Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16].CC(C)=[O:23].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:18]([O:17][C:15]([C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[CH2:4][CH2:3][C:2]([OH:23])=[O:1])=[O:16])[CH:19]=[CH2:20]
Reactant: C=CCOC(=O)c1c(CCCO)ccc2ccccc12
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C=CCOC(=O)c1c(CCC(=O)O)ccc2ccccc12
Yield: 86 %

Procedure:
A solution of Example 11B (1.4 g, 5.18 mmol) in acetone (20 mL) was treated with Jones reagent (CrO3/H2SO4) until the orange color persisted, quenched with isopropyl alcohol, partitioned between ethyl acetate and water. The organic layer was washed with water, dried (Na2SO4), filtered, concentrated, and purified on silica gel with a gradient of 30% ethyl acetate/hexanes to 10% MeOH/dichloromethane to provide 1.27 g (86%) of the desired compound as an yellow oil.
Reaction SMILES: CC1C(C)=CC=CC=1OC1N=CC(N)=CC=1.[CH3:17][CH:18]([C:20]1[CH:21]=[C:22]([O:26][C:27]2[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH:23]=[CH:24][CH:25]=1)[CH3:19].C[O:35][C:36]([NH:38][N:39]=[CH:40]OC)=O>>[CH3:19][CH:18]([C:20]1[CH:21]=[C:22]([O:26][C:27]2[N:32]=[CH:31][C:30]([N:33]3[CH:40]=[N:39][NH:38][C:36]3=[O:35])=[CH:29][CH:28]=2)[CH:23]=[CH:24][CH:25]=1)[CH3:17]
Reactant: COC=NNC(=O)OC
Reactant: CC(C)c1cccc(Oc2ccc(N)cn2)c1
Agent: Cc1cccc(Oc2ccc(N)cn2)c1C
Product: CC(C)c1cccc(Oc2ccc(-n3cn[nH]c3=O)cn2)c1

Procedure:
The title compound was prepared in a similar way with respect to Example 50 replacing 6-[(2,3-dimethylphenyl)oxy]-3-pyridinamine with 6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinamine and methyl (2E/Z)-2-(1-methoxyethylidene)hydrazinecarboxylate (Intermediate 21) with methyl-2-[1-(methyloxy)methylidene]hydrazinecarboxylate (Intermediate 28). The title compound, 21 mg, was obtained by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](C2C(N3N=CC=N3)=CC=CN=2)=[O:20])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.Cl.CN(C1C=NC(C(F)(F)F)=CN=1)[C@H]1CCC[C@@H]1N.[F:51][C:52]1[CH:53]=[CH:54][C:55]([C:61]2[N:66]=[CH:65][CH:64]=[CH:63][N:62]=2)=[C:56]([CH:60]=1)C(O)=O>>[F:51][C:52]1[CH:60]=[CH:56][C:55]([C:61]2[N:62]=[CH:63][CH:64]=[CH:65][N:66]=2)=[C:54]([CH:53]=1)[C:19]([NH:18][C@H:14]1[CH2:15][CH2:16][CH2:17][C@@H:13]1[NH:12][C:3]1[C:2]([CH3:1])=[N:7][C:6]([C:8]([F:10])([F:9])[F:11])=[CH:5][N:4]=1)=[O:20]
Reactant: Cc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Agent: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1N
Agent: Cl
Product: Cc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1cc(F)ccc1-c1ncccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-{ [3-methyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 76) from (1S,2S)-1-N-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 23; 60 mg, 0.20 mmol) and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid (CAS number 1293284-57-7; 41 mg, 0.20 mmol) except this was purified only by column chromatography (silica, 0 to 100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH2:18][C:19]([NH2:21])=[S:20].II.[O-]S([O-])(=S)=O.[Na+].[Na+]>CCO>[NH2:21][C:19]1[S:20][C:9]([C:10]#[N:11])=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:18]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: NC(N)=S
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: N#Cc1sc(N)nc1-c1ccccc1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To a solution of benzoylacetonitrile derivative (1 eq.) in EtOH is added pyridine (1 eq.). The resulting mixture is stirred at 70° C. for 15 min then cooled at r.t. A previously stirred suspension of thiourea (2 eq.) and iodine (1 eq.) in EtOH is then slowly added. After 1 h at r.t. a cold 1 M Na2S2O3 solution is added under stirring. The resulting precipitate is filtered, washed with water, and finally dried under vacuo to afford the amino-4-phenyl-thiazole-5-carbonitrile derivative.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42]C1C=NC=CC=1)[CH2:4][CH2:3]2.Cl.Br[C:51]1[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=1.CC(C)([O-])C.[Na+].C(O)(C(F)(F)F)=O>C1COCC1>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][C:51]1[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=1)[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNc3cccnc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: Brc1ccncc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)[C@@H]1CC[C@]2(NCCNc3ccncc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following a similar procedure as described for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-(2-(pyridin-3-ylamino)ethylamino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 4-bromopyridine hydrochloride (0.018 g, 0.091 mmol) was used in place of 3-bromopyridine, and an additional 1.2 equivalents of sodium tert-butoxide, 2.0M solution in THF (for a total of 5.6 equivalents, 0.212 mL, 0.424 mmol) was employed. The product was isolated after reverse phase preparative HPLC purification using Prep HPLC Method 7 as a beige solid (74 mg, 54% yield) bis TFA salt. LCMS: m/e 650.4 (M+H)+, 3.85 min (method 16). 1H NMR (500 MHz, 1:1 mixture of CDCl3 and MeOD, MeOD lock) δ ppm 8.19-7.97 (m, 2H), 7.91 (d, J=8.2 Hz, 2H), 7.19 (d, J=8.2 Hz, 2H), 7.06 (br. s., 2H), 5.28 (d, J=4.6 Hz, 1H), 4.83 (s, 1H), 4.73 (s, 1H), 3.96-3.81 (m, 2H), 3.31-3.19 (m, 2H), 2.88-2.76 (m, 1H), 2.18-2.03 (m, 3H), 1.97 (dd, J=10.4, 6.4 Hz, 3H), 1.83 (d, J=12.5 Hz, 1H), 1.72 (s, 3H), 1.68 (br. s., 1H), 1.66-1.45 (m, 7H), 1.44-1.28 (m, 5H), 1.24 (d, J=8.2 Hz, 1H), 1.18-1.11 (m, 1H), 1.09 (s, 3H), 1.06 (s, 3H), 1.01 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[N:6]2[N:5]=1)=O.[CH3:24][N:25]1[C:29]2[CH:30]=[C:31]([NH2:34])[CH:32]=[CH:33][C:28]=2[N:27]=[CH:26]1>>[CH3:24][N:25]1[C:29]2[CH:30]=[C:31]([NH:34][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[N:6]4[N:5]=3)[CH:32]=[CH:33][C:28]=2[N:27]=[CH:26]1
Reactant: Cn1cnc2ccc(N)cc21
Reactant: CS(=O)c1ncc2ccc(-c3ccccc3NS(C)(=O)=O)n2n1
Product: Cn1cnc2ccc(Nc3ncc4ccc(-c5ccccc5NS(C)(=O)=O)n4n3)cc21

Procedure:
Following the synthetic and purification procedures described in Example 1293d, N-[2-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-methanesulfonamide (56 mg, 0.16 mmol) was coupled with 3-methyl-3H-benzimidazol-5-ylamine (40 mg, 0.28 mmol) at 105° C. for 86 h to afford the title compound. Yield of TFA salt: 19 mg (22%) of brown powder; LC/MS: 434 (M+H); HPLC: 95% pure, RT=2.19 min; 1H NMR: (DMSO, δ) 10.01 (s, 1H), 9.92 (s, 1H), 9.33 (s, 1H), 9.08 (s, 1H), 8.40 (s, 1H), 7.93 (d, J=7.7, 1H), 7.80 (m, 1H), 7.77 (d, J=9.0, 1H), 7.71 (d, J=9.0, 1H), 7.55 (t, J=7.8, 1H), 7.29 (d, J=7.9, 1H), 7.09 (d, J=4.8, 1H), 7.03 (d, J=4.8, 1H), 3.84 (s, 3H), 3.01 (s, 3H).
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]=[CH:7][CH:3]([CH2:4]2)[CH2:2]1.[CH2:8]=[CH:9][CH:10]=[CH2:11]>CC1C=CC(O)=CC=1>[CH:3]12[CH2:4][CH:5]([CH:1]3[C:2]1=[CH:11][CH2:10][CH2:9][CH2:8]3)[CH2:6][CH2:7]2
Reactant: C1=CC2CCC1C2
Reactant: C=CC=C
Agent: Cc1ccc(O)cc1
Product: C1=C2C3CCC(C3)C2CCC1
Temperature: 200 °C
Yield: 145.8 %

Procedure:
A 400 ml autoclave was charged with bicyclo[2,2,1]-2-heptene (152 g, Aldrich), 4-methylphenol (1 g, Aldrich), and butadiene (110 g). The mixture was heated at 200° C. for 10 hours. The reaction mixtures from four identical reactions were combined and distilled at atmosphere to give starting bicyclo[2,2,1]-2-heptene (307 g). Further distillation at reduced pressure afforded octahydro-1,4-methanonaphthalene (349 g with 97-98% purity, bp 47° C./0.05 Torr, yield 73%, based on consumed bicyclo[2,2,1]-2-heptene) and about 120 g of product with lower purity (bp 47° C./2 Torr to 58° C./0.16 Torr).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].[Cl:10][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1>O1CCCC1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:5]2[C:4]([CH3:3])=[C:8]([CH3:9])[N:7]=[CH:6]2)=[CH:17][CH:16]=1
Reactant: Cc1nc[nH]c1C
Reactant: Clc1cccc(Oc2ccc(CBr)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncn(Cc2ccc(Oc3cccc(Cl)c3)cc2)c1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
While stirring thoroughly, 1.91 g of 80% strength sodium hydride is introduced into a solution of 6.04 g of 4,5-dimethylimidazole in 80 ml of tetrahydrofuran. Upon completion of the exothermic reaction, the mixture is kept for 3 hours at 60° C., ad then cooled. A solution of 17.85 g of p-(3-chlorophenoxy)-benzyl bromide in 20 ml of tetrahydrofuran is then added. The reaction batch is stirred for 12 hours at 20° C., then poured into about 750 ml of ice water and extracted by shaking with methyl tertbutyl ether. The extract is washed twice with 5% strength aqueous sodium hydroxide solution and twice with water. After the extract has been dried over sodium sulfate, the solvent is removed under reduced pressure and the residue is chromatographed over silica gel 60 with acetone/ethyl acetate (2:1). There is obtained 12.1 g (65%) of N-[p-(3-chlorophenoxy)-benzyl]-4,5-dimethylimidazole as a resin-like liquid which slowly crystallizes on standing.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][C@H:4]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=1)[C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:9][CH:10]=1.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:45]([O:47][C:48](=[O:52])[CH2:49][CH2:50][NH2:51])[CH3:46].C(N(CC)CC)C>ClCCl>[CH2:45]([O:47][C:48](=[O:52])[CH2:49][CH2:50][NH:51][C:26]([C:25]1[CH:24]=[N:23][C:22]([NH:21][C@H:4]([C:5]2[CH:6]=[N:7][C:8]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=3)=[N:9][CH:10]=2)[CH2:3][CH:2]([CH3:31])[CH3:1])=[CH:30][CH:29]=1)=[O:28])[CH3:46]
Reactant: CC(C)C[C@H](Nc1ccc(C(=O)O)cn1)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(N[C@@H](CC(C)C)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-{(S)-3-Methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylamino}-nicotinic acid (31.1 g wet with ethyl acetate, theoretical 65.8 mmol) was dissolved in dichloromethane (270 mL). 1-Hydroxybenotriazole hydrate (15.1 g, 98.7 mmol) was added followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodimide hydrochloride (18.9 g, 98.7 mmol). beta-Alanine ethyl ester hydrochloride (12.1 g, 79.0 mmol) was added and the reaction was placed in an ice bath. When only slightly cool, triethylamine (18.3 mL, 132 mmol) was added over 3 min. The bath was then removed and the reaction was stirred at room temperature as a solution. At 16 h, most of the dichloromethane was rotovapped off. The residue was partitioned between ethyl acetate and sat. NH4Cl. The aqueous was extracted with additional ethyl acetate and the combined organics were washed with sat. NaHCO3 two times. The first aqueous was back extracted with ethyl acetate to remove a small amount of product. The combined organics were washed with brine and dried over MgSO4. The material was purified by silica gel flash chromatography (ethyl acetate/heptane) and then further purified by chiral SFC. Column: Chiralcel OJ-H. Dimensions: 21 mm×250 mm. Mobile Phase: 80/20 CO2/ethanol. Flow Rate: 65 ml/min. The purified material was taken up in ethyl acetate, filtered through a course frit and concentrated in vacuo to give 3-[(6-{(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylamino}-pyridine-3-carbonyl)-amino]-propionic acid ethyl ester with ethyl acetate (29.2 g) as a white foam. 1H NMR (400 MHz, CDCl3, δ): 8.83 (s, 2 H) 8.54 (d, J=8.0 Hz, 2 H) 8.46 (d, J=2.0 Hz, 1 H) 7.81 (dd, J=8.7, 2.2 Hz, 1 H) 7.73 (d, J=8.4 Hz, 2 H) 6.64 (t, J=5.8 Hz, 1 H) 6.36 (d, J=8.6 Hz, 1 H) 5.13 (d, J=6.7 Hz, 1 H) 4.97-5.08 (m, 1 H) 4.09-4.21 (m, 2 H) 3.68 (q, J=5.9 Hz, 2 H) 2.60 (t, J=5.9 Hz, 2 H) 1.81-1.95 (m, 1 H) 1.67-1.81 (m, 2 H) 1.26 (t, J=7.1 Hz, 3 H) 1.03 (d, J=6.1 Hz, 3 H) 1.00 (d, J=6.1 Hz, 3 H); MS (M+1): 530.2. Analytical chiral SFC: Column—Chiralcel OJ-H. Dimensions: 4.6 mm×25 cm. Mobile Phase: 80/20 CO2/ethanol. Flow Rate: 2.5 mL/min. Retention time: 5.18 minutes.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]([NH:28][C@H:29]([C:33](O)=[O:34])[C@@H:30]([CH3:32])[OH:31])=[O:27])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:51][C@H:52]([C:65]([O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:66])[CH2:53][CH2:54][C:55]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56]>>[C:1]([O:18][CH:19]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]([NH:28][C@H:29]([C:33]([NH:51][C@H:52]([C:65]([O:67][CH2:68][C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1)=[O:66])[CH2:53][CH2:54][C:55]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])=[O:34])[C@@H:30]([CH3:32])[OH:31])=[O:27])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCC(=O)N[C@H](C(=O)O)[C@@H](C)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)[C@@H](C)O
Yield: 38.7 %

Procedure:
Starting from N-[N-(3-hexadecanoyloxyoctadecanoyl)-β-alanyl]-L-threonine (450 mg) prepared by the method of Preparation B-4 and dibenzyl L-glutamate (210 mg), dibenzyl N-[N-[N-(3-hexadecanoyloxyoctadecanoyl)-β-alanyl]-L-threonyl]-L-glutamate (250 mg) was obtained as crystals according to a similar manner to that of Example 2.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:12][C:13]1[N:17]3[N:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]3=[N:15][N:14]=1)=[CH:7][CH:6]=2.[CH3:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:23][N:24]1[CH:28]=[C:27]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][C:8]([S:12][C:13]2[N:17]4[N:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]4=[N:15][N:14]=2)=[CH:7][CH:6]=3)[CH:26]=[N:25]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc2nnc(Sc3ccc4ncc(Br)cc4c3)n2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc2nnc(Sc3ccc4ncc(-c5cnn(C)c5)cc4c3)n2n1
Yield: 27.5 %

Procedure:
A microwave vessel was charged with 3-bromo-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline (40 mg, 0.107 mmol), 1-methyl-4-pyrazoleboronic acid pinacol ester (27 mg, 0.129 mmol), and dichlorobis(triphenylphosphine) palladium(0) (4 mg, 0.005 mmol). 1,2-Dimethoxyethane (0.5 mL) and a 2 M aqueous solution of sodium carbonate (0.5 mL) were added. The vessel was capped and microwaved at 120° C. for 30 min. The organic layer was separated, the aqueous layer was extracted with 10% methanol/dichloromethane (2×), and the combined organics were adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-6% methanol/dichloromethane afforded 28 mg of an off white solid. The solid was further purified by mass-triggered HPLC (5-95% CH3CN/H2O, 0.1% HCOOH modifier) to provide 11 mg of 3-(1-methyl-1H-pyrazol-4-yl)-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline as a white solid (28% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH:11][C:12](=[O:15])[CH2:13]Cl.[CH3:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:19](C(O)=O)[C:18]=1N.NC1C=CC=C(C)C=1>CN(C)C=O>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH:11][C:12](=[O:15])[CH2:13][C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([CH3:16])[CH:18]=1
Reactant: Cc1cccc(C(=O)O)c1NC(=O)CCl
Reactant: Cc1cccc(C(=O)O)c1N
Solvent: CN(C)C=O
Solvent: Cc1cccc(N)c1
Product: Cc1cccc(CC(=O)Nc2c(C)cccc2C(=O)O)c1
Temperature: 90 °C
Yield: 49 %

Procedure:
3-Methyl-N(chloroacetyl)anthranilic acid 7.5 g (33 mmol)(synthesized from 3-methylanthranilic acid by the same procedures as those of Example 9) and m-toluidine 11 ml (0.10 mol) were dissolved in 60 ml of dimethylformamide and heated at 90° C. for 4 hours. The reaction solution was poured into ice water and extracted with ether. The resulting ether solution was extracted with 10% sodium hydroxide and the resluting aqueous solution was neutralized with 10% HCl solution. The neutralized solution was extracted with ether, and the ether solution was washed with water and dried. The solvent was distilled off and the residue was recrystallized from benzene-toluene to obtain 3-methyl-N[(3-methylphenyl)acetyl]anthranilic acid 4.8 g (yield: 49%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=O)[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[CH2:5][C:4]=2[N:3]=1.NC1N=CC2C(=[N:37][OH:38])CC(C3C=CC(F)=CC=3C3C=NC=CC=3)CC=2N=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[N:37][OH:38])[CH2:7][CH:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: Cn1cc(-c2cc(F)ccc2C2CC(=O)c3cnc(N)nc3C2)cn1
Reactant: Nc1ncc2c(n1)CC(c1ccc(F)cc1-c1cccnc1)CC2=NO
Product: Cn1cc(-c2cc(F)ccc2C2CC(=NO)c3cnc(N)nc3C2)cn1

Procedure:
The title compound was prepared from 2-amino-7-[4-fluoro-2-(1-methyl-1H-pyrazol-4-yl)-phenyl]-7,8-dihydro-6H-quinazolin-5-one from stage 1, following the procedure describing the synthesis of 2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-7,8-dihydro-6H-quinazolin-5-one oxime (example 4/a stage 2).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([NH:13][CH2:14][C:15]3[C:16]([OH:23])=[N:17][C:18]([CH3:22])=[CH:19][C:20]=3[CH3:21])=[O:12])=[C:9]([CH3:24])[N:8]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[C:6]=2[N:7]=1.[OH-].[NH4+:34]>>[NH2:34][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([NH:13][CH2:14][C:15]3[C:16]([OH:23])=[N:17][C:18]([CH3:22])=[CH:19][C:20]=3[CH3:21])=[O:12])=[C:9]([CH3:24])[N:8]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[C:6]=2[N:7]=1
Reactant: Cc1cc(C)c(CNC(=O)c2c(C)n([C@H](C)c3ccccc3)c3nc(Cl)ncc23)c(O)n1
Reactant: [NH4+]
Agent: [OH-]
Product: Cc1cc(C)c(CNC(=O)c2c(C)n([C@H](C)c3ccccc3)c3nc(N)ncc23)c(O)n1
Yield: 38 %

Procedure:
A solution of (R)-2-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (70 mg, 0.15 mmol) in ammonium hydroxide (5 mL) was stirred at 150° C. for 30 minutes under microwave (pressure: 17.2 bar, equipment power: 150 W). The mixture was concentrated in vacuo and purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to afford (R)-2-amino-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (25 mg, 38%). LRMS (M+H+) m/z: calcd 430.21. found 430. HPLC purity (214 nm): 93%. 1H NMR (300 MHz, CD3OD): δ 8.57 (s, 1H), 7.34-7.19 (m, 5H), 6.19-6.17 (m, 1H), 6.10 (s, 1H), 4.47 (s, 2H), 2.33 (s, 3H), 2.30 (s, 3H), 2.23 (s, 3H), 1.99 (d, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].C=O.[C:14]1(B(O)O)C=CC=CC=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[CH2:14])[C:6]2=[O:11]
Reactant: OB(O)c1ccccc1
Reactant: O=C1CCc2c(F)cccc21
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C=C1Cc2c(F)cccc2C1=O
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a 1000 mL round bottle flask were charged 4-fluoro-2,3-dihydro-1H-inden-1-one (249a) (5.04 g, 33.6 mmol), paraformaldehyde (10.08 g, 336 mmol), phenylboronic acid (4.92 g, 40.3 mmol) followed by toluene (235 mL), to the suspension was added TFA 2.6 mL, 33.6 mmol), and the resulting suspension was refluxed for 4 hrs, which resulted a clear yellowish solution. The solution was cooled to room temperature, and the pH was adjusted to 7-8 by adding saturated NaHCO3. After extracting with ethyl acetate, the organic layers were combined, and evaporated. The residue was purified by flash chromatography (0 to 30% EtOAc/Hexane) to give 4-fluoro-2-methylene-2,3-dihydro-1H-inden-1-one (249b) (3.91 g, 72%). LC-MS tR=1.49 min in 3 min chromatography, MS (ESI) m/z 163 [M+H]+
Reaction SMILES: C([O:3][C:4](=O)[C:5]([N:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH:16]=[CH:17][C:10]=2[CH2:9][CH2:8]1)=[O:6])C.Cl.FC1C=C(C=CC=1)COC1C=CC2CC[NH:41]CCC=2C=1.C([ClH]C(=O)C(Cl)=O)C>C(N(CC)CC)C>[F:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:10]2[CH2:9][CH2:8][N:7]([C:5](=[O:6])[C:4]([NH2:41])=[O:3])[CH2:13][CH2:12][C:11]=2[CH:14]=1
Reactant: Fc1cccc(COc2ccc3c(c2)CCNCC3)c1
Reactant: CCOC(=O)C(=O)N1CCc2ccc(OCc3cccc(F)c3)cc2CC1
Agent: Cl
Solvent: CCN(CC)CC
Product: NC(=O)C(=O)N1CCc2ccc(OCc3cccc(F)c3)cc2CC1
Yield: 88 %

Procedure:
[7-(3-Fluoro-benzyloxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-oxo-acetic acid ethyl ester: The title compound was prepared in analogy to Example 1d) from 7-(3-fluoro-benzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride [Example 1c)] and ethyl oxalic acid chloride with triethylamine as the base. Yield: 88% of theory as a colourless oil; MS: m/e=372 (M+H)+.