Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]([CH3:45])[CH3:44])=O>>[CH3:44][N:43]([CH3:45])[CH2:41][CH2:40][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=3[CH2:18]2)=[CH:37][CH:38]=1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Reactant: CN(C)C(=O)CCl
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN(C)C)cc2)C(C)C)c1
Yield: 45.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-N,N-dimethylacetamide (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (13 mg) was obtained.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[O-]S([O-])(=O)=O.[Mg+2].[NH:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH2:19]>C(Cl)Cl>[C:1]([N:5]1[CH2:10][CH2:9][C:8](=[N:19][NH:18][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)(C)N1CCC(=O)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN=C1CCN(C(C)(C)C)CC1
Yield: 84 %

Procedure:
To a solution of 1-tert-butylpiperidin-4-one (1.0 g, 6.5 mmol) in DCM (20 mL) was added MgSO4 (1.5 g, 13 mmol) and tert-butyl hydrazinecarboxylate (0.7 g, 5.3 mmol). The reaction mixture was heated to reflux overnight. The solid was filtered off and the filtrate was concentrated. The residue was purified by silica gel chromatography eluting with EtOAc/petroleum ether (1:20) to give tert-butyl 2-(1-tert-butylpiperidin-4-ylidene)hydrazinecarboxylate (1.2 g, 84% yield) as a colorless oil. LCMS (ESI) m/z: 270.3 [M+H+].
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C[Si](C)(C)[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[CH2:25]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C:29]1=O)[CH:26]=[CH2:27]>C1COCC1>[CH2:25]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C:29]1=[CH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:26]=[CH2:27]
Reactant: CC(C)(C)OC(=O)C[Si](C)(C)C
Reactant: C=CCC1CCCCC1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=CCC1CCCCC1=CC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 96.4 %

Procedure:
To a solution of diisopropylamine (6.60 mL, 46.6 mmol) in THF (200 mL) at −10° C., was added a solution 2.22M of n-butyllithium (20.4 mL, 44.4 mmol). The solution was stirred 15 min at −10° C., cooled down to −78° C. and tert-butyl 2-trimethylsilylacetate (9.7 mL, 44.4 mmol) in 1 mL of THF was added dropwise. The solution was stirred 15 min at −78° C., and 2-allylcyclohexanone (3.3 mL, 22.2 mmol) was added dropwise. The reaction mixture was stirred 1 h at −78° C. and 3 h at −25° C. It was then quenched with saturated NH4Cl, extracted with ethylacetate, washed with brine, dried and concentrated. Purification by flash chromatography (cyclohexane) gave tert-butyl 2-(2-allylcyclohexylidene)acetate (5.06 g, 96%) as a colorless liquid. 1H NMR (400 MHz, CDCl3) 5.62 (1H, m), 5.41 (1H, s), 4.89 (2H, m), 3.83 (1H, m), 2.16 (3H, m), 1.90 (1H, m), 1.73 (1H, m), 1.61 (1H, m), 1.47-1.22 (4H, m), 1.36 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH:26]=O.[CH:28]([NH2:31])([CH3:30])[CH3:29].Cl.C([BH3-])#N.[Na+]>CO.O>[CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH2:26][NH:31][CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)N
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(CNC(C)C)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 5-methyl-1-(triphenylmethyl)-1H-imidazole-4-carboxaldehyde (3.5 g) and isopropylamine (10 ml) in methanol (125 ml) was stirred at 20° for 1h. The resulting solution was treated with ethanolic hydrogen chloride (0.027 g/ml; 15 ml), cooled to 0° and treated with sodium cyanoborohydride (0.94 g). After stirring for 2.5 h, water (15 ml) was added and the resulting mixture was stirred at 20° for 0.5 h and treated with concentrated hydrochloric acid (6 ml). The mixture was warmed to 40°, stirred at 40° for 0.5h and concentrated in vacuo to ca. 50 ml. The concentrate was then basified (to pH9) with a saturated solution of potassium carbonate (200 ml) and extracted with ethyl acetate (3×100 ml). The organic extracts were combined, dried and evaporated to leave a gum (ca. 5 g) which was purified by FCC eluting with System A (100:8:1) to give the title compound (1.9 g) as a solid, m.p. 154°-156°. A second crop of product (0.4 g) has m.p. 150°-154°.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[Br:29][C:30]1[CH:31]=[C:32]2[C:37](=[N:38][CH:39]=1)[N:36]=[C:35]([NH2:40])[CH:34]=[CH:33]2>C(Cl)Cl>[Br:29][C:30]1[CH:31]=[C:32]2[C:37](=[N:38][CH:39]=1)[N:36]=[C:35]([NH:40][C:4](=[O:5])[CH2:3][N:2]([CH3:7])[CH3:1])[CH:34]=[CH:33]2
Reactant: CN(C)CC(=O)O
Reactant: Nc1ccc2cc(Br)cnc2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(C)CC(=O)Nc1ccc2cc(Br)cnc2n1
Yield: 59.5 %

Procedure:
Add N,N-dimethylglycine (0.28 g, 2.68 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (0.47 g, 2.45 mmol), 1-hydroxybenzotriazole (0.33 g, 2.45 mmol), and methylene chloride (111 mL) to 6-bromo-[1,8]naphthyridin-2-ylamine (Reichardt, C. et al, Tetrahedron Lett. 1977, 2087; 0.50 g, 2.23 mmol). Stir the reaction at room temperature for 19 h, concentrate in vacuo and purify by flash column chromatography to provide the subtitled compound (0.41 g, 60%) as an orange solid. MS ESI+ m/e 309/311 (M+1). 1H NMR (DMSO-d6) δ 10.52 (m, 1H), 8.96 (m, 1H), 8.71 (m, 1H), 8.35 (m, 2H), 3.15 (s, 2H), 2.25 (s, 6H). TLC (SiO2): Rf0.3 (1:4 [80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]/dichloromethane).
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:7]=2[CH2:6][CH2:5]1)[C:2]#[CH:3].Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:26][C:25]=2[O:36][CH3:37])[C:20]([Cl:38])=[CH:19][N:18]=1>>[Cl:38][C:20]1[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[CH:26][C:25]=2[O:36][CH3:37])=[N:22][C:17]([NH:15][C:12]2[CH:13]=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:1][C:2]#[CH:3])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:18][CH:19]=1
Reactant: C#CCN1CCc2ccc(N)cc2CC1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: C#CCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)cc2CC1

Procedure:
5-Chloro-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-N*2*-(3-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-pyrimidine-2,4-diamine was prepared from 3-prop-2-ynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 322. Product isolated as a pale yellow solid (120 mg, 46%). m.p.=151-152° C.; LCMS (m/e) 519 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.27 (d, 1H, J=8.7 Hz), 8.02 (s, 1H), 7.61 (s, 1H), 7.48 (s, 1H), 7.23-7.16 (m, 1H), 7.04 (d, 1H, J=8.0 Hz), 6.89 (s, 1H), 6.56 (s, 1H), 6.55-6.49 (m, 1H), 3.94 (s, 3H), 3.91 (m, 4H,), 3.45 (s, 2H), 3.21-3.15 (m, 4H), 2.98-2.89 (m, 4H), 2.82-2.70 (m, 4H), 2.25-2.21 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([O:26][C:27]4[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=4)[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].[OH:34][C:35]([CH3:50])([CH3:49])[CH2:36][CH2:37]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([O:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:37][CH2:36][C:35]([OH:34])([CH3:50])[CH3:49])=[CH:29][CH:28]=4)[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Oc4ccc(O)cc4)ccc(F)c32)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Oc4ccc(OCCC(C)(C)O)cc4)ccc(F)c32)cc1
Reaction time: 8 h

Procedure:
(1S,2S)-2-{4-[(R)-7-Fluoro-4-(4-hydroxy-phenoxy)-indan-1-yloxy]-phenyl}-cyclopropanecarboxylic acid ethyl ester (Intermediate 7, 47 mg, 0.10 mmol), toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester (Intermediate 10, 54 mg, 0.21 mmol), and cesium carbonate (107 mg, 0.21 mmol) are suspended in dry N,N-dimethylformamide (2 mL) and stirred overnight. The mixture is diluted with ethyl acetate, washed with water, dried and the solvent removed. The residue is purified by flash chromatography (gradient of ethyl acetate in cyclohexane) to give the title compound. (Yield 60 mg). LC (METHOD 6): tR=0.75 min; Mass spectrum (ES+): m/z=535 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:11]=[C:10]([O:12][C@H:13]3[C@H:17]4[O:18][CH2:19][C@@H:20]([OH:21])[C@H:16]4[O:15][CH2:14]3)[N:9]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:5]2=[N:6][C:7]=1I.[Br:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([C:7]2[N:6]=[C:5]3[N:9]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:10]([O:12][C@H:13]4[C@H:17]5[O:18][CH2:19][C@@H:20]([OH:21])[C@H:16]5[O:15][CH2:14]4)=[N:11][C:4]3=[CH:3][C:2]=2[Cl:1])=[CH:33][CH:32]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(I)nc21
Reactant: OB(O)c1ccc(Br)cc1
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(Br)cc3)nc21

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-iodo-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and 4-bromophenylboronic acid following a procedure analogous to that described for Intermediate 3. LC (method 2): tR=1.24 min; Mass spectrum (ESI+): m/z=582 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:12][O:11][C:9]([C:8]1[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[O:14][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:10]
Reactant: CCOC(=O)CCCBr
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc([N+](=O)[O-])cc1C(=O)OC
Temperature: 110 °C
Reaction time: 5 h
Yield: 80.6 %

Procedure:
In DMF (50 ml) was dissolved methyl 5-nitrosalicylate (1.97 g, 10.0 mmol), and to the mixture were added ethyl 4-bromobutyrate (1.57 ml, 11.0 mmol) and potassium carbonate (2.76 g, 20.0 mmol). The mixture was stirred at 110° C. for 5 hours, and the mixture was concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was washed with water and 10% potassium carbonate solution. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel 30 g, ethyl acetate/hexane=1/5→1/3), and the desired fraction was concentrated under reduced pressure to give ethyl 4-(2-methoxycarbonyl-4-nitrophenoxy)butyrate (2.51 g, 8.06 mmol, 81%).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9](=[O:18])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:21][C:22]([F:26])([F:25])[CH2:23]I.O>CN(C)C=O>[F:21][C:22]([F:26])([F:25])[CH2:23][N:10]1[C:11]2[C:16](=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]1=[O:18]
Reactant: O=c1nc(-c2ccccc2)c2cc(Cl)ccc2[nH]1
Reactant: FC(F)(F)CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1nc(-c2ccccc2)c2cc(Cl)ccc2n1CC(F)(F)F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
To a suspension of 5.13 g of 4-phenyl-6-chloro-2(1H)-quinazolinone in 60 ml of dimethylformamide was added 0.85 g 62% sodium hydride, and the resulting mixture was stirred at 100° C. for 30 minutes. Thereafter, 10.0 g of 2,2,2-trifluoroethyl iodide was added and the mixture was stirred at 140° C. for 8 hours. After cooling, the reaction mixture was poured into 300 ml of water and the resulting mixture was extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The oily residue was absorbed on a silica gel column, eluted with chloroform to obtain 3.5 g of 1-(2,2,2-trifluoroethyl)-4-phenyl-6-chloro-2(1H)-quinazolinone which was recrystallized from ethanol to give pale yellow leaflets melting at 185.0°-186.0° C., and 2.0 g of 2-(2,2,2-trifluoroethoxy)-4-phenyl-6-chloroquinazoline which was recrystallized from ethanol to give pale yellow needles melting at 113.0°-114.0° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:9]([OH:11])=O)=[C:5]([CH2:7][CH3:8])[N:6]=1.CN(C)C=O.C(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([C:9]([Cl:19])=[O:11])=[C:5]([CH2:7][CH3:8])[N:6]=1
Reactant: CCc1nc(C)sc1C(=O)O
Reactant: O=C(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCc1nc(C)sc1C(=O)Cl

Procedure:
In a similar apparatus to Example 1, 18.8 g (0.11 mole) of 2-methyl-4ethylthiazole-5carboxylic acid were suspended in 150 ml of toluene, followed by the addition of 0.1 g of N,N-dimethylformamide. Under heating and reflux, phosgene was blown at a rate of 1.5 l/hr for 4 hours (0.27 mole). After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 20.3 g of 2-methyl-4-ethylthiazole-5-carboxylic acid chloride. Its purity and yield were 98.0% and 97.5%, respectively.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]C)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:15]([O:17]C)=[O:16].C(COC1C=C2C(=CC=1)C=C(C(O)=O)C=C2)OC1C=C2C(=CC=1)C=C(C(O)=O)C=C2>[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4].C(O)CO>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1ccc2cc(C(=O)OC)ccc2c1
Agent: [Ti+4]
Agent: CCCC[O-]
Agent: O=C(O)c1ccc2cc(OCCOc3ccc4cc(C(=O)O)ccc4c3)ccc2c1
Solvent: OCCO
Product: O=C(O)c1ccc2cc(C(=O)O)ccc2c1

Procedure:
Further, an esterification reaction and a transesterification reaction were carried out among dimethyl 2,6-naphthalenedicarboxylate, 6,6′-(ethylenedioxy)di-2-naphthoic acid and ethylene glycol in the presence of titanium tetrabutoxide and then a polycondensation reaction was carried out to obtain an aromatic polyester (B-1) for the film layer (B) which comprised 73 mol % of a 2,6-naphthalenedicarboxylic acid component and 27 mol % of a 6,6′-(alkylenedioxy)di-2-naphthoic acid component based on the total of all the acid components and 98 mol % of an ethylene glycol component and 2 mol % of a diethylene glycol component based on the total of all the glycol components. This aromatic polyester (B-1) had a melting point of 240° C. and a glass transition temperature of 117° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[CH2:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C12BC(CCC1)CCC2.Br[C:26]1[C:27]2[N:34]([CH2:35][CH3:36])[C:33]([C:37]3[C:38]([NH2:42])=[N:39][O:40][N:41]=3)=[N:32][C:28]=2[CH:29]=[N:30][CH:31]=1.[OH-].[Na+]>O1CCCC1.ClCCl>[CH2:35]([N:34]1[C:27]2[C:26]([CH2:15][CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:31][N:30]=[CH:29][C:28]=2[N:32]=[C:33]1[C:37]1[C:38]([NH2:42])=[N:39][O:40][N:41]=1)[CH3:36]
Reactant: C=CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCn1c(-c2nonc2N)nc2cncc(Br)c21
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCn1c(-c2nonc2N)nc2cncc(CCC3CCNCC3)c21
Temperature: 25 °C
Reaction time: 6 h
Yield: 6.7 %

Procedure:
A solution of 4-vinyl-piperidine-1-carboxylic acid tert-butyl ester (WO 9620192) (1.2 mM: 252 mg) in dry tetrahydrofuran (4 ml) was treated with a 0.5M solution of 9-borabicyclo[3.3.1]-nonane in tetrahydrofuran (1.2 mM; 2.4 ml) and stirred at room temperature for 6 hours under argon. The mixture was treated with the product of Example 100 (1.0 mM; 309 mg), 1,1′-bis(diphenylphosphino)ferrocene dichloro palladium(II) complex with dichloromethane (25 mg) and a 3M aqueous solution of sodium hydroxide (1 ml). The resulting mixture was heated at reflux under argon for 18 hours and purified on a 5 g SCX ion exchange cartridge. After removal of the solvent in vacuo the resulting yellow gum was treated with trifluoroacetic acid at room temperature for 2 hours and the solution passed through a 5 g SCX ion exchange cartridge. The solvent was removed in vacuo and the residue purified on a 5 g silica solid phase extraction cartridge eluting with 1-5-94 ammonia-methanol-dichloromethane to give the title compound as a white solid (23 mg). MS (ES+) m/e 342 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[F:9].[Li]CCCC.CON(C)[C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)=[O:19]>C1COCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([F:9])=[C:2]([CH:7]=1)[C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)=[O:19]
Reactant: Fc1ccc(Cl)cc1Br
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(Cl)ccc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
A solution of 2-bromo-4-chloro-1-fluorobenzene (175 μL, 1.377 mmol) in THF (4.59 mL) at 78° C. was treated with n-BuLi (2.6 M, 741 μL, 1.928 mmol) and the reaction mixture was stirred for 30 min. To this was added tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (250 mg, 0.918 mmol) in one portion. The cooling bath was removed and the resulting reaction mixture was allowed to warm to rt and stirred for 1.5 h. Purification by automated flash silica gel chromatography using 10% EtOAc in hexanes afforded tert-butyl 4-(5-chloro-2-fluorobenzoyl)piperidine-1-carboxylate (287.9 mg, 92%) as a yellow oil. ESI-MS m/z [M+Na]+ 364.20.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13]([C:19](=[O:25])[CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])=[C:12]([O:26][CH2:27][CH3:28])[CH:11]=2)=[CH:4][N:3]=1.C(O)C.[BH4-].[Na+]>O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:26][CH2:27][CH3:28])[C:13]([CH:19]([OH:25])[CH2:20][S:21]([CH3:24])(=[O:22])=[O:23])=[C:14]([O:16][CH2:17][CH3:18])[CH:15]=2)=[CH:4][N:3]=1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1C(=O)CS(C)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1C(O)CS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
To a suspension of 1 g. of 4'-[(2,4-diamino-5-pyrimidinyl)-methyl]-2',6'-diethoxy-2-(methylsulfonyl)-acetophenone in a mixture of 25 ml. of ethanol and 10 ml. of water there is added portionwise with stirring over a period of 30 minutes 500 mg. of sodium borohydride. First the solution becomes clear, and after an additional 30 minutes of stirring, there crystallizes 4-[(2,4-diamino-5-pyrimidinyl)-methyl]-2,6-diethoxy-α-[(methylsulfonyl)-methyl]-benzyl alcohol, having a m.p. of 205°-206° after recrystallization from methanol.
Reaction SMILES: [Na].Cl.[NH2:3][OH:4].[F:5][C:6]([F:27])([F:26])[C:7]1[C:12]2[C:13](=[O:25])[N:14]3[CH2:24][CH2:23][C@H:15]3[C:16]3[N:17]([CH:18]=[N:19][C:20]=3[C:21]#[N:22])[C:11]=2[CH:10]=[CH:9][CH:8]=1>CO>[F:27][C:6]([F:5])([F:26])[C:7]1[C:12]2[C:13](=[O:25])[N:14]3[CH2:24][CH2:23][C@H:15]3[C:16]3[N:17]([CH:18]=[N:19][C:20]=3[C:21](=[N:3][OH:4])[NH2:22])[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: NO
Reactant: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1c-2cccc1C(F)(F)F
Agent: Cl
Agent: [Na]
Solvent: CO
Product: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
730 mg (31.8 mmol) of sodium were dissolved in 40 ml of methanol. 2.37 g (34.1 mmol) of hydroxylamine hydrochloride and 7.1 g (22.3 mmol) of (S)-8-trifluoromethyl-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile were added in succession at room temperature and the mixture was stirred at room temperature overnight. By evaporating the solvent there were obtained 7.8 g (100%) of (S)-8-trifluoromethyl-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime, which was used in the next step without further purification.
Reaction SMILES: [CH2:1](C(CCCCCCCCC)C=O)CCC.[CH2:17]([CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:20]=[O:21])C>>[CH3:17][CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:1])[CH:20]=[O:21]
Reactant: CCCCCCCCCC(C=O)CCCC
Reactant: CCCCCCCCCCCC(C=O)CC
Product: CCCCCCCCCCCCC(C)C=O

Procedure:
MS: m/z (%)=168 (9, M+−58), 95 (6), 81 (8), 71 (19), 58 (100), 43 (23).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=2)=[O:10])[CH2:4]1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl>[CH3:46][S:47]([NH:2][CH:3]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=2)=[O:10])[CH2:4]1)(=[O:49])=[O:48]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2CCC(N)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2CCC(NS(C)(=O)=O)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
In a round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-amino-cyclopentyl)-amide hydrochloride (145 mg, 0.23 mmol) was suspended in dichloromethane (2.5 ml). The suspension was cooled to 0° C. and triethylamine (0.10 ml, 0.72 mmol) was added followed by methanesulfonyl chloride (0.02 ml, 0.26 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with dichloromethane (2×). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-5% MeOH) to afford 111 mg (79%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-methanesulfonylamino-cyclopentyl)-amide as a light yellow solid.