Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[OH:16])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].Cl.C(OCC)(=O)C>CN(C=O)C.C(OCC)(=O)C>[ClH:17].[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=2[O:16][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: ClCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCOCC2)c(OCCN2CCOCC2)c1

Procedure:
2-Morpholin-4-yl-5-nitrophenol and 4-(2-chloroethyl)morpholine were allowed to undergo the reaction in DMF in the presence of potassium carbonate, and then the resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 and further treated with 4 M hydrogen chloride/ethyl acetate solution in ethyl acetate to obtain 4-morpholin-4-yl-3-(2-morpholin-4-ylethoxy) aniline hydrochloride. F: 308.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][C:7]1[N:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[NH2:27])=[CH:22][C:21]=2[CH3:29])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)C.O.[OH-].[Na+]>C(O)C>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([N:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:10][CH:11]=[C:7]2[CH2:6][CH2:5][C:4]([OH:30])=[O:3])=[C:21]([CH3:29])[CH:22]=1)(=[O:28])[NH2:27]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(OC)cc2)n1-c1ccc(C(N)=O)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ccc(CCC(=O)O)n2-c2ccc(C(N)=O)cc2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(4-methoxy-phenyl)-1H-pyrrol-2-yl]propanoic acid ethyl ester (86 mg, 0.216 mmol) was dissolved in ethanol (4 mL). Water (0.5 mL) was added to the ethanolic solution followed by the addition of 1N NaOH (0.51 mL, 0.51 mmol). The reaction mixture was stirred at room temperature for 1 h and then at 45° C. for an additional hour. After removal of the solvent in vacuo, the residue was diluted with water (6 mL) and extracted with ethyl acetate (2×6 mL). The pH of the aqueous layer was adjusted to 2 with 1N HCl and then extracted with ethyl acetate (6 mL). The combined organic layer was dried over anhydrous Na2SO4 and the solvent removed in vacuo to obtain 3-[1-(4-Carbamoyl-2-methyl-phenyl)-5-(4-methoxy-phenyl)-1H-pyrrol-2-yl]-propanoic acid as the product (68 mg, 85%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([O:29][CH2:30][O:31][CH3:32])[CH:21]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][C:22]=2[O:29][CH2:30][O:31][CH3:32])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCOc1cc(F)ccc1B(O)O
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: COCOc1cc(F)ccc1-c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 4-fluoro-2-methoxymethoxybenzene boronic acid [prepared from 1-bromo-4-fluoro-2-(methoxymethoxy)benzene (CAS-no. 162269-78-5) by reaction with n-BuLi at −78° C. followed by treatment with B(OMe)3 and subsequent hydrolysis] according to the general procedure B. Obtained as a yellow solid (0.96 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.[OH-].[Na+]>C(O)C.C1(C)C=CC=CC=1.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>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:10]2[NH:11][C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:31]4[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=4)=[CH:3][CH:4]=3)[N:9]=2)=[CH:20][CH:21]=1
Reactant: Clc1ccc(-c2nc(-c3ccc(Br)cc3)c(-c3ccncc3)[nH]2)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(-c3nc(-c4ccc(Cl)cc4)[nH]c3-c3ccncc3)cc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a solution of 60 mg (0.146 mmol) of 4-(4-bromophenyl)-2-(4-chlorophenyl)-5-(4-pyridyl)imidazole (from Step C) in 1 mL of ethanol and 1.5 mL of toluene was added 56 mg (0.365 mmol) of 4-methoxybenzeneboronic acid, followed by 0.73 mmol (584 μL of a 1.25 N solution) of aqueous NaOH, and 17 mg (0.146 mmol) of tetrakis(triphenylphosphine)palladium(0). The resulting reaction mixture was stirred at 90° C. overnight. After being cooled to room temperature, the reaction was quenched by addition of water and extracted with ethyl acetate twice. The organic layers were combined, washed with water and brine, and dried over sodium sulfate. After filtration and removal of volatiles, the crude product was flash chromatographed over silica gel (gradient elution using 20-50% EtOAc in hexane). This material appeared to be homogeneous by TLC but contained some uncoupled material as shown by HPLC trace. Therefore, it was further purified via a chromatotron, eluting slowly using a 5:95:0.5 mixture of methanol/DCM/HOAc to provide 16 mg of the desired product as a pale yellow solid, homogeneous by TLC, mass spectrum (CI) m/e 438 (M+1)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:15](=[O:16])[CH2:14][C:13](=[O:17])[CH3:12]
Reactant: CNCC=Cc1ccccc1
Reactant: C=C1CC(=O)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)N(C)CC=Cc1ccccc1

Procedure:
0.736 g (5.0 mmol) of methyl-(3-phenyl-2-propene-1-yl)amine, 0.386 ml (5.0 mmol) of ketene dimer and 0.07 ml (0.50 mmol) of triethylamine were heated at 70° C. under stirring in 5 ml of toluene overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. After the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the thin-layer silica gel chromatography (ethyl acetate) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=3[F:27])[C:9]3[C:14]([C:15]=2/[C:16](=[N:18]/O)/[NH2:17])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:28])[O:4][N:3]=1.C(OC(=O)C)(=O)C>C(O)(=O)C.[Pd]>[CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=3[F:27])[C:9]3[C:14]([C:15]=2[C:16](=[NH:17])[NH2:18])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1c(/C(N)=N/O)c2ccccc2n1-c1ccc(O)cc1F
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1noc(C)c1-c1c(C(=N)N)c2ccccc2n1-c1ccc(O)cc1F

Procedure:
0.5 mmol (Z)-2-(3,5-dimethylisoxazol-4-yl)-1-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-1H-indole-3-carboximidamide (Example 235) was dissolved in 5 ml acetic acid. Acetic acid anhydride (4 eq) was slowly added and the mixture was stirred over night. A Pd—C catalyst (10% on carbon) was added and the mixture was placed in a hydrogenation apparatus under 50 psi H2 over night. The mixture was filtered through celite and concentrated. The crude product was purified on HPLC: (Column: Sunfire, 20 min acidic gradient: 5-50% MeCN. ES/MS m/z: 365.15 (M+H), 363.18 (M−H); 1H NMR (MeOD, 500 MHz): 7.86 (m, 1H), 7.41-7.31 (m, 2.5H), 7.25-7.13 (m, 1.5H), 6.76 (m, 1H), 6.67 (m, 1H), 2.21, 2.15 (two s, 3H) and 2.08, 2.06 (two s, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=[C:11]2[NH:10][C:9]1=[O:20].[C:21]1([O:27][CH2:28][CH2:29][CH2:30]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N12CNCC1=CCCC2>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=[C:11]2[N:10]([CH2:30][CH2:29][CH2:28][O:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]1=[O:20]
Reactant: BrCCCOc1ccccc1
Reactant: CC1CCCCC1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Agent: C1=C2CNCN2CCC1
Product: CC1CCCCC1n1c(=O)n(CCCOc2ccccc2)c2cnc3[nH]ccc3c21
Temperature: 60 °C

Procedure:
A mixture of 1-(2-methylcyclohexyl)-3,6-dihydroimidazo-[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (0.030M solution in N,N-dimethylformamide, 1.00 mL), 3-bromopropyl phenyl ether (12.9 mg), 1,8-diazabicyclo[4,3,0]non-5-ene (0.013 mL), was heated at 60° C. for 16 hours. The solvent was removed in vacuo and purification by preparative high performance liquid chromatography gave 1-(2-methylcyclohexyl)-3-(3-phenoxypropyl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (2.6 mg).
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:11]=1)[C:6]([O-])=[O:7].[Na+].C(Cl)(=O)C(Cl)=O.C[N:24](C=O)C>O>[C:6]([C:5]1[CH:9]=[C:10]([CH:11]=[C:3]([I:2])[CH:4]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:7])[NH2:24]
Reactant: COC(=O)c1cc(I)cc(C(=O)[O-])c1
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(I)cc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
20 ml of 1 M hydrochloric acid were added to a solution of 3.88 g (11.8 mmol) of sodium 3-iodo-5-(methoxycarbonyl)benzoate [J. H. Ackermann et al., J. Med. Chem. 1966, 9 (1), 165-168] in 100 ml of water. After 10 min, the mixture was extracted three times with in each case about 100 ml of ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution and dried over anhydrous magnesium sulphate. After filtration, the solvent was removed on a rotary evaporator. The residue that remained was dissolved in 75 ml of dichloromethane, and 5.2 ml (59.1 mmol) of oxalyl chloride and a small drop of DMF were added at RT. After 1 h of stirring at RT, all volatile components were removed on a rotary evaporator. The residue was then dissolved in 50 ml of dioxane and, at a temperature of about 0° C., slowly added dropwise to 44 ml of a 25% strength aqueous ammonia solution. After the dropwise addition had ended, the cooling bath was removed and stirring was continued at RT for 30 min. The precipitated product was then filtered off with suction, washed with cold water and dried under high vacuum. This gave 3.02 g (81% of theory, 97% pure) of the title compound.
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][C@H:22]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:23]([O:25]C)=[O:24])(=[O:19])=[O:18])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1.O>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][C@H:22]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:23]([OH:25])=[O:24])(=[O:19])=[O:18])=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2ccccc2)cc1)N1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](CNS(=O)(=O)c1ccc(OCc2ccccc2)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
1.6 ml (1.6 mmol) of an aqueous solution of lithium hydroxide having a concentration of 1N are added to a solution of 450 mg (1.1 mmol) of methyl(S)-3-(4-benzyloxybenzenesulfonylamino)-2-piperidin-1-ylpropanoate in 15 ml of tetrahydrofuran and 0.5 ml of water. After stirring at ambient temperature for 18 h, the tetrahydrofuran is evaporated off under vacuum and then 1.8 ml of an aqueous solution of acetic acid having a concentration of 1N and 15 ml of water are added. The product precipitates and is filtered off. 420 mg (98%) of (S)-3-(4-benzyloxybenzenesulfonylamino)-2-piperidin-1-ylpropanoic acid are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]=1[C:18]([F:21])([F:20])[F:19].[OH-].[Li+]>C1COCC1.O>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[C:18]([F:20])([F:19])[F:21]
Reactant: COC(=O)c1ccc(N2CCCCC2C)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of methyl 4-(2-methylpiperidin-1-yl)-3-(trifluoromethyl)benzoate obtained in step 2 (6.6 g, 21.9 mmol) in THF (50 mL) and water (5 mL) was added lithium hydroxide (1.84 g, 43.8 mmol). The resulting mixture was stirred at RT for 12 h. Solvents were removed under vacuum and the resulting mass was diluted with water. The aqueous layer was washed with DCM (2×50 mL) and was acidified with conc HCl (pH=4). It was extracted with EtOAc (2×100 mL). The EtOAc layer was washed with brine and dried over sodium sulfate, affording the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 13.30 (bs, 1H), 8.15-8.19 (m, 2H), 7.67-7.70 (d, 1H), 3.08 (m, 1H), 2.86-2.89 (m, 1H), 2.49-2.50 (m, 1H), 1.89-1.90 (m, 2H), 1.74-1.76 (m, 2H), 1.43-1.46 (m, 1H), 1.40-1.41 (m, 1H), 0.77 (d, 3H). LC/MS (Method A): 288.1 (M+H)+. HPLC (Method B) Rt 3.71 min (Purity: 98.3%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=O)[C:8]3[N:9]2[CH:12]=[CH:13][N:14]=3)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:31])=O>O.[OH-].[Na+]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([Cl:31])[C:8]3[N:9]2[CH:12]=[CH:13][N:14]=3)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cc(C(F)(F)F)c(Br)cc2n2ccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)c1ccccc1
Solvent: O
Product: FC(F)(F)c1cc2nc(Cl)c3nccn3c2cc1Br
Temperature: 120 °C
Yield: 80.4 %

Procedure:
8-Bromo-7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-4(5H)-one (9.4 g, 0.0283 mol) is stirred under nitrogen with N,N-dimethylaniline (14.5 mL, 0.1123 mol) and phosphoryl chloride (190 mL, 2.0119 mol) at reflux (120° C.) for 1.5 hour. After cooling down to room temperature, the mixture is slowly poured in a mixture of water (2 L) and sodium hydroxide 5N (1 L) below 10° C. The mixture is extracted four times with ethyl acetate (200 mL) and the combined organic phases are washed with water (200 mL), dried over sodium sulfate and concentrated to about 100 mL. Cyclohexane (500 mL) is added at room temperature. The mixture is cooled to 0-5° C. and filtered. The cake is washed with cyclohexane and dried under vacuum to afford the title compound as a yellow solid (7.98 g, 80.4%)
Reaction SMILES: [H-].[Na+].[Br-].[C:4]([CH2:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:6])=[O:5].[C:30]1([CH2:36][CH2:37][CH:38]=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CS(C)=O>[C:30]1([CH2:36][CH2:37]/[CH:38]=[CH:10]\[CH2:9][CH2:8][CH2:7][C:4]([OH:6])=[O:5])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCCc1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)CCC/C=C\CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A stirred suspension of sodium hydride (12.0 g, 50% dispersion in oil) in dry dimethyl sulphoxide (100 ml) was heated to 70° to 75° C. under nitrogen for 40 minutes. The dark solution was cooled, a solution of 4-carboxybutyltriphenylphosphonium bromide (53 g) in dry dimethyl sulphoxide (100 ml) was added over 20 minutes at 20° to 25° C., and the solution was stirred for a further 10 minutes. 3-Phenyl-propionaldehyde (12.5 ml) was added with cooling to maintain a temperature of 30° to 35° C. and the mixture was stirred for a further 4 hours at room temperature, then poured on to ice-water (600 ml) and washed with chloroform. The aqueous phase was acidified and extracted with chloroform. The extract was washed with water, dried, and evaporated. The residual oil was distilled under vacuum to give the above product, b.p. 134° to 139° C./0.07 mm. 13C NMR spectroscopy showed the presence of about 5% (E)-isomer.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:28])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[CH2:37]([O:39][C:40](=[O:46])[C:41](=[N+]=[N-])[CH2:42][CH3:43])[CH3:38]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:10](=[O:28])[N:11]([C@H:21]3[CH2:26][CH2:25][C@H:24]([O:27][CH:41]([CH2:42][CH3:43])[C:40]([O:39][CH2:37][CH3:38])=[O:46])[CH2:23][CH2:22]3)[C:12]3[N:13]([N:18]=[CH:19][N:20]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])=[C:2]([F:1])[CH:3]=1)#[N:36]
Reactant: CCOC(=O)C(CC)=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(CC)C(=O)OCC)CC2)c2ncnn12
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.50 g), rhodium(II) acetate (dimer) (0.0050 g) and toluene (5 mL) was heated to 80° C. under an argon atmosphere, a solution of 2-diazobutyric acid ethyl ester (0.87 g) in toluene (5 mL) was added dropwise, and the mixture was stirred at 80° C. for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.35 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][C:3]=1[NH2:4].[CH3:11][S:12](Cl)(=[O:14])=[O:13]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][C:3]=1[NH:4][S:12]([CH3:11])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Cl)c(Cl)cc1Cl
Solvent: Cc1ccccc1C
Product: CS(=O)(=O)Nc1cc(Cl)c(Cl)cc1Cl

Procedure:
A mixture of 2,4,5-trichloroaniline (39.3 g.), methane sulfonyl chloride (22.9 g.) and 100 ml. of xylene were heated together under reflux conditions for 18 hours. The mixture was then allowed to cool, which formed a brown precipitate. The product was worked up in the same manner as set forth in Example 1 to yield 24.0 g. of product, m.p. 144°-145° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].F[C:21]1[CH:22]=[N+:23]([O-:30])[CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28].O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:21]2[CH:22]=[N+:23]([O-:30])[CH:24]=[CH:25][C:26]=2[N+:27]([O-:29])=[O:28])=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Reactant: COc1ccc(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2c[n+]([O-])ccc2[N+](=O)[O-])c2ccccc12
Reaction time: 0.25 h

Procedure:
To a solution of 4-methoxy-1-naphthol (8.87 g) in 50 ml of DMF was added sodium carbonate (7.8 g) portionwise, and after the addition was complete the mixture was stirred for 15 minutes. Then a solution of 3-fluoro-4-nitropyridine-N-oxide (8.0 g) in 50 ml DMF was added dropwise at room temperature. The reaction was then allowed to proceed for 4 hours at room temperature. The mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with NaCl (sat) and dried (anhy. MgSO4).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C:15]([OH:17])=O)[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:21])=O>C(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C:15]([Cl:21])=[O:17])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(-c2csc(C(=O)O)n2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccc(-c2csc(C(=O)Cl)n2)cc1
Reaction time: 3 h

Procedure:
4-(4-Isopropyl-phenyl)-thiazole-2-carbonyl chloride was prepared by refluxing a mixture of 4-(4-Isopropyl-phenyl)-thiazole-2-carboxylic acid (50 mg) and oxalyl chloride (300 μl) in chloroform (5 mL). After 3 h, the volatiles were evaporated and the residue was dried under high vacuum to provide the acid chloride (50 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([NH:27][NH2:28])=[O:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:37](Cl)(Cl)=[O:38]>C(Cl)Cl.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[O:26][C:37](=[O:38])[NH:28][N:27]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)NN)cc32)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(-c4n[nH]c(=O)o4)cc32)cc1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
To a solution of 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbohydrazide (intermediate 57, 0.040 g, 0.0771 mmol) in DCM (0.2 mL) at −78° C. was added phosgene (0.081 mL of a ˜20% solution in toluene) dropwise. After stirring at −20° C. overnight, the reaction was quenched with saturated aqueous NaHCO3, and the product was extracted with EtOAc and DCM. The combined extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified via SiO2 column chromatography, eluting with mixtures of EtOAc and hexane, to afford the title compound. LC/MS: m/e 546.1 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.96 (1H, d, J=6.4 Hz), 7.62 (11-1, d, J=8.4 Hz), 7.54 (1H, d, J=7.8 Hz), 7.29 (1H, d, J=5.5 Hz), 7.03-7.04 (3H, m), 6.86-6.89 (3H, m), 4.50-4.90 (2H, br), 1.14 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[CH:7]=1.[CH3:22][C:23]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])([CH3:26])[C:24]#[CH:25].O1CCCC1.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[C:14]([NH:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([C:23]([CH3:22])([CH3:26])[C:24]#[CH:25])[CH:28]=4)[CH:21]=[CH:20][CH:19]=3)[CH:18]=[CH:17][C:9]=2[N:10]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)cc2s1
Reactant: C#CC(C)(C)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C#CC(C)(C)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(C)=O)sc4c3)c2)c1
Yield: 22.3 %

Procedure:
Using N-[6-(3-aminophenoxy)-1,3-benzothiazol-2-yl]acetamide (160 mg, 0.534 mmol) produced in Example A40(x), 3-(1,1-dimethylprop-2-yn-1-yl)benzoic acid (201 mg, 1.07 mmol), tetrahydrofuran (4 mL), N,N-dimethylformamide (10 μL), oxalyl chloride (170 mg, 1.34 mmol) and N,N-dimethylformamide (4 mL), and in the same manner as in Example A40(xi), the title compound (56 mg, 22%) was obtained as a colorless solid.