Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([CH3:14])=[N:8][C:7]=2[N:6]([CH3:15])[C:4]1=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=2)=[O:28])=[CH:25][CH:24]=1>CN(C=O)C.O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33][N:10]3[C:11]4[C:12](=[O:13])[N:3]([CH2:1][CH3:2])[C:4](=[O:5])[N:6]([CH3:15])[C:7]=4[N:8]=[C:9]3[CH3:14])=[CH:31][CH:30]=2)=[O:28])=[CH:37][CH:38]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: CCn1c(=O)c2[nH]c(C)nc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)c2c(nc(C)n2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 24.4 %

Procedure:
To a solution of l-ethyl-3,8-dimethylxanthine (170 mg), a synthetic process for which is described in Journal of American Chemical Society , 75, 114 (1953), in DMF (8 ml) were added potassium carbonate (169 mg) and 4-(4-chlorobenzoyl)benzyl bromide (278 mg) and the mixture was stirred at room temperature for 20 hours. This reaction mixture was diluted with water and extracted with ethyl acetate, and the extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was recrystallized (ethyl acetate-hexane) to provide the title compound as colorless powder (87 mg, 24%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=O)[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].[CH3:51][O:52][CH2:53][CH2:54][CH2:55][NH2:56]>CO>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15]/[C:16](=[N:56]\[CH2:55][CH2:54][CH2:53][O:52][CH3:51])/[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: COCCCN
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Solvent: CO
Product: COCCC/N=C1\C=C(N[C@H]2O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]2OC)C(=O)c2cc3c(c(O)c21)C(=O)[C@]1(OC)[C@H](O)Cc2cc(C)c(C(=O)OC)c(O)c2[C@]1(O)C3=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.5 %

Procedure:
To a solution of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (100 mg, 0.14 mmol) in methanol (3 mL) was added 3-methoxypropan-1-amine (127 mg, 1.43 mmol). The reaction mixture was stirred at room temperature under nitrogen for 2 h. The reaction was quenched by adding saturated ammonium chloride solution (25 mL). Then it was extracted with chloroform (75 mL) and washed with water (2×25 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the crude product. The crude material was purified by preparative TLC (silica gel, 90:10 chloroform/methanol) to afford (6R,6aS,14aR,E)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-9-(3-methoxypropylimino)-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (53.3 mg, 48.3%) as a dark blue solid: 1H NMR (500 MHz, CDCl3) δ 11.95 (s, 1H), 7.90 (s, 1H), 6.94 (d, J=8.8 Hz, 1H), 6.49 (s, 1H), 6.04 (s, 1H), 5.27 (s, 1H), 5.01-4.98 (m, 1H), 4.73 (d, J=8.6 Hz, 2H), 3.83 (s, 3H), 3.79 (s, 3H), 3.75-3.72 (m, 3H), 3.69-3.68 (m, 1H), 3.62 (s, 4H), 3.46 (t, J=6.1 Hz, 2H), 3.40 (s, 3H), 3.32 (s, 4H), 3.28 (s, 1H), 3.14 (t, J=9.2 Hz, 1H), 2.48 (d, J=4.9 Hz, 1H), 2.37 (s, 3H), 2.07-2.00 (m, 2H), 1.37 (d, J=6.2 Hz, 3H); MS (ESI+) m/z 769 (M+H); HPLC 89.1% (AUC), tR=11.35 min.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Br:14])=[C:10]([CH3:15])[C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH3:28])[CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Br:14])=[C:10]([CH3:15])[C:6]=1[C:7]([C:19]1[C:20]([CH3:28])=[CH:21][C:22]([O:26][CH3:27])=[C:23]([O:24][CH3:25])[C:18]=1[O:17][CH3:16])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(Br)c(C)c1C(=O)O
Reactant: COc1cc(C)cc(OC)c1OC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: COc1cc(C)c(C(=O)c2c(OC(C)=O)ccc(Br)c2C)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1C (6.83 g, 25 mmol), 3,4,5-trimethoxytoluene (4.56 g; 25 mmol), P2O5 (15.0 g) and dichloromethane (100 ml) is stirred at room temperature for 16 hours. Subsequently, the dichloromethane is distilled off and the residue is diluted with water and ethyl acetate. The organic phase is washed with water and concentrated. The residue is purified by preparative HPLC with acetonitrile:water 9:1 as eluent yielding the pure product as a yellow oil, 1.1 g, (10.1%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:12]([OH:14])=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(N(CC)CC)C.Cl.[N:23]1([CH2:29][CH:30]([N:34]2[CH:38]=[C:37]([C:39]3[C:40]4[CH:47]=[CH:46][N:45](COCC[Si](C)(C)C)[C:41]=4[N:42]=[CH:43][N:44]=3)[CH:36]=[N:35]2)[CH2:31][C:32]#[N:33])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1COCC1>[F:1][C:2]1[C:3]([C:12]([N:26]2[CH2:25][CH2:24][N:23]([CH2:29][CH:30]([N:34]3[CH:38]=[C:37]([C:39]4[C:40]5[CH:47]=[CH:46][NH:45][C:41]=5[N:42]=[CH:43][N:44]=4)[CH:36]=[N:35]3)[CH2:31][C:32]#[N:33])[CH2:28][CH2:27]2)=[O:14])=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CCC(CN1CCN(C(=O)c2ncc(C(F)(F)F)cc2F)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 0.25 h

Procedure:
N,N,N′,N-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (16.2 mg, 0.0000426 mol) was added to a solution of 3-fluoro-5-(trifluoromethyl)pyridine-2-carboxylic acid (11 mg, 0.053 mmol) and triethylamine (30 microL, 0.21 mmol) in THF (0.4 mL). After stirring for 15 minutes, 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (21 mg, 0.035 mmol; from Example 12, Step 2) was added and the reaction was stirred for two hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with water, 0.1N NaOH and brine, dried over sodium sulfate and concentrated. The residue was dissolved and stirred in a 1:1 mixture of DCM:TFA for 1 hour, concentrated, then stirred in methanol (1 mL) containing ethylenediamine (0.2 mL) for one hour. Preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH, was used to purify the product (9 mg, 48%). 1H NMR (300 MHz, d6-dmso): δ □8.88 (s, 1H), 8.81 (s, 1H), 8.67 (s, 1H), 8.48 (dd, 1H), 8.37 (s, 1H), 7.60 (d, 1H), 6.97 (d, 1H), 4.99 (tt, 1H), 3.67-3.56 (m, 2H), 3.25-3.12 (m, 4H), 2.92-2.79 (m, 2H), 2.66-2.55 (m, 1H), 2.55-2.38 (m 2H), 2.38-2.25 (m, 1H); LCMS (M+H)+: 528.3.
Reaction SMILES: C(N(CC)CC)C.Cl[CH:9]1[S:13][C:12]2[C:14]([C:19]#[N:20])=[CH:15][CH:16]=[C:17]([F:18])[C:11]=2[CH:10]1[Cl:21]>ClCCl>[Cl:21][C:10]1[C:11]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]([C:19]#[N:20])[C:12]=2[S:13][CH:9]=1
Reactant: N#Cc1ccc(F)c2c1SC(Cl)C2Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(F)c2c(Cl)csc12
Temperature: 25 °C
Reaction time: 168 h

Procedure:
Triethylamine (1.70 mL, 12.2 mmol) was added to a solution of 2,3-dichloro-4-fluoro-2,3-dihydrobenzo[b]thiophene-7-carbonitrile (1.57 g, 5.93 mmol) in dichloromethane (50 mL). The mixture was stirred at room temperature for 7 days, then the solvent was removed and the residue extracted with EtOAc. The organic extracts were then washed with water, brine and dried over Na2SO4. After removal of the solvent, the residue was purified by silica gel column chromatography to give 3-chloro-4-fluorobenzo[b]thiophene-7-carbonitrile as a white solid (1.19 g, 95% for two steps). 1H NMR (400 MHz, CDCl3, δ in ppm) 7.73 (dd, J=4.1, 8.2 Hz, 1H), 7.42 (s, 1H), 7.17 (dd, J=8.2, 10.5 Hz, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](O)=[O:20])[CH:17]=2)[N:12](C2CCCCO2)[N:11]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:52][N:53]([CH3:58])[CH2:54][CH2:55][CH2:56][NH2:57]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:57][CH2:56][CH2:55][CH2:54][N:53]([CH3:58])[CH3:52])=[O:20])[CH:17]=2)[NH:12][N:11]=1
Reactant: CN(C)CCCN
Reactant: O=C(O)c1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN(C)CCCNC(=O)c1ccc2[nH]nc(-c3cc4ccccc4o3)c2c1
Yield: 34 %

Procedure:
The title compound was prepared as described in Example 277 using of 3-benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylic acid (250 mg, 0.7 mmol), O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (292 mg, 0.77 mmol) and 3-dimethylaminopropyl amine (176 μL, 1.4 mmol); (87 mg, 34% yield). 1H NMR (DMSO-d6) δ 13.8 (s, 1H), (8.7–8.8 (m, 2H), 8.0 (d, 1H), 7.6–7.8 (m, 4H), 7.3–7.5 (m, 2H), 2.3 (s, 2H), 1.75 (m, 2H), ES-MS (m/z) 363 [M+1]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[CH3:36][C:37]1([C:40](O)=[O:41])[CH2:39][CH2:38]1>>[CH3:36][C:37]1([C:40]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH:11]=[C:10]([C:12]4[CH:17]=[N:16][N:15]5[C:18]([C:21]6[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:24]=[CH:25][CH:26]=6)=[CH:19][N:20]=[C:14]5[CH:13]=4)[CH:9]=[N:8]3)[CH2:3][CH2:2]2)=[O:41])[CH2:39][CH2:38]1
Reactant: CC1(C(=O)O)CC1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Product: CC1(C(=O)N2CCC(n3cc(-c4cnn5c(-c6cccc(NC(=O)NCC(F)(F)F)c6)cnc5c4)cn3)CC2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and 1-methylcyclopropanecarboxylic acid (Aldrich, Cat. No. 205605). LCMS (M+H)+: m/z=567.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=O.[NH2:14][C:15]1[CH2:16][C:17]([C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:28])=[CH:18][C:19]2[CH:25]=[CH:24][C:23](Br)=[CH:22][C:20]=2[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:14][C:15]1[CH2:16][C:17]([C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:28])=[CH:18][C:19]2[CH:25]=[CH:24][C:23]([C:5]3[CH:10]=[CH:9][C:1]([O:2][CH2:3][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:7][CH:6]=3)=[CH:22][C:20]=2[N:21]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(N)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(OCc4ccccc4)cc3)cc2N=C(N)C1
Temperature: 100 °C
Yield: 36 %

Procedure:
(1E,4E)-2-Amino-8-(4-(benzyloxy)phenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide (36%) was prepared as follows, substituting 4-(benzyloxy)phenylboronic acid for 4-(methoxycarbonyl)phenylboronic acid. (1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide (75.0 mgs, 0.206 mmol), 4-(methoxycarbonyl)phenylboronic acid (55.6 mgs, 0.309 mmol, tetrakis(triphenylphosphine)palladium(0) (23.8 mgs, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) was then used. m/z (APCI-pos) M+1=468.2.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[NH:15][C:14]([N+]([O-])=O)=[N:13][C:12]=3[N:11]([CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BrH:29]>>[CH:1]1([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[NH:15][C:14]([Br:29])=[N:13][C:12]=3[N:11]([CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Br
Reactant: O=c1c2[nH]c([N+](=O)[O-])nc2n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Product: O=c1c2[nH]c(Br)nc2n(CC2CCCCC2)c(=O)n1CC1CCCCC1

Procedure:
The title compound was prepared from 1,3-di-cyclohexylmethyl-8-nitro xanthine (1 g, 0.0026 mol) and concentrated hydrobromic acid (40 ml, 48%) over 32 hours using an analogous procedure to that described in Example 15. The title product was obtained as a crystalline solid, m.pt. 247° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([NH:20][C:2]2[C:7]([CH:8]=[O:10])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Product: CSc1ncc(C=O)c(NC2CCCC2)n1
Yield: 49.1 %

Procedure:
Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (17 g, 73 mmol) and cyclopentylamine (12.4 g, 146 mmol) were combined by the 3-step procedure of Example C1 to provide 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (8.5 g, 49% yield over 3 steps). 1H NMR (400 MHz, DMSO-d6): δ 9.73 (s, 1 H), 8.55 (d, J=6.4 Hz, 1 H), 8.51 (s, 1 H), 4.43 (m, 1 H), 2.50 (s, 3 H, obscured by DMSO), 2.03-1.98 (m, 2 H), 1.69-1.48 (m, 6 H); MS (ESI) m/z: 238.3 [M+H]+.
Reaction SMILES: C(P([CH2:7][S:8]([O:11][CH2:12][CH3:13])(=[O:10])=[O:9])(CC)=O)C.C([Li])CCC.[CH:19]([CH:21]([N:25]([CH3:48])[C:26]([CH:28]([NH:33][C:34](=[O:47])[CH:35]([NH:45][CH3:46])[C:36]([CH3:44])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:37])[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:22]([CH3:24])[CH3:23])=O>C1COCC1>[CH3:46][NH:45][C@H:35]([C:34]([NH:33][C@H:28]([C:26]([N:25]([C@@H:21]([CH:22]([CH3:24])[CH3:23])/[CH:19]=[CH:7]/[S:8]([O:11][CH2:12][CH3:13])(=[O:9])=[O:10])[CH3:48])=[O:27])[C:29]([CH3:30])([CH3:31])[CH3:32])=[O:47])[C:36]([CH3:37])([CH3:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCOS(=O)(=O)CP(=O)(CC)CC
Reactant: CNC(C(=O)NC(C(=O)N(C)C(C=O)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOS(=O)(=O)/C=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)(C)c1ccccc1)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 30.6 %

Procedure:
To a solution of ethyl diethylphosphorylmethanesulfonate (260 mg, 1.0 mmol) in anhydrous THF (3 mL) at −78° C. is added n-butyllithium (in hexanes, 0.44 mL, 1.1 mmol). After stirring for 20 min at −78° C., a solution of N-{1-[(1-Formyl-2-methyl-propyl)-methyl-carbamoyl]-2,2-dimethyl-propyl}-3-methyl-2-methylamino-3-phenyl-butyramide (1.0 mmol) in anhydrous THF (7 mL), which is freshly prepared as described in Reference Example 12, is added. The reaction mixture is stirred at −78° C. for additional 30 min, and then gradually warmed to room temperature. After 40 h, the reaction is quenched with water and extracted with CH2Cl2. The combined organic layers are washed with brine, dried (Na2SO4), filtered and concentrated. The residue is chromatographed on a silica gel column, eluting with 4:1 CH2Cl2/EtOAc to give 160 mg (31%) of the title compound as a yellow oil. HRMS (ESI) calcd for C27H45N3O5S [M+H] 524.3153, found 524.3157.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=3[O:21][Si](C(C)C)(C(C)C)C(C)C)[N:10]([C:32]([C:34]3[C:39]([F:40])=[CH:38][C:37]([F:41])=[CH:36][C:35]=3[F:42])=[O:33])[N:9]=2)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.Br[CH2:67][C:68]([NH2:70])=[O:69]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=3[O:21][CH2:67][C:68]([NH2:70])=[O:69])[N:10]([C:32](=[O:33])[C:34]3[C:35]([F:42])=[CH:36][C:37]([F:41])=[CH:38][C:39]=3[F:40])[N:9]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)CBr
Reactant: COc1cccc(C2SC(c3ccc(F)cc3)=NN2C(=O)c2c(F)cc(F)cc2F)c1O[Si](C(C)C)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cccc(C2SC(c3ccc(F)cc3)=NN2C(=O)c2c(F)cc(F)cc2F)c1OCC(N)=O

Procedure:
To [5-(4-fluoro-phenyl)-2-(3-methoxy-2-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone (32.3 μmol) is added tetrabutylammonium fluoride in tetrahydrofuran (1 M) (48.5 μmol). The mixture is stirred for an hour and 2-bromo-acetamide (48.5 μmol) is added. The mixture is stirred at room temperature for 12 hours. After evaporation of the solvent the residue is purified by preparative LC/MS (20-100% MeCN/H2O) to give 2-{2-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-6-methoxy-phenoxy}-acetamide: 1H NMR (400 MHz, CDCl3): δ 7.63-7.62 (m, 2H), 7.57 (s, 1H), 7.22-7.12 (m, 3H), 7.02 (dd, J1=8.4 Hz, J2=2 Hz, 2H), 6.9 (bs, 1H), 6.85 (t, J=8.4 Hz, 2H), 6.10 (s, 1H), 4.83 (d, J=15.2 Hz, 1H), 4.68 (d, J=15.2 Hz, 1H), 3.94 (s, 3H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.Cl[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28]>>[N:21]1([C:18]2[N:19]=[CH:20][C:15]([O:14][CH2:13][C:11]3[CH:10]=[N:9][N:8]([CH:5]4[CH2:4][CH2:3][N:2]([C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[CH2:7][CH2:6]4)[N:12]=3)=[CH:16][CH:17]=2)[CH:25]=[N:24][N:23]=[N:22]1
Reactant: C=CCOC(=O)Cl
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Agent: Cl
Product: C=CCOC(=O)N1CCC(n2ncc(COc3ccc(-n4cnnn4)nc3)n2)CC1

Procedure:
The title compound was synthesized from Intermediate 15 and allyl chloroformate in a manner similar to that described in Journal of Medicinal Chemistry 1998, 41, 4983-4994. 1H NMR (CDCl3): δ 9.46 (1H, s), 8.28 (1H, m), 8.04 (1H, m), 7.73 (1H, s), 7.61 (1H, m), 5.95 (1H, m), 5.40-5.20 (4H, m), 4.64 (3H, m), 4.24 (2H, m), 3.10 (2H, m), 2.16 (4H, m).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:14]([N:16]2[CH2:20][C@@H:19]([CH:21]3[CH2:23][CH2:22]3)[C@H:18]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)[CH2:17]2)=[O:15])[CH:7]=[CH:6]1.C(N(CC)CC)C.[CH3:45][C:46](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:47]>C(Cl)Cl>[C:46]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:14]([N:16]2[CH2:20][C@@H:19]([CH:21]3[CH2:23][CH2:22]3)[C@H:18]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)[CH2:17]2)=[O:15])[CH:7]=[CH:6]1)(=[O:47])[CH3:45]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: NCCCn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](C4CC4)C3)c21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](C4CC4)C3)c21
Yield: 78 %

Procedure:
A solution of 0.02 g (0.04 mmol) of 1-(N-(3-aminopropyl)-7-indolecarbonyl)-3-(R)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(cyclopropyl)pyrrolidine, 0.025 mL (0.18 mmol) of triethylamine and 0.015 mL (0.16 mmol) of acetic anydride in 2 mL of CH2Cl2 was stirred for 12 h at rt. The reaction mixture was partitioned between EtOAc and water. The organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, acetone:hexanes, 1:1) to give 17 mg of the title compound. Mass Spectrum (EI) m/e 545 (M+1).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>O>[NH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CN(C)c1ccc(-c2cc3ncccc3c(Cl)n2)cc1
Reactant: NCCCN
Solvent: O
Product: CN(C)c1ccc(-c2cc3ncccc3c(NCCCN)n2)cc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 5-chloro-7-(4-dimethylaminophenyl)-[1,6]naphthyridine (Example 2) (10 mg, 0.035 mmol) and 1,3-diaminopropane (200 microL, 2.4 mmol) was stirred at 100 ° C. for 5 hours. After cooling to room temperature, water was added and the resulting mixture was extracted with dichloromethane (2×3 mL). Purification by preparative thin layer chromatography afforded the title compound as a yellow film (8.5 mg). 1H NMR (CDCl3, 400 MHz) δ 8.85 (dd, 1H), 8.10 (d, 2H), 8.07 (d, 1H), 7.50 (s, 1H), 7.21 (dd, 1H), 6.81 (d, 2H), 3.87 (t, 2H), 3.02 (s, 6H), 2.97 (t, 2H), 1.90 (quint, 2H); MS (m/e) calculated for C19H23N5 321.2, found 322.4 (M+H).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[N:6]=[C:5]1[CH3:12])([CH3:3])[CH3:2].[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1.C1C=CC2N(O)N=NC=2C=1.CN(C=O)C>O>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:9]([C:7]3[N:6]=[C:5]([CH3:12])[N:4]([CH:1]([CH3:2])[CH3:3])[CH:8]=3)=[O:11])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: Cc1nc(C(=O)O)cn1C(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1C(C)C
Yield: 79.3 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) using 1-isopropyl-2-methyl-1H-imidazole-4-carboxylic acid (0.303 mmol, 51 mg), (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.253 mmol, 70.4 mg) and only a catalytic amount of HOBt (0.025 mmol, 3.41 mg). DMF (2 ml) was used as the solvent in the reaction. The work up was done by adding water to the reaction mixture and extracting it three times with DCM. The combined organics were washed twice with water. The organic phase was evaporated and the residue was purified by flash chromatography. 86 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.06 (d, 3H), 1.34 (d, 6H), 2.35 (s, 3H), 4.23-4.47 (m, 4H), 7.02 (d, 1H), 7.62 (s, 1H), 7.86 (d, 1H), 7.90-7.96 (m, 1H), 8.00 (s, 1H), 8.04 (d, 1H).