11]([NH:12][C:1](=[O:3])[CH3:2])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N)cc1Br
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(NC(C)=O)cc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.5 %

Procedure:
Acetic anhydride (3.11 ml, 3.37 g, 33 mmol) was added dropwise to a stirred, cooled (0° C.) solution of 3-bromo-4methoxyaniline (6.06 g, 30 mmol) in dichloromethane (60 ml). The mixture was stirred at room temperature for 90 minutes, methanol (10 ml) was added and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate (100 ml) and water (50 ml) were added and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic fractions were washed with aqueous hydrochloric acid (1M, 100 ml), saturated aqueous sodium hydrogen carbonate (100 ml) and brine (100 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate (20 ml)/hexane (50 ml) and the solid was collected and dried in vacuo to give the title compound as a tan solid (6.41 g, 88%), 1H NMR (360 MHz, CDCl3) δ 7.68 (1H, d, J=2.5 Hz), 7.45 (1H, dd, J=8.8, 2.5 Hz), 7.36 (1H, br s), 6.84 (1H, d, J=8.8 Hz), 3.87 (3H, s), and 2.16 (3H, s).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17](=[O:33])[N:18]([CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH:19]=2)=[CH:11][CH:10]=1>ClCCl>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17](=[O:33])[N:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:19]=2)=[CH:11][CH:10]=1
Reactant: Cc1ccc(-c2cn(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)[nH]2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2cn(C3CCNCC3)c(=O)[nH]2)cc1
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (0.600 mL) was added to a solution tert-butyl 4-[4-(4-methylphenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]piperidine-1-carboxylate (178.4 mg, 0.50 mmol) in dichloromethane (3 mL). After 16 h, the reaction was concentrated and purified by reverse phase HPLC (C-18 column, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) to give the title product. MS 258.1 (M+1).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][OH:17])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][O:17][Si:22]([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CCCN1C(=O)OCc1ccccc1
Yield: 88.8 %

Procedure:
A solution 58.0 g of (S)-2-hydroxymethyl-1-pyrrolidine carboxylic acid phenylmethyl ester, 45.0 g of (1,1-dimethylethyl)dimethylsilylchloride, 69 ml of triethylamine, 1.50 g of 4-(dimethylamino)pyridine and 450 ml of methylene chloride is stirred at room temperature for 18 hours. The resulting solution is washed with water, 2N hydrochloric acid, saturated sodium bicarbonate and sodium chloride. The organic layer is dried and concentrated in vacuo. The residue, dissolved in methylene chloride, is filtered through a silica gel pad and concentrated in vacuo to give 76.5 g of the desired product as a colorless oil.