Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH2:10][C:11](=[O:24])[CH:12]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C(=O)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].O.OS(O)(=O)=O>C(OCC)C>[CH2:1]([S:8][CH2:9][CH2:10][C:11](=[O:24])[CH2:12][C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C(C(=O)CCSCc1ccccc1)C(=O)c1ccccc1
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(CCSCc1ccccc1)CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
34.0 g (0.1 mol) of 1-benzylthio-4-benzoyl-3,5-hexanedione (see Example 17) are initially placed in a 100 ml flask equipped with a thermometer, a stirrer, a dropping funnel and a reflux condenser. 19.8 g (0.11 mol) of sodium methylate solution (30% in methanol) are added dropwise, with stirring, in the course of 40 minutes. In the course of this the reaction temperature rises from room temperature to approx. 32° C. The mixture is stirred for a further hour at room temperature and for a further 3 hours at approx. 45° C. and is then cooled to room temperature and stirred into 200 ml of water and 12 g of concentrated H2SO4. 180 ml of diethyl ether are added and the organic phase is separated off. The aqueous phase is washed with a further 50 ml of diethyl ether. The combined organic phases are washed with water, sodium bicarbonate and water again and are then dried, concentrated and fractionated. The resulting product, which has a boiling point of 180°-183° C. at 0.001 bar, is recrystallized from 20 ml of isopropanol.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH3:28])[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[C:19]2[CH2:18][CH:17]([C:25]([OH:27])=[O:26])[CH2:16][C:15]1=2.[CH2:29](I)[CH2:30][CH2:31][CH2:32][CH3:33].Cl>O1CCCC1>[CH3:24][C:20]1([CH3:23])[CH2:21][CH2:22][C:14]([CH3:28])([CH3:13])[C:15]2[CH2:16][C:17]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:25]([OH:27])=[O:26])[CH2:18][C:19]1=2
Reactant: CC1(C)CCC(C)(C)C2=C1CC(C(=O)O)C2
Reactant: CCCCCI
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCCC1(C(=O)O)CC2=C(C1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.7 %

Procedure:
13.6 g of diisopropylamine were dissolved in 200 ml of THF (tetrahydrofuran) abs. and treated dropwise at −10° with 84 ml of butyl lithium (1.6 molar in hexane). After 15 minutes of stirring at 0° C., a solution of 12 g of 4,4,7,7-tetramethyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carboxylic acid in 40 ml of THF was dropped in. The reaction mixture was stirred for one hour at room temperature, cooled again to 0° C. and treated dropwise with a solution of 26.4 g of pentyl iodide in 30 ml of THF. After stirring for 90 minutes at room temperature, the reaction mixture was poured onto ice/water, acidified with 3N HCl and extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4 and evaporated to yield a pale yellow, partially crystalline oil. Flash chromatography (SiO2, hexane/ethyl acetate=6:1) and crystallization from pentane yielded 12.9 g of 4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carboxylic acid as white crystals, m.p. 57-58° C.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]([O:10][C:11](=[O:26])[NH:12][C:13]([CH3:25])([CH3:24])[CH2:14][NH:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH3:23])([CH3:9])([CH3:8])[CH3:7].C(=O)(O)[O-].[Na+]>CN(C)C(=O)C>[C:6]([O:10][C:11](=[O:26])[NH:12][C:13]([CH3:25])([CH3:24])[CH2:14][N:15]([C:3](=[O:4])[CH2:2][Br:1])[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH3:23])([CH3:9])([CH3:8])[CH3:7]
Reactant: Cc1ccc(F)cc1NCC(C)(C)NC(=O)OC(C)(C)C
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(F)cc1N(CC(C)(C)NC(=O)OC(C)(C)C)C(=O)CBr
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
1.67 ml of bromoacetyl bromide (19.1 mmol) was added to a solution of 5.68 g of [1,1-dimethyl-2-(5-fluoro-2-methylphenylamino)ethyl]carbamic acid t-butyl ester obtained in Example (70a) (19.1 mmol) in N,N-dimethylacetamide (95 ml) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. Hexane was added to the residue, and the solid was collected by filtration to obtain 7.1 g of the title compound (yield: 89%).
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[NH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].[C:26](Cl)(=[O:30])[C:27](Cl)=[O:28]>CO>[C:21]([C:20]1[CH:19]=[C:18]([N:17]2[C:8]3[CH:9]=[CH:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:7]=3[NH:6][C:27](=[O:28])[C:26]2=[O:30])[CH:25]=[CH:24][CH:23]=1)#[N:22]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cccc(Nc2ccc3ccccc3c2N)c1
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cccc(-n2c(=O)c(=O)[nH]c3c4ccccc4ccc32)c1
Temperature: 25 °C
Yield: 9.5 %

Procedure:
To an anhydrous tetrahydrofuran (18 mL) solution of 3-(1-amino-2-naphthylamino)benzonitrile (200 mg, 0.771 mmol) was added an anhydrous tetrahydrofuran (2 mL) solution of oxalyl chloride (66 μL, 0.771 mmol) under cooling in an ice-bath. The mixture was stirred under cooling in an ice-bath for 30 minutes and at room temperature for one hour. After addition of methanol (1 mL), the solvent was removed by evaporation under reduced pressure. The mixture was suspended by chloroform, and washed with a saturated aqueous sodium hydrogen carbonate solution. The precipitated solid was collected by filtration, and washed with water. The obtained solid was purified by silica gel chromatography (chloroform/methanol=9/1) to obtain the titled compound as a white powder (23 mg, yield 10%).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1>ClCCl.N1C=CC=CC=1>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:21]1[CH:22]=[CH:23][C:18]([C:17]([F:26])([F:25])[F:16])=[CH:19][CH:20]=1)(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Oc1ccc(C(F)(F)F)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
A solution of trifluoromethanesulphonic anhydride (1.0 g) in dichloromethane (2 ml) was added dropwise to a solution of 4-(trifluoromethyl)phenol (0.5 g) in dichloromethane (10 ml) and pyridine (0.5 ml) at 0° under nitrogen. The resulting suspension was stirred for 1 h at room temperature, diluted with dichloromethane (20 ml) and washed with aqueous sodium carbonate (2N; 20 ml). The dried organic phase was evaporated and the residue was purified by FCC eluting with ether to give the title compound as a colourless oil (710 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[C:4]2[N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][C:3]=12.[CH2:22]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)C(C)C)(C)C>O>[CH2:22]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:2]2[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[C:4]3[N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][C:3]=23)[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)c(C(N)=O)cnc21
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(NC3CCN(Cc4ccccc4)CC3)c(C(N)=O)cnc21
Temperature: 25 °C
Yield: 80.7 %

Procedure:
4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (456 mg, 1.40 mmol) was stirred with 1-benzyl-4-aminopiperidine (900 mg, 4.73 mmol) and N,N-diisopropylethylamine (250 μL, 1.44 mmol) at 140° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and, after addition of water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform→ethyl acetate/methanol=1/0→5/1 (v/v)) to give the title compound as a colorless solid (542 mg, yield 81%).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH2:11]([OH:13])C>>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:13])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Reactant: CCO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
All strains used glucose efficiently; however, strains 22-1-12 and 14-2-6 achieved the highest ethanol levels, productivities, and fermentation efficiencies, while having the lowest residual sugar levels (Table 2, top). When cellobiose was provided as the carbon source, all strains performed poorly, but in these trials strains WT-2-1 and 22-1-1 performed slightly better than the other strains (Table 2, middle). The results using xylose as the carbon source showed that the strains performing best were 14-2-6 and 22-1-12 (Table 2, bottom). However, compared to the results with glucose (about 18 g/L ethanol), these strains produced only about 3 g/L on xylose, which is about 12% of the theoretical yield (25.6 g/L for xylose). Yet the fermentation efficiency was about 30%, indicating that less than half the consumed xylose was converted to ethanol. The fermentation efficiency of the mutagenized strain on the individual sugar substrates is compared graphically in FIG. 1B. Initial concentrations of all sugar carbon sources were 50 g/L. Theoretical ethanol yield for glucose is 50 g/L [(2×46)/180]=25.6 g/L; for cellobiose is 50 g/L [(4×46)/342]=26.9 g/L; and for xylose is 50 g/L [(10×46)/(6×150)]=25.6 g/L. Fermentation efficiency was calculated by (50 g/L−residual sugar g/L)×100/50 g/L.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24](O)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.ClC1C(C2C=CC=CC=2)=NN=C2N(CC(N3CCN(C)CC3)=O)N=C(C3C=CC=CC=3)C=12.[CH:59]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)([CH3:61])[CH3:60]>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:65]3[CH2:66][CH2:67][N:62]([CH:59]([CH3:61])[CH3:60])[CH2:63][CH2:64]3)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: CC(C)N1CCNCC1
Agent: CN1CCN(C(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Product: CC(C)N1CCN(C(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1

Procedure:
Compound 38 was synthesised from 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid following a similar procedure outlined in Example 17 (Compound 1), using N-isopropylpiperazine instead of N-methylpiperazine in the final step.
Reaction SMILES: [H-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][SH:9].Cl[C:11]1[CH:16]=[CH:15][N+:14]([O-:17])=[C:13]([CH3:18])[C:12]=1[CH3:19]>O1CCOCC1.O>[CH3:18][C:13]1[C:12]([CH3:19])=[C:11]([S:9][CH2:8][C:4]2[O:3][CH:7]=[CH:6][CH:5]=2)[CH:16]=[CH:15][N+:14]=1[O-:17]
Reactant: SCc1ccco1
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(SCc2ccco2)cc[n+]([O-])c1C
Reaction time: 0.25 h
Yield: 79.9 %

Procedure:
6 g (60% strength) of NaH are added in portions to 50 ml of dry dioxane, the mixture is stirred for 15 minutes, 11.7 g (0.11 mol) of 2-furylmethylmercaptan are metered in over a period of 20 minutes and the mixture is stirred again for 30 minutes until the evolution of gas has ended. A solution of 14.4 g (0.1 mol) of 4-chloro-2,3-dimethylpyridine N-oxide in 100 ml of dioxane is then added dropwise in the course of 20 minutes, and the reaction mixture is stirred at RT for 1 h, subsequently at 70° C. for 1 h and then at 100° C. for another 1 h. When the reaction has ended, the mixture is allowed to cool and is diluted with 500 ml of water and extracted 4 times with 300 ml of ethyl acetate each time. The combined organic phases are washed with water, dried over magnesium sulfate and concentrated and the residue is crystallized by addition of diisopropyl ether. 18.8 g (80% of theory) of 2,3-dimethyl-4-(2-furylmethylthio)-pyridine N-oxide of m.p. 111-112° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.S(Cl)([Cl:17])=O.CN(C=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([Cl:17])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)c1ccc2cc(Br)ccc2c1
Temperature: 60 °C

Procedure:
A suspension of 6-bromo-2-naphthoic acid (100 g), thionyl chloride (37.7 ml) and DMF (0.5 ml) in THF (1000 ml) was stirred at 60° C. with heating for 90 min. After cooling to room temperature, the solvent was evaporated under reduced pressure. The resulting solid was dissolved in toluene and the solvent was evaporated to give 6-bromo-2-naphthoyl chloride as a pale yellow powder.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[C:19]([Cl:25])[C:18]=3[F:26])[C:11]=2[C:27](=[O:29])[NH2:28])C=CC=CC=1.[CH2:31]([N:33]([CH2:39]C)[CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])C>>[Cl:25][C:19]1[C:18]([F:26])=[C:17]([C:22]([F:23])=[CH:21][C:20]=1[CH3:24])[CH2:16][O:15][C:12]1[C:11]([C:27]([NH2:28])=[O:29])=[C:10]([NH:9][C:8]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][N:33]([CH3:39])[CH3:31])=[O:30])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1Cl
Reactant: CCN(CC)CCCCN
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN(C)C)c2C(N)=O)c(F)c1Cl

Procedure:
The title compound was prepared [4-carbamoyl-3-(3-chloro-2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and N,N-diethyl-butane-1,4-diamine by the procedure analogous to Example 1. MS (APCl, m/z): 476 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:4][N:5](S(C2C=NC=CC=2)(=O)=O)[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[OH-].[Na+]>O1CCCC1.CC(O)C>[F:1][C:2]1[C:3]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccnc2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 108 %

Procedure:
tert-Butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (1.0 g) was dissolved in tetrahydrofuran (8 mL) and 2-propanol (2 mL), and 1 mol/L aqueous sodium hydroxide solution (5 mL) was added under ice-cooling. After stirring at room temperature for 18 hr, the solvent evaporated under reduced pressure, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:1) to give the title compound as a pale-yellow oil (yield 752 mg, quantitative).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][N:16]([C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[CH2:39][C:40](O)=[O:41])=[CH:29][CH:28]=4)=[O:26])[C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.CNC.[CH2:46]([NH:48][CH2:49][CH3:50])[CH3:47]>>[CH2:46]([N:48]([CH2:49][CH3:50])[C:40](=[O:41])[CH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:30]1[CH:31]=[CH:32][C:27]([C:25]([N:16]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][N:20]3[C:11]([C:9]([NH:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:10])=[CH:12][CH:13]=[C:14]3[CH2:15]2)=[O:26])=[CH:28][CH:29]=1)[CH3:47]
Reactant: CCNCC
Reactant: O=C(O)Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Agent: CNC
Product: CCN(CC)C(=O)Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Yield: 60 %

Procedure:
The title compound was prepared in essentially the same manner as Example 68, replacing 4′-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1′-biphenyl-2-carboxylic acid with (4′-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1′-biphenyl-2-yl)acetic acid of Example 35, and dimethylamine with diethylamine. Purification by flash chromatography using a solvent gradient of 1 to 4% methanol in dichloromethane gave the title compound (0.158 g, 60%) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(N(CC)CC)C.[Br:19][C:20]([CH3:25])([CH3:24])[C:21](Br)=[O:22]>C1(C)C=CC=CC=1>[Br:19][C:20]([CH3:25])([CH3:24])[C:21]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])=[O:22]
Reactant: CC(C)(Br)C(=O)Br
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(Br)C(=O)Nc1ccc(O)c(C(=O)O)c1

Procedure:
To a suspension of 5-amino-2-hydroxybenzoic acid (3.0 g, 19.6 mmol) in a solution of freshly distilled triethylamine (4.1 mL, 29.4 mmol, 1.5 eq.) in 100 mL of anhydrous toluene was added dropwise 2-bromoisobutyryl bromide (6.8 mL, 53.8 mmol). Addition was performed at 0° C. under inert atmosphere. The mixture was then refluxed for 15 hours. Volatiles were removed under vacuum leaving oily crude materials. The product initiator C was extracted with ethanol concentrated and crystallized at −30° C. Yield: 30%. Analysis: 1H NMR (CDCl3, 300 MHz, 298 K): δ 9.81 (s broad, 3H, NHCO and OH), 8.24 (s, 1H, Hortho), 7.76 (d, 1J=10.5 Hz, 1H, Hmeta), 6.82 (d, 1J=9.8 Hz, 1H, Hpara), 2.10 (s, 6H, Me). 13C NMR (CDCl3, 125 MHz, 298 K): δ 170.6 (CO—N), 167.2 (CO—O), 160.0 (C(aromatic)-OH), 130.8 (C(aromatic)-NH), 124.1 (C(aromatic)-H), 122.2 (C(aromatic)-H), 118.6 (C(aromatic)-H), 114.2 (C(aromatic)-CO2H), 58.9 (C—Br), 33.6 (CH3), confirming the product to be 5-(2-bromo-2-methylpropanamido)-2-hydroxybenzoic acid initiator (initiator C).
Reaction SMILES: C(NO)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[C:17]1([CH3:28])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25].[Br:29]N1C(=O)CCC1=O>C(#N)C>[Br:29][CH2:28][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)Cc1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(NO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1ccccc1CBr
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of 102 g (0.74 mol) of benzohydroxamic acid 2, 111 g (0.80 mol) of pulverised potassium carbonate and 1400 ml of acetonitrile is heated to 60° C. After 0.5 h, 162 g of methyl o-bromomethylphenylacetate 1, which is obtained as 68% crude product from the bromination of methyl o-tolylacetate with N-bromosuccinimide, dissolved in 100 ml of acetonitrile, is added dropwise over 0.5 h at 60° C.-65° C. and the reaction mixture is stirred for 5.5 h at this temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](B(O)O)=[CH:7][CH:6]=[CH:5][N:4]=1.I[C:13]1[C:21]2[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:19][CH:18]=[N:17][C:16]=2[NH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd]>[CH3:1][O:2][C:3]1[C:8]([C:13]2[C:21]3[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:19][CH:18]=[N:17][C:16]=3[NH:15][CH:14]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Ic1c[nH]c2ncnc(-c3ccccc3)c12
Reactant: COc1ncccc1B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncccc1-c1c[nH]c2ncnc(-c3ccccc3)c12
Temperature: 170 °C

Procedure:
A mixture of (2-methoxypyridin-3-yl)boronic acid (36 mg, 0.23 mmol), 5-iodo-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine (50 mg, 0.16 mmol), sodium carbonate (83 mg, 0.78 mmol) and SiliaCat® heterogeneous catalysts DPP-Pd (loading=0.28 mmol/g, 111 mg, 0.031 mmol) in dioxane (1.30 mL) and water (0.26 mL) was heated to 170° C. under the microwave irradiation for 15 minutes. The reaction mixture was concentrated, redissolved in DMSO, filtered and the resulting solution was reconcentrated. Purification by reverse phase HPLC using an acetonitrile gradient in water with 0.1% formic acid modifier afforded 5-(2-methoxypyridin-3-yl)-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine. LRMS (ESI) calc'd for C18H15N4O [M+H]+: 303, found 303. 1H NMR (600 MHz, DMSO-D6) δ 12.40 (s, 1H), 8.82 (s, 1H); 7.97 (dd, 1H, J=1.1, 4.3 Hz); 7.65 (s, 1H); 7.64 (dd, 1H, J=1.1, 5.6 Hz); 7.28 (d, 2H, J=6.6 Hz), 7.24 (t, 1H, J=6.1 Hz); 7.08 (dd, 2H, J=6.1, 6.6 Hz); 6.94 (dd, 1H, J=4.3, 5.6 Hz); 3.05 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](=[O:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[I:15]Cl.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.CC(O)=O>[I:15][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[NH:11][C:12](=[O:14])[CH3:13]
Reactant: ClI
Reactant: COc1ccc(NC(C)=O)cc1OC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(I)c(NC(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
To a solution of N-(3,4-dimethoxyphenyl)acetamide (6.3 g, 32.0 mmol) in DCM (100 mL) and AcOH (6.5 mL) was added a solution of iodine monochloride (6.3 g, 39 mmol) in DCM (50 mL) dropwise. The reaction mixture was stirred at r.t. for 16 h. Aqueous sat. Na2S2O3 (500 mL) was added. The organic fraction was separated, washed with water (2×250 mL), then brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 50% EtOAc/hexanes) gave the title compound (7.5 g, 72%) as a dark solid. LCMS (ES+) 321.8 (M+H)+, RT 2.67 minutes (Method 4).
Reaction SMILES: [Na].[H-].[Na+].[CH3:4][SH:5].[Cl:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9](Cl)[N:8]=1>C1C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([S:5][CH3:4])[N:8]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CS
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: c1ccccc1
Product: CSc1cncc(Cl)n1

Procedure:
A mixture of 0.13 mole of sodium methylmercaptide (prepared from 3.12 g. sodium hydride and excess methyl mercaptan), 20 g. (0.13 mole) of 2,6-dichloropyrazine and 200 ml. benzene is heated at reflux for 24 hours, cooled and washed twice with 50 ml. water. The benzene layer is separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Distillation of the residue gives 2-chloro-6-methylthiopyrazine.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.N(OC(C)(C)C)=O.[ClH:25].CO>C(#N)C.[Cu](Cl)Cl>[Cl:25][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1
Reactant: N#Cc1ccc(-c2cc(N)cc(CO)c2)cc1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: CO
Product: N#Cc1ccc(-c2cc(Cl)cc(CO)c2)cc1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
A solution of 3′-amino-5′-(hydroxymethyl)biphenyl-4-carbonitrile (120 mg, 0.54 mmol) in dry acetonitrile (1 mL) was added dropwise to a solution of copper (II) chloride (86 mg, 0.64 mmol) and tert-butyl nitrite (91 μL, 0.78 mmol) in acetonitrile (2 mL) at 65° C. After stirring for 30 min at 65° C., the reaction mixture was cooled to room temperature, poured into a 1 N hydrochloric acid solution, and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) afforded 46 mg (35%). LC/MS: tR=2.54 min, 244.03 (MH)+. (Phenomenex C18 4.6×50 mm, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA, Gradient time=4 min., Flow rate=4 mL/min.).