Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([S:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:7]
Reactant: CCCCOC(=O)c1ncc2ccc(Sc3ccccc3)cc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1ncc2ccc(Sc3ccccc3)cc2c1O

Procedure:
127 mg of 4-hydroxy-6-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (0.36 mmol) were reacted with glycine and sodium methylate analogously to Example D-1 g). 118 mg of the title compound were obtained; 1H NMR (DMSO-d6): δ=9.33 (t, 1H), 8.80 (s, 1H), 8.11 (d, 1H), 7.79 (s, 1H), 7.49 to 7.65 (m, 6 H), 4.01 (d, 2 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[CH2:30][CH:29]([N:34]([CH3:36])[CH3:35])[CH2:28]5)[N:19]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:37][C:38]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:39]=1[C:40](Cl)=[O:41]>C1COCC1.C(Cl)Cl>[CH3:35][N:34]([CH3:36])[CH:29]1[CH2:28][C:27]2[C:31](=[CH:32][CH:33]=[C:25]([NH:24][C:20]3[N:19]=[C:18]([C:17]4[C:9]([C:4]5[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:40](=[O:41])[C:39]6[C:38]([F:37])=[CH:46][CH:45]=[CH:44][C:43]=6[F:47])[CH:3]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:23]=[CH:22][N:21]=3)[CH:26]=2)[CH2:30]1
Reactant: CN(C)C1Cc2ccc(Nc3nccc(-c4c(-c5ccc(F)c(N)c5)nn5ccccc45)n3)cc2C1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C1Cc2ccc(Nc3nccc(-c4c(-c5ccc(F)c(NC(=O)c6c(F)cccc6F)c5)nn5ccccc45)n3)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.1 %

Procedure:
To a solution of {4-[2-(3-amino-4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}[2-(dimethylamino)-2,3-dihydro-1H-inden-5-yl]amine (80 mg, 0.17 mmol) in THF (3 mL) was added TEA (25 μL, 0.25 mmol) and 2,6-difluorobenzoyl chloride (22 μL, 0.18 mmol). The reaction was stirred at rt for 2 h, and the reaction was diluted with 30 mL DCM and adsorbed onto silica. The crude product was purified by flash chromatography and reversed-phase HPLC to generate, after lyophilization, the title compound as a TFA salt (38 mg, 37% yield). 1H NMR (400 MHz, d6-DMSO): δ 10.84 (s, 1H), 9.59 (s, 1H), 8.88 (d, J=6.7 Hz, 1H), 8.44 (d, J=8.4 Hz, 1H), 8.30 (d, J=5.3 Hz, 1H), 8.24 (d, J=7.0 Hz, 1H), 7.75 (s, 1H), 7.58-7.62 (m, 1H), 7.41-7.52 (m, 4H), 7.24 (t, J=8.0 Hz, 2H), 7.13-7.16 (m, 2H), 6.61 (d, J=5.3 Hz, 1H), 4.04-4.12 (m, 1H), 3.22-3.28 (m, 2H), 3.06-3.12 (m, 2H), 2.82 (s, 6H). MS (ESI) m/z=620 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:18])[O:9][C:10]3[C:15]([C:16]=2[OH:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24]Cl>>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][O:17][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9][C:8](=[O:18])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1oc2ccccc2c(O)c1-c1ccccc1
Reactant: CN(C)CCCCl
Agent: Cl
Product: CN(C)CCCOc1c(-c2ccccc2)c(=O)oc2ccccc12
Yield: 59 %

Procedure:
By treating 10 g. (0.042 mol) of 3-phenyl-4-hydroxy-coumarin with 87 g. (0.055 mol) of 3-dimethylamino-1-chloropropane hydrochloride as described in Example 1, there are obtained 8.1 g. of a yellow oil which cannot be crystallised. Yield 59% (theoretical yield 13.6 g.).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH3:43])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)=[O:21]>>[CH2:1]([NH:8][C:9](=[O:10])[NH:11][N:12]([CH2:14][C:15]([NH:18][C@@H:19]([CH3:43])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)=[O:21])=[O:17])[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)N
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)NC(=O)CN(C)NC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 99 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-11) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][N:7]([C:9]([O:11]C(C)(C)C)=O)[C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:34]=[CH:33][C:29](C(O)=O)=[CH:28][CH:27]=1>>[CH3:1][O:2][N:3]=[C:4]1[CH2:8][N:7]([C:9](=[O:11])[C:29]2[CH:28]=[CH:27][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)=[CH:34][CH:33]=2)[C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: CON=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)OC)N(C(=O)c2ccc(-c3ccccn3)cc2)C1
Yield: 45 %

Procedure:
Following the general method as outlined in Example 4 (Method B), starting from 1-tert-butyl 2-methyl (2S,4EZ)-4-(methoxyimino)-1,2-pyrrolidinedicarboxylate and 4-(2-pyridinyl)benzoic acid, the title compound was obtained, after flash-chromatography (eluent cyclohexane/ethyl acetate 8:2), as a mixture of two isomers in 45% yield (95% purity by HPLC).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[CH3:17][O:18][C:19](=[O:22])[CH2:20]Br>CN(C=O)C>[CH3:17][O:18][C:19](=[O:22])[CH2:20][O:16][C:13]1[CH:14]=[N:15][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[F:3])=[CH:11][CH:12]=1
Reactant: COC(=O)CBr
Reactant: Oc1ccc(-c2ccccc2F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(-c2ccccc2F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon, 157.3 mg (3.6 mmol) of sodium hydride (55% suspension in mineral oil) were added to 620 mg (3.27 mmol) of 6-(2-fluorophenyl)pyridin-3-ol in 25 ml of DMF. After stirring at room temperature for 60 min, 551.4 mg (3.6 mmol) of bromoacetic acid methyl ester were added, and the reaction mixture was stirred at room temperature for 2 h. After concentrating, water was added, and the mixture was extracted with ethyl acetate. The organic phase was separated and concentrated. Yield: 687 mg (80%).
Reaction SMILES: [Br:1][CH2:2][C:3]([O:5]CC)=[O:4].[N:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15].[I-].[Na+]>C(#N)C>[Br:1][CH2:2][C:3]([O-:5])=[O:4].[N:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15]
Reactant: CCOC(=O)CBr
Agent: [I-]
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: O=C([O-])CBr

Procedure:
The his(methylhydrazine)terpyridine of Part A (3.50 g, 82 mmol), ethyl bromoacetate (13.2 mL, 820 mmol), 2,6-lutidine (9.6 mL, 820 mmol), and sodium iodide (0.35 g, 2 mmol) were added to 350 mL of acetonitrile, and the solution was refluxed under N2 for 48 hours, when an additional 4.1 mL (370 mmol) of ethyl bromoacetate and 4.8 mL (410 mmol) of 2,6-lutidine were added. The reaction solution was refluxed for an additional 48 hours, and cooled. A copious amount of white salt resulting from excess bromoacetate and lutidine was filtered and discarded. The filtrate was concentrated, and the concentrated material was dissolved in dichloromethane, and extracted two times with dilute aqueous sodium chloride. The organic phase was concentrated under high vacuum until free of odors of bromoacetate and lutidine. The crude oil was purified on a Woelm silica gel column (36×2 in.). The column was eluted initially with 100% dichloromethane followed by 50/1 dichloromethane/acetone, with gradual increase of the concentration of acetone to 25/1 dichloromethane/acetone. Concentration of purified fractions gave 2.91 g (46%) of light straw-colored oil. A fraction of the purified oil, upon standing at room. temperature, crystallized, and after trituration with methanol gave a white solid, mp 100°-103° C. Anal. calcd for C40H49N7O9 : C, 62.24; H, 6.40; N, 12.70. Found: C, 62.31; H, 6.32; N, 12.69. The NMR and IR spectra were consistent with the assigned structure, and the product was homogeneous by TLC.
Reaction SMILES: [C:1]([O:6][CH:7]1[C:10]([CH3:12])([CH3:11])[CH:9]([OH:13])[C:8]1([CH3:15])[CH3:14])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:16]=[C:17]1[O:21][C:19](=[O:20])[CH2:18]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:21]=[C:17]([CH3:16])[CH2:18][C:19]([O:13][CH:9]1[C:10]([CH3:12])([CH3:11])[CH:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[C:8]1([CH3:15])[CH3:14])=[O:20]
Reactant: C=C(C)C(=O)OC1C(C)(C)C(O)C1(C)C
Reactant: C=C1CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)OC1C(C)(C)C(OC(=O)CC(C)=O)C1(C)C
Temperature: 2.5 °C
Reaction time: 8 h

Procedure:
To a 3-L flask was charged 2,2,4,4-tetramethylcyclobutane-1,3-diol (423.26 g, 3.0 moles), THF (550 g), DMAP (0.5 g) and N-diphenylnitrosoamine (2 g) and methacrylic anhydride (308 g, 2 moles). Mixture heated to reflux (81° C.) and held for six hours. Reaction cooled and THF removed with a rotary evaporated. To the crude residue was added heptane (1200 mL) and cooled to 0-5° C. for 30 minutes. The precipitated unreacted starting material was filtered off and the cake washed with cold heptanes (600 mL). Heptane removed from filtrate with rotary evaporator and the crude product distilled through a 12×1 inch Penn State packed column to produce 3-hydroxy-2,2,4,4-tetramethylcyclobutyl methacrylate in 97.3% NMR assay. To a 500 mL flask was charged 3-hydroxy-2,2,4,4-tetramethylcyclobutyl methacrylate (32 g, 0.151 moles), methylene chloride (75 g), DMAP (0.04 g) and the mixture cooled to 0-5° C. To this was added dropwise over one hour freshly distilled diketene (12.7 g) dissolved in methylene chloride (20 g). After addition, the reaction was allowed to warm to room temperature and stir overnight. Once reaction was complete, the dichloromethane was removed at 60° C. with house vacuum. Crude product distilled via Kugelrohr distillation to provide desired product of 94.8% GC assay.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][C:24]=1[CH3:38]>>[CH3:38][C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:27]=[CH:28][C:23]=1[NH:22][CH3:21]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CNc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C
Product: CNc1ccc(-c2ccn3c(=O)c(C(=O)OC)cc(C4CC4)c3c2C)cc1C
Yield: 39.1 %

Procedure:
Methyl 8-(3-methyl-4-(methylamino)phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and N,2-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (101.5 mg, 0.41 mmol). The residue was rinsed with DCM and dried in a vacuum stove to afford the title compound as a yellow solid (50 mg, 39%).
Reaction SMILES: [OH:1][CH:2]1[C:11]2[N:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:12][C:8]1[CH:9]=[N:10][C:11]2[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=2[CH:7]=1
Reactant: Cc1cnc2c(c1)CCCC2O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1cnc2c(c1)CCCC2=O

Procedure:
8-Hydroxy-3-methyl-5,6,7,8-tetrahydroquinoline (42.5g) in methylene chloride (21/21) was stirred at room temperature with manganese dioxide (425g) for 16 hours. The manganese dioxide was removed by filtration and washed with methylene chloride. The filtrate was evaporated to dryness under reduced pressure and the residue was distilled to give 5,6-dihydro-3-methyl-7H-quinolin-8-one (30g) b.p. 142°-4° C. at 0.5mm.
Reaction SMILES: C([O:8][C@H:9]([CH3:48])[CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1([CH3:47])[CH2:20][CH2:19][N:18]([C:21]2[N:26]3[N:27]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:29]=[C:25]3[N:24]=[C:23]([CH3:35])[C:22]=2[C@H:36]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:17][CH2:16]1)C1C=CC=CC=1.[H][H]>CCO.[Pd]>[C:43]([O:42][C@@H:36]([C:22]1[C:23]([CH3:35])=[N:24][C:25]2[N:26]([N:27]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:29]=2)[C:21]=1[N:18]1[CH2:19][CH2:20][C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([OH:8])[CH3:48])([CH3:47])[CH2:16][CH2:17]1)[C:37]([O:39][CH2:40][CH3:41])=[O:38])([CH3:44])([CH3:45])[CH3:46]
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCCCC[C@@H](C)OCc4ccccc4)CC3)n2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCCCC[C@@H](C)O)CC3)n2n1
Yield: 81.6 %

Procedure:
To a solution of ethyl 7-(4-(((R)-5-(benzyloxy)hexyl)oxy)-4-methylpiperidin-1-yl)-6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (1.7 g, 2.55 mmol) in EtOH (25 mL) was added 10% Pd/C (0.271 g, 0.255 mmol) and the resulting mixture was stirred under balloon hydrogen atmosphere for 5 h. Mixture was then filtered and concentrated to afford ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-(((R)-5-hydroxyhexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (1.2 g, 2.081 mmol, 82% yield) as viscous oil. LCMS (M+H)=577.3. Used as is in the next step without further purification.
Reaction SMILES: C1(C)C=CC(S([CH2:10][C:11]2[N:16]=[C:15]([CH2:17][OH:18])[N:14]=[C:13]([CH2:19][OH:20])[N:12]=2)(=O)=O)=CC=1.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[N:22]([CH2:10][C:11]1[N:12]=[C:13]([CH2:19][OH:20])[N:14]=[C:15]([CH2:17][OH:18])[N:16]=1)=[N+:23]=[N-:24]
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(CO)nc(CO)n2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1nc(CO)nc(CO)n1
Temperature: 50 °C

Procedure:
4-(p-Toluenesulfonylmethyl)-2,6-dihydroxymethyl-s-triazine is dissolved in DMF and sodium azide (1.1 eq.) is added. The reaction mixture is heated to 50° C. for 4 hours. The DMF is removed under reduced pressure and the residue is partitioned between CH2Cl2 and water. The CH2Cl2 layer is separated and the water layer is extracted several times with CH2Cl2. The CH2Cl2 layers are combined, dried (MgSO4), and concentrated. The resultant residue is purified by silica gel flash column chromatography to give 4-(azidomethyl)-2,6-dihydroxymethyl-s-triazine.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([CH2:11][CH3:12])[NH:5][N:4]=1)[CH3:2].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([C:6]1[C:7]([CH2:8][CH2:9][O:10][S:14]([CH3:13])(=[O:16])=[O:15])=[C:3]([CH2:1][CH3:2])[N:4]([S:14]([CH3:13])(=[O:16])=[O:15])[N:5]=1)[CH3:12]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1n[nH]c(CC)c1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nn(S(C)(=O)=O)c(CC)c1CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.4 %

Procedure:
To a solution of 2-(3,5-diethyl-1H-pyrazol-4-yl)-ethanol (0.8 g, 4.8 mmol) in methylene chloride (20 mL) was added methanesulfonyl chloride (0.92 mL, 12 mmol) and triethylamine (2.0 mL, 14 mmol). The mixture was stirred at room temperature for 16 h and was loaded directly on to a silica gel column and eluted (methylene chloride/heptane followed by ethyl acetate/methylene chloride) to provide methanesulfonic acid 2-(3,5-diethyl-1-methanesulfonyl-1H-pyrazol-4-yl)-ethyl ester (940 mg, 41% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=O.[C:11]([O:15][C:16]([NH:18][CH:19](P(OC)(OC)=O)[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].CC(C)=O.C(=O)=O.CN(C)C(N(C)C)=N>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6](/[CH:7]=[C:19](\[NH:18][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])/[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH:9]=1
Reactant: COP(=O)(OC)C(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: O=Cc1cc(Br)ccc1F
Agent: CN(C)C(=N)N(C)C
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N/C(=C\c1cc(Br)ccc1F)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6.0 g (30 mmol) of 5-bromo-2-fluorobenzaldehyde and 12.7 g (34 mmol) of benzyl [(tert-butoxycarbonyl)amino](dimethoxyphosphoryl)acetate are introduced into 90 ml of THF and, while cooling with acetone/dry ice at −78° C., 3.91 g (34 mmol) of 1,1,3,3-tetramethylguanidine are added. After 4 h in the cold bath, the mixture is slowly warmed to RT and stirred at RT for a further 12 h. The solvent is distilled off in vacuo, and the crude product is taken up in ethyl acetate and washed once each with a saturated sodium bicarbonate solution and a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The crude product is purified by chromatography (silica gel, cyclohexane/ethyl acetate 2:1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[C:3]=1[CH:14]=O.[C:16](#[N:19])[CH:17]=[CH2:18].N12CCN(CC1)CC2>C(OCC)(=O)C>[CH3:13][O:12][C:6]1[CH:7]=[CH:8][C:9]2[CH:10]=[CH:11][C:2]3[O:1][CH2:18][C:17]([C:16]#[N:19])=[CH:14][C:3]=3[C:4]=2[CH:5]=1
Reactant: C=CC#N
Reactant: COc1ccc2ccc(O)c(C=O)c2c1
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Product: COc1ccc2ccc3c(c2c1)C=C(C#N)CO3

Procedure:
Under an anhydrous atmosphere, the aldehyde obtained in Step C (2 g:9.9 mmol) is partially solubilized in acrylonitrile (6.5 ml:49.4 mmol:10 eq.). The solution becomes clear after the addition of 1,4-diazabicyclo[2.2.2]octane (227 mg:2.47 mmol:0.25 eq.) and becomes a red colour when heated at reflux for a period of 18 hours. The reaction medium is then diluted with ethyl acetate and washed in succession with a 1N sodium hydroxide solution (20 ml) and then a 1N hydrochloric acid solution (20 ml). The concentrated organic phases are purified on a flash silica column eluted with an AcOEt/PE mixture (0.1/1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=2[CH3:31])[CH2:15][CH2:14]1)[CH:9]1[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:40][N:41]1[C:50]2[NH:49][C:48]3[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=3[NH:46][CH2:45][C:44]=2[CH:43]=[N:42]1>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH:9]1[CH2:11][CH2:10]1)[CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19](=[O:32])[CH2:20][CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([N:46]3[CH2:45][C:44]4[CH:43]=[N:42][N:41]([CH3:40])[C:50]=4[NH:49][C:48]4[CH:51]=[CH:52][CH:53]=[CH:54][C:47]3=4)=[O:27])=[CH:24][C:23]=2[CH3:31])[CH2:17][CH2:18]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Reactant: Cc1cc(C(=O)O)ccc1CCC(=O)N1CCC(CN(C(=O)OC(C)(C)C)C2CC2)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCC(CN(C(=O)OC(C)(C)C)C2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
WSCD (1.08 g, 5.6 mmol) and DMAP (343 mg, 2.8 mmol) were added to a solution of 4-(3-{4-[(tert-butoxycarbonyl-cyclopropyl-amino)-methyl]-piperidin-1-yl}-3-oxo-propyl)-3-methyl-benzoic acid from Example E86.2 (1.25 g, 2.8 mmol) in dichloromethane (100 ml) and triethylamine (0.783 ml, 5.6 mmol). The mixture was stirred for 1 h at room temperature then 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (676 mg, 3.4 mmol) was added. The mixture was heated at reflux for 2 days, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 2% methanol:98% EtOAc to 5% methanol:95% EtOAc) to yield the title compound (1.1 g, 62%).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[N:7]=1)=O.N>CO>[NH2:5][C:6]1[CH2:10][CH:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:28])[C:24]([F:25])([F:27])[F:26])=[CH:19][CH:18]=2)[N:7]=1
Reactant: O=C(NC1=NN(c2ccc(C(=O)C(F)(F)F)cc2)C(c2ccccc2)C1)C(F)(F)F
Agent: N
Solvent: CO
Product: NC1=NN(c2ccc(C(=O)C(F)(F)F)cc2)C(c2ccccc2)C1
Reaction time: 16 h

Procedure:
A solution of 1.0 g. of 2,2,2-trifluoro-N-[5 -phenyl-1-(p-trifluoroacetylphenyl)-2-pyrazolin-3-yl]acetamide (prepared as described in Example 9) in 100 ml. of methanol is saturated with ammonia gas, then is stored in a refrigerator for 16 hours. The solution is evaporated to dryness in vacuo. The residue is chromatographed by preparative column chromatography using silica gel and eluting with acetone:hexane, 50:50, to collect the most polar product. The product is recrystallized from dichloromethanehexane to yield 0.25 g. of the product of the Example as yellow needles, m.p. 214°-216° C.
Reaction SMILES: Cl[C:2]1[C:31](Cl)=[CH:30][C:29]2[C:4](=[N:5][C:6]3[C:7]4[C:16]([C:17]5[C:26]([C:27]=3[N:28]=2)=[N:25][C:24]2[C:19](=[CH:20][C:21](Cl)=[C:22](Cl)[CH:23]=2)[N:18]=5)=[N:15][C:14]2[C:9](=[CH:10][C:11](Cl)=[C:12](Cl)[CH:13]=2)[N:8]=4)[CH:3]=1.[CH2:37]([SH:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:37]([S:47][C:2]1[C:31]([S:47][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:30][C:29]2[C:4](=[N:5][C:6]3[C:7]4[C:16]([C:17]5[C:26]([C:27]=3[N:28]=2)=[N:25][C:24]2[C:19](=[CH:20][C:21]([S:47][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[C:22]([S:47][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH:23]=2)[N:18]=5)=[N:15][C:14]2[C:9](=[CH:10][C:11]([S:47][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[C:12]([S:47][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH:13]=2)[N:8]=4)[CH:3]=1)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCCS
Reactant: Clc1cc2nc3c4nc5cc(Cl)c(Cl)cc5nc4c4nc5cc(Cl)c(Cl)cc5nc4c3nc2cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCSc1cc2nc3c4nc5cc(SCCCCCCCCCC)c(SCCCCCCCCCC)cc5nc4c4nc5cc(SCCCCCCCCCC)c(SCCCCCCCCCC)cc5nc4c3nc2cc1SCCCCCCCCCC
Temperature: 80 °C
Reaction time: 72 h
Yield: 55.5 %

Procedure:
A mixture of 2,3,8,9,14,15-hexachloro-5,6,11,12,17,18-hexaazatrinaphthylene (3.00 g, 5.08 mmol), 1-decanethiol (13.74 mL, 66.75 mmol) and K2CO3 (25.55 g, 185.00 mmol) in DMF (250 mL) was stirred at 80° C. for 72 hrs under nitrogen. After cooled down to room temperature, solvent was removed in vacuo. To the solid residue, water and dichloromethane was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane (100 mL) twice. The combined organic layer was dried over magnesium sulfate and filtered. Solvent was evaporated under reduced pressure to give a yellow solid. The yellow solid was purified by flash chromatography on silica gel eluting with hexane:dichloromethane (1:1) to give a solid (4.00 g, 56% yield). The yellow product was washed with hot acetone in a Soxhlet extractor for 12 hrs before sending for elemental analysis. 1H (300 MHz, CD2Cl2) δ 7.49 (s, 6H), 2.81 (t, J=6.8 Hz, 12H), 1.55 (p, J=6.6 Hz, 12H), 1.50-1.25 (m, 84H), 0.93 (t, J=6.3 Hz, 18H). 13C NMR (75 MHz, CD2Cl2): 143.36, 141.84, 140.42, 122.26, 33.22, 32.36, 30.14, 30.07, 29.91, 29.82, 28.24, 23.13, 14.32. HRMS MALDI-TOF (with CHCA as matrix), 1417.8975; calcd. For C84H133N6S6 (M+H), 1417.8911. Anal. Calcd. For C84H132N6S6: C, 71.13; H, 9.38; N, 5.93. Found: C, 70.92; H, 9.38; N, 5.90.