Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH:5][C:6](=[O:26])[C@@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:8]C(OCC1C=CC=CC=1)=O.[ClH:32].[H][H]>CO.[Pd]>[ClH:32].[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH:5][C:6](=[O:26])[C@@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:8]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1ccccc1

Procedure:
A solution of 7 g. (0.016 mol) of Nα -benzyloxycarbonyl-D-phenylalanyl-L-leucine methyl ester in 120 ml. of methanol is treated with 6.12 ml. of 2.680N hydrogen chloride in methanol and reduced with hydrogen and 500 mg. of 10% palladium on carbon at atmospheric pressure. The reaction is monitored by thin layer chromatography. The mixture is filtered to separate the catalyst and the solution evaporated; 5.4 g. as a glass; [α]D23 -82.5° (c 1.02, methanol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([O-:15])=[O:14].C(O)(C(F)(F)F)=O>>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Yield: 85 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (2.0 g, 12.5 mmol), 4-nitrobenzaldehyde (1.88 g, 1 equiv.) and TFA (1.9 mL, 2 equiv.) to give the title compound (3.1 g, 86%) as a yellow powder. MP: 190° C.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[NH:26]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C@H:27]([C:31]([OH:33])=O)[CH:28]([CH3:30])[CH3:29].[NH2:44][C@H:45]([C:54]([OH:56])=[O:55])[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=1.[N:57]1([NH-:63])[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>C(Cl)Cl>[NH:26]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C@H:27]([C:31]([NH:44][C@H:45]([C:54]([OH:56])=[O:55])[CH2:46][C:47]1[CH:48]=[CH:49][C:50]([OH:53])=[CH:51][CH:52]=1)=[O:33])[CH:28]([CH3:29])[CH3:30].[N:57]1([NH-:63])[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [NH-]N1CCOCC1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reaction time: 0.33 h

Procedure:
At 0° C., 5.18 g (25 mmol) of DCC and 3.73 g (27.5 mmol) of HOBT are added to a solution of 6.3 g (25 mmol) of Z-(L)-Val-OH in 400 ml of methylene chloride and the mixture is then stirred for 20 min. A solution of 6.27 g (25 mmol) of H-(L)-Tyr-morpholin-4-ylamide in 600 ml of methylene chloride is subsequently added. After the mixture has been stirred for 18 h at RT, working up is carried out as described in Example 41 A) a): TLC Rf (B)=0.50.
Reaction SMILES: [C:1]([C:4]1[C:5](Cl)=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[NH2:11][C:12]1[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([OH:29])[CH:27]=2)[N:22]=[CH:21][N:20]=1>>[CH3:17][N:14]1[CH:15]=[CH:16][C:12]([NH:11][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][C:5]4[C:4]([C:1](=[O:3])[CH3:2])=[CH:9][CH:8]=[CH:7][N:6]=4)[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[N:13]1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: CC(=O)c1cccnc1Cl
Reactant: Cn1ccc(N)n1
Product: CC(=O)c1cccnc1Oc1ccc2ncnc(Nc3ccn(C)n3)c2c1

Procedure:
The compound of Example 126 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 3-acetyl-2-chloropyridine, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH:9]1[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:17][O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH:9]([CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10]1)=[O:15]
Reactant: COC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCOc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1CCNC(CCOc2ccccc2)C1
Yield: 99.2 %

Procedure:
A solution of (RS)-1-(tert-butyloxycarbonyl)-4-methoxycarbonyl-2-(2-phenoxyethyl)piperazine (D8) (1.4 g, 3.85 mmol) in dichloromethane (30 ml) and trifluoroacetic acid (5 ml) was stirred at 35° C. for 0.75 h. On cooling, the mixture was evaporated in vacuo and the residue partitioned between dichloromethane and 1N sodium hydroxide (50 ml each). The organic layer was dried (Na2SO4) and evaporated in vacuo to afford the title compound as a colourless oil (1.01 g, 99%). Mass spectrum (AP+): Found 265 (MH+). C14H20N2O3 requires 264.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl>O1CCCC1>[Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1nccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)nccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-chloro-1H-pyrrolo[3,2-c]pyridine (98%, 2.0 g, 13 mmol) and tetrahydrofuran (20 mL) was cooled to 0° C. Sodium hydride (60% in oil, 1.03 g, 25.8 mmol) was added portion-wise over 5 minutes, and the reaction mixture was allowed to stir at 0° C. for 10 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (3.40 mL, 19.3 mmol) was then added drop-wise over 5 minutes, and stirring was continued at 0° C. for 15 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride solution; the aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 10% to 20% ethyl acetate in heptane) afforded the product as a colorless oil. Yield: 2.64 g, 9.33 mmol, 72%. LCMS m/z 283.0 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J=5.8 Hz, 1H), 7.34 (dd, J=5.8, 0.7 Hz, 1H), 7.25 (d, J=3.3 Hz, 1H), 6.69 (dd, J=3.3, 0.7 Hz, 1H), 5.48 (s, 2H), 3.46 (dd, J=8.2, 8.1 Hz, 2H), 0.89 (dd, J=8.2, 8.1 Hz, 2H), −0.05 (s, 9H).
Reaction SMILES: OO.C([OH:7])(C)(C)C.C=CCCCCCC.[O:16]([CH:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][OH:20])O>[W].C(OC)(C)(C)C>[O:20]([CH2:19][CH:18]([OH:16])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[OH:7]
Reactant: CCCCCCC(CO)OO
Reactant: CC(C)(C)O
Agent: [W]
Agent: OO
Solvent: C=CCCCCCC
Solvent: COC(C)(C)C
Product: CCCCCCC(O)COO
Temperature: 50 °C
Yield: 42 %

Procedure:
To a 50 mL flask equipped with a magnetic stirrer and a refluxing condensing tube were added 300 mg of the tungsten-containing mesoporous silicate prepared in Example 2, 760 mg of 60% by weight aqueous hydrogen peroxide solution, 3 g of tert-butanol and 500 mg of 1-octene, and the mixture was stirred and maintained at an inner temperature of 50° C. for 16 hours to react these materials. To the resulting reaction mixture was added 5 g of methyl tert-butyl ether, and the mixture was stirred, and allowed to stand. The supernatant organic layer was analyzed by LC, and it was found that 2-hydroperoxy-1-hydroxyoctane and 1-hydroperoxy-2-hydroxyoctane were produced. When the organic layer was analyzed by GC, 2-hydroperoxy-1-hydroxyoctane and 1-hydroperoxy-2-hydroxyoctane were thermally decomposed at an injection inlet, and detected as 1-heptanal. Then, the yield of 1-heptanal was determined by GC analysis (internal standard method), and this was regarded as the yield of 2-hydroperoxy-1-hydroxyoctane and 1-hydroperoxy-2-hydroxyoctane. Yield: 42%
Reaction SMILES: C1(C2C=CC(CNCCC3C=CC(F)=C(C(F)(F)F)C=3)=CC=2)CC1.[CH:25]1([C:29]2[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=2)[CH2:28][CH2:27][CH2:26]1.[Cl:37][C:38]1[CH:39]=[C:40]([CH2:45][CH2:46][NH2:47])[CH:41]=[CH:42][C:43]=1[Cl:44].[BH4-].[Na+]>>[CH:25]1([C:29]2[CH:36]=[CH:35][C:32]([CH2:33][NH:47][CH2:46][CH2:45][C:40]3[CH:41]=[CH:42][C:43]([Cl:44])=[C:38]([Cl:37])[CH:39]=3)=[CH:31][CH:30]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: O=Cc1ccc(C2CCC2)cc1
Agent: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: Clc1ccc(CCNCc2ccc(C3CCC3)cc2)cc1Cl

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 200 mg of 4-cyclobutyl-benzaldehyde (1.25 mmol), 237 mg of 2-(3,4-dichloro-phenyl)-ethylamine (1.25 mmol) and 71 mg of sodium borohydride (1.87 mmol). The isolated yellow oil (416 mg, 100%) was used in the following step without further purification. 1H NMR (CDCl3, 300 MHz): δ 1.84 (m, 1H), 1.95-2.21 (m, 3H), 2.33 (m, 2H), 2.76 (m, 2H), 2.87 (m, 2H), 3.53 (quint, J=9 Hz, 1H), 3.76 (s, 2H), 7.03 (dd, J=8 and 2 Hz, 1H), 7.19 (m, 4H), 7.29 (d, J=2 Hz, 1H), 7.34 (d, J=8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1ccc(F)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)(C)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
1-Fluoro-4-t-butylbenzene (10 g, 65.79 mmol) was dissolved in concentrated sulfuric acid (40 ml) at 0° C. Solid potassium nitrate (6.64 g, 65.79 mmol) was added in small portions during 1 hour. The temperature was kept below 5° C. Following the addition stirring was continued for 2 hours. The reaction mixture was poured into ice-water (400 ml) and extracted with dichloromethane (3×50 ml). The organic phase was washed with water, aqueous sodium bicarbonate (1 M) and water successively, dried over MgSO4 and filtered through silica gel (5 g). Evaporation of solvent left the crude product (10.32 g). Column chromatography on silica gel using petroleum ether containing 1% dichloromethane as the eluent afforded the pure product (7.6 g colorless oil).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24]2[C@@H:33]3[C@@H:28]([CH2:29][CH:30]=[CH:31][CH2:32]3)[C:27](=[O:34])[N:26]([CH:35]3[CH2:40][CH2:39][N:38](C4C=CC([N+]([O-])=O)=CC=4)[CH2:37][CH2:36]3)[N:25]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>O>[ClH:1].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24]2[C@@H:33]3[C@@H:28]([CH2:29][CH:30]=[CH:31][CH2:32]3)[C:27](=[O:34])[N:26]([CH:35]3[CH2:40][CH2:39][N:38]([CH2:2][C:3]4[CH:12]=[C:11]5[C:6]([CH:7]=[CH:8][C:9](=[O:13])[O:10]5)=[CH:5][CH:4]=4)[CH2:37][CH2:36]3)[N:25]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(C2=NN(C3CCN(c4ccc([N+](=O)[O-])cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Reactant: O=c1ccc2ccc(CCl)cc2o1
Solvent: O
Product: COc1ccc(C2=NN(C3CCN(Cc4ccc5ccc(=O)oc5c4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Product: Cl

Procedure:
Prepared from 7-Chloromethyl-chromen-2-one and starting compound A1 as described for compound 11. After the addition of water, the mixture is extracted with diethyl ether. The ether solution is dried over magnesium sulfate. After the addition of a saturated solution of hydrochloric acid in ether, the compound precipitates. M. p. 264-267° C.
Reaction SMILES: [CH:1]1([CH:6]=[CH:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCN2C(=NCCC2)CC1.[NH:21]1[CH:25]=[C:24]([C:26]2[C:27]3[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:28]=3[N:29]=[CH:30][N:31]=2)[CH:23]=[N:22]1>C(#N)C.ClCCl>[CH:1]1([CH:6]([N:21]2[CH:25]=[C:24]([C:26]3[C:27]4[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:28]=4[N:29]=[CH:30][N:31]=3)[CH:23]=[N:22]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#CC=CC1CCCC1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4CCCC4)c3)ncnc21
Temperature: 55 °C
Yield: 97.7 %

Procedure:
Method A. 3-Cyclopentylacrylonitrile (8, 273.5 g, 2.257 mol, 1.20 equiv) and DBU (28 mL, 0.187 mol, 0.10 equiv) was added to a suspension of 4-(1H-pyrazol-4-yl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 591.8 g, 1.876 mol) in acetonitrile (4.7 L) at room temperature. The resulting reaction mixture was heated to 50-60° C. for 17 hours (a clear solution developed midway through heating) then to 70-80° C. for 8 hours. When LCMS analysis showed the reaction was deemed complete, the reaction mixture was cooled to room temperature. The cooled solution was then concentrated under reduced pressure to give the crude product (9) as a thick amber oil. The crude product was dissolved in dichloromethane (DCM) and absorbed onto silica gel then dry-loaded onto a silica column (3 Kg) packed in 33% EtOAc/heptanes. The column was eluted with 33% EtOAc/heptanes (21 L), 50% EtOAc/heptanes (28 L), 60% EtOAc/heptanes (12 L) and 75% EtOAc/heptanes (8 L). The fractions containing the desired product (9) were combined and concentrated under reduced pressure to generate a yellow oil, which was transferred to a 3 L flask with EtOAc. The solvent was removed under reduced pressure and the residual EtOAc by co-evaporating with heptanes. The residue was further dried under high vacuum for overnight to afford racemic 3-cyclopentyl-3-{4-[7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile (9, racemic SEM-protected compound, 800 g, 819.1 g theoretical, 97.7% yield) as an extremely viscous yellow oil. For 9: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.83 (s, 1H), 8.75 (s, 1H), 8.39 (s, 1H), 7.77 (d, 1H, J=3.7 Hz), 7.09 (d, 1H, J=3.7 Hz), 5.63 (s, 2H), 4.53 (td, 1H, J=19.4, 4.0 Hz), 3.51 (t, 2H, J=8.1 Hz), 3.23 (dq, 2H, J=9.3, 4.3 Hz), 2.41 (m, 1H), 1.79 (m, 1H), 1.66-1.13 (m, 7H), 0.81 (t, 2H, J=8.2 Hz), 0.124 (s, 9H); C23H32N6OSi (MW, 436.63), LCMS (EI) m/e 437 (M++H) and 459 (M++Na).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:13][OH:14])[CH:9]=[CH:10][C:11]=1[I:12])[CH2:2][CH2:3][CH3:4]>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:11]=1[I:12])[CH:13]=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(CO)ccc1I
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCOc1cc(C=O)ccc1I
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.4 %

Procedure:
21.2 g (207 mmol) of manganese dioxide are added to 10.6 g (34.5 mmol) of (3-butoxy-4-iodophenyl)methanol in 70 mL of dichloromethane. The reaction mixture is stirred at room temperature for 2 days. The reaction medium is filtered through Celite. The filtrate is evaporated and the oil obtained (9.45 g) is purified by chromatography on silica gel eluted with a 90/10 heptane/ethyl acetate mixture. 7.7 g (73%) of 3-butoxy-4-iodobenzaldehyde are obtained in the form of a yellow oil.
Reaction SMILES: Br[C:2]1[CH:13]=[N:12][C:5]2[NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.CC1NC2C(C=1[CH2:24][N:25](C)[C:26](=[O:29])[CH:27]=[CH2:28])=CC=CC=2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:24][NH:25][C:26](=[O:29])/[CH:27]=[CH:28]/[C:2]1[CH:13]=[N:12][C:5]2[NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: C=CC(=O)N(C)Cc1c(C)[nH]c2ccccc12
Reactant: O=C1CCCc2cc(Br)cnc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CNC(=O)/C=C/c1cnc2c(c1)CCCC(=O)N2
Yield: 57.1 %

Procedure:
A solution of 3-bromo-5,6,7,9-tetrahydro-pyrido[2,3-b]azepin-8-one (0.60 g, 2.50 mmole), N-(2-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide (0.85 g, 3.75 mmole), Pd(OAc)2 (0.06 g, 0.25 mmole), tri-ortho-tolylphosphine (0.15 g, 0.50 mmole) and diisopropylethylamine (0.87 mL, 5.00 mmole) in propionitrile (50 mL) was deoxygenated, then was and heated to reflux under a N2 overnight. The dark mixture was filtered through a pad of celite®, and the filter pad was rinsed with acetonitrile (200 mL). The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (10% MeOH/CHCl3). The title compound (0.35 g. 35%) was obtained as a light tan solid after drying in vacuo: MS (ES) m/e 246 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][C@H:4]([C:5]3[CH:16]=[N:15][NH:14][C:6]=3[C@H:7]2[C:10]([O:12][CH3:13])=[O:11])[N:3]1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O=C(Cl)[O:27][C:28](Cl)(Cl)Cl.[NH3:33]>ClCCl>[NH2:33][C:28]([N:15]1[CH:16]=[C:5]2[C:6]([C@@H:7]([C:10]([O:12][CH3:13])=[O:11])[N:8]3[CH2:9][C@H:4]2[N:3]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:2]3=[O:1])=[N:14]1)=[O:27]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)[C@@H]1c2[nH]ncc2[C@H]2CN1C(=O)N2OCc1ccccc1
Reactant: N
Solvent: ClCCl
Product: COC(=O)[C@@H]1c2nn(C(N)=O)cc2[C@H]2CN1C(=O)N2OCc1ccccc1
Reaction time: 1 h
Yield: 15 %

Procedure:
0.188 g of the product obtained in Stage K of Example 1 is dissolved in 30 ml of dichloromethane, in a round-bottomed flask placed under an argon atmosphere at 0° C. 70 μl of diphosgene are added and then after 1 h 15 min 0.49 ml of a concentrated aqueous ammonia solution is added. After one hour, methylene chloride is added to the reaction medium and the organic phase is washed with an aqueous NaH2PO4 solution and then with an aqueous NaCl solution. The organic phases are dried over magnesium sulfate, filtered and the solvent is evaporated under reduced pressure. The crude product obtained is purified by chromatography on silica, eluting with a methylene chloride/ethyl acetate/triethylamine, 8/2/0.1%, mixture, and then next eluting with a dichloromethane/ethyl acetate/triethylamine, 7/3/0.1%, mixture. After evaporation of the fractions, 32 mg of the isomer A of compound methyl trans-1-(aminocarbonyl)-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-1H-4,7-methanopyrazolo[3,4-e][1,3]diazepine-8-carboxylate are obtained with a yield of 15%, and 79 mg of the isomer B of the compound methyl trans-2-(aminocarbonyl)-2,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-4H-4,7-methanopyrazolo[3,4-e][1,3]diazepine-8-carboxylate with a yield of 37%. The empirical formulae of the isomers are C17H17N5O5 (M=371.36 g).
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[CH3:13][N:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.O>C(O)(=O)C.ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:13][N:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:3]1[C:4](=[O:11])[C:5]2[C:10]([C:1](=[O:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cn1cccc1
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: Cn1cccc1C1=CC(=O)c2ccccc2C1=O
Yield: 79 %

Procedure:
According to the procedure described in the article Chemistry Express 1990, Vol. 5, No. 10, pages 749-752, the disclosure of which is specifically incorporated by reference herein, 3.16 millimol of 1,4-naphthoquinone were stirred with 25 millimol of N-methylpyrrole and 3.16 millimol of copper acetate in 50 ml of acetic acid in a round-bottomed flask at room temperature for 1 hour. The reaction mixture was diluted with 300 ml of dichloromethane and the resulting mixture was then poured into a large volume of water (300 ml). The organic phase was then separated out and washed four times with 100 ml of water and finally with saturated aqueous NaCl solution. The resulting organic phase was dried over Na2SO4 and then concentrated under vacuum. The product 2-(1-methyl-1H-pyrrol-2-yl)-[1,4]-naphthoquinone was thus isolated in a yield of 79% after purification by chromatography on a column of silica.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:6][N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:17][N:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[C:20]([CH3:33])[C:19]1=[O:34].[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37]>>[CH:10]1([CH2:9][O:8][C:7]2[C:2]([C:22]3[CH:21]=[C:20]([CH3:33])[C:19](=[O:34])[N:18]([CH3:17])[CH:23]=3)=[N:3][C:4]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[N:5][CH:6]=2)[CH2:11][CH2:12]1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cn(C)c1=O
Reactant: CS(=O)(=O)c1ncc(OCC2CC2)c(Cl)n1
Reactant: CS(N)(=O)=O
Product: Cc1cc(-c2nc(NS(C)(=O)=O)ncc2OCC2CC2)cn(C)c1=O

Procedure:
The title compound of Example 152, step 4 was reacted with 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one in a manner similar to Example 152, step 5 and the resulting product was treated with MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 10.97 (s, 1H), 8.67 (s, 1H), 8.42 (s, 1H), 8.14 (s, 1H), 4.03 (d, J=6.4 Hz, 2H), 3.54 (s, 3H), 3.35 (s, 3H), 2.08 (s, 3H), 1.33-1.31 (m, 1H), 0.63-0.61 (m, 2H), 0.38-0.37 (m, 2H). LCMS: 365.0 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C@H:9]3[C@@H:11]([O:30][C:31](=[O:33])[CH3:32])[C@@H:12]([O:26][C:27](=[O:29])[CH3:28])[C@@H:13](OS(C4C=CC(C)=CC=4)(=O)=O)[O:14][C@H:8]3[N:7]([CH2:34][CH2:35][N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])[C:6]=2[CH:41]=1.[N-:42]=[N+:43]=[N-:44].[Na+].[CH:46](Cl)(Cl)Cl.CC(C)=O>CS(C)=O>[N:42]([CH2:46][C@H:13]1[O:14][C@@H:8]2[C@@H:9]([S:10][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:41][C:6]=3[N:7]2[CH2:34][CH2:35][N:36]([CH2:37][CH3:38])[CH2:39][CH3:40])[C@@H:11]([O:30][C:31](=[O:33])[CH3:32])[C@@H:12]1[O:26][C:27](=[O:29])[CH3:28])=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=[N-]
Reactant: CCN(CC)CCN1c2cc(Cl)ccc2S[C@H]2[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](OS(=O)(=O)c3ccc(C)cc3)O[C@H]21
Reactant: ClC(Cl)Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(C)=O
Product: CCN(CC)CCN1c2cc(Cl)ccc2S[C@H]2[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](CN=[N+]=[N-])O[C@H]21
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 90.2 %

Procedure:
To the solution of 14.0 g of the compound (36) obtained in Example 35 in 140 ml of dimethylsulfoxide, 14.0 g of sodium azide was added, and the mixture was heated with stirring for 45 minutes at 100 ° C. The reaction solution was poured into ice water, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride. The solution was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 10.1 g (yield 90.2%) of the title compound from the fraction of chloroform-acetone (1:1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][OH:25])[CH:19]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[C:5]([C:11]#[N:12])=[C:6]([O:25][CH2:24][C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Reactant: OCc1cccnc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2cccnc2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 3-pyridinemethanol and DBU in DME. EI-MS m/e (%): 293 (M+, 100), 92 (60), 65 (29), 39 (24).