Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][C:6]=1[Cl:15])[CH:2]=[CH2:3].[CH:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18](O)[CH:17]=1.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1.C(Cl)(Cl)Cl>[N+:22]([C:21]1[CH:16]=[CH:17][C:18]([O:13][C:12](=[O:14])[CH2:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[C:6]([Cl:15])[CH:7]=2)=[CH:19][CH:20]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: C=CCOc1ccc(CC(=O)O)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C=CCOc1ccc(CC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Allyloxy-3-chloro-phenylacetic acid (4.3 g) was dissolved in dry tetrahydrofuran (20 ml). To the solution was added p-nitrophenol (2.28 g) in dry chloroform (30 ml). DCC (4.1 g) was then added and the whole was then stirred at room temperature overnight.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:15]=[N:16][C:17]3[CH2:18][CH:19]([NH:24][C:25](=O)[CH2:26][CH3:27])[CH2:20][CH2:21][C:22]=3[CH:23]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:15]=[N:16][C:17]3[CH2:18][CH:19]([NH:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][C:22]=3[CH:23]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCC(=O)NC1CCc2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)cnc2C1
Agent: B
Solvent: C1CCOC1
Product: CCCNC1CCc2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)cnc2C1
Yield: 61 %

Procedure:
Following the same procedure as described above, N-[3-(4-isopropylbenzenesulfonylamino)-5,6,7,8-tetrahydro-quinolin-7-yl]-propionamide (90 mg, 0.22 mmol) in THF (5 ml) was treated with 1M BH3.THF (2.2 ml). Purification of the crude product by flash column chromatography (CH2Cl2:MeOH, 95:5) provides the title compound (52 mg, 60%) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH:8]([P:11]([CH:15]([CH3:17])[CH3:16])[CH2:12][CH2:13][NH2:14])([CH3:10])[CH3:9]>>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[N:14][CH2:13][CH2:12][P:11]([CH:15]([CH3:17])[CH3:16])[CH:8]([CH3:10])[CH3:9]
Reactant: O=Cc1ccc[nH]1
Reactant: CC(C)P(CCN)C(C)C
Product: CC(C)P(CCN=Cc1ccc[nH]1)C(C)C
Yield: 97.2 %

Procedure:
Replicate the preparation of the ligand used in Ex. 7 except use 0.2 g (2.103 mmol) of pyrrole-2-carbaldehyde and use adding 0.356 g (2.208 mmol) of 2-(di-isopropylphosphino)ethanamine instead of N1,N1-dimethylethane-1,2-diamine to give 0.487 g (97%) of N-((1H-pyrrol-2-yl)methylene)-2-(di(propan-2-yl)phosphino)ethanamine as a colorless, semi solid, which is analytically pure by GC-MS and 1H-NMR: 1H NMR (400 MHz, Benzene): δ 10.05 (s, 1H), 7.83 (s, 1H), 6.51 (s, 1H), 6.44 (m, J=2.2 Hz, 1H), 6.28-6.14 (m, 1H), 3.67 (dd, J=15.2, 6.9 Hz, 2H), 1.75-1.64 (m, 2H), 1.58 (dq, J=6.9, 5.3 Hz, 2H), 1.00 (ddd, J=14.8, 12.3, 7.1 Hz, 12H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH2:7])[CH2:5][CH3:6].C([O-])([O-])=O.[K+].[K+].[C:14](Cl)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O1CCOCC1>[CH2:17]([O:16][C:14](=[O:15])[NH:7][CH:4]([CH2:3][O:2][CH3:1])[CH2:5][CH3:6])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCC(N)COC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCC(COC)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of 1-methoxymethyl-propylamine (2.50 g, 24.3 mmol, 1.0 eq.) in dioxane (15 mL) was added an aqueous solution of K2CO3 (15 g in 15 mL of H2O) and the mixture was cooled to 0° C. CBZ-Cl (4.16 mL, 1.2 eq.) was then introduced and, the resulting mixture was warmed to room temperature and stirred for 3 h, extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (hexanes to 40% EtOAc/hexanes) to give (1-methoxymethyl-propyl)-carbamic acid benzyl ester (4.4 g, 76%) as a white solid.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[CH3:17].[CH3:18]I.O>CS(C)=O>[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:15])([CH3:16])[CH2:9][C:10](=[O:14])[N:11]2[CH3:18])=[CH:6][C:5]=1[CH3:17]
Reactant: CI
Reactant: Cc1cc2c(cc1Br)NC(=O)CC2(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc2c(cc1Br)N(C)C(=O)CC2(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 101.3 %

Procedure:
A mixture of powdered KOH (14.06 g, 0.250 mol) in DMSO (150 mL) was stirred at 0° C. for 10 min. 7-Bromo-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (33.59 g, 0.125 mol) was added cautiously, followed immediately by the addition of methyl iodide (39 mL, 0.625 mol). The reaction mixture was kept at 0° C. for 30 min then slowly warmed up to room temperature and stirred overnight at room temperature. The reaction mixture was poured into water and extracted with dichloromethane washed with water and brine, dried (Mg2SO4), filtered and evaporated to give 35.74 g of 7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one (99%) and used without further purification in the Suzuki coupling (step a). 1H NMR (300 MHz; CDCl3): 1.27 (s, 6 H), 2.37 (s, 3 H), 2.48 (s, 2 H), 3.35 (s, 3 H), 7.12 (s, 1 H), 7.16 (s, 1 H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:27][CH2:28][N:29]([CH2:37][CH2:38][OH:39])[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:7]=[C:8]3[C:17]4[C:12](=[C:13]([O:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:14]=[CH:15][CH:16]=4)[C:11](=[O:26])[C:10]=1[C:9]=23.[NH2:40][CH2:41][CH2:42][NH:43][CH2:44][CH2:45][OH:46]>CC(O)C>[OH:46][CH2:45][CH2:44][NH:43][CH2:42][CH2:41][NH:40][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:27][CH2:28][N:29]([CH2:37][CH2:38][OH:39])[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:7]=[C:8]3[C:17]4[C:12](=[C:13]([O:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:14]=[CH:15][CH:16]=4)[C:11](=[O:26])[C:10]=1[C:9]=23
Reactant: O=C1c2c(OCc3ccccc3)cccc2-c2nn(CCN(CCO)Cc3ccccc3)c3ccc(Cl)c1c23
Reactant: NCCNCCO
Solvent: CC(C)O
Product: O=C1c2c(OCc3ccccc3)cccc2-c2nn(CCN(CCO)Cc3ccccc3)c3ccc(NCCNCCO)c1c23
Temperature: 160 °C
Yield: 60.4 %

Procedure:
A mixture of 6.0 g (11.2 mmol) of 5-chloro-2-[2-[(2-hydroxyethyl)(phenylmethyl)amino]ethyl]-7-(phenylmethoxy)anthra[1,9-cd]pyrazol-6(2H)-one (8) and 12.2 ml (121 mmol) of 2-(2-aminoethylamino)-ethanol was heated at 160° C. for 24 hr. The cooled mixture was diluted with 60 ml of 2-propanol then maintained at 0°-5° C. for several days. The precipitate was collected, washed with cold 2-propanol then diethyl ether, and dried at 60° C. under vacuum for 18 hours to give 4.1 g (60%) of 10, mp 134°-137° C., 97% pure by HPLC.
Reaction SMILES: C[Mg]Cl.[CH2:4]([O:11][C:12](=[O:26])[NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20](=[O:25])N(OC)C)[CH2:16][CH2:15]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:27](OCC)(=O)C>O1CCCC1>[CH2:4]([O:11][C:12](=[O:26])[NH:13][C@H:14]1[CH2:15][CH2:16][C@H:17]([C:20](=[O:25])[CH3:27])[CH2:18][CH2:19]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(C)=O
Reactant: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
Methylmagnesium chloride (3M solution in tetrahydrofuran, 31 mg, 0.41 mmol, 2.2 eq) is added at −10° C. to a stirred solution of [trans-4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid benzyl ester (60 mg, 0.19 mmol, 1.0 eq) in tetrahydrofuran (5 mL). After 3 hours stirring at −10° C., solvent is evaporated and the residue is extracted with ethyl acetate (3×10 mL) and a saturated ammonium chloride aqueous solution (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 2:1, v/v) to afford (trans-4-acetyl-cyclohexyl)-carbamic acid benzyl ester as a white solid (20 mg, 39% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:18]=[C:17]([C:19]4([CH2:25][CH2:26][CH2:27][CH2:28]Cl)[S:24][CH2:23][CH2:22][CH2:21][S:20]4)[NH:16][N:15]=3)=[CH:9][C:8]=2[O:30][CH3:31])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:18]=[C:17]4[C:19]5([CH2:25][CH2:26][CH2:27][CH2:28][N:16]4[N:15]=3)[S:20][CH2:21][CH2:22][CH2:23][S:24]5)=[CH:9][C:8]=2[O:30][CH3:31])[CH:6]=1
Reactant: COc1cc(Nc2n[nH]c(C3(CCCCCl)SCCCS3)n2)ccc1-n1cnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc3n(n2)CCCCC32SCCCS2)ccc1-n1cnc(Cl)c1
Temperature: 72 °C
Reaction time: 5 h
Yield: 84.1 %

Procedure:
To a solution of N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-5-(2-(4-chlorobutyl)-1,3-dithian-2-yl)-1H-1,2,4-triazol-3-amine (110 mg, 0.220 mmol) in DMF (3 mL) was added potassium carbonate (122 mg, 0.881 mmol) and potassium iodide (73.1 mg, 0.440 mmol). The mixture was stirred at 72° C. for 5 h. The mixture was concentrated in vacuo. The residue was purified using silica gel column chromatography (0-80% EtOAc/hexanes, linear gradient) to afford N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-5,6,7,8-tetrahydrospiro[[1,2,4]triazolo[1,5-a]azepine-9,2′-[1,3]dithian]-2-amine (90 mg, 0.185 mmol, 84% yield). LC-MS (M+H)+=463.1.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([OH:13])(=O)[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:19]([CH:21]=1)[NH2:20].[OH-].[Na+]>C(N(CC)CC)C.O1CCCC1>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:19]([CH:21]=1)[NH:20][C:5](=[O:13])[C:6]1[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1cc(Cl)ccc1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1cc(Cl)ccc1Oc1ccccc1)c1ccncc1
Reaction time: 0.5 h

Procedure:
A 100 ml. portion of thionyl chloride is added dropwise to 28.0 g. of isonicotinic acid over 30 minutes. After an additional 30 minutes the mixture becomes homogeneous. The volatiles are removed in vacuo, 250 ml. of benzene is added and then removed to leave a residue. This residue is suspended in 300 ml. of dry tetrahydrofuran and a solution of 25.0 g. of 5-chloro-2-phenoxyaniline in 63 ml. of triethylamine is added dropwise over 30 minutes and the mixture is stirred overnight. The mixture is poured into 500 ml. of 1 N-sodium hydroxide. The organic layer is separated. The basic layer is extracted with two 100 ml. portions of ether. The ether extracts and organic layer are combined, washed with 250 ml. of water and then with four 200 ml. portions of 10% hydrochloric acid. The combined acid washings are neutralized with concentrated ammonium hydroxide and extracted with three 250 ml. portions of ether. These ether extracts are dried and evaporated yielding 5'-chloro-2'-phenoxyisonicotinanilide as a brown solid.
Reaction SMILES: [F:1][C:2]1([F:15])[CH2:7][CH2:6][CH:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.[Li+].[CH3:17]C([N-]C(C)C)C.CI>C1COCC1>[F:1][C:2]1([F:15])[CH2:3][CH2:4][CH:5]([C:8]([CH3:17])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:7]1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C(C)C1CCC(F)(F)CC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)(C)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of Intermediate 232A (0.27 g, 1.226 mmol) in THF (5 mL) was added LDA (1.226 mL, 2.452 mmol, 2M in THF) dropwise at −78° C. and the resulting solution was stirred at the same temperature for 45 min. MeI (0.307 mL, 4.90 mmol) was then added at −78° C. and the reaction mixture was allowed to warmed to RT and stir for 12 h. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc (2×25 mL). The combined organic layer was dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (12 g REDISEP® column, eluting with 2% EtOAc in hexane.) Fractions containing the product were combined and evaporated to afford Intermediate 232B as a pale yellow liquid. (0.15 g, 55%). 1H NMR (300 MHz, DMSO-d6) δ ppm 4.07 (q, J=7.2 Hz, 2H), 2.01 (d, J=12.1 Hz, 2H), 1.92-1.74 (m, 2H), 1.73-1.53 (m, 4H), 1.31-1.20 (m, 2H), 1.11 (br. s., 4H), 1.03 (d, J=2.6 Hz, 6H).
Reaction SMILES: [CH2:1]([OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12].[OH-:15].[Na+]>>[C:1]([OH:15])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)CCCCCCCCCCO
Reactant: [OH-]
Agent: [Na+]
Product: CC(C)CCCCCCCCCC(=O)O
Temperature: 340 °C

Procedure:
180 kg of isotridecyl alcohol and 33.6 kg of NaOH were introduced into the 350 liter reactor and heated to 340° C. under a nitrogen pressure of 6 bar. The process was otherwise carried out as described in Example 1. The product obtained had an acid value of 240 and an OH value of 6.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH:12]C(=O)C)[NH:8][C:5]2=[N:6][CH:7]=1.Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH2:12])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)NCc1nc2cc(Br)cnc2[nH]1
Agent: Cl
Solvent: CCO
Product: NCc1nc2cc(Br)cnc2[nH]1
Temperature: 40 °C

Procedure:
2.03 g (7.54 mmol) of N-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)methylacetamide is combined with 30 mL of 6 molar hydrochloric acid solution in 15 mL of ethanol and heated to 40° C. for 2 hours. After cooling to ambient temperature, the mixture is extracted with dichloromethane, and the organic phase is extracted with 5% sodium hydrogen carbonate solution. The aqueous phase is concentrated in vacuo and the residue treated with diethyl ether. After the solvent has been eliminated in vacuo the residue is combined with 30 mL of 6 molar hydrochloric acid solution and heated to 50° C. for 16 hours. After elimination of the solvent, the residue is twice taken up in methanol and in each case concentrated in vacuo. The crystals formed are washed with methanol and dried at 50° C. Yield: 560 mg (28%; hydrochloride); Rf value: 0.15 (silica gel; dichloromethane/ethanol=9:1+2% ammonia solution); C7H7BrN4 x HCl (227.06/263.53); mass spectrum: (M−H)−=225/227 (bromine isotope).
Reaction SMILES: C([O:5][C:6](=[O:35])[C@@H:7]([NH:12][C:13]([C:15]1[CH:34]=[CH:33][C:18]2[N:19]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:20]([CH2:22][CH:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[N:21][C:17]=2[CH:16]=1)=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:29]([CH:28]([N:19]1[C:18]2[CH:33]=[CH:34][C:15]([C:13]([NH:12][C@@H:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:35])=[O:5])=[O:14])=[CH:16][C:17]=2[N:21]=[C:20]1[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][O:24]1)[CH2:31][CH3:32])[CH3:30]
Reactant: CCC(CC)n1c(CC2CCCO2)nc2cc(C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)n1c(CC2CCCO2)nc2cc(C(=O)N[C@@H](CC(C)C)C(=O)O)ccc21
Temperature: 25 °C
Yield: 34.7 %

Procedure:
75 mg of (S)-2-{[1-(1-Ethyl-propyl)-2-(tetrahydro-furan-2-ylmethyl)-1H-benzoimidazole-5-carbonyl]-amino}-4-methyl-pentanoic acid tert-butyl ester were dissolved in 0.6 ml dichloromethane and 0.18 μl of trifluoroacetic acid were added. After stirring at room temperature over night the reaction mixture was concentrated. The residue was dissolved in 1 M aqueous sodium hydroxide solution, and precipitated by addition of 2 M aqueous hydrochloric acid. The solid was taken up in ethyl acetate, dried over sodium sulphate and concentrated. The obtained residue was precipitated by addition of pentane. 23 mg (35%) of (S)-2-{[1-(1-Ethyl-propyl)-2-(tetrahydro-furan-2-ylmethyl)-1H-benzoimidazole-5-carbonyl]-amino}-4-methyl-pentanoic acid were obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](Br)=[CH:4][C:3]=1[CH3:10].C([O-])([O-])=O.[Na+].[Na+].[O:17]1[CH2:22][CH2:21]O[CH2:19][CH2:18]1>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:19]2[CH:21]=[CH:22][O:17][CH:18]=2)=[CH:4][C:3]=1[CH3:10]
Reactant: C1COCCO1
Reactant: Cc1cc(Br)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(-c2ccoc2)cc(C)c1Br
Temperature: 100 °C

Procedure:
A mixture of 2,5-dibromo-1,3-dimethylbenzene (2.00 g), 1-furan-3-ylboronic acid (856 mg), and 2 M aqueous Na2CO3 solution (11 mL) in 1,4-dioxane (40 mL) is purged with argon for 5 min. Tetrakis-triphenylphosphine-palladium-(0) (270 mg) is added and the mixture is stirred at 100° C. over night. More tetrakis-triphenylphosphine-palladium-(0) (50 mg) is added and the mixture is stirred for another 5 h at 100° C. After cooling to room temperature the mixture is diluted with ethyl acetate and aqueous NH4Cl solution. The aqueous phase is extracted with ethyl acetate and the combined extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 100:0→90:10) to give the title compound. LC (method 7): tR=1.22 min; Mass spectrum (EI+): m/z=250 [M]+.
Reaction SMILES: [Cl:1][C:2]1[C:7](S)=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]([Cl:11])[C:3]=1[Cl:12].[N+:13]([O-])([OH:15])=[O:14].ClC1C(Cl)=C(Cl)C(Cl)=C(Cl)C=1Cl>OS(O)(=O)=O.O=S(=O)=O>[C:7]1([N+:13]([O-:15])=[O:14])[C:2]([Cl:1])=[C:3]([Cl:12])[C:4]([Cl:11])=[C:5]([Cl:10])[C:6]=1[Cl:9]
Reactant: Sc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: O=[N+]([O-])O
Agent: Clc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=[N+]([O-])c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.5 %

Procedure:
Pentachlorothiophenol (10.0 g, 0.035 mol) was added to 60.0 g of 70% nitric acid at room temperature. The reaction mixture was heated at reflux 7 hr followed by stirring at room temperature 16 hr. At this point, 40 mL of 30% oleum (30% by weight sulfur trioxide in sulfuric acid) was added at such a rate that the temperature was maintained between 55° and 60° C. After the addition was complete (30 min), the reaction mixture was heated at 108° C. for 30 minutes. The reaction mixture was then cooled to room temperature, filtered, the product washed with water and dried in vacuo to give 7.6 g (74% yield) of 99.0% PCNB with 1.0% hexachlorobenzene (GC assay).
Reaction SMILES: FC(F)(F)C([CH:5]([NH2:22])[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)=O.[OH-].[Na+]>O1CCOCC1>[NH2:22][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:8][CH2:7]1
Reactant: NC(C(=O)C(F)(F)F)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: NCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
27.5 g (79.88 mmol) 4-(trifluoroacetyl-aminomethyl)-N(benzyloxycarbonyl)-piperidine are dissolved in 150 ml dioxane and 150 ml 1 N NaOH solution are added. The mixture is stirred for 3 hours at 40° C. and then the solvent is concentrated under vacuum. The residue is collected in water and extracted three times with DCM. The combined DCM phases are dried over Na2SO4 and then the solvent is concentrated under vacuum.
Reaction SMILES: Br[CH:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)[CH3:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[CH3:29][N:30]1[CH2:43][CH2:42][C:33]2[NH:34][C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][C:40]=3[C:32]=2[CH2:31]1>CN(C=O)C.[Cu]I>[CH3:29][N:30]1[CH2:43][CH2:42][C:33]2[N:34](/[CH:2]=[C:3](/[C:5]3[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=3)\[CH3:4])[C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][C:40]=3[C:32]=2[CH2:31]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CSc1ccc(C(C)=CBr)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CSc1ccc(/C(C)=C/n2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
(4-(1-Bromoprop-1-en-2-yl)phenyl) (methyl)sulfane (241 mg, 1 mmol) was dissolved in DMF (5 mL) and potassium phosphate (424 mg, 2 mmol) was added followed by copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol). 2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was added and the mixture purged with nitrogen for 2 min. The reaction mixture was stirred at 85° C. overnight. Water was added and the solid mass was filtered under vacuum. The crude compound was purified on silica gel (100-200 mesh) using 0-3% MeOH:DCM as eluent. Yield: 72 mg. 1H NMR (CD3OD, oxalate salt) δ (ppm): 7.59 (d, 2H), 7.30 (m, 3H), 7.10 (m, 2H), 7.0 (s, 1H), 4.60 (m, 2H), 3.70 (m, 2H), 3.28 (m, 2H), 3.10 (s, 3H), 2.54 (s, 3H), 2.42 (s, 3H), 1.96 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:24]([F:27])([F:26])[F:25])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:13])[CH:11]=2)[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:5](=[O:23])[NH:4]1.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1.O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>O.CN(C=O)C>[Br:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:5](=[O:23])[NH:4][C:3]2([CH2:2][NH:1][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=1)[C:24]([F:26])([F:27])[F:25]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COc1ccc(CN2C(=O)NC(CN)(C(F)(F)F)c3cc(Br)ccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C(=O)NC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of DMF (5 mL) containing 4-(aminomethyl)-6-bromo-1-(4-methoxybenzyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (710 mg, 1.60 mmol), 4-fluorobenzoic acid (246 mg, 1.76 mmol), hydroxybenzotriazole monohydrate (245 mg, 1.60 mmol) and triethylamine (0.22 mL, 1.6 mmol) at 0° C., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (368 mg, 1.9 mmol) was added little by little thereto. After the reaction solution was stirred overnight at room temperature, water was slowly added thereto under stirring. After a solid began to precipitate, further excess water was added thereto, and the mixture was stirred at room temperature for 2 hours. The solid was collected by filtration and washed with water and then dried under reduced pressure, whereby the objective compound (815 mg, 90%) was obtained as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH:14]=[O:15])[CH:13]=1)[N:10]([CH2:16][CH3:17])[CH2:9][CH2:8][C:7]2([CH3:19])[CH3:18])([CH3:3])[CH3:2].[CH3:20][Mg]Br>C1COCC1>[CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH:14]=[O:15])[CH:13]=1)[N:10]([CH2:16][CH2:17][CH3:20])[CH2:9][CH2:8][C:7]2([CH3:19])[CH3:18])([CH3:2])[CH3:3]
Reactant: C[Mg]Br
Reactant: CCN1CCC(C)(C)c2cc(C(C)C)cc(C=O)c21
Solvent: C1CCOC1
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(C=O)c21
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 6-isopropyl-4,4-dimethyl-1-ethyl-1,2,3,4-tetrahydro-quinoline-8-carbaldehyde (Intermediate 7, 2.00 g, 9.00 mmol) and 35 ml of anhydrous THF under argon at −78° C. was slowly added 3 M solution of methyl magnesium bromide in THF (7.5 ml, 22.5 mmol). The resulting solution was stirred at −78° C. for 45 minutes. The reaction was quenched with saturated NH4Cl and the product was extracted with diethyl ether. The organic extract was washed with water, and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography using 5% ethyl acetate in hexane to yield the title compound as light yellow oil.