Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH2:11][CH2:12][CH3:13])[NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C([O-])(=O)C.[Na+].CO[CH:21]1[CH2:25][CH2:24][CH:23](OC)O1>C(O)(=O)C>[CH2:11]([C:4]1[NH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([N:1]2[CH:21]=[CH:25][CH:24]=[CH:23]2)[N:3]=1)[CH2:12][CH3:13]
Reactant: CCCc1nc(N)c(C(=O)OC)[nH]1
Reactant: COC1CCC(OC)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1nc(-n2cccc2)c(C(=O)OC)[nH]1
Yield: 46.2 %

Procedure:
To stirred acetic acid (1.5 L) at 80° C. was added over a 5-minute period a mixture of methyl 4-amino-2-propylimidazol-5-carboxylate (Example 4, 145 g, 0.798 mol) and sodium acetate (388 g, 4.73 mol). The mixture was heated at reflux for 5 minutes and then 2,5-dimethoxy-tetrahydrofuran (117 g, 0.885 mol) added all at once. The resulting dark solution was refluxed for 20 minutes, then poured onto ice. The gummy mixture was extracted with dichloromethane, the combined organic layers washed with water and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue dissolved in dichloromethane (2 L). The dichloromethane solution was treated with silica gel (500 g) and the suspension filtered through a bed of silica gel (300 g) eluting with dichloromethane. The filtrate was evaporated to dryness under reduced pressure and the crude product recrystallized from ether/hexane (2:1) to provide 86 g (46% yield) methyl 2-propyl-4-(1H-pyrrol-1-yl)imidazol-5-carboxylate, mp 135°-138° C. MS (DEI) 234 (M+1).
Reaction SMILES: O[C:2]1([C:17]2[C:25]([OH:26])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=2)[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]1=[O:16].C(N(C(C)C)CC)(C)C.S(Cl)(Cl)=O>ClCCl.[Zn]>[OH:26][C:25]1[C:17]([CH:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]2=[O:16])=[CH:18][C:19]2[O:23][CH2:22][O:21][C:20]=2[CH:24]=1
Reactant: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2cccnc21
Agent: [Zn]
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2cccnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a solution of 3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (4.00 g, 11.2 mmol) in anhydrous dichloromethane (80.0 mL) was added diisopropylethylamine (6.10 mL) and thionyl chloride (2.77 g, 23.5 mmol) under nitrogen at 0° C. The reaction mixture was stirred at 0° C. for 1 h and concentrated in vacuo to dryness. The residue was dissolved in THF/acetic acid (7:3, 100 mL) followed by the addition of Zn dust (3.08 g, 47.1 mmol) in one portion. The reaction mixture was stirred at ambient temperature for 16 h, filtered and the residue was washed with ethyl acetate (30.0 mL). The filtrate was concentrated in vacuo to dryness. The residue was dissolved in ethyl acetate (200 mL), washed with saturated ammonium chloride (3×50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography to give the title compound (2.92 g, 76%): 1H NMR (300 MHz, CDCl3) δ 8.64 (br, 1H), 8.26 (d, 1H), 7.52 (d, 1H), 7.05 (dd, 1H), 6.53 (s, 1H), 6.25 (s, 1H), 5.84 (d, 2H), 5.02 (s, 1H), 3.86-3.75 (m, 2H), 1.76-1.67 (m, 2H), 1.33-1.28 (m, 4H), 0.85 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 178.5, 157.4, 150.9, 147.8, 147.5, 141.6, 133.2, 121.7, 118.7, 114.1, 106.4, 101.2, 101.1, 46.5, 39.8, 28.9, 27.3, 22.3, 13.9; MS (ES+) m/z 341 (M+1).
Reaction SMILES: C(#N)C.[Si:4]([O:11][C@@H:12]([C@@H:14]1[C@@H:17](SC2C=CC=CC=2)[NH:16][C:15]1=[O:25])[CH3:13])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5].[O:26]1[CH2:30][CH2:29][CH2:28][C@@H:27]1[C:31](=[S:33])[OH:32]>[Cu-]=O.C1(C)C=CC=CC=1>[Si:4]([O:11][C@@H:12]([C@@H:14]1[C@@H:17]([S:33][C:31]([C@H:27]2[CH2:28][CH2:29][CH2:30][O:26]2)=[O:32])[NH:16][C:15]1=[O:25])[CH3:13])([C:7]([CH3:10])([CH3:8])[CH3:9])([CH3:6])[CH3:5]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1Sc1ccccc1
Reactant: OC(=S)[C@H]1CCCO1
Agent: O=[Cu-]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1SC(=O)[C@H]1CCCO1

Procedure:
15 ml of acetonitrile, 15 ml of toluene and 0.8 g of copper (I) oxide (5.6 mmol) were added to (3S,4R)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-phenylthio-2-azetidinone (2.7 g, 8.0 mmol), and (2R)-tetrahydrofuran-2-thiocarboxylic acid (1.2 g, 9.1 mmol) was added dropwise into the resulting mixture at 10° C. while being stirred.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[N:11]=[C:10]([S:17][CH2:18][C:19]#[N:20])[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[N:11]=[C:10]([S:17][CH2:18][C:19](=[N:24][OH:25])[NH2:20])[N:9]=2)=[CH:21][CH:22]=1
Reactant: NO
Reactant: CCCc1cc(NCc2ccc(Cl)cc2)nc(SCC#N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cc(NCc2ccc(Cl)cc2)nc(SCC(N)=NO)n1

Procedure:
A mixture of 6.60 g. (0.02 mole) of [4-(p-chlorobenzylamino)-6-propyl-2-pyrimidinylthio]acetonitrile, 2.76 g. (0.04 mole) of hydroxylamine hydrochloride and 8.48 g. (0.08 mole) of sodium carbonate in 100 ml of N,N-dimethylformamide was heated on a steam bath for three and one-half hours. The mixture was filtered, diluted with 250 ml of water and extracted with 100 ml of ether. The ether layer was dried over magnesium sulfate, filtered and evaporated in a rotary evaporator. The residue was dissolved in ethanol, diluted with petroleum ether and cooled in ice. The precipitate which formed was collected and recrystallized from a mixture of ethanol-petroleum ether to give the analytical sample, m.p. 50° dec.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[NH:16][C:15](=O)[CH2:14][O:13][C:12]([CH3:23])([C:18]4[CH:22]=[CH:21][S:20][CH:19]=4)[C:11]=3[CH:24]=2)=[CH:5][CH:4]=[C:3]1[C:25]#[N:26].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[NH:16][C:15](=[S:36])[CH2:14][O:13][C:12]([CH3:23])([C:18]4[CH:22]=[CH:21][S:20][CH:19]=4)[C:11]=3[CH:24]=2)=[CH:5][CH:4]=[C:3]1[C:25]#[N:26]
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(c1ccsc1)OCC(=O)N2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(c1ccsc1)OCC(=S)N2

Procedure:
Prepared from 1-methyl-5-[5-methyl-2-oxo-5-(3-thienyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl]-1H-pyrrole-2-carbonitrile and Lawesson's reagent generally according to example 10. 1H NMR (DMSO-d6): δ 12.11 (s, 1H), 7.45-7.54 (m, 3H), 7.37 (d, J=1.62 Hz, 1H), 7.29 (dd, J=2.87, 1.3 Hz, 1H), 7.06 (dd, J=5.02, 1.28 Hz, 1H), 7.03 (d, J=4.09 Hz, 1H), 6.37 (d, J=4.09 Hz, 1H), 4.46 (d, J=15.33 Hz, 1H), 4.35 (d, J=15.33 Hz, 1H), 3.70 (s, 3H), 1.99 (s, 3H); MS (ESI) m/z 378 ([M−H]−); Anal. calcd for C20H17N3OS2: C, 63.3; H, 4.52; N, 11.07. Found: C, 63.06; H, 4.76; N, 10.29.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[C:24]([O:28][C:29]([N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([CH:41]([CH3:48])[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:39]=2)[NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O1CCCC1>[C:24]([O:28][C:29]([N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([CH:41]([CH3:48])[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:39]=2)[N:34]([C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: CCOC(=O)CC(C)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCN2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Reaction time: 18 h
Yield: 51.7 %

Procedure:
A mixture of [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid (0.536 g) and 7-(2-ethoxycarbonyl-1-methyl-ethyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester (396 mg, Reference Example 19) in tetrahydrofuran (10 ml) containing 4 Angström molecular sieves (0.5 g) was treated with triethyl amine (638 μl), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (518 mg) and 4-dimethyl-aminopyridin (14 mg). After stirring for 5 hours further aliquots of [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid (0.178 g) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (172 mg) were added and stirring was continued for a further 18 hours. The reaction mixture was filtered through a celite and the filter pad was washed with ethyl acetate (50 ml). The combined filtrate and washings were washed three times with aqueous saturated ammonium chloride (20 ml), then dried over magnesium sulfate and then evaporated (40° C., 40 mbar). The residue (1.2 g) was submitted to chromatography (36 g silica, 0.040-0.063 mm particle size) eluting with a mixture of cyclohexane and ethyl acetate (70:30, v/v) to afford the title compound as a white powder (379 mg). TLC: RF=15/65 (cyclohexane:ethyl acetate, 1:1). 1H NMR (400 HMz, (CD3)2SO, at room temperature, we observe a mixture of rotamers): δ1.14 (t, J=7 Hz, 31); 1.24 (d, J=7 Hz, 3H); 1.48 (s, 9 H); 2.26 (s, 3H); 2.58 (d, J=7.5 Hz, 2H); 3.17 (m, 1H); 3.64 (m, 2H); from 3.75 to 3.90 (m, 7H); 4.04 (q, J=7 Hz, 2H); from 6.55 to 6.85 (very broad band, 2H); 6.96 (t, J=7.5 Hz, 1H); 7.00 (broad d, J=8 Hz, 1H); from 7.10 to 7.20 (m, 2H); 7.46 (broad band, 1H); 7.64 (broad s, 1H); 7.78 (d, J=8 Hz, 1H); 8.01 (d, J=8 Hz, 1H); 8.48 (s, 1H); 8.54 (broad s, 1H). MS (EI): 644 (M+).
Reaction SMILES: [CH:1]1[C:16]2=[C:17]3[C:4]([CH2:5][CH2:6][CH2:7][N:8]3[CH2:9][C@@H:10]3[C@H:15]2[CH2:14][NH:13][CH2:12][CH2:11]3)=[CH:3][CH:2]=1.C=O.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:34]>ClCCCl.C(O)C.CCOCC.C(O)(=O)C>[ClH:34].[ClH:34].[CH3:20][N:13]1[CH2:12][CH2:11][C@H:10]2[C@H:15]([C:16]3[CH:1]=[CH:2][CH:3]=[C:4]4[C:17]=3[N:8]([CH2:7][CH2:6][CH2:5]4)[CH2:9]2)[CH2:14]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1CN3CCC2
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCOCC
Product: CN1CC[C@@H]2CN3CCCc4cccc(c43)[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (±)-cis 5,6,8a,9,10,11,12,12a-octahydro-4H,8H-quino[1,8-bc]-2,6-naphthyridine free base from EXAMPLE 123 (50 mg, 0.22 mmol) in 10 mL of 1,2-dichloroethane was added 37% aqueous formaldehyde (0.05 mL, 0.58 mmol) and sodium triacetoxyborohydride (0.19 g, 0.87 mmol) and a couple drops of acetic acid. The resulting mixture was stirred at ambient temperature for 1 h and then the reaction was quenched with water. The mixture was partitioned between chloroform and saturated aqueous sodium carbonate. The organics were washed with brine, dried (K2CO3) and concentrated in vacuo. The residue (40 mg, 0.16 mmol) was dissolved in 1 mL ethanol and 5 mL of ether and then there was added 2M HCl in ether (0.25 mL, 0.5 mmol). A solid precipitated out of solution. The solvents were decanted and the solid was triturated twice with ether and dried in vacuo to afford the title compound of EXAMPLE 125 as an off white powder. 1H NMR (dmso-D6) δ: 10.65 (broad s, 1H), 6.77 (d, 1H, J=7.0 Hz), 6.73 (d, 1H, J=7.7 Hz), 6.47 (t, 1H, J=7.4 Hz), 3.45-3.35 (m, 1H), 3.30-2.85 (overlapping m, 8H), 2.80-2.58 (m, 8H), 2.35-2.25 (m, 1H), 2.22-2.15 (m, 1H), 1.90-1.75 (m, 3H). LRMS (ES)+: 243.4 (M+H)+.
Reaction SMILES: [CH2:1]([N:13]1[N:17]=[N:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Br:22]Br>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:22][CH:18]([C:15]1[N:16]=[N:17][N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:14]=1)[C:19]([OH:21])=[O:20]
Reactant: BrBr
Reactant: CCCCCCCCCCCCn1nnc(CC(=O)O)n1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCn1nnc(C(Br)C(=O)O)n1
Temperature: 45 °C
Reaction time: 5 h
Yield: 89.4 %

Procedure:
The 2-dodecyltetrazoleacetic acid (4.7 g, 15.8 mmol) was suspended in carbon tetrachloride (5 mL) and warmed to 45° C. The solution was diluted by dropwise addition of bromine (2.6 g, 16.3 mmol), and the mixture was further heated to reflux with stirring for 5 hours. The solution was cooled to room temperature, diluted with 50 mL of ethyl acetate, washed with brine, dried (MgSO4), and filtered. The filtrate was concentrated in vacuo to give α-bromo-2-dodecyltetrazoleacetic acid (5.3 g, 86%) as an orange colored liquid;
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.S(Cl)([Cl:25])=O>CN(C=O)C>[Cl:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(O)ncnc2cc1OCCCN1CCCC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1

Procedure:
A mixture of 4-hydroxy-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (1.7 g, 5 mmol) and thionyl chloride (25 ml) containing DMF (0.2 ml) was heated at reflux for 3 hours. Excess thionyl chloride was removed by evaporation and by azeotroping with toluene (×2). The residue was suspended in ether and 10% aqueous solution of sodiurn hydrogen carbonate was added to the mixture. The organic layer was separated, dried (MgSO4) and the solvent removed by evaporation to give 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (1.94 g, quantitative).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:15]([F:18])([F:17])[F:16])=[N:12]2)=[C:7]([OH:19])[CH:6]=1)=[O:4].[N+:20]([O-])([OH:22])=[O:21].CCCCCC.C(OCC)(=O)C>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:15]([F:18])([F:16])[F:17])=[N:12]2)=[C:7]([OH:19])[C:6]=1[N+:20]([O-:22])=[O:21])=[O:4]
Reactant: COC(=O)c1cc(O)c2ccc(C(F)(F)F)nc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2nc(C(F)(F)F)ccc2c(O)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
5-Hydroxy-2-trifluoromethyl-quinoline-7-carboxylic acid methyl ester (46.0 g) is dissolved in concentrated sulfuric acid (200 mL, 97%) at 0-5° C. To this cooled solution is added drop wise fuming nitric acid (7 mL, 100%). After the addition is complete, the reaction mixture is allowed to warm to room temperature. TLC analysis (hexane/ethyl acetate=4:1) after 30 min shows reaction completion. The reaction mixture is slowly poured onto an ice/water mixture (ca. 2 mL) and the crystals were filtered off, washed thoroughly with water and dried in vacuum to afford 47.0 g of the title compound of the formula
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:44]1[C:51]([CH3:52])=[CH:50][CH:49]=[CH:48][C:45]=1[C:46]#[N:47].[O:53]1[CH2:58][CH2:57][N:56]([C:59]2[C:60]([NH2:78])=[N:61][C:62]3[C:67]([CH:68]=2)=[CH:66][C:65](B2OC(C)(C)C(C)(C)O2)=[CH:64][CH:63]=3)[CH2:55][CH2:54]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[NH2:78][C:60]1[C:59]([N:56]2[CH2:57][CH2:58][O:53][CH2:54][CH2:55]2)=[CH:68][C:67]2[C:62](=[CH:63][CH:64]=[C:65]([C:44]3[C:51]([CH3:52])=[CH:50][CH:49]=[CH:48][C:45]=3[C:46]#[N:47])[CH:66]=2)[N:61]=1
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Reactant: Cc1cccc(C#N)c1Br
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(C#N)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 140 °C

Procedure:
To a mixture of potassium phosphate (5.98 g, 28.2 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.54 g, 1.13 mmol), Pd2(dba)3 (0.26 g, 0.28 mmol), 2-bromo-3-methylbenzonitrile (2.21 g, 11.26 mmol) and 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (2.00 g, 5.63 mmol, prepared as in Example 2, Step 1-2) was added dioxane (50.0 mL) and water (25.0 mL). The mixture was heated to 140° C. for 10 min. The reaction mixture was allowed to cool to RT, filtered and then partitioned between EtOAc and water. The organic layer was washed with water and brine, and concentrated. The residue was diluted with EtOAc and then filtered. The solid was dried in air to afford 2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylbenzonitrile as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=O.[C:24]([CH2:27][C:28](=O)[CH3:29])(=[O:26])[CH3:25]>C(O)(C)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:4]=3)[N:1]=[C:28]([CH3:29])[C:27]=2[C:24](=[O:26])[CH3:25])=[CH:18][CH:19]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1ccc(Oc2ccccc2)cc1C(=O)c1ccc(Cl)cc1
Solvent: CC(C)O
Product: CC(=O)c1c(C)nc2ccc(Oc3ccccc3)cc2c1-c1ccc(Cl)cc1
Reaction time: 16.5 h
Yield: 42 %

Procedure:
The title compound was prepared from (2-Amino-5-phenoxy-phenyl)-(4-chloro-phenyl)-methanone [example A5] and acetylacetone according to the method of example 1, except that the solvent was isopropanol, the reaction time was of 16.5 h and the residue was purified by spontaneous crystallization from the reaction mixture. Yield: 42%; MS: m/z=387 (M).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.[CH3:14][NH:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CN(C=O)C>[Br:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[N:15]([CH3:14])[CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: CNC1CCOCC1
Reactant: COC(=O)c1nc(Cl)cc(Cl)c1Br
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Cl)cc(N(C)C2CCOCC2)c1Br
Temperature: 80 °C
Yield: 14.4 %

Procedure:
To a stirred solution of methyl 3-bromo-4,6-dichloropyridine-2-carboxylate (600 mg, 2.1 mmol) in DMF (5 ml) was added TEA (587 μl, 4.21 mmol) followed by N-methyloxan-4-amine (240 mg, 2.1 mmol) and the reaction mixture was heated at 80° C. for 20 h. The reaction mixture was then cooled to room temperature and poured onto water (100 ml), followed by extraction of the product into EtOAc (3×100 ml), washing of the combined organics with brine (50 ml), drying with Na2SO4 and evaporation. The crude product was then purified over a 10 g silica Isolute column eluting with a gradient of 0% to 100% EtOAc in heptane to afford the title compound as a white solid (110 mg, 14%). LC-MS 100%, 1.94 min (3.5 minute LC-MS method), m/z=362.8/365.2/346.8, 1H NMR (250 MHz, Chloroform-d) δ 6.87 (s, 1H), 4.17-3.99 (m, 2H), 3.98 (s, 3H), 3.93-3.70 (m, 1H), 3.41 (t, J=10.9 Hz, 2H), 2.81 (s, 3H), 1.93 (dd, J=11.9, 4.6 Hz, 2H), 1.71 (d, J=10.3 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C[CH2:11][O:12]CC>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:8][CH3:9])[CH:11]=[O:12]
Reactant: CCOCC
Reactant: COc1ccccc1F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C=O)cc1F
Temperature: 15 °C
Reaction time: 1 h

Procedure:
To a solution of o-fluoroanisole, 101 g (0.80 mol) in 500 ml dry methylene chloride is added dropwise over 30 minutes a solution of titanium tetrachloride, 182 g (0.96 mol, 1.2 equiv.) and α,α-dichloromethylmethyl ether, 110 g (0.96 mol) in an equal volume of methylene chloride. The temperature is maintained at 10-20° C. with an ice-bath. The mixture is stirred at room temperature for 1 hour longer and then poured over crushed ice-water with stirring. Ether (1) is added, and the mixture stirred under nitrogen until solution occurs. The organic layer is extracted with water (3×), sodium bicarbonate solution (3×) and dried (MgSO4). The solvent is evaporated off at 30° C. to give crude product as an oil. The oil is vacuum distilled through a jacketed Vigreoux column when it gives 3-fluoro-4-methoxybenzaldehyde, B.P. 120-121 ° C., at 10 mm Hg; Rf 0.6 on a silica-gel G plate with methylene chloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:18]3[N:23]=[C:22]4[S:24][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][C:28]=5[F:35])=[N:26][C:21]4=[CH:20][CH:19]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:37]1[CH2:40][CH:39]([C:41]([O:43][CH3:44])=[O:42])[CH2:38]1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([C:18]3[N:23]=[C:22]4[S:24][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH2:31][N:37]6[CH2:40][CH:39]([C:41]([O:43][CH3:44])=[O:42])[CH2:38]6)=[CH:29][C:28]=5[F:35])=[N:26][C:21]4=[CH:20][CH:19]=3)[CH2:17][CH2:16]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccc(OCc6ccccc6)cc5)CC4)nc3s2)c(F)c1
Reactant: COC(=O)C1CNC1
Agent: Cl
Product: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccc(OCc7ccccc7)cc6)CC5)nc4s3)c(F)c2)C1

Procedure:
Synthesized from 4-(5-(1-(4-(benzyloxy)phenyl)cyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-3-fluorobenzaldehyde (0.224 g, 0.466 mmol) and methyl azetidine-3-carboxylate hydrochloride (0.177 g, 1.17 mmol) according to the general procedure for reductive amination to give methyl 1-(4-(5-(1-(4-(benzyloxy)phenyl)cyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)-3-fluorobenzyl)azetidine-3-carboxylate as a yellow solid. MS (ESI) m/z: calculated: 579.2; Observed: 580.1 (M++1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]Cl)=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[CH:11][CH:10]=1
Reactant: ClCCc1ccc(Cl)cc1
Reactant: O=C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1CN(CCc2ccc(Cl)cc2)CCN1
Temperature: 85 °C
Yield: 60.8 %

Procedure:
Piperazinone (1.04 g, 10.4 mmol), 1-chloro-4-(2-chloroethyl)benzene (2.28 g, 10.4 mmol) and K2CO3 (1.72 g, 12.4 mmol) were combined in DMSO (12 mL) and heated to 85° C. for 2 h. The mixture was partitioned between H2O (20 mL) and CH2Cl2 (20 mL), and the organic layer was removed. The aqueous layer was extracted with CH2Cl2 (3×20 mL), the combined organics were concentrated, and the residue was dissolved in 2 N HCl (50 mL). This acidic mixture was washed with CH2Cl2 (3×20 mL) and then made basic with 6 N NaOH. The basic mixture was extracted with CH2Cl2 (3×20 mL), and the extracts were combined, dried and concentrated to provide the title compound (1.51 g, 60%) as an orange solid: 1H NMR (500 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.32 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H), 3.14-3.10 (m, 2H), 2.96 (s, 2H), 2.74 (t, J=6.6 Hz, 2H), 2.62-2.53 (m, 4H).