Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].C([O:14][C:15]([C:17]1[C:24]([CH3:25])=[CH:23][C:20]([CH:21]=O)=[C:19]([O:26][CH3:27])[C:18]=1[CH3:28])=[O:16])C>>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH:10]=[CH:21][C:20]1[CH:23]=[C:24]([CH3:25])[C:17]([C:15]([OH:16])=[O:14])=[C:18]([CH3:28])[C:19]=1[O:26][CH3:27]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CCOC(=O)c1c(C)cc(C=O)c(OC)c1C
Product: COc1c(C=CC(=O)c2ccc(O)cc2O)cc(C)c(C(=O)O)c1C

Procedure:
This compound was synthesized from 2′,4′-dihydroxyacetophenone and 4-ethoxycarbonyldimethylmethyloxybenzaldehyde (starting material 4) according to general method 2 described earlier.
Reaction SMILES: Br[C:2]1[N:3]([C:7]2[N:16]=[CH:15][C:14]3[N:13]([CH3:17])[C:12](=[O:18])[C@@H:11]([CH2:19][CH3:20])[N:10]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[C:9]=3[N:8]=2)[CH:4]=[CH:5][N:6]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31].CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Cu]I>[CH:21]1([N:10]2[C:9]3[N:8]=[C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[N:28]4[CH2:29][CH2:30][O:26][C:27]4=[O:31])[N:16]=[CH:15][C:14]=3[N:13]([CH3:17])[C:12](=[O:18])[C@H:11]2[CH2:19][CH3:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3Br)nc2N1C1CCCC1
Reactant: O=C1NCCO1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3N3CCOC3=O)nc2N1C1CCCC1
Temperature: 110 °C
Reaction time: 18 h
Yield: 6.4 %

Procedure:
(R)-2-(2-bromo-1H-imidazol-1-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 65, 0.11 g, 0.271 mmol), oxazolidin-2-one (35 mg, 0.406 mmol), CuI (10 mg, 0.054 mmol), trans-1,2-bis(methylamino)cyclohexane (15 mg, 0.108 mmol) and K2CO3 (74 mg, 0.542 mmol) were dissolved in 1 mL of dioxane in a screw cap vial and a stream of nitrogen was bubbled through the mixture for 2 minutes. The resulting solution was stirred at 110° C. for 18 h. The reaction mixture filtered and concentrated, then purified by preparative HPLC to give the title compound (7.1 mg). LCMS: 412.2 m/z (M+H)+; ret. Time: 3.24 min (Analytical Method A).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([CH2:10][N:11]3[C:19]4[CH:18]=[CH:17][C:16]([F:20])=[C:15]([C:21]([O:23]C)=[O:22])[C:14]=4[C:13]([CH3:25])=[N:12]3)[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Li+]>C1COCC1.Cl>[CH:1]1([C:4]2[N:9]=[C:8]([CH2:10][N:11]3[C:19]4[CH:18]=[CH:17][C:16]([F:20])=[C:15]([C:21]([OH:23])=[O:22])[C:14]=4[C:13]([CH3:25])=[N:12]3)[CH:7]=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1c(F)ccc2c1c(C)nn2Cc1cccc(C2CC2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nn(Cc2cccc(C3CC3)n2)c2ccc(F)c(C(=O)O)c12
Yield: 69.4 %

Procedure:
Methyl 1-((6-cyclopropylpyridin-2-yl)methyl)-5-fluoro-3-methyl-1H-indazole-4-carboxylate (0.310 g, 0.913 mmol) was subjected to 1M aqueous lithium hydroxide (1.83 mL, 1.83 mmol) in 10 mL of THF for 16 hours at reflux. The mixture was then diluted with 1M aqueous HCl (to pH 4), and extracted twice with EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated to give 0.206 g (69%) of the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[S:7]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=2)/[CH:15]=[CH:16]/[C:17](OCC)=[O:18])=[CH:8]1.BrC1C=C(C=CC=1)/C=C/C(OCC)=O.C([Sn](CCCC)(CCCC)C1C=CSC=1)CCC>O1CCCC1>[S:7]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]([CH2:15][CH2:16][CH2:17][OH:18])[CH:22]=[CH:23][CH:24]=2)=[CH:8]1
Reactant: CCOC(=O)/C=C/c1cccc(-c2ccsc2)c1
Agent: CCCC[Sn](CCCC)(CCCC)c1ccsc1
Agent: CCOC(=O)/C=C/c1cccc(Br)c1
Agent: [Al+3]
Solvent: C1CCOC1
Product: OCCCc1cccc(-c2ccsc2)c1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a suspension (20 ml) of 0.4 g of lithium aluminum hydride in terahydrofuran was added, under ice cooling, a tetrahydrofuran solution (10 ml) of 2.1 g of ethyl (E)-3-(3-thienyl)cinnamate [synthesized by the same reaction as in Referential Example 12 using ethyl (E)-3-bromocinnamate [see Org. Syn. I, 252] and tri-n-butyl(3-thienyl)tin ]. The mixture was sirred at room temperature for 30 minutes, and then refluxed for 30 minutes. The solution was worked up in a customary manner, and the product was purified by medium-pressure liquid chromatography [silica gel column, hexane/ethyl acetate=5/1→5/2] to give 1.1 g of 3-[3-(3thienyl)phenyl]-1-propanol as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]#[N:9].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1.C(N(CC)CC)C.O>CN(C)C=O>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[C:8]#[N:9])=[CH:14][CH:13]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: N#Cc1cnccc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C#Cc2ccncc2C#N)cc1
Yield: 84 %

Procedure:
4-Chloro-3-cyanopyridine (1.50 g) and 4-methoxyphenylacetylene (1.60 g) were reacted in the presence of dichlorobistriphenylphosphinepalladium (0.14 g), cuprous iodide (75 mg) and triethylamine (10 ml) in N,N-dimethylformamide (25 ml) in nitrogen atmosphere at 100° C. overnight. The reaction mixture was poured into water (100 ml), and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give 4-(4-methoxyphenylethynyl)-3-cyanopyridine (2.13 g, 95%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([NH:14][CH2:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.CCN(CC)CC.C(Cl)CCl.[CH:36]1[CH:37]=[CH:38][C:39]2[N:44](O)N=[N:42][C:40]=2[CH:41]=1.C1(N)C=CC=CC=1N>CC#N>[NH2:42][C:40]1[CH:41]=[CH:36][CH:37]=[CH:38][C:39]=1[NH:44][C:20](=[O:22])[C:19]1[CH:18]=[CH:17][C:16]([CH2:15][NH:14][C:12]2[NH:11][N:10]=[C:9]([C:6]3[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:13]=2)=[CH:24][CH:23]=1
Reactant: On1nnc2ccccc21
Reactant: COc1ccc(-c2cc(NCc3ccc(C(=O)O)cc3)[nH]n2)cn1
Agent: Nc1ccccc1N
Solvent: CC#N
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc(NCc3ccc(C(=O)Nc4ccccc4N)cc3)[nH]n2)cn1
Reaction time: 8 h
Yield: 13.8 %

Procedure:
A solution of 385 (640 mg, 1.97 mmol) in MeCN (10 mL) was sequentially treated with Et3N (831 μL, 603 mg, 5.96 mmol), EDC (571 mg, 2.98 mmol), HOBT (334 mg, 2.18 mmol) and 1,2-phenylene diamine (429 mg, 3.97 mmol) and allowed to stir overnight. The reaction mixture was concentrated and partitioned between DCM (15 mL) and saturated NH4Cl (15 mL). The organic phase was collected, dried with Na2SO4, filtered and concentrated. The resultant solid was purified by flash chromatography using the gradient 3-15% MeOH in DCM to afford the title compound (113 mg, 14% yield). 1H NMR (DMSO-d6) δ9.65 (s, 1H), 8.43 (s, 1H), 7.92 (m, 3H), 7.48 (d, J=8.0 Hz, 2H), 7.16 (d, J=7.4 Hz, 1H), 6.97 (t, J=7.6 Hz, 1H), 6.81 (t, J=8.2 Hz, 2H), 6.63 (t, J=7.4 Hz, 1H), 5.85 (s, 1H), 4.34 (s, 2H), 3.85 (s, 3H). LRMS: (calc) 414.2; (found) 415.3 (M+H1)
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:22])[C@@H:15]([NH:20][CH3:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:5][CH:4]=1.[C:30]([C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:22])[C@@H:15]([N:20]([CH2:38][C:37]2[CH:40]=[CH:41][C:34]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:35][CH:36]=2)[CH3:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:7][CH:8]=1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: CN[C@@H](CC(C)C)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1)N(C)Cc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-4-Methyl-2-methylamino-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide monohydrochloride (0.25 g, 0.58 mmol, Example 12) and 4-t-butylbenzaldehyde (94 mg, 0.58 mmol, Aldrich, Milwaukee, Wis.) were mixed in CH2Cl2 (10 mL). After stirring at ambient temperature under nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.18 g, 0.87 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Six milliliters of saturated aqueous NaHCO3 solution was added to the reaction mixture, and the resulting mixture was stirred for 5 minutes. The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic solution was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified first by flash chromatography (25% EtOAc in hexanes), then by preparative plate (5% acetonitrile in chloroform). The free amine was dissolved in 5 mL of ethyl ether and treated with ethereal HCl to afford 130 mg (42% over 2 steps) of the pure titled compound as a white foam: mp 87-95° C. APCI-MS m/z 535.0 (MH+).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25]C(=O)C)=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.[CH3:31][NH2:32]>C(#N)C>[CH3:31][NH:32][C:2]1[O:3][C:4]2[C:24]([OH:25])=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reactant: CN
Solvent: CC#N
Product: CNc1oc2c(O)c(OC)ccc2c1C(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
To a stirred solution of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (20 mg, 0.066 mmol) in acetonitrile (3 mL) was added the solution of methyamine (1 mL, excess as reactant and base), and the reaction mixture was stirred at room temperature for 1 hour when the precipitates appeared. The solvent was distilled under vacuo and the crude was dissolved in tetrahydrofuran (2 mL), 1M hydrochloric acid (1 mL) was added and the reaction mixture was stirred for 1 hour then diluted with dichloromethane (10 mL) and washed with water. The organic layer was dried over magnesium sulfate and solvent was distilled under vacuo. The crude was purified by PTLC (eluent=Hexane:ethylacetate:triethylamine; 2:8:1%) to gave the title compound as a yellow-green solid (5 mg, 29%); 1H NMR (300 MHz, CDCl3) δ 8.91 (broad, 1H, NH), 6.93 (s, 2H, benzoyl Hs), 6.59 (d, 1H, J=8.56 Hz), 6.46 (d, 1H, J=8.51 Hz), 5.61 (bs, 1H, OH), 3.91 (s, 3H, OMe), 3.86 (s, 3H, OMe), 3.84 (s, 6H, 2×OMe), 3.28 (d, 3H, J=5.28 Hz).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][O:8][C:9]([C:11]1[CH:15]=[C:14]([CH3:16])[S:13][C:12]=1[NH2:17])=[O:10].O>CN(C)P(N(C)C)(N(C)C)=O>[C:9]([C:11]1[CH:15]=[C:14]([CH3:16])[S:13][C:12]=1[NH:17][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])([O:8][CH3:7])=[O:10]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1cc(C)sc1N
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)c1cc(C)sc1NC(=O)C(C)C
Reaction time: 16 h
Yield: 82.1 %

Procedure:
isoButyryl chloride (22.4 g) was added dropwise during 40 minutes to a stirred solution of methyl-2-amino-5-methyl-3-thiophenecarboxylate (34.2 g, 0.2 mol) in dry hexamethylphosphoramide (100 ml) kept at 5°-10° C. This temperature was maintained for a further 1 hour and then the reaction was kept at room temperature for 16 hours. The reaction mixture was poured into water (1600 ml) and the yellow precipitate was filtered off, washed with water and dried at 50° C. Recrystallisation of the solid from petroleum ether (b.p. 60°-80° C yielded cream crystals (39.6 g, 88%), m.p. 63°-65° C.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[C:16]([C:18]1[C:23]2[N:24]=[C:25]([N:27]3[CH2:30][CH:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:28]3)[O:26][C:22]=2[C:21](F)=[C:20]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:19]=1[CH3:46])#[N:17]>CS(C)=O>[C:16]([C:18]1[C:23]2[N:24]=[C:25]([N:27]3[CH2:28][CH:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:30]3)[O:26][C:22]=2[C:21]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[C:20]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:19]=1[CH3:46])#[N:17]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N3CC(NC(=O)OC(C)(C)C)C3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CC(NC(=O)OC(C)(C)C)C3)nc2c1C#N
Temperature: 130 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (180 μl, 1.42 mmol) and triethylamine (238 μl, 1.70 mmol) were added to a dimethyl sulfoxide (5 ml) solution of tert-butyl [1-(4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazol-2-yl)azetidin-3-yl]carbamate (I-194) (400 mg, 0.947 mmol), followed by stirring in an oil bath at 130° C. for 3 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform (100 ml) and washed with saturated brine (100 ml). After drying over anhydrous sodium sulfate and concentration, the resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=10:1) to obtain the entitled compound (260 mg, 53.2%) as a colorless solid.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=1)(O)=[O:2].C(Cl)(=O)C([Cl:23])=O>ClCCl>[Cl:23][C:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=1)=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc2c(c1)C(=O)c1ccccc1C2=O

Procedure:
The compound of Structure (I-C) was prepared as follows. 2-carboxyanthraquinone was reacted with oxalyl chloride in dichloromethane (catalyzed by dimethylformamide) to yield 2-chlorocarbonylanthraquinone, which was then reacted with 1-hexanol in tetrahydrofuran (in the presence of triethylamine) to yield 2-n-hexoxycarbonylanthraquinone, which was then treated in a manner similar to Preparation A to prepare the Structure (I-C) compound with a yield of 50%. Structure was confirmed by IR and NMR spectroscopy.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[S:21][C:22]([C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[S:21][C:22]=3[C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)sc3-c3cccc(C)c3)n2)o1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[CH:8]([OH:10])[CH3:9].CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:27](=[N:28][CH:29]=2)[NH:26][CH2:25][CH2:24][CH2:23]3)O1>>[Cl:11][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:24]2[CH:25]=[N:26][C:27]3[NH:28][CH2:29][CH2:20][CH2:21][C:22]=3[CH:23]=2)[C:7]=1[CH:8]([OH:10])[CH3:9]
Reactant: CC1(C)OB(c2cnc3c(c2)CCCN3)OC1(C)C
Reactant: CC(O)c1c(Cl)cncc1Br
Product: CC(O)c1c(Cl)cncc1-c1cnc2c(c1)CCCN2

Procedure:
1-[3-Chloro-5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-4-yl]-ethanol is synthesized according to the procedure of Suzuki Coupling Method VI using 1-(3-bromo-5-chloro-pyridin-4-yl)-ethanol (which is prepared according to Step 1 of Example 78) and crude 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (that is prepared according to Step 4 of Example 105).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+].CCOC(C)=O>CN(C=O)C.CC(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C@@H:12]([N:15]=[N+:16]=[N-:17])[C@H:10]([OH:11])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC2OC2C1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H](O)C1
Temperature: 80 °C
Yield: 61.2 %

Procedure:
To a stirred solution of 7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (15.5 mmol, 3.1 g) in DMF (25 mL) was added a solution of sodium azide (23.3 mmol, 1.5 g) in acetone-water (2:1, 30 mL) (WO 2005/066176). The reaction mixture was heated at 80° C. for 12 h. The reaction mixture was cooled to room temperature, and EtOAc (100 mL) was added. The organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a SiO2 cartridge (5% EtOAc in hexane-25% EtOAc in hexane) to provide (±)-trans-4-azido-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (2.3 g) (faster moving compound) 1H NMR (400 MHz, CDCl3) δ 4.12 (1 H, dd), 3.95 (1 H, bs), 3.50 (1 H, bs), 3.30-3.42 (1 H, m), 2.90 (1 H, bs), 2.79 (1 H, dd), 2.30-2.70 (1 H, bs), 1.96-2.05 (1 H, m), 1.48-1.6 (1 H, m), 1.46 (9 H, s). and (±)-trans-3-azido-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.57 g) (slower moving compound) 1H NMR (400 MHz, CDCl3) δ 4.21 (1 H, bs), 4.00 (1 H, d), 3.56 (1 H, bs), 3.21-3.35 (1 H, m), 2.55-2.95 (2 H, m), 2.24 (1 H, bs), 1.92-2.04 (1 H, m), 1.49-1.6 (1 H, m), 1.47 (9 H, s)
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH3:40])[CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])=[CH:34][C:35]=1[CH3:40]
Reactant: Cc1cc([C@H](N)CN(C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)ccc1Cl
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(Cl)c(C)c1

Procedure:
Compound 44 was prepared following general synthesis scheme 8 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(4-chloro-3-methyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [371 (M+H)]; 1H NMR (500 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.08 (s, 1H), 8.99 (d, J=4.3 Hz, 1H), 8.53 (s, 1H), 8.37 (d, J=4.3 Hz, 1H), 8.17 (s, 1H), 7.43 (s, 1H), 7.34 (d, J=8.2 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 5.54-5.26 (m, 1H), 3.21-3.03 (m, 1H), 3.00-2.77 (m, 1H), 2.30 (s, 6H), 1.78 (s, 1H).
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[CH:29][CH:30]=2)[CH:22]=[N:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:20]1[CH:24]=[C:23]([C:25]2[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[CH:29][CH:30]=2)[CH:22]=[N:21]1
Reactant: Nc1ccc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)c(N)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2cn[nH]c2)c(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.3 %

Procedure:
To a solution of 3-(1-trityl-1H-pyrazol-4-yl)-pyridin-2,6-diamine (10.0 g, 25.7 mmol) described in Manufacturing Example 36-1-1 in methylene chloride (14 mL) was added trifluoroacetic acid (7 mL) under nitrogen atmosphere, which was stirred for 1 hour at room temperature. The reaction mixture was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate, then ethyl acetate:methanol=10:1) to obtain the title compound (600 mg, 60%).
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[C:42]1([CH2:52][NH2:53])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][CH:43]=1>C1COCC1>[C:42]1([CH2:52][NH:53][C:30]([C:28]2[CH:27]=[CH:26][C:12]3[N:13]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=4)[C:9]([CH2:8][O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:10][C:11]=3[CH:29]=2)=[O:31])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44][CH:43]=1
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Reactant: NCc1cccc2ccccc12
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: O=C(NCc1cccc2ccccc12)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of naphthalen-1-ylmethyl-amine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 582.3 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18](O)=[O:19])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:26]([NH:33][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=1[S:15][C:12]1[CH:13]=[CH:14][C:9]2[N:10]([CH:25]=[C:7]([NH:6][C:4]([CH:1]3[CH2:2][CH2:3]3)=[O:5])[N:8]=2)[N:11]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 88.9 %

Procedure:
In the same manner as in Example 278 and using 2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoic acid (250 mg, 0.71 mmol), benzylamine (212 mg, 2.0 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (380 mg, 1.0 mmol), N,N-diisopropylethylamine (270 mg, 2.0 mmol) and N,N-dimethylformamide (7 mL) as starting materials, the title compound (280 mg, 89%) was obtained as a white solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][NH2:22])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:32][CH:31]([CH3:33])[C:30]([NH:22][CH2:21][CH2:20][O:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])[CH:11]=[CH:12]2)=[O:34]
Reactant: CC(C)C(=O)Cl
Reactant: NCCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 264.7 %

Procedure:
2-{[1-(Phenylsulfonyl)-1H-indol-5-yl]oxy}ethanamine (Intermediate 24, 0.20 g, 0.63 mmol) in DCM (100 mL) was treated with triethylamine (0.27 mL, 1.9 mmol) and 4-dimethylaminopyridine (39 mg, 0.32 mmol). The solution was cooled to 0° C. and was treated with isobutyryl chloride (0.14 g, 0.13 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was washed with saturated aqueous NaHCO3 (50 mL) and 1 M HCl (2×40 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (133 mg). MS m/z 387 [M+H]+.