Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[ClH:18].[OH-].[Na+]>O1CCCC1.CCOCC>[ClH:18].[N:1]1([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH2:12][NH2:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccccc1N1CCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCc1ccccc1N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
A solution of 17.18 g (0.078 mole) of 2(1-indolinyl)benzonitrile of Example 1a in 150 ml dry tetrahydrofuran (THF) was added dropwise to a rapidly stirred ice cold solution of BH3 in THF (236 ml of 1 M solution; 0.236 mole) under nitrogen. At the end of the addition the resultant solution was permitted to warm to room temperature and stir for 3 hours and then heated at reflux for 50 minutes. The product was then cooled to 0° C., treated dropwise with 6 N HCl (100 ml), and permitted to stand overnight (about 16 hours) at room temperature. The reaction mixture was cooled to 0° C. and made basic using solid NaOH. The resulting aqueous layer was extracted with ether (200 ml) and the combined organic portions were washed twice with brine (200 ml portions), dried over K2CO3, and concentrated to afford 21.1 g of crude free base. The free amine was dissolved in dry ether (300 ml), cooled to 0° C., and treated with gaseous HCl. The resulting salt was filtered, washed with dry ether (300 ml), and dried under vacuum at 40° C. thus affording 19.25 g (94.4%) of crude salt, m.p. 226°-228° C. Recrystallization of 15.59 g of the crude salt from methanol-ether afforded 10.49 g (67.3% recovery) of 2-(1-indolinyl) benzenemethanamine hydrochloride, m.p. 231°-232° C.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCOC(C)=O>CN(C=O)C>[CH2:17]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(Cn2c3ccccc3c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.3 %

Procedure:
A 100-mL round-bottomed flask was charged with a solution of 9H-carbazole (1.67 g, 9.90 mmol, 1.00 equiv, 99%) in DMF (20 mL) followed by addition of NaH (400 mg, 16.50 mmol, 1.00 equiv, 99%) in small portions at 0° C. over 5 minutes. 1-(Bromomethyl)benzene (1.7 g, 9.90 mmol, 1.00 equiv, 99%) was then added drop wise at 0° C. over 5 minutes. The resulting mixture was stirred at room temperature for 16 hours. The progress was monitored by TLC (EtOAc:PE=1:5). Upon completion, the reaction was then quenched by the addition of water/ice (100 mL). The solids were collected by filtration and dried in an oven under reduced pressure to afford 9-benzyl-9H-carbazole as white solid (2.3 g, 90%). LCMS: [M+H]+: 258.
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[CH3:28][O:29][CH:30]1[C:35](=O)[CH2:34][CH2:33][O:32][CH2:31]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:35]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[O:29][CH3:28])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CC=C(c3cncc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1
Reactant: COC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CC=C(c3cncc(C(F)(F)F)c3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-{[5-(trifluoromethyl)-3′,6′-dihydro-3,4′-bipyridin-1′(2′H)-yl]carbonyl}cyclopentanamine (9.0 mg, 0.024 mmol), 3-methoxytetrahydro-4H-pyran-4-one (12.3 mg, 0.0709 mmol) and triethylamine (6.58 μL, 0.0472 mmol) in dry methylene chloride (2.0 mL) was added sodium triacetoxyborohydride (15.0 mg, 0.0708 mmol). After being stirred at room temperature overnight, the reaction was quenched with aqueous NaHCO3 and diluted with methylene chloride. The organic layer was separated and the aqueous layer was extracted with methylene chloride three times. The organic layers were combined, dried over MgSO4, filtered and evaporated under reduced pressure. The crude product (45 mg) was purified by silica gel column (30:70 MeOH/EtOAc) to provide 1.6 mg (14%) of pure product. LC-MS calculated for C26H36F3N3O3:(M+H) 496; found 496.1.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25][NH2:26]>>[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25][NH:26][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: NCCc1ccccc1F
Product: COc1cc(CNCCc2ccccc2F)ccc1Oc1ccc(C(N)=O)cn1
Yield: 84.5 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 2-fluorophenethylamine (0.0256 g, 0.184 mmol) gives the title compound (0.0615 g, 84.7%): TOF MS ES+ 396.2 (M+H)+, HRMS calcd for C22H23N3O3F 396.1723 (M+H)+, found 396.1722, min 0.39; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=6.8 min, 98.9% purity.
Reaction SMILES: ClCC(=O)CCCC[N:8]1[C:12](=O)[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=C2C1=O.[F:20][C:21]([F:31])([F:30])[CH2:22][NH:23][C:24]([NH:26][C:27]([NH2:29])=[S:28])=[NH:25]>C(O)C>[F:31][C:21]([F:20])([F:30])[CH2:22][N:23]=[C:24]([NH2:25])[NH:26][C:27]1[S:28][CH:17]=[C:16]([CH2:15][CH2:14][CH2:11][CH2:12][NH2:8])[N:29]=1
Reactant: O=C(CCl)CCCCN1C(=O)c2ccccc2C1=O
Reactant: N=C(NCC(F)(F)F)NC(N)=S
Solvent: CCO
Product: NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
To a solution of N-(6-chloro-5-oxohexyl)phthalimide (3.4 g.) in ethanol was added N-(2,2,2-trifluoroethylamidino)thiourea (2.75 g.) in ethanol (30 ml.). The mixture was heated under reflux for 2 hours and the reaction mixture concentrated to small volume by evaporation. Following treatment of the resulting solution with ether until the solution was just turbid, crystalline 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-phthalimidobutyl)thiazole hydrochloride (3.6 g.) was precipitated. This material (2.1 g.) in ethanol (20 ml.) and water (5 ml.) was heated to boiling and the solution pH was adjusted to 12 by addition of 2N sodium hydroxide. After heating on a steam bath for 10 minutes, the solution pH was adjusted to 3 with conc. hydrochloric acid and heating continued for a further 0.5 hour. The solution was cooled, adjusted to pH 12 with 2N sodium hydroxide and extracted with ethyl acetate (2×30 ml.). Evaporation of the washed (H2O), dried (magnesium sulphate) extract gave 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)-thiazole as a pale yellow gum which was used without further purification.
Reaction SMILES: [CH3:1][CH:2]([NH:5][C:6](=S)[NH:7][NH2:8])[CH2:3][CH3:4].[Cl:10][CH:11]([C:17]([CH3:19])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl>C(O)C>[ClH:10].[CH3:19][C:17]1[NH:8][N:7]=[C:6]([NH:5][CH:2]([CH3:1])[CH2:3][CH3:4])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCC(C)NC(=S)NN
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(NC(C)CC)n[nH]c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.7 %

Procedure:
A stirred solution of 5.1 g (0.035 mole) of 4-(2-butyl)-3-thiosemicarbazide in 40 mL of absolute ethanol was treated with 5.7 g (0.035 mole) of ethyl 2-chloroacetoacetate and stirred at ambient temperature for 3 hr. The mixture was treated with 20 mL of 2N ethanolic hydrogen chloride, heated at reflux for 1 hr and stirred for ~16 hr at ambient temperature. The reaction mixture after filtering and concentrating in vacuo gave a crude orange solid. A second reaction mixture was prepared with 8.0 g (0.054 mole) of crude 4-(2-buytl)-3-thiosemicarbazide, 50 mL of absolute ethanol, 8.9 g (0.054 mole) of ethyl 2-chloroacetoacetate, and 25 mL of 2N ethanolic hydrogen chloride as described above and gave a crude orange solid. The TLC of both crude products (10% methanol/benzene; silica gel) were identical. Recrystallization of the first batch from acetone/isopropyl ether gave 4 g of fine white crystals, mp 147°-148.5° C. Recrystallization of the second batch from benzene/ligroin gave 2.5 g of pale yellow crystalline product, mp 146°-148.5° C. The 2 solids were combined (6.5 g) and recrystallized from 200 mL of acetone/isopropyl ester (3:1) to give 3.6 g of white fluffy crystals, mp 147°-149° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH:25]1([NH2:29])[CH2:28][CH2:27][CH2:26]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:29][CH:25]4[CH2:28][CH2:27][CH2:26]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: NC1CCC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NC3CCC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and cyclobutylamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55-1.71 (m, 2 H) 1.95-2.09 (m, 2 H) 2.11-2.24 (m, 2 H) 2.36 (s, 3 H) 4.28-4.48 (m, 1 H) 7.59 (dd, J=8.08, 1.52 Hz, 1 H) 7.66 (s, 1 H) 7.70 (br. s., 1 H) 8.10 (br. s., 1 H) 8.35 (d, J=6.57 Hz, 2 H) 8.78 (d, J=7.33 Hz, 1 H) 8.81-8.91 (m, 1H) 13.12 (br. s., 1 H). MS m/z [M+H]+ 374.2
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.Cl.[N:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.[CH2:33]([S:37](Cl)(=[O:39])=[O:38])[CH2:34][CH2:35][CH3:36]>ClCCl>[N:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([CH2:29][NH:30][S:37]([CH2:33][CH2:34][CH2:35][CH3:36])(=[O:39])=[O:38])=[CH:31][CH:32]=3)[CH2:19][CH2:18]2)=[CH:15][CH:16]=1
Reactant: NCc1ccc(CCN2CCN(c3ccncc3)CC2)cc1
Reactant: CCCCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)NCc1ccc(CCN2CCN(c3ccncc3)CC2)cc1
Reaction time: 0.08 h

Procedure:
Triethylamine (0.41 ml) was added to a stirred suspension of 4-[2-[4-(4-pyridyl)piperazin-1-yl]ethyl]benzylamine, trihydrochloride (300 mg) in dry dichloromethane (20 ml). After 5 minutes, 1-butanesulphonyl chloride (0.10 ml) was added and the mixture stirred overnight. Dichloromethane (80 ml) was added and the solution washed with water (2×25 ml), dried (MgSO4) and the solvent removed in vacuo. Trituration of the residue with a small volume of ethyl acetate gave the title compound, 50 mg, as an off-white solid: m.p. 154°-156° C.; NMR (d6DMSO) δ8.16 (2H, d), 7.53 (1H, t), 7.22 (4H, m), 6.37 (2H, d), 4.10 (2H, d), 3.35 (6H, m+H2O), 2.81 (4H, m), 2.54 (4H, m+DMSO), 1.56 (2H, m) 1.29 (2H, m) 0.82 (3H, t); m/e 417 (M+H)+ ; calculated for C22H32N4O2S.0.75H2O: C, 61.5; H, 7.8; N, 13.0. found: C, 61.5; H, 7.6; N, 12.7%.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1.[Cl-:21]>C(Cl)(Cl)Cl>[Cl:21][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1
Reactant: [Cl-]
Reactant: COc1cc(-c2cc(CO)ccn2)cc(OC)c1OC
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-hydroxymethyl-2-(3,4,5-trimethoxyphenyl)pyridine (19.18 g) was dissolved in chloroform (100 mL), and to the solution thinly chloride (10.2 mL) was added at 0° C. After 30 minutes, the mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was washed with aqaueous saturated sodium hydrogendcarbonate and brine, dried over anhydrous sodium sulfate and evaporated. The residue was then recrystallized from ethyl acetate-hexane to give the title compound as pale yellow crystalline powder.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1B(O)O>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:32]4[CH:33]=[C:28]([Cl:27])[CH:29]=[CH:30][C:31]=4[Cl:34])=[CH:19][CH:18]=3)=[O:24])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(I)cc3)cc2s1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(-c4cc(Cl)ccc4Cl)cc3)cc2s1

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using N-{2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-4-iodo-benzamide (0.12 g, 0.25 mmol) and 2,5-dichloro-phenyl boronic acid (0.057 g, 0.30 mmol) to afford 0.098 g, (79%). LC/MS, Retention time=5.29 min; (m/z): calcd for C25H24Cl2N4OS: 499.5; found: 499.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=1)[C:10](=[O:17])[NH:11]2.I[CH3:33]>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=1)[C:10]([O:17][CH3:33])=[N:11]2
Reactant: CI
Reactant: COC(=O)COc1ccc(F)c2[nH]c(=O)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Product: COC(=O)COc1ccc(F)c2nc(OC)c(Cc3ccc(-n4cccn4)cc3)c(C)c12

Procedure:
The title compound was prepared by the method of Preparation 11e using [8-fluoro-4-methyl-2-oxo-3-(4-pyrazol-1-ylbenzyl)-1,2-dihydroquinolin-5-yloxy]acetic acid methyl ester and iodomethane.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH2:18][CH2:19][NH:20][C:21]([P:23]([O:29]C(C)C)([O:25]C(C)C)=[O:24])=[O:22])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](Br)(C)C.CC#N>C(Cl)(Cl)Cl>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH2:18][CH2:19][NH:20][C:21]([P:23]([OH:29])([OH:25])=[O:24])=[O:22])(=[O:15])=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OP(=O)(OC(C)C)C(=O)NCCNS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=C(NCCNS(=O)(=O)c1ccc(Oc2ccccc2)cc1)P(=O)(O)O
Temperature: 50 °C
Yield: 77.9 %

Procedure:
To the 1-[4-phenoxybenzenesulfonamido]-2-[diisopropylphophonoform amido]ethane (0.45 g, 0.93 mmol) in 10 ml CHCl3 was added TMSBr (5 eq, 0.62 ml, 4.6 mmol) and reaction was stirred and heated at 50° C. for 2.5 hours. The reaction mixture was monitored by 31P NMR. The solvent was evaporated and to the mixture reaction was added 5 ml MeOH for one hour. The solvent was evaporated to give a yellow oil. The product was solidified from MeCN to give 0.29 g (78%) a white solid, m.p.=166-169° C.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:20][C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][NH:27]2)=[CH:23][CH:22]=1.N1C=CC=CC=1>ClCCCl>[Cl:20][C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][N:27]2[C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([N:13]4[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]4)[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[CH:23][CH:22]=1
Reactant: CN1CCN(c2ccc3ncnc(Cl)c3c2)CC1
Reactant: Clc1ccc2c(c1)NCC2
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CN1CCN(c2ccc3ncnc(N4CCc5ccc(Cl)cc54)c3c2)CC1

Procedure:
4-Chloro-6-(4-methylpiperazin-1-yl)-quinazoline hydrochloride (537 mg, 1.80 mmol) and 6-chloroindoline (169 mg, 1.10 mmol) were refluxed in 10 mL of 1,2-dichloroethane and pyridine (350 mg, 4.40 mmol) for 48 hours. The product was isolated as the (58%); using the analogous method of Example 120; 267 mg (58%); M.P. 289°-290° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:13]=[C:12]([NH:14]C(=O)C(C)C)[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@@H:20]2[CH2:24][C@H:23]([CH2:25][OH:26])[CH:22]=[CH:21]2)[CH2:3][CH2:2]1.[OH-].[Na+].COC(C)(C)C>C(O)(C)C>[CH:8]1[N:9]([C@H:20]2[CH:21]=[CH:22][C@@H:23]([CH2:25][OH:26])[CH2:24]2)[C:10]2[N:11]=[C:12]([NH2:14])[N:13]=[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)[C:6]=2[N:7]=1
Reactant: CC(C)C(=O)Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 22.5 °C
Yield: 77.3 %

Procedure:
N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purin-2-yl}isobutyramide (1.0 g, 2.80 mmol) was slurried in a mixture of isopropanol (2 ml) and 10% solution of NaOH (1.1 ml, 2.80 mmol). The mixture was refluxed for 1 h. The resulting solution was cooled to 20-25° C. and tert-butyl methyl ether (2 ml) was added. The aqueous layer was discarded, the organic phase was cooled to 0-5° C. and the resulting slurry filtered off. The solid was dried under vacuum at 40° C. Abacavir (0.62 g, 77%) was obtained as a white powder.
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[N+:13]([O-])=O)[N:6]([CH2:16][C:17]3[CH:21]=[CH:20][N:19]([CH2:22][CH3:23])[N:18]=3)[N:5]=2)[CH2:3][CH2:2]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH:1]1([C:4]2[C:12]3[C:11]([NH2:13])=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]([CH2:16][C:17]3[CH:21]=[CH:20][N:19]([CH2:22][CH3:23])[N:18]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: CCn1ccc(Cn2nc(C3CC3)c3c([N+](=O)[O-])cccc32)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCn1ccc(Cn2nc(C3CC3)c3c(N)cccc32)n1
Temperature: 60 °C
Yield: 103.8 %

Procedure:
To a suspension of 3-cyclopropyl-1-((1-ethyl-1H-pyrazol-3-yl)methyl)-4-nitro-1H-indazole (7.55 g, 24.3 mmol) in EtOH/H2O (70 mL/15 mL) was added iron powder (27.1 g, 485 mmol) and NH4Cl (1.30 g, 24.3 mmol). The reaction mixture was heated to reflux for 3 hours. The mixture was cooled to 60° C. and filtered through a pad of Celite washing with a 20:1 EtOH/Et3N (300 mL) and 1:1 MeOH/DCM (300 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (300 mL), washed with saturated NaHCO3 solution, dried (Na2SO4) and concentrated under reduced pressure to give the product (7.1 g).
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].C(N)C.Cl[C:12]1[N:20]2[CH:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][O:23][C:18]3=[C:19]2[C:14](=[C:15]([F:37])[CH:16]=[C:17]3[C:30]2[C:31]([CH3:36])=[N:32][O:33][C:34]=2[CH3:35])[N:13]=1>CN1CCCC1=O.CO>[CH3:36][C:31]1[C:30]([C:17]2[C:18]3[O:23][CH2:22][CH:21]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[N:20]4[C:12]([NH:3][CH2:1][CH3:2])=[N:13][C:14]([C:19]=34)=[C:15]([F:37])[CH:16]=2)=[C:34]([CH3:35])[O:33][N:32]=1
Reactant: CCN(CC)CC
Reactant: Cc1noc(C)c1-c1cc(F)c2nc(Cl)n3c2c1OCC3c1cccnc1
Agent: CCN
Solvent: CO
Solvent: CN1CCCC1=O
Product: CCNc1nc2c(F)cc(-c3c(C)noc3C)c3c2n1C(c1cccnc1)CO3
Temperature: 150 °C
Yield: 19.1 %

Procedure:
Triethylamine (16 μL, 0.12 mmol) and ethylamine (0.2 mL, 3 mmol) were added to 2-chloro-7-(3,5-dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (15 mg, 0.040 mmol) in N-methylpyrrolidinone (0.41 mL) and the mixture was heated in a microwave at 150° C. for 20 min. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to afford the title compound (3.0 mg, 19%). LCMS calc. for C21H21FN5O2 (M+H)+: m/z=394.2. found: 394.1.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH2:17]([O:19][C:20]1[CH:30]=[CH:29][C:23]([CH:24]=[CH:25][C:26](O)=O)=[CH:22][CH:21]=1)[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:30]=[CH:29][C:23](/[CH:24]=[CH:25]/[C:26]2[NH:1][C:2]3[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=3[N:8]=2)=[CH:22][CH:21]=1)[CH3:18]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: CCOc1ccc(C=CC(=O)O)cc1
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OCC)cc3)nc2n(CCC)c1=O
Yield: 70.2 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.0 g (13.3 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.80 g (14.6 mmol) of 4-ethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 3.57 g (yield 70%) of Compound 47 as pale yellow needles.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]3[CH:12]=[CH:13][N:14]=[CH:15][C:10]3=[N:9][N:8]=2)=[CH:3][CH:2]=1>[Pd].C(O)C>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:11]3[CH2:12][CH2:13][NH:14][CH2:15][C:10]3=[N:9][N:8]=2)=[CH:5][CH:6]=1
Reactant: c1cc(-c2nnc3cnccn23)ccn1
Agent: [Pd]
Solvent: CCO
Product: c1cc(-c2nnc3n2CCNC3)ccn1
Yield: 52.4 %

Procedure:
3-(4-Pyridinyl)[1,2,4]triazolo[4,3-a]pyrazine (538 mg, 2.73 mmol) was hydrogenated under atmospheric hydrogen with 10% Pd/C as a catalyst in ethanol at ambient temperature for 36 hours. The catalyst was filtered off and the solvent was evaporated. The residue was purified on silica gel chromatography using 0-20% of 2M methanol in ammonia—Dichloromethane as eluent to give 3-(4-pyridinyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.288 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[OH:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[CH3:23])[NH2:19].C(=O)(O)[O-].[Na+]>C(O)C.[Cl-].[Na+].O>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][N:8]=1)[N:5]=[CH:4][C:3]([C:13]#[N:14])=[C:2]2[NH:19][C:18]1[CH:20]=[CH:21][C:22]([CH3:23])=[C:16]([OH:15])[CH:17]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Reactant: Cc1ccc(N)cc1O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(Nc2c(C#N)cnc3cnc(F)cc23)cc1O
Yield: 89.4 %

Procedure:
To 1.5 g of 4-chloro-6-fluoro-[1,7]naphthyridine-3-carbonitrile in 40 mL of absolute ethanol was added 1.1 g of 3-hydroxy-4-methylaniline. After stirring the reaction under an inert atmosphere for 16 hours, the reaction mixture was poured into a mixture of brine and saturated aqueous sodium bicarbonate and the resultant crystals were filtered and washed with water. The product was then recrystallized from chloroform/ether/hexanes. Drying in vacuo yielded 1.9 g (90%) of 6-fluoro-4-(3-hydroxy-4-methyl-phenylamino)-[1,7]naphthyridine-3-carbonitrile as a yellow powder: melting point 236-239° C. (decomposed); mass spectrum (m/e): M+H 294.9.