Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[Cl:10][CH2:11][C:12](O)=O>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:12]([CH2:11][Cl:10])[NH:9][C:4]=2[CH:3]=1
Reactant: O=C(O)CCl
Reactant: Nc1ccc(Cl)cc1N
Agent: Cl
Product: ClCc1nc2ccc(Cl)cc2[nH]1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
The solution of 4-chloro-1,2-phenylenediamine (1.43 g) and chloroacetic acid (1.43 g) in 4M HCl (10 ml) was heated to reflux for 1 h. After cooling to rt overnight the mixture was filtered and the filtrate was cooled in an ice bath. With stirring the solution was adjusted to pH 8 with 25% ammonia solution. A gummy precipitate is formed which is cooled for 1 h. The aqueous layer is removed by decantation and the residue crystallised from acetone/water to yield 5-chloro-2-chloromethylbenzimidazole (1.4 g) as brownish solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Cl:36][C:37]1[C:38]([F:46])=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](O)=[O:41]>C(Cl)(Cl)Cl>[Cl:36][C:37]1[C:38]([F:46])=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40]([N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)=[O:41]
Reactant: O=C(O)c1cccc(Cl)c1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(Cl)c2F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 19.4 g of 1-Boc-piperazine, 24.0 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 19.1 g of 1-hydroxybenzotriazole, 20.0 g of 3-chloro-2-fluorobenzoic acid and 200 ml of chloroform was stirred at room temperature for 4 hours. The resulting mixture was diluted with chloroform, and an insoluble matter was filtered off using Celite. Then, the filtrate was washed with water and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=9/1 to 1/1) to give title compound.
Reaction SMILES: N1C=CN=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[N:22]=[CH:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8].CN(C(O[N:39]1N=N[C:41]2[CH:42]=[CH:43][CH:44]=C[C:40]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)C(N)=CC=CC=1>CN(C=O)C>[NH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:2]=1[NH:6][C:7]([C:9]1[C:17]2[NH:16][C:15]([NH:18][C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][N:22]=3)=[O:20])=[N:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1cc2ccccc2cn1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1cccc2nc(NC(=O)c3nccc4ccccc34)[nH]c12
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 80 %

Procedure:
To a solution of 0.33 g (1.0 mmol) of -[(isoquinoline-1-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid (from Example 58) in DMF (5 mL) was added 0.47 g (1.25 mmol) of HBTU and DIEA (0.5 mL). The mixture was stirred for 5 min, then 0.22 g (2.0 mmol) of benzene-1,2-diamine was added in one portion. The reaction mixture was heated at 50° C. for 1 h, after cooling to room temperature, the coupling product was precipitated by addition of sat. aq. sodium carbonate solution (15 mL). The solid was filtered, washed with water, and dried to provide 0.35 g (80%) of isoquinoline-1-carboxylic acid [7-(2-amino-phenylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 443 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:11](=O)/[CH:12]=[CH:13]/[CH3:14].[OH-].[K+]>Cl.C1(C)C=CC=CC=1>[CH3:14][C:13]1[CH:12]=[CH:11][C:9]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=2)[N:8]=1
Reactant: C/C=C/C=O
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc2cc([N+](=O)[O-])ccc2n1
Temperature: 100 °C

Procedure:
4-Nitroaniline (6 g, 38 mmol) was dissolved in HCl (6N, 200 mL), the mixture was heated at 100° C. A solution of (E)-but-2-enal (7.2 mL, 76 mmol) in toluene (60 mL) was added dropwise, and the reaction was heated at 100° C. overnight. The reaction mixture was cooled to room temperature and basified with aqueous KOH until pH=12. The mixture was extracted with EtOAc and the organic layer was washed with brine and dried over anhydrous Na2SO4. 2-Methyl-6-nitroquinoline was obtained after purification by column chromatography (hexane:EtOAc=20:1) (5.8 g, 81.2%). MS [M++1]=189, LC-MS: tR=1.64 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:9]=1)=[O:4].[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13][CH2:23][C:22]2[CH:21]=[CH:20][C:19]([C:15]3[S:14][CH:18]=[CH:17][N:16]=3)=[CH:26][CH:25]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(CCCN)s1
Reactant: O=Cc1ccc(-c2nccs2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CCCNCc2ccc(-c3nccs3)cc2)s1

Procedure:
The title compound of Step A was prepared from 5-(3-amino-propyl)-thiophene-2-carboxylic acid methyl ester, of Preparation 5, and 4-thiazol-2-yl-benzaldehyde, of Preparation 25, using the method described in Example 1, Step A, except N,N-diisopropylethylamine was used in place of triethylamine. 1H NMR (400 MHz, CDCl3) δ 8.97-7.32 (m, 7H), 6.72 (d, 1H, J=4 Hz), 3.82 (s, 3H), 3.70 (s, 2H), 2.91 (t, 2H, J=7 Hz), 2.62 (t, 2H, J=7 Hz), 1.90 (m, 2H); MS 373 (M+1).
Reaction SMILES: [CH2:1]([CH:3]([C:6](=O)[CH3:7])[CH:4]=O)[CH3:2].[Na].[C:10]([CH2:12][C:13]([NH2:15])=[O:14])#[N:11].C([O-])(=O)C.[NH2+]1CCCCC1>O.C(O)(=O)C>[C:10]([C:12]1[C:13](=[O:14])[NH:15][C:1]([CH3:2])=[C:3]([CH2:6][CH3:7])[CH:4]=1)#[N:11]
Reactant: N#CCC(N)=O
Reactant: CCC(C=O)C(C)=O
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(C#N)c(=O)[nH]c1C
Temperature: 25 °C

Procedure:
According to the method described in J. Heterocyclic Chem., 24, 351 (1987), a mixture of 2-ethyl-3-oxobutanal, sodium salt (37.5 g, 0.275 mmol), cyanoacetamide (25.2 g, 0.30 mol), aqueous piperidinium acetate (22 mL) [prepared from glacial acetic acid (4.2 mL), water (10 mL) and piperidine (7.2 mL)] in water (775 ml) was refluxed for four hours. Glacial acetic acid (30 ml) was added cautiously (much foaming) as the product precipitated. Upon cooling to room temperature,the product was collected by filtration, washed with cold water and air dried to yield 22.3 g (50%), m.p. 237°-240° C.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[CH:4][CH:3]=1.I[CH2:33][CH3:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:33][CH3:34])[C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)=[CH:30][CH:31]=1
Reactant: CCI
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(C(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(=O)c2c(nc(Oc3cccc(C(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 28.5 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione (50 mg, 0.11 mmol, example 1) in DMF (1 mL) was added iodoethane (18.7 mg, 0.12 mmol) followed by potassium carbonate (23 mg, 0.16 mmol). Then the mixture was stirred at 50° C. for 3 h. The mixture was diluted with ethyl acetate and extracted with brine and saturated aqueous ammonium chloride solution. The organic phase was dried and concentrated to give crude solid product which was collected and washed with ethanol to give 7-(4-chlorobenzyl)-1-ethyl-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione (15 mg, 26.7% yield) as white solid. 1H-NMR (DMSO-d6) δ 7.77 (s, 1H), 7.69-7.73 (m, 3H), 7.43 (s, 4H), 5.46 (s, 2H), 3.91-3.93 (q, 2H), 3.29 (s, 3H), 1.11-1.14 (t, 3H). LCMS retention time 3.109 min; LCMS MH+ 479.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([CH:11](OCC)[O:12]CC)[NH:10][C:4]=2[CH:3]=1>C1COCC1.O>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([CH:11]=[O:12])[NH:10][C:4]=2[CH:3]=1
Reactant: CCOC(OCC)c1cc2cnc(Br)cc2[nH]1
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc2cnc(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 105.9 %

Procedure:
To a solution of 6-Bromo-2-(diethoxymethyl)-1H-pyrrolo[3,2-c]pyridine (Preparation 137, 142 mg, 0.47 mmole) in THF (1.4 mL) and water (0.28 mL) was added tosic acid hydrate (134 mg, 0.705 mmole) and the reaction was stirred at 25° C. for 55 minutes. The reaction was partitioned between ethyl acetate (20 mL) and sodium bicarbonate (5 mL). The layers were separated and the aqueous layer again extracted with ethyl acetate (7 mL). The combined organic layers were washed with sodium bicarbonate and brine and concentrated in vacuo to afford the title compound (112 mg). 1H-NMR (CDCl3, 500 MHz): δ 7.37 (s, 1H), 7.62 (t, J=0.95 Hz, 1H), 8.88 (d, J=0.95 Hz, 1H), 9.32 (br s, 1H), 9.93 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([OH:30])[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]2[S:25][C:24]([C:26]([O:28]C)=[O:27])=[CH:23][CH:22]=2)=[CH:4][C:3]=1[Cl:31].[OH-].[Na+].CO>CCCCCC>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([OH:30])[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]2[S:25][C:24]([C:26]([OH:28])=[O:27])=[CH:23][CH:22]=2)=[CH:4][C:3]=1[Cl:31]
Reactant: COC(=O)c1ccc(CCOCCCCCCNCC(O)c2cc(Cl)c(N)c(Cl)c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCCC
Product: Nc1c(Cl)cc(C(O)CNCCCCCCOCCc2ccc(C(=O)O)s2)cc1Cl
Yield: 86 %

Procedure:
A solution of methyl 5-[2-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]ethyl]-2-thiophenecarboxylate (0.274 g) in a 2N sodium hydroxide solution (4.5 ml) and methanol (20 ml) was stirred at room temperature under nitrogen for 28 h. Dowex 50 (H+) methanol-washed ion exchange resin was added portionwise to neutralise the mixture to pH7. The mixture was filtered and evaporated in vacuo to give an orange solid. Trituration with hexane gave the title compound as a yellow solid (229 mg), m.p. 178°-185° (decomp).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:4]=[CH:5][C:6]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([N:29]([CH:31]3[CH2:33][CH2:32]3)[CH3:30])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[N:7][C:8]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([OH:19])=[N:14][CH:13]=[CH:12]2.COC(OC)N(C)C.[Br:42]N1C(=O)CCC1=O>CN(C=O)C>[ClH:1].[NH2:2][C:3]1[N:4]=[CH:5][C:6]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([N:29]([CH:31]3[CH2:32][CH2:33]3)[CH3:30])(=[O:27])=[O:28])=[CH:24][CH:25]=2)=[N:7][C:8]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([OH:19])=[N:14][CH:13]=[C:12]2[Br:42]
Reactant: CN(C1CC1)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc4c(O)nccc4c3)n2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: COC(OC)N(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C1CC1)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc4c(O)ncc(Br)c4c3)n2)cc1
Yield: 41.3 %

Procedure:
To a room temperature slurry of 4-(5-amino-6-(1-hydroxyisoquinolin-6-yl)pyrazin-2-yl)-N-cyclopropyl-N-methylbenzenesulfonamide hydrochloride (1.00 g, 2.07 mmoL, prepared by general method C) in DMF (10 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (1 mL). Within minutes, the slurry discharged to a solution. Then, N-bromosuccinimide (386 mg, 2.17 mmol) was added in one portion. After 1 h the reaction was concentrated and flashed over silica gel (4-8% MeOH/DCM eluent) to provide 4-(5-amino-6-(4-bromo-1-hydroxyisoquinolin-6-yl)pyrazin-2-yl)-N-cyclopropyl-N-methylbenzenesulfonamide hydrochloride (480 mg, 43% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.59-11.67 (br. s, 1H), 8.77 (s, 1H), 8.36 (d, J=8.3 Hz, 1H), 8.24-8.30 (m, 2H), 8.17 (d, J=1.5 Hz, 1H), 7.99 (dd, J=8.3, 1.5 Hz, 1H), 7.86 (d, J=8.5 Hz, 2H), 7.62 (d, J=6.0 Hz, 1H), 6.76 (br. s, 2H), 2.69 (s, 3H), 1.80-1.90 (m, 1H), 0.76 (s, 2H), 0.65-0.73 (m, 2H); MS (EI) m/z=527.4 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9](O)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[F:8].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:18][S:17][C:14]1[CH:13]=[CH:12][C:11](/[CH:10]=[CH:9]/[C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: CSc1ccc(CC(O)c2ccc(F)c(F)c2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CSc1ccc(/C=C/c2ccc(F)c(F)c2)cc1
Temperature: 25 °C

Procedure:
The alcohol from step 3 (3.78 g) was dissolved in toluene (45 mL) and p-TsOH (260 mg) was added. The mixture was refluxed with azeotropic removal of water for 18 hr, cooled to r.t., washed with saturated NaCHO3 sol., brine, dried (MgSO4) and the solvent evaporated. The residue was purified by flash chromatography (silica gel; hexane/EtOAc (95:5)) to give the title product as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])[C:3]=1[NH:17][C:18](=S)[NH:19][C:20]1[C:21]([CH3:29])=[N:22][C:23]([N:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:3]2[N:17]=[C:18]([NH:19][C:20]3[C:21]([CH3:29])=[N:22][C:23]([N:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=3)[N:12]([CH2:13][CH2:14][CH2:15][OH:16])[C:4]=2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ccc(N(C)C)nc2C)c1NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c2nc(Nc3ccc(N(C)C)nc3C)n(CCCO)c12
Temperature: 50 °C
Reaction time: 3 h
Yield: 50.6 %

Procedure:
A mixture of the resulting thiourea (1.09 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (509 mg, 2.65 mmol), and triethylamine (0.37 mL) in tetrahydrofuran (10 mL) was stirred at 50° C. for 3 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-80% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless solid (510 mg, 1.22 mmol, 28% in 2 steps).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1.[CH:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)=[O:16].O>C1(C)C=CC=CC=1.C1(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)C=CC=CC=1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:15]=[O:16])[CH:22]=2)=[CH:9][CH:10]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1cccc(-c2ccc(Br)cc2)c1
Temperature: 25 °C
Yield: 33.2 %

Procedure:
89 ml (180 mmol) of a 2M solution of potassium carbonate are added to a solution containing 20 g (71 mmol) of p-iodobromobenzene and 14 g (92 mmol) of 3-formylbenzeneboronic acid in toluene, followed by addition of 4.1 g (3.5 mmol) of tetrakis(triphenylphosphino)palladium. The reaction medium is refluxed for 16 hours. After cooling to room temperature, water is added and the organic products are extracted with ethyl acetate. The solvents are evaporated off and the residue obtained is purified by chromatography on silica with a 99/1 heptane/ethyl acetate mixture. 6.2 g (23.6 mmol) of the expected aldehyde, an orange solid, are isolated in a yield of 33%.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[CH2:2].[CH:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=1)=C>>[CH:3]1(/[CH:1]=[CH:2]\[O:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:9])=[CH:13][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C=COc1ccc(OC)cc1
Reactant: C=CC1CCCCC1
Product: COc1ccc(O/C=C\C2CCCCC2)cc1
Reaction time: 24 h
Yield: 75.3 %

Procedure:
Following the general procedure, vinylcyclohexane (20.0 mg, 0.182 mmol) was treated with p-methoxyphenyl vinyl ether (55.0 mg, 0.363 mmol) and 5 mol % of in situ-generated complex 1a (91.0 μL, 0.10 M, 9.08 μmol; final substrate concentration=2.0 M) and allowed to stir for 24 h. The unpurified product is >98% Z (as determined by 400 MHz 1H NMR analysis). Excess p-methoxyphenyl vinyl ether was removed by vacuum distillation (1.0 torr, 80° C.). The resulting oil was purified by neutral alumina chromatography (50:1 hexanes:Et2O) to afford 10d (31.8 mg, 0.137 mmol, 75.0% yield, >98% Z isomer) as a colorless oil. IR (neat): 2925 (m), 2850 (m), 1664 (w), 1505 (s), 1465 (w), 1447 (w), 1392 (w), 1293 (w), 1244 (m), 1224 (s), 1180 (w), 1102 (w), 1040 (m); 1H NMR (400 MHz, CDCl3): δ 6.95-6:91 (2H, m), 6.86-6.82 (2H, m), 6.17 (1H, dd, J=6.4, 1.2 Hz), 4.63 (1H, d, J=9.2, 6.0 Hz), 3.78 Hz (3H, s), 2.65-2.54 (1H, m), 1.78-1.60 (5H, m), 1.39-1.06 (5H, m); 13C NMR (100 MHz, CDCl3): δ 155.2, 151.9, 139.8, 118.6, 117.5, 114.8, 55.9, 33.6, 33.5, 26.3, 26.1; HRMS (ESI+) [M+H]+ calcd for C15H21O2: 233.1542, found: 233.1542.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35](=[O:36])[NH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)[CH3:39]
Reactant: N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from cis-4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A141) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: CS[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.O.[S:13]([Cl:17])(Cl)(=[O:15])=[O:14]>ClC1C=CC=CC=1>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([S:13]([Cl:17])(=[O:15])=[O:14])=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: O=S(=O)(Cl)Cl
Reactant: CSc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: Clc1ccccc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Temperature: 10 °C
Reaction time: 6 h
Yield: 95.2 %

Procedure:
A 2-liter, 4-necked flask equipped with a stirrer, thermometer, condenser and a dropping funnel having a by-pass was charged with 20.4 g (0.10 mole) of 4-nitrophenyl methyl sulfide, 10 g of water and 200 g of monochlorobenzene. Then, 94.5 g (0.70 mole) of sulfuryl chloride was added dropwise at 10° C. over a period of about 2 hours. Thereafter the mixture was stirred at 10° C. for 6 hours to complete the reaction. After completion of the reaction, the oil layer was separated and 10 g of water was added to accomplish washing. Then, the oil layer was separated and left to stand for about 1 hour with the addition of about 5 g of anhydrous sodium sulfate to remove the water. The solvent was distilled off to give crude crystals. The crude crystals were dissolved in monochlorobenzene and a poor solvent was added for recrystallization, giving 21.1 g of 4-nitrobenzenesulfonyl chloride as white crystals in a yield of 95% as calculated based on 4-nitrophenyl methyl sulfide.
Reaction SMILES: [C:1]1([B:7]([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:10]([O-])(O)=O>C(OC(=O)C)(=O)C>[NH2:10][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[B:7]([OH:9])[OH:8]
Reactant: O=[N+]([O-])O
Reactant: OB(O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: Nc1ccccc1B(O)O
Temperature: 25 °C

Procedure:
To a three necked round bottom flask equipped with an addition funnel (and argon inlet), thermometer and septum is added phenylboronic acid (40.13 g, 0.33 moles). Acetic anhydride (400 ml) is charged through the septum via syringe. Using a stir bar the mixture is then stirred under argon until the temperature reaches 0° C. with external cooling (ice bath). Fuming nitric acid (25.01 g, 0.397 moles) is added slowly over the course of thirty minutes. The reaction is then allowed to stir an additional two hours at 0° C., before removing the ice bath and allowing the reaction to warm to room temperature. The reaction is poured into ice water (1 L) at which point it appears cloudy. After stirring overnight, however, it becomes homogeneous. The solution is paced on a rotary evaporator at 40° C. under a 5 mm vacuum. When the volume is reduced by about 50%, enough water is added to bring the volume back to 100%. This process is repeated twice more, before bringing the volume to about 300 ml on the rotary evaporator when a precipitate is noticed. Twenty hours are allowed for complete crystallization, and the solids (p-nitrobenzeneboronic acid, 3.66 g) are removed by filtration. Enough water is then added to the filtrate to bring the total volume to 800 mi. The volume is reduced once more under reduced pressure to about 150 ml when a precipitate begins to form. The solids (o-nitrophenylboronic acid, 48.04 g) are collected by filtration and dried in a vacuum oven. To a pressure vessel is added o-nitrophenylboronic acid (31.64 g), 10% palladium on carbon (6.3 g) and ethanol (100 ml). The vessel is shook at room temperature under 50 psi hydrogen on a PARR shaker. After four hours the catalyst is removed by filtration, and the filtrate taken to dryness under reduced pressure. The solids (o-aminophenylboronic acid, 24.4 g) are dried under vacuum for 18 hours.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:38][CH3:39])([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]4([OH:36])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[C:24]([CH3:37])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:40])[CH:12]=1>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:41])=[O:4])[CH:8]=[N:9][CH:10]=2)=[C:14]([CH3:40])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2([OH:36])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:24]([CH3:37])[CH:23]=1)[CH2:38][CH3:39])[CH3:21]
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCOCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(C#CC2(O)CCOCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)O)c2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.251 mL, 0.251 mmol) was added to a solution of [5-(4-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 132-(2); 44.0 mg, 0.084 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and the mixture was stirred at room temperature for two hours. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:methanol:water=4:1:0.3) to give the target compound as a colorless oil (40.2 mg, 94%).