Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.[N:58]([CH2:61][CH2:62][CH2:63][C:64]([O:66][CH2:67][CH2:68][Si:69]([CH3:72])([CH3:71])[CH3:70])=[O:65])=[C:59]=[O:60]>C(N(CC)CC)C.C1C=CC=CC=1>[CH2:35]([CH:30]1[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]2[O:10][C:9]([OH:52])([CH:8]([CH3:53])[CH2:7][CH:6]2[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]2[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]2)[C:21](=[O:22])[O:23][CH:24]([C:40]([CH3:51])=[CH:41][CH:42]2[CH2:43][CH2:44][CH:45]([O:50][C:59](=[O:60])[NH:58][CH2:61][CH2:62][CH2:63][C:64]([O:66][CH2:67][CH2:68][Si:69]([CH3:70])([CH3:72])[CH3:71])=[O:65])[CH:46]([O:48][CH3:49])[CH2:47]2)[CH:25]([CH3:39])[CH:26]([OH:38])[CH2:27][C:28]1=[O:29])[CH:36]=[CH2:37]
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Reactant: C[Si](C)(C)CCOC(=O)CCCN=C=O
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(=O)NCCCC(=O)OCC[Si](C)(C)C)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 2 h

Procedure:
A solution of the FR-900506 substance (310 mg), 2-trimethylsilylethyl 4-isocyanatobutyrate (350 mg) and triethylamine (6 drops) in anhydrous benzene (4 ml) was heated at 50° C. with stirring for 2 hours. The reaction mixture was allowed to stand at room temperature overnight. The mixture was concentrated to dryness under reduced procedure to leave a residue, which was chromatographed on silica gel in chloroform. Elution was carried out with chloroform to give 17-allyl-12-[2-[3-methoxy-4-[3-(2-trimethylsilylethoxycarbonyl)propylcarbamoyloxy]cyclohexyl]-1-methylvinyl]-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (99 mg). This product was treated with tetra(n-butyl)ammonium fluoride (0.12 m mole) in tetrahydrofuran (2.5 ml) at room temperature for 20 minutes. The reaction mixture was concentrated to dryness under reduced pressure to leave a residue, which was purified with preparative thin layer chromatography on silica gel. Elution with a mixture of chloroform and methanol (5:1) gave 17-allyl-12-[2-[4-(3-carboxypropylcarbamoyloxy)-3-methoxycyclhexyl]-1-methylvinyl]-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (18.1 mg).
Reaction SMILES: [Br-].[CH2:2]([Zn+])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:10][C:11]1[CH:18]=[CH:17][C:16](I)=[CH:15][C:12]=1[C:13]#[N:14]>C1COCC1>[NH2:10][C:11]1[CH:18]=[CH:17][C:16]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: [Zn+]Cc1ccccc1
Reactant: N#Cc1cc(I)ccc1N
Agent: [Br-]
Solvent: C1CCOC1
Product: N#Cc1cc(Cc2ccccc2)ccc1N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 51 %

Procedure:
(DPPF)PdCl2—CH2Cl2 (82 mg, 0.1 mmol) was added to 0.5 M benzylzinc bromide in dry THF (10 mL, calculated to contain 5 mmol), and the mixture was stirred at room temperature for 5 min under N2. A solution of 9 (488 mg, 2 mmol) in dry THF (2 mL) was then added, and the reaction was heated under reflux and monitored by TLC (silica gel, 2:1 CH2Cl2-hexanes). After 30 min the reaction was quenched by addition of saturated aqueous NH4Cl (10 mL) followed by saturated aqueous Na2EDTA (10 mL), and stirring was continued for another 30 min. The brown mixture was extracted several times with CH2Cl2, and the combined extracts were washed with brine, dried over Na2SO4, and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (2:1 CH2Cl2-hexanes) to obtain 2-amino-5-benzylbenzonitrile (10a) as a white powder (210 mg, 51%): mp 68-69° C.; 1H NMR (DMSO-d6) δ 3.75 (s, 2H, CH2), 5.85 (br s, 2H, NH2), 6.70 (d, J=8 Hz, 1H, H-3), 7.13-7.26 (m, 7H, aromatic protons). The product was used directly in the next reaction (Step 3).
Reaction SMILES: [O:1]([CH:3]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]([O:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39])=[C:22]([F:40])[CH:21]=1)[C:4]([O:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[NH2:2].O=[C:42]([C:46]1[N:47]=[C:48]([NH:51][C:52]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[S:49][CH:50]=1)[C:43]([OH:45])=[O:44]>CO>[F:40][C:22]1[CH:21]=[C:20]([CH:3]([O:1][N:2]=[C:42]([C:46]2[N:47]=[C:48]([NH:51][C:52]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)([C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[S:49][CH:50]=2)[C:43]([OH:45])=[O:44])[C:4](=[O:5])[O:6][CH:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:25]=[C:24]([O:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=1[O:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39]
Reactant: O=C(O)C(=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: COCCOCOc1cc(C(ON)C(=O)OC(c2ccccc2)c2ccccc2)cc(F)c1OCOCCOC
Solvent: CO
Product: COCCOCOc1cc(C(ON=C(C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc(F)c1OCOCCOC
Yield: 56 %

Procedure:
0.640 g of the product of Step D and and 0.474 g of oxo-[2-[(triphenylmethyl)-amino]-thiazol-4-yl]-acetic acid (Belgian Patent Application No. 864,828) were stirred for 4 and a half hours under nitrogen and at ambient temperature in the presence of 20 ml of methanol. Then, the solvent was eliminated, and the residue was chromatographed on silica, eluting with a dichloromethane-methanol (95-5) mixture to obtain 0.612 g of the expected product with a Rf=0.35 [eluant: dichloromethane-methanol (9-1)].
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]([C:19]1[C:24]([O:25][CH3:26])=[N:23][C:22]([CH3:27])=[CH:21][N:20]=1)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1I)(=[O:11])=[O:10])=[O:7])[CH:2]([CH3:4])[CH3:3].[C:28]1([CH3:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([O:5][C:6]([N:8]([C:19]1[C:24]([O:25][CH3:26])=[N:23][C:22]([CH3:27])=[CH:21][N:20]=1)[S:9]([C:12]1[C:13]([C:31]2[CH:32]=[CH:33][C:28]([CH3:34])=[CH:29][CH:30]=2)=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:11])=[O:10])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1ccccc1
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1-c1ccc(C)cc1

Procedure:
A mixture of N-(isobutoxycarbonyl)-N-(3-methoxy-5-methyl-2-pyrazinyl)-2-iodobenzenesulphonamide (0.252 g) 4-methylbenzeneboronic acid (0.068 g), tetrakis(triphenylphosphine)palladium(0) (0.0115 g), toluene (2.5 ml), ethanol (1.25 ml) and 2M sodium carbonate solution (3.75 ml) was stirred vigorously and heated under reflux for 2 hours under an atmosphere of argon. Water (10 ml) was added and the mixture was extracted with ethyl acetate (2×10 ml). The combined extracts were washed with saturated sodium chloride solution (25 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:4 v/v), to give N-(isobutoxycarbonyl)-N-(3-methoxy-5-methyl-2-pyrazinyl)-4'-methyl-2-biphenylsulphonamide (0.182 g); 1H NMR (DMSO-d6): 0.6 (d,6H), 1.55-1.75 (m,1H), 2.35 (s,3H), 2.5 (s,3H), 3.85 (d,2H), 3.95 (s,3H), 7.15-7.25 (m,4H), 7.35-7.45 (m,1H), 7.7-7.8 (m,2H), 8.15 (s,1H), 8.45-8.55 (m,1H); mass spectrum (+ve FAB, methanol/NBA): 470 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10][CH2:11][CH2:12][CH3:13])[N:7]=[C:6](Cl)[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C@@H:68]([NH2:72])([CH2:70][CH3:71])[CH3:69]>CCOCC.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10][CH2:11][CH2:12][CH3:13])[N:7]=[C:6]([NH:72][CH:68]([CH2:70][CH3:71])[CH3:69])[CH:5]=1
Reactant: CCCSc1cc(C(=O)OC)cc(Cl)n1
Reactant: CC[C@H](C)N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCSc1cc(C(=O)OC)cc(NC(C)CC)n1
Temperature: 90 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
Add 2-chloro-6-propylsulfanyl-isonicotinic acid methyl ester (1.35 g, 5.49 mmol) palladium acetate (0.123 g, 0.549 mmol, 0.1 eq.), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.342 g, 0.549 mmol, 0.1 eq.), cesium carbonate (2.68 g, 8.24 mmol, 1.5 eq.) and toluene (20 mL) into a sealed vessel flushed with nitrogen. Slowly add (S)-sec-butylamine (0.824 mL, 8.24 mmol) and heat and stir the reaction mixture at 90° C. for 18 h. Cool the reaction mixture to room temperature, dilute with ether and filter through a filtering agent. Concentrate the filtrate and purify (silica gel chromatography, eluting with the 5:95 to 10:90 ethyl acetate:hexanes) to give the title compound (55%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[CH:4][CH:3]=1.[CH:10](OC)([O:13][CH3:14])[O:11][CH3:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>CO>[CH3:12][O:11][CH:10]([O:13][CH3:14])[C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: COC(OC)OC
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(OC)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
21.1 g (114 mmol) of 4-bromobenzaldehyde and 20 ml (182 mmol) of trimethyl orthoformate (both Fluka, Buchs, Switzerland) are dissolved in 35 ml of methanol, and 0.65 g (3.4 mmol) of ρ-toluenesulfonic acid monohydrate is added at room temperature (exothermic reaction). The reaction mixture is stirred at room temperature under nitrogen for 20 hours. The acid is then neutralised with 0.62 ml of 30% sodium methanolate solution in methanol (3.4 mmol); the reaction mixture is concentrated using a rotary evaporator and the residue is distilled. The title compound is obtained in the form of a colourless liquid. TLC: Rf =0.58 (hexane/ethyl acetate 2:1). B.p.: 90-92° C. (4 mbar). 1H-NMR (CDCl3 ; 200 MHz): 7.50 and 7.32/each d, J=9 (2×2H); 5.36/s (1H); 3.31/s (6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[C:19]2[CH:18]=[CH:17][S:16][C:15]=2[CH:14]=[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]=1)(=O)C>C(O)C>[OH:10][C:11]1[C:19]2[CH:18]=[CH:17][S:16][C:15]=2[CH:14]=[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]=1
Reactant: CCOC(=O)c1cc(OC(C)=O)c2ccsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cc(O)c2ccsc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium carbonate (400 mg) was added to a solution of ethyl 4-acetoxybenzo[b]thiophene-6-carboxylate (760 mg) synthesized according to the method described in WO 2005/007635 in ethanol (6 ml), and the reaction solution was stirred at room temperature for 1 hour. The insolubles were filtrated, then the solvent was evaporated under vacuum, and the residue was purified by column chromatography on silica gel (developing solvent:hexane-ethyl acetate) to obtain ethyl 4-hydroxybenzo[b]thiophene-6-carboxylate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]([OH:23])=O)[CH2:16][CH2:15]3)=[N:11][N:10]=2)=[CH:5][CH:4]=1.[NH2:24][CH2:25][C:26]1[NH:27][C:28](=[O:36])[C:29]2[CH2:35][O:34][CH2:33][CH2:32][C:30]=2[N:31]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][C:12]([CH:14]3[CH2:15][CH2:16][N:17]([CH2:20][C:21]([NH:24][CH2:25][C:26]4[NH:27][C:28](=[O:36])[C:29]5[CH2:35][O:34][CH2:33][CH2:32][C:30]=5[N:31]=4)=[O:23])[CH2:18][CH2:19]3)=[N:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Reactant: COc1ccc(-c2nnc(C3CCN(CC(=O)O)CC3)o2)cc1
Solvent: CC#N
Product: COc1ccc(-c2nnc(C3CCN(CC(=O)NCc4nc5c(c(=O)[nH]4)COCC5)CC3)o2)cc1
Yield: 7.3 %

Procedure:
The title compound (10 mg, 0.018 mmol) was prepared following the general procedure of Example 1 from {4-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-piperidin-1-yl}-acetic acid (100 mg, 0.246 mmol, 1.0 eq) and 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (46.8 mg, 0.258 mmol, 1.05 eq). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.43 (br s, 1H) 8.27 (br s, 1H) 7.92 (d, J=9.03 Hz, 2H) 7.14 (d, J=9.03 Hz, 2H) 4.34 (s, 2H) 4.20 (d, J=5.52 Hz, 2H) 3.73-3.92 (m, 5H) 2.86-3.11 (m, 5H) 2.18-2.36 (m, 2H) 2.01-2.10 (m, 2H) 1.87-1.98 (m, 2H). HR-MS (m/z, MH+): 481.2205, 482.2262. HPLC retention time: 2.69 min (Agilent column 3.0×100 mm 3 um C18 column; flow rate of 1.0 mL/min with gradient from 5% to 95% acetonitrile in 10 min, 0.1% FA).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].Cl.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([OH:35])=[O:34]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[C:33]([OH:35])=[O:34])=[C:4]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Reactant: O=C(O)C1COCCN1
Agent: Cl
Product: COC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 44.9 %

Procedure:
Methyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (3.02 g, 6.54 mmol) (The compound was synthesized according to the procedure as described in WO2010069147A) was reacted with morpholine-3-carboxylic acid hydrochloride (1.1 g, 6.54 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (1.5 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C>[CH2:1]([NH:8][CH:3]=[CH:2][C:1]#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Solvent: CCO
Product: N#CC=CNCc1ccccc1
Yield: 72.1 %

Procedure:
9.7 g (0.1 mol) of 3-EAN and 21.4 g (0.2 mol) of benzylamine are refluxed for 4 h with removal of ethanol by distillation. Subsequent vacuum distillation yields 11.4 g of 3-benzylaminoacrylonitrile (72% with respect to 3-EAN).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].CC([O-])(C)C.[K+].[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O-])=O>CS(C)=O>[NH2:4][C:3]1[N:5]=[N:12][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:2]=1
Reactant: N=C(N)N
Reactant: O=[N+]([O-])c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1nnc2ccccc2n1
Reaction time: 0.02 h
Yield: 71.8 %

Procedure:
To a stirring mixture of guanidine hydrochloride (160 mg, 1.7 mmol) and t-BuOK (670 mg, 6 mmol) in DMSO (4 mL) was added one portion of nitrobenzene (123 mg, 1 mmol) at room temperature. The mixture turned red in one minute. In 20 to 30 minutes the mixture was quenched with a saturated, aqueous solution of ammonium chloride. A yellow precipitate was formed and removed by filtration. The precipitate was then washed with water, dried in the air, and recrystallized from benzene or ethanol to give 105 mg (72%) of 3-amino-1,2,4-benzotriazine. The melting point was determined to be 203–205° C., consistent with the melting point (207° C.) of 3-amino-1,2,4-benzotriazine synthesized by other known methods (J. Chem. Soc. (B) (1970) 911).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11]1(C(C)C)[CH:16]=CC=C[CH:12]=1>>[CH:11]([C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1)([CH3:16])[CH3:12]
Reactant: c1ccc2ccccc2c1
Reactant: CC(C)c1ccccc1
Product: CC(C)c1cccc2ccccc12

Procedure:
Reaction was carried out as in Example 4, but by reacting naphthalene with cumene in a molar ratio of 1 to 0.8 for 4 hours. Yield of isopropylnaphthalene obtained was 37%%, with an isomer distribution of 92% β- and 8% α.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1.[NH2:31][C@H:32]1[CH2:37][CH2:36][CH2:35][C@@H:34]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:33]1>C1COCC1>[F:20][C:14]1[C:15]([NH:31][C@H:32]2[CH2:37][CH2:36][CH2:35][C@@H:34]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:43])([CH3:42])[CH3:44])[CH2:33]2)=[N:16][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:9]=2)=[N:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H](N)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(F)cnc32)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](NC(=O)OC(C)(C)C)C4)n3)c3cc(F)cnc32)cc1
Temperature: 50 °C

Procedure:
5-fluoro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 44c, (5.9 g, 10.5 mmol) and tert-butyl N-[(1R,3S)-3-aminocyclohexyl]carbamate (3 g, 12.60 mmol) were dissolved in THF (100 mL). The reaction mixture was heated to 50° C. for 6 hours, then cooled to room temperature. Celite was added and the solvent was removed under reduced pressure. The Celite-supported residue was purified by silica gel chromatography (20-80% EtOAc/hexanes gradient to provide 3.7 g of tert-butyl N-[(1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]carbamate.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].O=[C:15]([C:26](=[O:75])[NH:27][C:28]1[CH:29]=[N:30][N:31]([CH2:53][CH2:54][O:55][C:56]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:32]=1[NH:33][C:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].O>O1CCCC1>[C:1](/[CH:3]=[C:15](/[C:26]([NH:27][C:28]1[CH:29]=[N:30][N:31]([CH2:53][CH2:54][O:55][C:56]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:32]=1[NH:33][C:34]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:75])\[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])#[N:2]
Reactant: CC(C)(C)OC(=O)NCCC(=O)C(=O)Nc1cnn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCC/C(=C\C#N)C(=O)Nc1cnn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83.3 %

Procedure:
To a stirred solution of diethyl (cyanomethyl)phosphonate (311 mg) in tetrahydrofuran (13 ml) was added sodium hydride (70.3 mg, 60% oil suspension) under nitrogen atmosphere at 0° C., and the mixture was stirred for 45 minutes with warming to room temperature. tert-Butyl [3,4-dioxo-4-({5-(tritylamino)-1-[2-(trityloxy)ethyl]-1H-pyrazol-4-yl}amino)butyl]carbamate (1.32 g) was added to the mixture and the stirring was continued for 30 minutes. Water was added to the reaction mixture and the whole mixture was extracted with ethyl acetate. The extract was washed with water and brine and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave tert-butyl {(3E)-4-cyano-3-[({5-(tritylamino)-1-[2-(trityloxy)ethyl]-1H-pyrazol-4-yl}amino)carbonyl]-3-buten-1-yl}carbamate (1.13 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[CH2:5][C@@H:6]1[NH:31][C:30](=[O:32])[C@H:29]([CH:33]([CH3:35])[CH3:34])[NH:28][C:27](=[O:36])[C@H:26]([CH3:37])[C@H:25]([O:38][CH3:39])[CH2:24][CH2:23][CH:22]=[CH:21][C:20]2[CH:40]=[C:16]([CH:17]=[CH:18][CH:19]=2)[C@@H:15]([CH3:41])[O:14][C:13](=[O:42])[C@H:12]2[NH:43][N:8]([CH2:9][CH2:10][CH2:11]2)[C:7]1=[O:44]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[CH2:5][C@@H:6]1[NH:31][C:30](=[O:32])[C@H:29]([CH:33]([CH3:35])[CH3:34])[NH:28][C:27](=[O:36])[C@H:26]([CH3:37])[C@H:25]([O:38][CH3:39])[CH2:24][CH2:23][CH2:22][CH2:21][C:20]2[CH:40]=[C:16]([CH:17]=[CH:18][CH:19]=2)[C@@H:15]([CH3:41])[O:14][C:13](=[O:42])[C@H:12]2[NH:43][N:8]([CH2:9][CH2:10][CH2:11]2)[C:7]1=[O:44]
Reactant: CO[C@@H]1CCC=Cc2cccc(c2)[C@@H](C)OC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O)c2)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1C
Agent: [Pd]
Agent: CO[C@@H]1CC/C=C/c2cccc(c2)[C@@H](C)OC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O)c2)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1C
Solvent: CCOC(C)=O
Product: CO[C@@H]1CCCCc2cccc(c2)[C@@H](C)OC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](Cc2cccc(O)c2)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
A solution of (E)-(2R,5S,11S,14S,17R,18R)-11-(3-hydroxy-benzyl)-14-isopropyl-18-methoxy-2,17-dimethyl-3-oxa-9,12,15,28-tetraaza-tricyclo[21.3.1.1*5,9*]octacosa-1(27),21,23,25-tetraene-4,10,13,16-tetraone (12 mg, 0.0185 mmol) in ethyl acetate (2 mL) containing 10% palladium on carbon (10 mg) was hydrogenated at room temperature and pressure for 1 hour. The reaction mixture was filtered through filter aid and the filter pad was washed with ethyl acetate. The filtrate was evaporated and the residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 4:6 to afford the title compound (5.6 mg, 47%) as a white solid. 1H NMR (300 MHz, CD3CN) δ0.95 (d, J=6.7 Hz, 6H), 1.28 (d, J=7.4 Hz, 3H), 1.54 (d, J=6.7 Hz, 3H), 1.30-2.30 (m, 13H), 2.55-2.60 (m, 1H), 2.75-2.91 (m, 3H), 3.26-3.32 (m, 1H), 3.44 (s, 3H), 3.50-3.57 (m, 1H), 4.00 (d, J=11.4 Hz, 1H), 4.17-4.30 (m, 2H), 5.48-5.56 (m, 1H), 5.77 (q, J=6.5 Hz, 1H), 6.66 (dd, J=8.0, 1.6 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 7.02-7.15 (m, 7H), 7.22 (d, J=7.6 Hz, 1H), 7.95-8.05 (br s, 1H). LCMS (m/z) 651 [M+H], Tr=5.20 min.