Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([C:17]4[C:25]5[C:24](N)=[N:23][CH:22]=[N:21][C:20]=5[S:19][CH:18]=4)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2C=CC3C(=CC(C(=[O:45])C)=CC=3)N=2)C=CC=CC=1.C(CC(OCC)=O)#N>>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([C:17]4[C:25]5[C:24](=[O:45])[NH:23][CH:22]=[N:21][C:20]=5[S:19][CH:18]=4)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc2ccc(-c3ccccc3)nc2c1
Reactant: Nc1ncnc2scc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Solvent: CCOC(=O)CC#N
Product: O=c1[nH]cnc2scc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12

Procedure:
Following the procedure for the one-pot synthesis of 5-(2-phenylquinolin-7-yl)-thieno[2,3-d]pyrimidin-4-ylamine from 1-(2-phenylquinolin-7-yl)-ethanone, but using ethyl cyanoacetate instead of malononitrile, the title compound was obtained as brown solid. 1H NMR (CDCl3, 400 MHz): δ=7.38 (s, 1H), 7.45-7.56 (m, 3H), 7.76-7.79 (dd, 1H, J=1.6 & 8.4 Hz), 7.86-7.91 (m, 2H), 7.98 (s, 1H), 8.15-8.18 (m, 2H), 8.25-8.27 (d, 1H, J=8.8 Hz), 8.34 (d, 1H, J=2.0 Hz). MS (ES+): 356.2 [MH+]. HPLC: tR=4.3 min (MicromassZQ, polar—15 min).
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[C:6]([NH:9][C@H:10]([CH2:22][O:23][CH3:24])[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1)=[O:12])(=[O:8])[CH3:7].C(N(CC)CC)C.COCC#C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CS(C)=O.CCOC(C)=O.CCOCC>[C:6]([NH:9][C@H:10]([CH2:22][O:23][CH3:24])[C:11]([NH:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:2]#[C:1][CH2:5][O:4][CH3:3])=[CH:19][CH:20]=1)=[O:12])(=[O:8])[CH3:7]
Reactant: C1CCOC1
Reactant: COC[C@@H](NC(C)=O)C(=O)NCc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#CCOC
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCC#Cc1ccc(CNC(=O)[C@@H](COC)NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To an anhydrous THF (10 mL) solution of (R)-2-acetamido-3-methoxy-N-(4-iodobenzyl)propanamide (376 mg, 1.0 mmol), triethylamine (280 μL, 2.0 mmol), 3-methoxyprop-1-yne (125 μl, 1.5 mmol), dichlorobis(triphenylphosphine)-palladium (II) (70 mg, 0.1 mmol), and CuI (38 mg, 0.2 mmol) were sequentially added under Ar. The mixture was stirred at room temperature (4 h), and then Et2O (10 mL) added and the precipitate filtered through a Celite pad. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel with EtOAc/MeOH (9/1) as the eluant to obtain (R)-6 (260 mg, 82%) as a beige solid: Rf=0.27 (EtOAc); mp 141-142° C.; [α]27D =+4.4° (c 1, DMSO); IR (nujol) 3278, 3096, 1640, 1554, 1458, 1370, 1304, 1257, 1192, 1099, 966, 903, 810, 732 cm−1; 1H NMR (CDCl3) δ 2.02 (s, CH3CO), 3.37 (s, OCH3), 3.45-3.47 (m, CHH′ and OCH3), 3.78 (dd, J=4.2, 9.0 Hz, CHH′), 4.32 (s, C≡CCH2OCH3) 4.38-4.52 (m, CH2N), 4.54-4.61 (m, NC(H)CO), 6.52 (d, J=6.6 Hz, CHNH), 6.91-6.99 (br t, CH2NH), 7.19 (d, J=7.9 Hz, 2 ArH), 7.41 (d, J=7.9 Hz, 2 ArH); 13C NMR (CDCl3) δ 23.2 (CH3CO), 43.2 (CH2N), 52.5 (CHCH2), 57.7 (C≡CCH2OCH3), 59.1 (OCH3), 60.4 (C≡CCH2OCH3), 71.7 (CH2OCH3), 85.2 (C≡C), 86.0 (C≡C), 121.8, 127.3, 132.1, 138.4 (C6H4), 170.4 (2 C(O)); HRMS (M+H+)(ESI+) 319.1652 [M+H+] (calcd for C17H22N2O4H+ 319.1658); Anal. Calcd. for C17H22N2O4.0.33H2O: C, 62.95; H, 7.04; N, 8.64. Found: C, 62.98; H, 6.78; N, 8.47.
Reaction SMILES: [NH2:1][C:2]1[N:21]([CH:22]([CH3:24])[CH3:23])[C:5]2=[CH:6][C:7]3[C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=3[CH:12]=[C:4]2[N:3]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH:22]([N:21]1[C:5]2=[CH:6][C:7]3[C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=3[CH:12]=[C:4]2[N:3]=[C:2]1[NH:1][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:23])[CH3:24]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3c(cc21)nc(N)n3C(C)C
Product: CCCCCN1C(=O)C(C)(C)c2cc3c(cc21)nc(NC(=O)c1ccccc1)n3C(C)C
Yield: 67.9 %

Procedure:
The compound (170 mg) is prepared from D6 (190 mg) and benzoyl chloride (0.2 ml; 1.60 mmol) as described in Example 174.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[Cl:27][C:28]1[C:29]([F:50])=[CH:30][C:31]([OH:49])=[C:32]([CH:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:35]2=[O:48])[CH:33]=1>>[Cl:27][C:28]1[C:29]([F:50])=[CH:30][C:31]([OH:49])=[C:32]([C:34]2([CH2:5][OH:16])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:35]2=[O:48])[CH:33]=1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: CCCCCN1C(=O)C(c2cc(Cl)c(F)cc2O)c2ccccc21
Product: CCCCCN1C(=O)C(CO)(c2cc(Cl)c(F)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(5-chloro-4-fluoro-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (46%): MS (ES+) m/z 360 (M−17), 400 (M+23).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([OH:35])(=[S:34])[CH3:33].C(=O)([O-])O.[Na+].O[CH2:42][CH2:43][N:44]([CH2:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:45](=[O:61])[NH:46][C@@H:47]([CH2:57][CH:58]([CH3:60])[CH3:59])[C:48]([N:50]1[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]1)=[O:49]>O1CCCC1>[C:32]([S:34][CH2:42][CH2:43][N:44]([CH2:62][CH2:63][C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)[C:45](=[O:61])[NH:46][C@@H:47]([CH2:57][CH:58]([CH3:59])[CH3:60])[C:48]([N:50]1[CH2:51][CH2:52][N:53]([CH3:56])[CH2:54][CH2:55]1)=[O:49])(=[O:35])[CH3:33]
Reactant: CC(O)=S
Reactant: CC(C)C[C@H](NC(=O)N(CCO)CCc1ccccc1)C(=O)N1CCN(C)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)SCCN(CCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)N1CCN(C)CC1
Reaction time: 1 h
Yield: 82 %

Procedure:
In anhydrous tetrahydrofuran (3 ml) are dissolved 1-[(2S)-2-[3-(2-hydroxyethyl)-3-phenethylureido]-4-methylvaleryl]-4-methylpiperazine (Compound No. 18-1, 500 mg) and triphenylphosphine (654 mg) under a nitrogen atmosphere, and the solution is stirred under salt-ice cooling for 30 minutes. To the solution are added a solution of diethyl azodicarboxylate (435 mg) in anhydrous tetrahydrofuran (1 ml) and a solution of thioacetic acid (0.2 ml) in anhydrous tetrahydrofuran (2 ml) successively dropwise while keeping liquid temperature at 5° C. The mixture is stirred for one hour, a 10% aqueous sodium hydrogencarbonate solution is added to the reaction mixture, and the whole is extracted with ether. The organic layer is washed with a 10% aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give 472 mg (82%) of the titled compound (Compound No. 27-1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:13])[C:6]2=O.C1COCC1.CO.[BH4-].[Na+]>O>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][C:5]([CH3:13])=[CH:6]2
Reactant: CC1Cc2c(Br)cc(F)cc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1=Cc2cc(F)cc(Br)c2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 48.4 g (199 mmol) of 4-bromo-6-fluoro-2-methylindan-1-one in 270 ml of a mixture of THF-methanol (2:1, vol.), 11.3 g (299 mmol) of NaBH4 was added in small portions, while vigorously stirring, over 2 h at 0° C. This mixture was stirred for 12 h at room temperature and then added to 500 ml of cold water. The organic layer was separated, the aqueous layer was extracted with 3×200 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The residue was dissolved in 500 ml of toluene, and 2.0 g of p-TosOH was added. The resulting solution was refluxed for 4 h using a Dean-Stark trap to remove the water formed, and then it was passed through a short Silica Gel 60 column (40-63 um, d 100 mm, l 80 mm, eluent: hexanes). This column was additionally washed with 250 ml of toluene. The combined organic extract was evaporated to dryness. The residue was dried in vacuum to give the title compound. Yield 38.0 g (84%).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26](=[O:45])[NH:27][C:28]([N:37]1[CH2:42][CH2:41][CH:40]([O:43][NH2:44])[CH2:39][CH2:38]1)=[N:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:24])([CH3:23])[CH3:22].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:32]([O:31][C:30](=[O:36])[NH:29][C:28]([N:37]1[CH2:38][CH2:39][CH:40]([O:43][NH:44][C:18]([C@@H:13]2[CH2:12][CH2:11][C@@H:10]3[CH2:17][N:14]2[C:15](=[O:16])[N:9]3[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:20])[CH2:41][CH2:42]1)=[N:27][C:26](=[O:45])[O:25][C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:33])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(ON)CC1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.200 g, 0.723 mmol, US 2005/20572 A1) in DCM (6.0 mL) was added di-tert-butyl{[4-(aminooxy)piperidin-1-yl]methylylidene}biscarbamate 65 (0.389 g, 1.086 mmol), 1-hydroxybenzotriazole (0.147 g, 1.086 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.208 g, 1.086 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 66 (0.33 g, 74%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][OH:11])[CH:3]=1.[Br:12]Br>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][OH:11])[C:3]=1[Br:12]
Reactant: BrBr
Reactant: Nc1cc(OCCO)ncn1
Solvent: CO
Product: Nc1ncnc(OCCO)c1Br
Yield: 104.7 %

Procedure:
To a suspension of 2-(6-aminopyrimidin-4-yloxy)ethanol (400 mg) in methanol (4 ml) is added dropwise a solution of bromine (437 mg) in methanol (2 ml). The mixture is evaporated to remove the solvent, and the residue is dissolved in ethyl acetate. The mixture is treated with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate/tetrahydrofuran. The organic layer is washed, dried, and evaporated to remove the solvent to give 2-(6-amino-5-bromopyrimidin-4-yloxy)ethanol (632 mg).
Reaction SMILES: C(OC([N:8]([C:29]1[N:30]=[C:31]2[CH:37]=[CH:36][N:35]([S:38]([C:41]3[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=3)(=[O:40])=[O:39])[C:32]2=[N:33][CH:34]=1)[CH2:9][C:10]([CH:12]1[CH:17]([CH3:18])[CH2:16][CH2:15][N:14]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:13]1)=[O:11])=O)(C)(C)C.Cl>>[CH3:18][CH:17]1[CH2:16][CH2:15][N:14]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[CH2:13][CH:12]1[C:10](=[O:11])[CH2:9][NH:8][C:29]1[N:30]=[C:31]2[CH:37]=[CH:36][N:35]([S:38]([C:41]3[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=3)(=[O:40])=[O:39])[C:32]2=[N:33][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(N(CC(=O)C4CN(C(=O)OCc5ccccc5)CCC4C)C(=O)OC(C)(C)C)cnc32)cc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(NCC(=O)C4CN(C(=O)OCc5ccccc5)CCC4C)cnc32)cc1
Yield: 99.5 %

Procedure:
Benzyl 3-(2-(tert-butoxycarbonyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)-4-methylpiperidine-1-carboxylate (1.45 g, 2.2 mmol) was stirred in HCl (4 N in 1,4-dioxane, 0.55 mL, 2.2 mmol) at ambient temperature for about 90 min. The solvent was removed under reduced pressure and the residue was neutralized with saturated aqueous NaHCO3. The aqueous phase was extracted with EtOAc (2×20 mL) and the combined organic extracts were washed with brine (16 mL), dried over anhydrous MgSO4, filtered, and concentrated to yield benzyl 4-methyl-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)acetyl)piperidine-1-carboxylate (1.23 g, 100%) as a brown amorphous solid: LC/MS (Table 2, Method a) Rt=2.74 min; MS m/z: 562 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=1.[H][H]>[Ni].CO>[C:28]([O:27][C:25]([NH:24][CH:20]([CH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:32])=[CH:14][CH:15]=1)[C:21]([OH:23])=[O:22])=[O:26])([CH3:30])([CH3:31])[CH3:29]
Reactant: [H][H]
Reactant: COC(=O)C=Cc1ccccc1Oc1ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: [Ni]
Solvent: CO
Product: COC(=O)CCc1ccccc1Oc1ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc1
Yield: 87.6 %

Procedure:
Raney nickel 2800 (2.5 g) was added to a degassed solution of the unsaturated ester 59 (2.5 g) in MeOH (50.0 mL) and the resulting suspension was treated with hydrogen at atmospheric pressure for 18 h. The suspension was filtered over a Celite® bed and concentrated. Flash chromatography (30-50% ethyl acetate in hexane containing 1% acetic acid) of the resulting residue gave the desired saturated ester 60 (2.2 g, 98%). 1H NMR (400 MHz, DMSO-d6): 12.63 (s, 1H), 7.31 (dd, J=7.6 and 1.6 Hz, 1H), 7.21 (m, 3H), 7.08 (m, 2H), 6.85 (d, J=8.4 Hz, 2H), 6.77 (d, J=7.6 Hz, 1H), 4.06 (m, 1H), 3.55 (s, 3H), 3.0 (m, 1H), 2.84 (t, J=7.2 Hz, 2H) 2.76 (m, 1H) 2.61 (t, J=7.2 Hz, 2H), 1.31 (s, 9H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[N:14][CH:13]=[C:12]([CH3:16])[N:11]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)[Cl:18]>C(OCC)C>[ClH:18].[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[N:14][CH:13]=[C:12]([CH3:16])[N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCl
Agent: Cc1cncc(C#Cc2cccc(F)c2)n1
Solvent: CCOCC
Product: Cl

Procedure:
2-[(3-Fluorophenyl)ethynyl]-6-methylpyrazine (520 mg, 2.45 mmol) was dissolved in CH2Cl2 (3 mL), and the resulting solution was treated with HC1 in diethyl ether (2.7 mL of a 1.0M solution, 2.7 mmol). The mixture was sonicated, and the solvent decanted. The remaining solid was dried under high vacuum to afford 2-[(3-fluorophenyl)ethynyl]-6-methylpyrazine hydrochloride (338 mg, 60% yield) as a light yellow solid. M.p. 62-63° C. 1H NMR (CDCl3, 300 MHz) Δ8.73 (s, 1H), 8.57 (s, 1H), 7.54-7.35 (m, 3H), 7.28-7.20 (m, 3H), 2.84 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH:12]=2)[CH:6]=1)C.[OH-].[Li+]>O1CCOCC1>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:12]=[C:11]([C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[C:4]([OH:23])=[O:3])[O:15][N:14]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cccc(-c2cc(-c3ccc(Cl)cc3)no2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cccc(-c2cc(-c3ccc(Cl)cc3)no2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In a 25 ml round flask, 250 mg (0.76 mmol) of 3-[3-(4-chloro-phenyl)-isoxazol-5-yl]-benzoic acid ethyl ester are dissolved in 5 ml of dioxane. After addition of 1M aqueous lithium hydroxide (0.99 ml, 0.99 mmol, 1.3 eq.), the mixture is stirred at room temperature for 20 h. Then, the dioxane is removed in vacuo, 5 ml of water is added and the pH adjusted to 2 by addition of 1M hydrochloric acid. The precipitate is filtered off, washed with water and dried. This yields the title compound as a white solid. Mass spectrum: m/z (M−H)−: 298.1; 300.1
Reaction SMILES: C(OC1C(=O)N=C(CC2(N3C4=NC=CC=C4C=C3)CCCC2)N2CCN(C)C(=O)C=12)C1C=CC=CC=1.[CH:37]1([N:40]([CH2:73][CH2:74]O)[C:41]([C:43]2[C:48]([O:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[C:47]([OH:57])[N:46]=[C:45]([CH2:58][C:59]3([N:64]4[C:68]5=[N:69][CH:70]=[CH:71][CH:72]=[C:67]5[CH:66]=[CH:65]4)[CH2:63][CH2:62][CH2:61][CH2:60]3)[N:44]=2)=[O:42])[CH2:39][CH2:38]1>>[CH2:50]([O:49][C:48]1[C:47](=[O:57])[N:46]=[C:45]([CH2:58][C:59]2([N:64]3[C:68]4=[N:69][CH:70]=[CH:71][CH:72]=[C:67]4[CH:66]=[CH:65]3)[CH2:60][CH2:61][CH2:62][CH2:63]2)[N:44]2[CH2:74][CH2:73][N:40]([CH:37]3[CH2:39][CH2:38]3)[C:41](=[O:42])[C:43]=12)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: O=C(c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CC1
Agent: CN1CCn2c(CC3(n4ccc5cccnc54)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(n4ccc5cccnc54)CCCC3)n2CCN1C1CC1

Procedure:
9-Benzyloxy-2-cyclopropyl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (419) was prepared following the same method as described for 9-benzyloxy-2-methyl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (407) from 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclopropyl-(2-hydroxyethyl)-amide (418) (60 mg, 0.11 mmol) and was obtained as white sticky solid (45 mg, 80%).
Reaction SMILES: [CH:1]1([C:6]2[N:7]=[C:8]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26](OC)=[O:27])=[CH:21][CH:20]=3)[C:9]3[S:15](=[O:17])(=[O:16])[CH2:14][CH2:13][CH2:12][C:10]=3[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C>>[CH:1]1([C:6]2[N:7]=[C:8]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][OH:27])=[CH:21][CH:20]=3)[C:9]3[S:15](=[O:17])(=[O:16])[CH2:14][CH2:13][CH2:12][C:10]=3[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)Cc1ccc(Cc2nc(C3CCCC3)nc3c2S(=O)(=O)CCC3)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: O=S1(=O)CCCc2nc(C3CCCC3)nc(Cc3ccc(CCO)cc3)c21
Yield: 73.9 %

Procedure:
Following general procedure E1, methyl 2-(4-((2-cyclopentyl-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)methyl)phenyl)acetate (0.060 g, 0.14 mmol) was reacted with DIBAL (1.0 M, 0.58 mL, 0.58 mmol) to afford the title compound (0.040 g, 71%) as a white solid. MW=386.51. 1H NMR (DMSO-d6, 500 MHz) δ 7.26 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.5 Hz, 2H), 4.58 (t, J=5.5 Hz, 1H), 4.38 (s, 2H), 3.69-3.62 (m, 2H), 3.59-3.52 (m, 2H), 3.23 (quin, J=8.0 Hz, 1H), 3.06 (t, J=6.5 Hz, 2H), 2.66 (t, J=7.0 Hz, 2H), 2.33-2.25 (m, 2H), 2.00-1.91 (m, 2H), 1.81-1.56 (m, 6H); APCI MS m/z 387 [M+H]+.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)=O>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)=[S:10]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(Nc1ccc(F)cc1F)c1ccccn1
Solvent: Cc1ccccc1
Product: Fc1ccc(NC(=S)c2ccccn2)c(F)c1
Yield: 94.7 %

Procedure:
Lawesson's reagent (29.8 g, 74 mmol) and N-(2,4-difluorophenyl)-2-pyridinecarboxamide (14.37 g, 61 mmol) were combined in toluene (185 mL) and refluxed for 3 hours. After evaporation of the solvent, the residue was dissolved in dichloromethane, preadsorbed on silica gel, and flash chromatographed (eluted with 2% acetate in petroleum ether) to provide N-(2,4-difluorophenyl)-2-pyridinecarbothioamide as a yellow solid (14.45 g, 94%) m.p. 124°-129° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2.N1C=CC=CC=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(Cl)Cl.CCOC(C)=O>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:1][CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]3)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=C1CCc2cc(OCCO)ccc2N1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)CCC(=O)N3)cc1
Reaction time: 4 h
Yield: 26.8 %

Procedure:
To a solution of 6-(2-hydroxyethoxy)-3,4-dihydroquinolin-2(1H)-one (0.15 g, 0.724 mmol) in DCM (2 mL) was added pyridine (0.117 mL, 1.448 mmol) and 4-methylbenzene-1-sulfonyl chloride (0.152 g, 0.796 mmol) and the reaction was stirred for 4 h. The reaction was diluted with EtOAc (25 mL), washed with 0.1 N HCl (10 mL), brine (10 mL), and sat. NaHCO3 solution (10 mL). The organic layer was dried over sodium sulfate, evaporated to dryness, and purified by flash chromatography on silica gel (4 g, 50% EtOAC in hexanes) to yield 2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)ethyl 4-methylbenzenesulfonate (0.07 g, 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13](=[O:39])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([C:29](=[O:38])[C:30]#[C:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2I)[CH:15]=1>>[CH3:11][O:12][C:13](=[O:39])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)/[C:30](=[C:31](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)/[C:29]2=[O:38])[CH:15]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#CC2CCCCC2)c2ccccc2I)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(/c3ccc(Cl)cc3)C3CCCCC3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 84 starting from 4-chlorophenylboronic acid (commercially available) and 3-{[(3-cyclohexyl-propynoyl)-(2-iodo-phenyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.02 (s, 1H), 7.93 (d, 1H), 7.47-7.51 (m, 13H), 7.39 (t, 1H), 7.10 (d, 2H), 7.01 (t, 1H), 6.59-6.63 (m, 2H), 5.71 (d, 2H), 5.02 (s, 2H), 4.62 (t, 1H), 3.91 (s, 3H), 1.44-1.76 (m, 6H), 1.01-1.18 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[C:37]2[C:32](=[CH:33][C:34](B(O)O)=[CH:35][CH:36]=2)[N:31]=[CH:30][CH:29]=1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:35]3[CH:36]=[C:37]4[C:32](=[CH:33][CH:34]=3)[N:31]=[CH:30][CH:29]=[N:28]4)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1ccc2nccnc2c1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Cl)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccc3nccnc3c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 46 using (R)-5-chloro-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 38.1) and quinoxalin-6-ylboronic acid. LC-MS (Condition 6) tR=1.64 min, m/z=496.0 [M+H]+.
Reaction SMILES: C(OC(N1[CH2:12][CH:11]([CH:13]=O)[CH:10]2OC[C:17]([O:20][CH3:21])([O:18]C)[CH:9]12)=O)(C)(C)C.[C:22](Br)(Br)(Br)Br.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>ClCCl.CCCC(C)C>[CH3:17][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12].[CH3:22][CH2:21][O:20][C:17]([CH3:9])=[O:18]
Reactant: COC1(OC)COC2C(C=O)CN(C(=O)OC(C)(C)C)C21
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCC(C)C
Solvent: ClCCl
Product: CCOC(C)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The aldehyde 9-1 (318.3 mg, 1.06 mmol) (see reference example 3) in 6 mL dichloromethane (DCM) was added dropwise to a solution of CBr4 (700 mg, 2.11 mmol) and Ph3P (1.10 g, 4.19 mmol) in 10 mL DCM, with cooling in an ice bath. After stirring at 0° C. for 2 h, the mixture was diluted with 30 mL iso-hexane and then filtered through a short Celite column. The column was washed with 20 mL i-hexane, followed by 3/1 i-hexane-DCM. The filtrate was concentrated in vacuo to give light yellow solids. Flash chromatography (silica, 3/1 i-hexane-EtOAc) gave compound 9-2 (339.5 mg, 70% yield).