Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:21]([O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:8][CH:9]=1)=[O:3])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C(=O)O)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C(=O)OCc3ccccc3)cc2)cc1

Procedure:
A solution of 11.64 g (40 mmol) of N-(4-carboxyphenyl)-4-toluenesulfonamide, 5.06 g (40 mmol) of benzyl chloride and 5.20 g (44 mmol) of di-i-propylethylamine in 100 ml of dimethylformamide is heated at 140° C. f or 4 hours. After the reaction is complete, the mixture is evaporated in vacuo, the residue is taken up in propyl acetate, and the solution is washed 2× with 2N hydrochloric acid and ##STR22## 2× with saturated NaHCO3 solution, dried over sodium sulfate and evaporated. 11.8 g (78% of theory) of N-(4-benzyloxycarbonylphenyl)-4-toluenesulfonamide, which are recrystallized from methanol, are obtained.
Reaction SMILES: [Cl:1][Si](C)(C)C.[CH3:6][CH2:7][C:8](=[O:14])[CH2:9][C:10](=[O:13])[CH2:11][CH3:12].CS(C)=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.O>[Cl:1][CH:9]([C:8](=[O:14])[CH2:7][CH3:6])[C:10](=[O:13])[CH2:11][CH3:12]
Reactant: CCC(=O)CC(=O)CC
Reactant: C[Si](C)(C)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: CC#N
Solvent: CS(C)=O
Product: CCC(=O)C(Cl)C(=O)CC
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.4 %

Procedure:
Chlorotrimethylsilane (29.7 ml, 0.234 mol) was added dropwise to a stirred pale yellow solution of tetrabutylammonium bromide (1.26 g, 3.9 mmol) in dry acetonitrile (116 ml) at room temperature under nitrogen. The resulting solution was cooled in ice and 3,5-heptanedione (10.6 ml, 78.0 mmol) and then dry dimethylsulphoxide (16.6 ml, 0.234 mol) were added dropwise over 5 minutes producing a yellow solution which was allowed to warm slowly to room temperature, with stirring, over 4 hours. The mixture was diluted with water (1 liter), stirred for 10 min and then extracted with ether (1×500 ml, 2×250 ml). The combined ether layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a yellow oil. The crude product was purified by distillation under reduced pressure to afford the title compound (5.5 g) as a pale yellow oil, b.p. 102–105° C./54 mmHg containing ca. 10% 4,4-dichloro-3,5-heptanedione as estimated by microanalysis.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:19]1[C:20]([C:28](O)=[O:29])=[CH:21][N:22]2[CH:27]=[CH:26][CH:25]=[N:24][C:23]=12>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:28]([C:20]3[N:19]=[C:23]4[N:24]=[CH:25][CH:26]=[CH:27][N:22]4[CH:21]=3)=[O:29])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1cn2cccnc2n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn2cccnc2n1

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.767 mmol) and imidazo[1,2-a]pyrimidine-2-carboxylic acid (163 mg, 0.997 mmol). The product was triturated with acetonitrile. Yield 168 mg (54%). 1H-NMR (400 MHz; d6-DMSO): δ 1.18 (d, 3H), 4.32-4.45 (m, 2H), 4.49-4.56 (m, 1H), 6.92 (d, 1H), 7.13-7.16 (m, 1H), 7.84 (d, 1H), 7.95 (d, 1H), 8.03-8.06 (m, 2H), 8.25 (s, 1H), 8.67-8.69 (m, 1H), 8.75 (d, 1H), 8.97-8.99 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:15]1([N:21]2[C:33]3[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.COCCOC.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:15]1([N:21]2[C:33]3[CH:32]=[CH:31][C:30]([C:2]4[CH:3]=[CH:4][C:5]5[NH:6][C:7]6[C:12]([C:13]=5[CH:14]=4)=[CH:11][CH:10]=[CH:9][CH:8]=6)=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Reactant: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: c1ccc(-n2c3ccccc3c3cc(-c4ccc5[nH]c6ccccc6c5c4)ccc32)cc1
Yield: 80.8 %

Procedure:
Into a 200 mL three-neck flask were put 2.5 g (10 mmol) of 3-bromocarbazole, 2.9 g (10 mmol) of N-phenyl-9H-carbazol-3-boronic acid, and 152 mg (0.50 mmol) of tri(ortho-tolyl)phosphine. The air in the flask was replaced with nitrogen. 50 mL of ethylene glycol dimethyl ether and 10 mL of potassium carbonate solution (2 mol/L) were added to the mixture. This mixture was stirred to be degassed while the pressure was reduced. After the degassing, 50 mg (0.2 mmol) of palladium(II) acetate was added. The mixture was stirred at 80° C. for 3 hours under a nitrogen stream. After the stirring, about 50 mL of toluene was added to the mixture and the mixture was stirred for about 30 minutes, and then the mixture was washed with water and saturated saline in this order. After the washing, the organic layer was dried with magnesium sulfate. The mixture was gravity filtered, and the obtained filtrate was concentrated, so that an oily substance was obtained. The obtained oily substance was dissolved in toluene, and this solution was filtered through Florisil (a product of Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), alumina, and Celite (a product of Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855). The obtained filtrate was concentrated to give 3.3 g of a white solid, which was the object of the synthesis, in a yield of 80%. A synthetic scheme of Step 1 is shown in the following (Z-1).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:30][CH3:31])[C:25](OCC)=[O:26])[C:5]1=[O:32])[CH:2]=[CH2:3].[N+](=[CH:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[N-]>C(Cl)Cl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:30][CH3:31])[CH2:25][O:26][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:5]1=[O:32])[CH:2]=[CH2:3]
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OCC)C1=O
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)COCC(=O)OCC)C1=O

Procedure:
To a solution of 203 mg (0.47 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one (Example 9, Step B) and rhodium(II)acetate dimmer (10.4 mg, 0.047 mmol) in CH2Cl2 (1.90 mL) was added dropwise ethyl diazoacetate (286 μL, 2.35 mmol) at 25° C. After being stirred at 25° C. for 14h, the reaction was concentrated under reduced pressure and purified by chromatography on silica gel (20% to 30% EtOAc/Hexanes, gradient elution) to provide the title compound as a colorless liquid:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=[CH:17][C:10]=2[N:9]([CH3:21])[C:8](=[O:22])[CH2:7]1)[CH3:2].C(N(CC)CC)C.C(O)=O>CC#N.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:10]=2[N:9]([CH3:21])[C:8](=[O:22])[CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CN1CC(=O)N(C)c2ccc([N+](=O)[O-])cc2C1=O
Agent: [Pd]
Solvent: CC#N
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CC(=O)N(C)c2ccc(N)cc2C1=O
Temperature: 5 °C
Yield: 65.2 %

Procedure:
To a solution of (1-methyl-7-nitro-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetic acid ethyl ester (3.21 g, 10 mmol) in MeCN(15 ml) was added triethylamine (5.85 ml, 42.5 mmol). After cooling of this mixture to about 5° C. Pd—C (10%, 200 mg) and a solution of formic acid (1.6 ml) in MeCN(2 ml) were added. The ice bath was removed, gas evolution started and the temperature of the reaction mixture rose to 35° C. After 1 h the reaction mixture was heated to reflux temperature until all starting material had disappeared according to TLC. After filtration, evaporation of the solvents, and chromatography (silica gel, dichloromethane/MeOH 19:1) (7-amino-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetic acid ethyl ester (1.9 g) was isolated: mp. 118-119° C.; MS (EI): 291 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]([NH2:26])=[O:25])=[CH:18][CH:17]=1)=[O:14].I[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1.C(NCC)C.C(O)=O>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19](/[C:22](/[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:23]\[C:24]([NH2:26])=[O:25])=[CH:18][CH:17]=1)=[O:14]
Reactant: NC(=O)C#Cc1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Reactant: COc1ccc(I)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: COc1ccc(/C(=C/C(N)=O)c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)cc1
Temperature: 75 °C
Yield: 31.1 %

Procedure:
A mixture of 3-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}prop-2-ynamide (31.0 mg, 0.085 mmol), 4-iodoanisole (0.010 mL, 0.089 mmol), diethylamine (0.029 mL, 0.281 mmol), formic acid (0.0083 mL, 0.221 mmol), and bis(dibenzylideneacetone)palladium(0) (3.4 mg, 0.006 mmol) in 1.4 mL EtOAc (degassed) was heated at 75° C. for 20 hours. The reaction was partitioned between EtOAc and H2O/brine mixture. The EtOAc layer was washed with dilute aqueous HCl, then aqueous NaHCO3, brine, and dried with anhydrous Na2SO4 to give 20 mL of EtOAc solution of crude material. The EtOAc solution was filtered past a plug of silica gel eluting with EtOAc, evaporated, and the resulting solid chromatographed eluting with EtOAc/CHCl3 to give the title compound as a grey-purple solid (12.5 mg, 31%). 1H NMR (Acetone-d6) δ: 8.80 (d, J=7.6 Hz, 1H), 8.42 (s, 2H), 7.32-7.45 (m, 4H), 7.21-7.26 (m, 2H), 7.10-7.16 (m, 2H), 6.98 (br. s., 1H), 6.88-6.94 (m, 2H), 6.63 (br. s., 1H), 6.43 (s, 1H), 3.81 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].C([O-])=O.[NH4+]>C1COCC1>[NH2:16][C:13]1[CH:14]=[CH:15][C:8]2[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C:2]([F:20])([F:1])[F:19])[CH2:11][CH2:10][C:9]=2[CH:12]=1
Reactant: O=C(N1CCc2ccc([N+](=O)[O-])cc2CC1)C(F)(F)F
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Yield: 84.7 %

Procedure:
Into a 500 ml round bottomed flask, the product from step (b) (17 g) and ammonium formate (17 g) in THF (250 ml) were added. To the nitrogen purged reaction mixture, 10% Pd—C (4 g) was added. The reaction mixture was stirred at reflux for 3 hours. The reaction mixture was allowed to cool to room temperature and filtered through celite. The filtrate was diluted with water (200 ml) and extracted with EtOAc (3×). The combined EtOAc extracts were washed with saturated NaHCO3, brine, dried over NaSO4, and solvent evaporated in vacuo to give the sub-title compound as an off-white solid (12.9 g). 1H NMR (300 MHz, DMSO-d6) δ 6.83-6.78 (m, 1H); 6.39-6.31 (m, 2H); 4.91 (s, 2H); 3.66-3.56 (m, 4H); 2.81-2.73 (m, 4H); MS: ESI (positive): 259 (M+H).
Reaction SMILES: O(C(OC1C=CC=CC=1)Cl)C1C=CC=CC=1.C1(C)C=CC=CC=1.CC(C)=O.O([C:35]1([CH:56]=[CH:55][CH:54]=[CH:53][CH:52]1C)[C:36](=[N:50][OH:51])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1OC1C=CC=CC=1)C1C=CC=CC=1>CCOCC>[C:36](=[N:50][OH:51])([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:35]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CC1C=CC=CC1(Oc1ccccc1)C(=NO)c1ccccc1Oc1ccccc1
Agent: ClC(Oc1ccccc1)Oc1ccccc1
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: ON=C(c1ccccc1)c1ccccc1
Yield: 76 %

Procedure:
are reacted in each case with 5 g of diphenoxy chloromethane. By a thin-layer chromatographic process (silica gel plates, 9:1 mixture of toluene and acetone as the eluant), practically uniform, oily crude products are obtained, viz. the following diphenoxy-methyloxime ethers: (a) Compound No. 86 (yield: 77% of theoretical), (b) Compound No. 87 (yield: 92% of theoretical), (c) Compound No. 88 (yield: 86% of theoretical), and d) the o-diphenoxy-methyl-benzophenone-oxime designated as Compound No. 89 (yield: 76% of theoretical) which is obtained by recrystallization of the crude product from ether and has a melting point of 89°-90° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([OH:13])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([O:13][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: BrCC1CCCCC1
Reactant: CCOC(=O)c1cc(O)cc(Br)c1
Product: CCOC(=O)c1cc(Br)cc(OCC2CCCCC2)c1

Procedure:
Alkylation of ethyl 3-bromo-5-hydroxybenzoate using (bromomethyl)cyclohexane gave ethyl 3-bromo-5-(cyclohexylmethoxy)benzoate. Yield (1.36 g, 100%): 1H NMR (400 MHz, CDCl3) δ 7.72 (t, J=1.6 Hz, 1H), 7.46 (dd, J=2.4, 1.2 Hz, 1H), 7.20 (dd, J=2.4, 1.6 Hz, 1H), 4.35 (q, J=7.2 Hz, 2H), 3.76 (d, J=6.4 Hz, 2H), 1.67-1.88 (m, 6H), 1.38 (t, J=7.2 Hz, 3H), 1.16-1.32 (m, 3H), 1.01-1.11 (m, 2H).
Reaction SMILES: S(C1C=CC(N2C(O[C:17]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[S:19][C:18]=3[S:26]([NH2:29])(=[O:28])=[O:27])=NN=N2)=CC=1)(=O)(=O)N.O.CCO.C(O)=O>C1C=CC=CC=1.[Pd]>[F:25][C:22]([F:23])([F:24])[C:20]1[S:19][C:18]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:17][CH:21]=1
Reactant: NS(=O)(=O)c1ccc(-n2nnnc2Oc2cc(C(F)(F)F)sc2S(N)(=O)=O)cc1
Agent: [Pd]
Solvent: O
Solvent: O=CO
Solvent: c1ccccc1
Product: NS(=O)(=O)c1ccc(C(F)(F)F)s1
Temperature: 80 °C
Yield: 16.6 %

Procedure:
To a solution of 3-[1-(4-sulfamoyl-phenyl)-1H-tetrazol-5-yloxy]-5-trifluoromethyl-thiophene-2-sulfonamide (210 mg, 0.47 mmol) in benzene (50 mL) is added H2O (2 mL), EtOH (3 mL), formic acid (2 mL) and 10% palladium on carbon (350 mg). The mixture is heated to 80° C. overnight. The reaction mixture is cooled to room temperature and diluted with benzene (50 mL). The reaction mixture is filtered. The benzene layer is dried (Na2SO4), filtered and concentrated. The crude product is chromatographed on silica gel, eluting with EtOAc:Hex (1:10) to afford the title compound (18 mg, 17%) as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH:19]1[CH2:31][OH:32])=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl.Cl>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH:19]1[CH:31]=[O:32])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)C1CO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)C1C=O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 99.4 %

Procedure:
A solution containing 2M oxalyl chloride in DCM (22 mL) in DCM (40 mL) was cooled to −78° C. A solution containing DMSO (3.2 mL, 45 mmol) in DCM (20 mL) was added in a dropwise fashion. After 45 min, alcohol 40 (9.5 g, 29 mmol) in DCM (50 mL) was added in a dropwise fashion. After 45 min, TEA (16 mL, 115 mmol) was added in a dropwise fashion. The reaction mixture was warmed and maintained at 0° C. for 15 min. The solution was diluted with 1M HCl, extracted with DCM, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 9.5 g (100%) of 41 as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ9.53 (d, J=29 Hz, 1H), 4.39-4.36 (m, 1H), 4.24 (m, rotomer, 0.5H), 3.93 (m, rotomer, 0.5H), 3.73-3.49 (m, 2H), 1.98-1.86 (m, 2H), 1.47 (s, minor rotomer), 1.41 (s, 9H), 0.88 (s, 9H), 0.09 (s, 6H), 0.07 (s, minor rotomer) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10](=[O:18])[C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=[N:6][CH:7]=1.[CH3:19]I.[H-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH3:19])[C:10](=[O:18])[C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(NCc1cncc(Br)c1)c1ncccc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CN(Cc1cncc(Br)c1)C(=O)c1ncccc1Cl

Procedure:
In analogy to the procedure described for the preparation of intermediate A-41, N-((5-bromopyridin-3-yl)methyl)-3-chloropicolinamide (intermediate A-56) was reacted with MeI in presence of NaH (60% in mineral oil) to give the title compound as a dark brown oil. MS: 340.2 and 342.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][N:4]=1)#[CH:2].[N:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)=[N+:14]=[N-:15]>O1CCOCC1.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][N:4]=[C:3]2[C:1]1[N:15]=[N:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([CH:20]=[O:21])=[CH:22][CH:23]=2)[CH:2]=1
Reactant: C#Cc1n[nH]c2ccc(C)cc12
Reactant: [N-]=[N+]=Nc1ccc(C=O)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc2[nH]nc(-c3cn(-c4ccc(C=O)cc4)nn3)c2c1
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 99.9 %

Procedure:
3-Ethynyl-5-methyl-1H-indazole (1.0 g; 6.4 mmol; 1.0 eq.) and 4-azidobenzaldehyde (prepared as described in Chem. Med. Chem. (2009), 4(7), 1182-1188; 1.30 g; 7.04 mmol; 1.1 eq.) were dissolved in 1,4-dioxane (15 mL). D-(−)-isoascorbic acid sodium salt (127 mg; 0.64 mmol; 0.10 eq.) followed by a solution of copper sulfate pentahydrate (32 mg; 0.13 mmol; 0.02 eq.) in water (1.5 mL) were added and the reaction mixture was stirred at 90° C. for 3.5 hours. To complete the reaction more D-(−)-isoascorbic acid sodium salt (127 mg; 0.64 mmol; 0.10 eq.) and copper sulfate pentahydrate (32 mg; 0.13 mmol; 0.02 eq.) were added again and the reaction mixture was heated at 10° C. for 8 h. 1,4-dioxane was removed under reduced pressure an the residue was sonicated in a mixture of EtOAc and water (1:1). The resulting solid was filtered and dried to afford the title compound as a beige solid (1.94 g, 100%). 1H NMR (300 MHz, DMSO-d6) δ: 13.29 (brs, 1H), 10.11 (s, 1H), 9.46 (s, 1H), 8.34 (d, J=8.6 Hz, 2H), 8.18 (d, J=8.6 Hz, 2H), 8.14 (m, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.28 (dd, J=8.4 Hz, 1.4 Hz, 1H), 2.49 (s, 3H).
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:20])[O:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][CH:14]=[C:13]([OH:19])[CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[N:22]1([C:32](N2C=C[N+](C)=C2)=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1>>[CH2:1]([C:8]1[C:9](=[O:20])[O:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][CH:14]=[C:13]([O:19][C:32]([N:22]1[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24][CH2:23]1)=[O:33])[CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Reactant: Cc1c(Cc2ccccc2)c(=O)oc2cc(O)ccc12
Agent: [I-]
Product: Cc1c(Cc2ccccc2)c(=O)oc2cc(OC(=O)N3CCCc4ccccc43)ccc12

Procedure:
The title compound was prepared from 3-benzyl-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=426 (M+1), Rt: 5.34 min.
Reaction SMILES: C[Si](Cl)(C)C.[I-].[Na+].[CH2:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([F:16])[C:11]=1[NH:17]C(=O)OCCCC)[CH3:9].CCOCC>C(#N)C>[NH2:17][C:11]1[C:12]([F:16])=[N:13][CH:14]=[CH:15][C:10]=1[CH2:8][CH3:9]
Reactant: CCCCOC(=O)Nc1c(CC)ccnc1F
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: CCc1ccnc(F)c1N
Temperature: 25 °C

Procedure:
Trimethylsilyl chloride (2.2 g, (0.18 mmol) and sodium iodide (2.7 g, 0.18 mmol) were added to a solution of 3.6 g (0.15 mmol) of [-butyl N-(4-ethyl-2-fluoro-3-pyridyl)carbamate in 50 mL of dry acetonitrile with stirring at ambient temperature. After 2 hours the mixture was poured into ether and and the resulting solution was washed with dilute aqueous sodium bisulfite, dried over magnesium sulfate, and filtered. The filtrate was concentrated by evaporation under reduced pressure to obtain an oil. This oil was purified by column chromatography to obtain 1.6 g (76 percent of theory) of the title compound as a gold oil.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[NH2:10]>C1C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([N:10]=[C:1]=[O:2])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(N)cc1OC
Solvent: c1ccccc1
Product: COc1ccc(N=C=O)cc1OC

Procedure:
Phosgene (4 eq) is bubbled at a moderate rate into a 3-neck flask containing a solution of 3,4-dimethoxyaniline (1 eq.), in benzene (2 liters). The flask is cooled in an ice bath for 15 minutes and then the solution is refluxed for 13/4 hours while excess phosgene is added. The reaction mixture is then refluxed overnight and the solvent removed under vacuum. Acetone is added and the solvent is again removed under vacuum leaving a dark brown oily residue which is distilled at 132°-134° C./0.6 mm. Yield: 22.5 g.
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]3[C:21](=[O:24])[NH:22][N:23]=[C:13]3[C:12]3[CH:25]=[CH:26][CH:27]=[N:28][C:11]2=3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:32][CH2:33][N:34]([CH3:36])[CH3:35]>CN(C)C=O.C1(C)C(C)=CC=CC=1>[CH3:35][N:34]([CH3:36])[CH2:33][CH2:32][N:22]1[C:21](=[O:24])[N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:10]([C:8](=[O:9])[CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:11]3[N:28]=[CH:27][CH:26]=[CH:25][C:12]=3[C:13]2=[N:23]1
Reactant: O=C(CN1CCCCC1)N1c2ccccc2-n2c(n[nH]c2=O)-c2cccnc21
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: CN(C)CCn1nc2n(c1=O)-c1ccccc1N(C(=O)CN1CCCCC1)c1ncccc1-2
Reaction time: 22 h

Procedure:
In the manner given in Example 25, to 2,9-dihydro-9-(piperidinoacetyl)-3 H-pyrido[3,2-c]-s-triazolo-[4,3-a][1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react at about 95° C. for 40 minutes and after cooling (2-chloroethyl)dimethylamine in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in example 25 to give 2,9-dihydro-2-[2-(dimethylamino)ethyl]-9-(piperidinoacetyl)-3H-pyrido[3,2-c]-s-triazolo[4,3-a]-[1,5]benzodiazepin-3-one.