Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2(O)[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC1(c2ccc(Cl)c(Cl)c2)CCCc2sccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(C2CCCc3sccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76.5 %

Procedure:
To a stirring solution of 4-(3,4-dichlorophenyl)-4,5,6,7-tetrahydro-1-benzothiophene-4-ol (4.50 g, 15.0 mmol) in methylene chloride (75 mL) were added triethylsilane (11 mL, 69 mmol) and trifluoroacetic acid (12.0 mL, 156 mmol). The solution became reddish orange but no exotherm was observed. The reaction was stirred for 2.5 hr at rt under an atmosphere of nitrogen. The resulting somewhat fluorescent reddish orange solution was concentrated on the rotovap. Ethyl acetate and water were added (˜100 ml each), the mixture was stirred, and a saturated solution of NaHCO3 was slowly added until the mixture became basic. The mixture was transferred to a separatory funnel, the organic layer was separated, and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to leave crude product as a light brown oil. The residue was purified using column chromatography on silica gel (80 g RediSep column, eluant 100% hexane) give the product (3.25 g, 76% yield) as a clear oil. LCMS: (FA) product did not give an ionization peak. 1H NMR (400 MHz, DMSO) δ 7.59-7.50 (d, J=8.3 Hz, 1H), 7.37-7.31 (d, J=2.1 Hz, 1H), 7.26-7.19 (d, J=5.2 Hz, 1H), 7.12-7.01 (dd, J=8.3, 2.1 Hz, 1H), 6.48-6.40 (d, J=5.2 Hz, 1H), 4.11-4.00 (t, J=6.2 Hz, 1H), 2.91-2.71 (m, 2H), 2.14-2.00 (m, 1H), 1.91-1.62 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:6][C:5]2[C:7]([O:20][C:21]3[CH:22]=[C:23]([F:30])[C:24]([C:27]([OH:29])=O)=[N:25][CH:26]=3)=[CH:8][C:9]([C:11](=[O:19])[NH:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)=[CH:10][C:4]=2[O:3]1.[CH2:32]([NH2:34])[CH3:33]>>[CH2:32]([NH:34][C:27]([C:24]1[C:23]([F:30])=[CH:22][C:21]([O:20][C:7]2[C:5]3[CH2:6][C:2]([CH3:1])([CH3:31])[O:3][C:4]=3[CH:10]=[C:9]([C:11](=[O:19])[NH:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)[CH:8]=2)=[CH:26][N:25]=1)=[O:29])[CH3:33]
Reactant: CCN
Reactant: Cn1ccc(NC(=O)c2cc(Oc3cnc(C(=O)O)c(F)c3)c3c(c2)OC(C)(C)C3)n1
Product: CCNC(=O)c1ncc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)cc1F

Procedure:
The title compound was prepared in a similar manner as described for Example 176, from 5-[2,2-dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-3-fluoro-pyridine-2-carboxylic acid (176a) and ethyl amine (1.0 mL, 2.0 M solution in THF) to give a white solid (203 mg, 64% yield). 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1 H) 8.12 (d, J=2.02 Hz, 1 H) 7.65 (t, J=5.43 Hz, 1 H) 7.23-7.32 (m, 1 H) 6.96-7.12 (m, 3 H) 6.78 (d, J=2.02 Hz, 1 H) 3.77 (s, 3 H) 3.40-3.58 (m, 2 H) 2.89 (s, 2 H) 1.50 (s, 6 H) 1.26 (t, J=7.20 Hz, 3 H); LCMS for C23H24FN5O4 m/z 454.20 (M+H+); Anal. Calcd. for C23H24FN5O4.0.10 AcOH: C, 60.65; H, 5.35; N, 15.24. Found: C, 60.62; H, 5.36; N, 15.28.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[C:4]([CH2:24][CH2:25][CH3:26])[N:3]=1.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C.Cl.[NH2:45][C@H:46]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:45][C@H:46]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[O:20])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[C:4]([CH2:24][CH2:25][CH3:26])[N:3]=1
Reactant: CCCc1nc(N)nc(N)c1N1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCc1nc(N)nc(N)c1N1CCN(c2ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.5 %

Procedure:
A mixture of 3.2 g (0.0091 mole) of 4-[4-(2,4-diamino-6-propyl-5-pyrimidinyl]-1-piperazinyl]benzoic acid, 4.9 g (0.030 mole) of diethyl phosphorocyanidate and 4.2 ml (0.030 mole) of triethylamine in 200 ml of of N,N-dimethylformamide (dried over 4 Å molecular sieves overnight) was stirred at room temperature for two hours. To the resulting clear solution was added a mixture of 2.4 g (0.010 mole) of diethyl glutamate hydrochloride and 1.4 ml (0.010 mole) of triethylamine in 10 ml of N,N-dimethylformamide, and the solution was stirred for another hour. The solvent was removed under high vacuum (0.1 mm, dry ice-2-propanol trap) at 40° C. The gummy residue was poured into 100 ml of ice water. The solid was collected and recrystallized from N,N-dimethylformamide to give 1.9 g of the product as an off-white powder; mp 175°-180° C.
Reaction SMILES: O.[NH2:2][NH2:3].C[O:5][C:6](=O)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[O:8]>C(O)C>[NH:2]([C:6](=[O:5])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[O:8])[NH2:3]
Reactant: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)OC)cc2)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Hydrazine hydrate (229 mg, 4.57 mmol) was added in one portion to a stirred solution of trans-ethyl 2-[4-(4-{[methoxy(oxo)acetyl]amino}phenyl)cyclohexyl]propanoate (1.3 g, 3.6 mmol) in ethanol (25 mL) and the reaction mixture was stirred at room temperature for 18 h. The mixture was filtered to leave a solid, which was washed with ethanol (10 mL) to give the title compound (Intermediate 99) (1.2 g, 92%) as a solid; 1H NMR δ 1.07 (3H, d), 1.1-1.3 (2H, m), 1.2 (3H, t), 1.36-1.5 (2H, m), 1.5-1.63 (1H, m), 1.65-1.72 (1H, m), 1.75-1.88 (3H, m), 2.2-2.32 (1H, m), 2.35-2.49 (1H, m), 4.0-4.17 (2H, m), 4.6 (2H, s), 7.19 (2H, d), 7.7 (2H, d), 10.44 (1H, s); MS m/e MH+ 362.
Reaction SMILES: [C:1]([N:4]1[C:8]2=[N:9][C:10]3[N:11]([CH3:27])[C:12](=[O:26])[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([N:23]=[N+]=[N-])[CH3:22])[C:14](=[O:16])[C:15]=3[N:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(O)C.[H][H]>[Pd].CO>[C:1]([N:4]1[C:8]2=[N:9][C:10]3[N:11]([CH3:27])[C:12](=[O:26])[N:13]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH2:23])[CH3:22])[C:14](=[O:16])[C:15]=3[N:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)N1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)N=[N+]=[N-])c(=O)n1C
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CC(=O)N1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)N)c(=O)n1C

Procedure:
A mixture of (R)-8-acetyl-3-(5-azidohexyl)-7,8-dihydro-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (200 mg, 0.534 mmol) and 10% palladium on carbon (50% water, 150 mg) in a solution of ethanol (50 ml) and methanol (10 ml) was treated with hydrogen gas (50 psi) on a Parr sharker at room temperature for 18 hours. After filtering through a pad of celite, the filtrate was concentrated under reduced pressure to provide (R)-8-acetyl-3-(5-aminohexyl)-7,8-dihydro-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione as a white powder.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N:31]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[N:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>C1COCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([N:31]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[NH:32][C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CCN(Cc2ccccc2)CC1
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 73.3 %

Procedure:
To a solution of diisopropylamine (153 mg, 1.5 mmol) in THF (20 mL) was added n-BuLi (2.5 M, 0.6 mL) at −75° C. under N2. After 5 min, ethyl 1-benzylpiperidine-4-carboxylate (247 mg, 1.0 mmol) was added and the resulting mixture then stirred at −70° C. for 10 min, before adding di-tert-butyl azodicarboxylate (345 mg, 1.5 mmol). The reaction was stirred for 30 min, then quenched with aqueous NH4Cl (10 mL) and extracted with EA (10 mL×3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product (350 mg, 72%) as an off-white solid. MS (ESI, m/e) [M+1]+ 478.3.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:23]([O:25]CC1C=CC=CC=1)=[O:24])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:13]([O:15]CC1C=CC=CC=1)=[O:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:6].C(O)C.[H][H]>[Pd].O>[NH2:1][C@H:2]([C:23]([OH:25])=[O:24])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]
Reactant: [H][H]
Reactant: CCCC[C@H](NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CCCC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)O
Reaction time: 8 h
Yield: 7.1 %

Procedure:
Z-Glu(Nle-OBzl)-OBzl (4.05 g) and 5% palladium on carbon (5% palladium/carbon, 0.40 g) were added to a mixed solution of ethanol (50 mL) and water (10 mL), and a catalytic reducing reaction was carried out at 50° C. overnight (14 hours) in a hydrogen gas atmosphere. Water (10 mL) was added to the reaction system in small portions during the reaction. The palladium/carbon was removed from the reaction system through filtration and the resulting filtrate was concentrated under reduced pressure. The residue was recrystallized from a small amount of water and ethanol to thus give γ-Glu-Nle (0.29 g) as hygroscopic crystals. Furthermore, the crystals were dissolved in water (30 mL) followed by the lyophilization of the solution to give γ-Glu-Nle (0.13 g, 0.50 mM) as a white powder. The characteristic values thereof will be given below:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:15](O)=[O:16])=[O:12])[NH:8][C:5]2=[N:6][CH:7]=1.[OH:26][C@@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C@H:14]([NH:13][C:11]([C:9]2[NH:8][C:5]3=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:12])[C:15]([N:29]2[CH2:30][CH2:31][CH:27]([OH:26])[CH2:28]2)=[O:16])=[CH:24][CH:23]=1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)cnc2[nH]1
Reactant: O[C@@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)C1)c1cc2cc(Cl)cnc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(S)-[(5-chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid (EXAMPLE 286, 30 mg, 0.08 mmol) in DMF (3 mL) was added (R)-(+)-3-hydroxypyrrolidine (7.2 mg, 0.08 mmol), HOBt (11.2 mg, 0.08 mmol) and DIPEA (30.3 μL, 0.17 mmol). After 5 min, EDCI (20.7 mg, 0.11 mmol) was added and the reaction was stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (20 mL) and ethyl acetate (3×20 mL). The combined organic fractions were washed with 2N sodium hydroxide solution (20 mL), brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude product was triturated from methanol to give the title compound. m/z (ES+)=431 [M+H]+; RT=3.44 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[C:18]3[CH2:17][N:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[C:15](=[O:28])[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:37](=[O:45])[C:38]([C:42](O)=[O:43])=[CH:39][NH:40][CH:41]=2)=[CH:32][CH:31]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:16]2[CH2:17][C:18]3[C:9]([O:8][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:42]([C:38]5[C:37](=[O:45])[C:36]([C:33]6[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=6)=[CH:41][NH:40][CH:39]=5)=[O:43])=[N:7][CH:6]=4)=[CH:10][CH:11]=[N:12][C:13]=3[NH:14][C:15]2=[O:28])=[CH:21][CH:22]=1
Reactant: O=C(O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(CN2Cc3c(Oc4ccc(N)nc4)ccnc3NC2=O)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3c(Oc4ccc(NC(=O)c5c[nH]cc(-c6ccc(F)cc6)c5=O)nc4)ccnc3NC2=O)cc1
Yield: 31.8 %

Procedure:
A solution of 5-[(6-aminopyridin-3-yl)oxy]-3-(4-methoxybenzyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one (100.00 mg; 0.26 mmol; 1.00 eq.), 5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (67.97 mg; 0.29 mmol; 1.10 eq.), pybop (179.26 mg; 0.34 mmol; 1.30 eq.), DMF (4.00 ml), and N,N-diisopropylethylamine (131.72 μl; 0.79 mmol; 3.00 eq.) was stirred at room temperature for 4 days. The reaction was concentrated, redissolved in DMSO, and purified via prep HPLC to afford 49 mg (26%) of 284 as a tan solid. LC-MS (M+H=593, obsd.=593).
Reaction SMILES: [CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:3][C:4]([OH:6])=[O:5].[CH:18]1([CH2:21]O)[CH2:20][CH2:19]1>C1C=CC=CC=1>[CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:3][C:4]([O:6][CH2:21][CH:18]1[CH2:20][CH2:19]1)=[O:5]
Reactant: OCC1CC1
Reactant: CC(C=CCC(C)CCCC(C)C)=CC(=O)O
Solvent: c1ccccc1
Product: CC(C=CCC(C)CCCC(C)C)=CC(=O)OCC1CC1

Procedure:
The acid chloride of 3,7,11-trimethyldodeca-2,4-dienoic acid (0.1 mole) is reacted with 0.2 mole of cyclopropylmethyl alcohol in benzene to yield cyclopropylmethyl 3,7,11-trimethyldodeca-2,4-dienoate.
Reaction SMILES: [CH3:1][C:2]([O:37]C(=O)C)([CH3:36])[C:3]([N:5]1[CH2:8][CH:7]([CH2:9][C:10]2[N:11]([CH3:35])[C:12]3[C:17]([N:18]=2)=[C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:15]=[C:14]([N:25]2[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]2[CH3:34])[N:13]=3)[CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.CO>[OH:37][C:2]([CH3:36])([CH3:1])[C:3]([N:5]1[CH2:8][CH:7]([CH2:9][C:10]2[N:11]([CH3:35])[C:12]3[C:17]([N:18]=2)=[C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:15]=[C:14]([N:25]2[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]2[CH3:34])[N:13]=3)[CH2:6]1)=[O:4]
Reactant: CC(=O)OC(C)(C)C(=O)N1CC(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)C(C)(C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
A mixture of acetic acid 1,1-dimethyl-2-{3-[9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purin-8-ylmethyl]azetidin-1-yl}-2-oxoethyl ester (125 mg, 0.23 mmol) and LiOH (114 μL, 0.46 mmol, 4M solution) in THF (3 mL) and MeOH (1 mL) was allowed to stir at r.t. for 18 h. Further LiOH (343 μL, 1.37 mmol, 4M solution) and the mixture stirred at 50° C. for 5 days. The reaction mixture was concentrated in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-10%) then dissolved in a mixture of MeCN and H2O and allowed to freeze-dry affording 855 as a white solid (88 mg, 77%). LCMS (method I): RT 2.88 min, [M+H]+ 505.3. 1H NMR (DMSO, 400 MHz): δ 8.09-8.08 (1 H, m), 7.64-7.61 (1 H, m), 7.28-7.27 (2 H, m), 5.02 (1 H, brd s), 4.57 (1 H, t, J=8.94 Hz), 4.26 (4 H, brd s), 4.17 (1 H, dd, J=10.24, 5.60 Hz), 4.03 (1 H, t, J=8.97 Hz), 3.77 (4 H, t, J=4.64 Hz), 3.74 (3 H, s), 3.67 (1 H, dd, J=9.96, 5.41 Hz), 3.21-3.20 (3 H, m), 2.85 (3 H, s), 1.28-1.21 (6 H, m)
Reaction SMILES: [C:1]([OH:9])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].C(Cl)(=O)C([Cl:13])=O>C(Cl)Cl.CN(C=O)C>[C:1]([Cl:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCCCCC(=O)Cl
Reaction time: 1 h

Procedure:
To a solution of 6-heptenoic acid (251 μL, 1.85 mmol) in CH2Cl2 (5 mL) at rt was added oxalyl chloride (476 μL, 5.55 mmol) and DMF (1 drop). After stirring for 1 hr, the reaction mixture was concentrated under reduced pressure and put under high vacuum for 15 min. The residual yellow oil was dissolved in CH2Cl2 (3 mL) and used as a stock solution (0.62M) for the subsequent acylation reactions.
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[CH:18][C:13]=3[C:12]([CH2:19][C:20]3[CH:21]=[N:22][C:23](S(C)(=O)=O)=[N:24][CH:25]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.CN1CCCC1=O.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][NH2:44].[OH-].[K+]>C(O)(=O)C>[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][NH:44][C:23]1[N:24]=[CH:25][C:20]([CH2:19][C:12]2[C:13]3[CH:18]=[N:17][CH:16]=[N:15][C:14]=3[NH:10][CH:11]=2)=[CH:21][N:22]=1
Reactant: NCc1ccccn1
Reactant: CS(=O)(=O)c1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncncc23)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: c1ccc(CNc2ncc(Cc3c[nH]c4ncncc34)cn2)nc1

Procedure:
In a microwave vial, 7-benzenesulfonyl-5-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (58, 12 mg, 0.028 mmol) was mixed with 600 μL of N-methylpyrrolidone and C-pyridin-2-yl-methylamine (59, 19.5 mg, 0.18 mmol). The reaction was irradiated at 160° C. for 40 minutes in microwave, then potassium hydroxide (500 μL, 4.00 M in water) was added and the reaction irradiated at 90° C. for 10 minutes in microwave. The reaction was neutralized with the addition of 120 μL of acetic acid, solvents were removed under vacuum, and the resulting material was dissolved in 400 μL at of dimethylsulfoxide for purification by HPLC. Samples were purified on Phenomenex C18 column (50 mm×10 mm ID) with mobile phase A of 0.1% trifluoroacetic acid in water, mobile phase B of 0.1% trifluoroacetic acid in acetonitrile, 20-100% B over 16 minutes at a flow rate of 6 mL/min. Appropriate fractions were collected and solvents removed under vacuum to provide the desired compound. MS (ESI) [M+H+]+=317.9.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([OH:6])=[O:5].O[Li].O.S(OC)(O[CH3:19])(=O)=O.[NH4+].[Cl-]>C1COCC1>[CH3:19][O:5][C:4](=[O:6])[C:3]1[C:7]([I:11])=[CH:8][CH:9]=[CH:10][C:2]=1[F:1]
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)c1c(F)cccc1I
Agent: [Cl-]
Agent: [Li]O
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(F)cccc1I
Temperature: 50 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a 200 mL round-bottomed flask were added 2-fluoro-6-iodo-benzoic acid (7.5 g, 28.2 mmol), LiOH.H2O (1.42 g, 33.8 mmol), and THF (100 mL). The resulting mixture was warmed to 50° C. and stirred for 2 h. Dimethyl sulfate (4.03 mL, 42.3 mmol) was then added and the mixture was warmed to 65° C. After 2 h, the mixture was cooled to room temperature and NH4Cl(aq) (50 mL, 13 wt % solution) was added. The two resulting layers were thoroughly mixed and then separated. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to a light brown oil (7.79 g, 99% yield). 1H NMR (400 MHz, CDCl3): 7.68-7.60 (m, 1H), 7.15-7.06 (m, 2H), 3.98 (s, 3H).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=1
Reactant: NCCc1ccccc1
Reactant: Clc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: Clc1cc2c(NCCc3ccccc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-phenethylamino-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[CH2:11][CH2:12][CH3:13].Br[CH2:15][C:16](=O)[CH2:17][CH3:18].C1(C)C=CC=CC=1>O1CCOCC1>[CH2:17]([C:16]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([CH2:11][CH2:12][CH3:13])[CH:4]=2)[O:7][CH:15]=1)[CH3:18]
Reactant: CCC(=O)CBr
Reactant: CCCc1cc(C(N)=O)ccc1O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCCc1cc(-c2nc(CC)co2)ccc1O
Yield: 48.8 %

Procedure:
A mixture of 4-hydroxy-3-propylbenzamide (200.0 mg, 1.1 mmol) (Example 43), 1-bromo-2-butanone (0.19 mL, 1.7 mmol), toluene (1.5 mL), and 1,4-dioxane (1.5 mL) was heated at reflux for 8 h with a Dean-Stark trap. The solvents were evaporated. The crude product was purified on HPLC to yield a solid (124.2 mg, 48%). LC/MS m/z 232 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 7.56-7.76 (m, 3H), 6.85 (d, J=8.4 Hz, 1H), 2.46-2.56 (m, 4H), 1.52-1.61 (m, 2H), 1.18 (t, J=7.6 Hz, 3H), 0.91 (t, J=7.3 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:11][CH:12]([N:14]1[C:27]2[CH:26]=[C:25]([C:28]#[N:29])[CH:24]=[CH:23][C:22]=2[S:21][C:20]2[C:15]1=[CH:16][CH:17]=[C:18]([Cl:30])[CH:19]=2)[CH3:13])(=O)=O>C1(C)C=CC=CC=1>[Cl:30][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:12]([CH3:13])[CH2:11][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[C:27]1[CH:26]=[C:25]([C:28]#[N:29])[CH:24]=[CH:23][C:22]=1[S:21]2
Reactant: C1CCNC1
Reactant: CC(COS(C)(=O)=O)N1c2ccc(Cl)cc2Sc2ccc(C#N)cc21
Solvent: Cc1ccccc1
Product: CC(CN1CCCC1)N1c2ccc(Cl)cc2Sc2ccc(C#N)cc21
Reaction time: 21 h

Procedure:
Pyrrolidine (21.1 cc) is added to a suspension of (2RS)-2-(7-chloro-2-cyano-10-phenothiazinyl)propyl methanesulphonate (72.1 g) in toluene (166 cc). The mixture is brought to 120° C. for 21 hours, and then to 150° C. for 12 hours. After cooling, the mixture is washed with distilled water (5×250 cc). The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) to give 7-chloro-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbonitrile (19.2 g).
Reaction SMILES: CC(C)([O-])C.[K+].COP([CH2:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=O)OC.[C:21]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=[O:29]>C(O)(C)(C)C>[CH3:19][C:16]([CH3:17])([CH3:18])[CH2:15][C:14](=[O:20])[CH2:13][C:21]1[C:22](=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=1
Reactant: COP(=O)(CC(=O)CC(C)(C)C)OC
Reactant: O=C1CCCCCCC1=O
Agent: CC(C)(C)CC(=O)C/C1=C/CCCCCC1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)CC(=O)CC1=CCCCCCC1=O

Procedure:
A solution of potassium tert-butoxide (0.192 g) in tert-butanol (10 mL) under an argon atmosphere was treated at 50° C. with (4,4-dimethyl-2-oxo-pentyl)-phosphonic acid dimethyl ester (0.38 g) and cyclooctane-1,2-dione (0,2 g), and the mixture was then heated at reflux for 12 h under an argon atmosphere. The reaction mixture was partitioned between water and AcOEt, the layers were separated, the aqueous layer extracted twice with AcOEt. The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (heptane/AcOEt 100% to 95%) to give (Z)-2-(4,4-dimethyl-2-oxo-pentyl)-cyclooct-2-enone (0.076 g) as a light yellow oil. MS (ESI): 237.0 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:8]([F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H][H]>[Pd].CO>[NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1c(C(=O)O)cc(F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)cc(C(=O)O)c1N
Yield: 95.1 %

Procedure:
2-Amino-5-fluoro-3-nitrobenzoic acid (142; 0.73 g) was dissolved into methanol (10 mL). To this solution was added 5% Pd/C (0.1 g). The resulting reaction mixture was stirred at room temperature under 1 atm of hydrogen for 18 h and then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford 2,3-diamino-5-fluorobenzoic acid 143 as a brown solid (0.59 g, 95%).