Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[NH2:12][CH2:13][CH2:14][OH:15]>C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:12][CH2:13][CH2:14][OH:15])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: NCCO
Solvent: CCCCO
Product: O=[N+]([O-])c1cc(Br)ccc1NCCO
Reaction time: 8 h
Yield: 101 %

Procedure:
A mixture of 4-bromo-1-fluoro-2-nitrobenzene (I-9, Aldrich, Wis.; 25 g, 0.11 mol) and 2-aminoethanol (13.9 g, 0.23 mol, 2.0 eq.) in n-butanol (300 mL) was heated under reflux for 1 hour. The reaction mixture was concentrated and the residue was dispersed in petrol ether (600 mL) and stirred overnight. The solids were iltered to give I-10 as a yellow powder (29 g, 98%). MS (ESI): m/z 262 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[C:7](=[O:8])[N:6]2[CH:9]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:10](=[O:16])[N:11]([CH:13]([CH3:15])[CH3:14])[CH2:12][CH:5]2[N:4]([S:25]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])(=[O:27])=[O:26])[CH2:3]1.[CH3:37][C:38]([CH3:40])=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.C1COCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH:9]2[N:6]3[C:7](=[O:8])[CH:2]([NH:1][CH:38]([CH3:40])[CH3:37])[CH2:3][N:4]([S:25]([C:28]4[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=4[O:35][CH3:36])(=[O:27])=[O:26])[CH:5]3[CH2:12][N:11]([CH:13]([CH3:14])[CH3:15])[C:10]2=[O:16])=[CH:19][CH:20]=1
Reactant: CC(C)=O
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CC(N)C(=O)N2C(Cc3ccc(Cl)cc3)C(=O)N(C(C)C)CC21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CC(NC(C)C)C(=O)N2C(Cc3ccc(Cl)cc3)C(=O)N(C(C)C)CC21
Reaction time: 3 h

Procedure:
50 mg of 6-(4-chlorobenzyl)-1-(2-methoxy-5-chlorobenzenesulfonyl)-3-amino-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione (Example 1) were dissolved in ml of methanol, and 200 μl of acetic acid were added. 400 μl of acetone and 1 ml of 1M sodium cyanoborohydride solution in THF were added to this solution. After 3 hours, the reaction mixture was evaporated, suspended in 5% Et3N in ethyl acetate and filtered through a small silica gel column. The eluent was evaporated, and the crude substance was dissolved in a mixture of acetonitrile and water and freeze dried. The pure title compound was removed after purification by HPLC. The system and process described under “general processes” was used for this. MW=596.16 (calculated, monoisotopic); measured value (M+H)+: 597.3.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:13]4[C:20]([C:21]([OH:23])=O)=[CH:19][NH:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:10][C:4]=2[S:3]1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.C(N(C(C)C)C(C)C)C.[OH-].[Na+]>O.CN(C)C=O>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:21]([C:20]2[C:13]3[C:12]([NH:11][C:9]4[CH:8]=[CH:7][C:5]5[NH:6][C:2](=[O:1])[S:3][C:4]=5[CH:10]=4)=[N:17][CH:16]=[N:15][C:14]=3[NH:18][CH:19]=2)=[O:23])[CH2:27][CH2:26]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1c[nH]c2ncnc(Nc3ccc4[nH]c(=O)sc4c3)c12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)c2c[nH]c3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)CC1
Yield: 46.7 %

Procedure:
A mixture comprising 18.7 mg (57 μmol) 4-[(2-Oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (prepared according to example 3), 0.64 mL N,N-dimethylformamide, 57.2 mg 1-methylpiperazine, 136 μL 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide solution (50% in ethyl acetate) and 29.9 μL N-ethyl-N-isopropylpropan-2-amine was stirred at 23° C. for 2 days. Water was added, the solution was neutralized by addition of sodium hydroxide solution, the solvents were removed and the residue purified by chromatography to give 10.9 mg (44%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12](=[O:19])[CH2:13][C:14](OCC)=[O:15])[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12]2[O:19][NH:30][C:14](=[O:15])[CH:13]=2)[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(F)c(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 32.3 %

Procedure:
Trans-methyl 2-(3,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.278 g, 0.73 mmol) (from example 120, step 1) was dissolved in MeOH (3 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.029 g, 0.73 mmol) dissolved in water (0.300 mL) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.044 mL, 0.73 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h 15 min. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (4 mL, 24.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow semi-solid. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Trans-methyl 2-(3,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (83 mg, 34%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.47-2.14 (m, 4H), 2.71-3.14 (m, 4H), 3.43-3.75 (m, 3H), 4.01-4.78 (m, 2H), 5.65 (s, 1H), 6.78-7.14 (m, 3H). MS m/z 353 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:19]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH:17]=[CH:16][C:12]=2[C:13]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(-c3ccc(F)cc3)ccc2C(=O)O)cc1OC
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(-c3ccc(F)cc3)ccc2C(=O)N2CCOCC2)cc1OC
Temperature: 20 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
2-(3,4-Dimethoxyphenyl)-4-(4-fluorophenyl)benzoic acid (compound 204 1.6 g; 0.00454 mole), tetrahydrofuran (50 ml) and diimidazolecarbonyl (0.92 g; 0.0057 mole) are introduced into a 100 ml flask. The mixture is stirred at 20° C. for 2 hours. Morpholine (1 ml; 0.0113 mole) is then added and the mixture is maintained under stirring for six hours. The reaction mixture is poured into distilled water (150 ml) and the precipitate is filtered, washed with water (100 ml) and then dried in the air. 2-(3,4-Dimethoxyphenyl)-4-(4-fluorophenyl)-1-morpholinocarbonylbenzene (1.3 g; yield: 68.4%) is thus obtained in the form of a white solid of m.p. 153° C. (compound 201).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[NH2:13].CCOC(C)=O>OS(O)(=O)=O>[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[NH2:13]
Reactant: Nc1ccc(F)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: Nc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 31.9 %

Procedure:
Concentrated nitric acid (8.8 g, 91 mmol) was added drop wise over 30 min to a stirred solution of 2-chloro-4-fluoro-phenylamine (12 g, 82.3 mmol) in conc H2SO4 acid (100 mL) at −10° C. The mixture was stirred at that temperature for 10 min. Then the reaction mixture was poured into cooled EtOAc, and ice water was added. The organic layer was separated and washed with brine and saturated NaHCO3 solution, dried (MgSO4) and concentrated in vacuo. Recrystallization (ethyl ether) provided 2-chloro-4-fluoro-5-nitroaniline (5.0 g, 32% yield). 1H NMR (400 MHz, DMSO-d6): δ7.59 (d, J=11.2 Hz, 1 H), 7.48 (d, J=7.2 Hz, 1 H), 5.84 (s, 2 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH3:10])[C:3]=1[Cl:11].C([Li])CCC.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C.C(Cl)(=O)C>C(OCC)C>[Cl:11][C:3]1[C:4]([O:9][CH3:10])=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[B:21]([OH:22])[OH:20]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1c(Cl)ccc(Br)c1Cl
Agent: [Li]CCCC
Solvent: CC(=O)Cl
Solvent: CCOCC
Product: COc1c(Cl)ccc(B(O)O)c1Cl
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of 1-bromo-2,4-dichloro-3-methoxybenzene (5.12 g, 20 mmol) in diethyl ether cooled to −70° C. was added 2.5M n-butyl lithium (8.8 mL, 22 mmol) in portions keeping the temperature below −60° C. The resulting reaction mixture was then stirred for 10 minutes before triisopropylborate (6.9 mL, 30 mmol) was added in portions keeping the temperature below −60° C. The reaction mixture was then allowed to warm to room temperature and acetyl chloride (60 mmol) was added. The reaction mixture was stirred for an hour at room temperature and concentrated. The residue was partitioned between ethyl acetate and 1N NaOH (40 mL) and the organic phase was extracted with additional 1N NaOH (10 mL). The sodium hydroxide extracts were combined, ice was added, and the solution was acidified to pH 3-4 with concentrated HCl. The product was then extracted with ethyl acetate and the organic phase was dried and concentrated to yield 2,4-dichloro-3-methoxyphenylboronic acid (3.27 g, 14.8 mmol): 1H NMR (CDCl3): δ 8.44 (br s, 2H), 7.42 (d, 1H), 7.15 (d, 1H), 3.8 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]([NH:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=3)[N:12]=2)=[CH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].O.Cl>CC(C)=O>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:20])([F:21])[F:22])[N:14]=[C:13]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)[N:12]=2)=[CH:34][CH:35]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(CNc2nc(Nc3ccc(C(=O)OC)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(CNc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 115 °C
Yield: 95.1 %

Procedure:
A mixture of methyl 4-(4-(4-(methoxycarbonyl)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (2.9 g) and K2CO3 (3.26 g) in acetone (20 mL)/water (20.00 mL) was heated at 115° C. for 24 hours. After cooling to room temperature, the mixture was acidified with 1 N HCl to pH=3. The white precipitate was collected, washed with water and dried under vacuum to give 4-(4-(4-carboxybenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (2.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Na].Cl.Cl[CH2:12][C:13](=[N:15][OH:16])[NH2:14]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:12][C:13](=[N:15][OH:16])[NH2:14]
Reactant: Nc1ccccc1S
Reactant: NC(CCl)=NO
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: NC(CSc1ccccc1N)=NO
Reaction time: 0.17 h

Procedure:
2-Aminobenzenethiol (3.75 g, 0.03 mol) was added to a solution of sodium (0,06 mol, 1.38 g) in ethanol (50 ml). Solid chloroacetamidoxime hydrochloride (4.35 g, 0.03 mol) was added in one portion. After stirring for 10 minutes the reaction mixture was filtered and the filtrate evaporated to dryness to give the crude product which was re-crystallised from iso-propanol to give 2-(2-aminophenylthio) acetamidoxime, m.p. 80°.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]([CH2:16][OH:17])([CH2:14][OH:15])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]12(CS(O)(=O)=O)C(C)(C)C(C[CH2:24]1)C[C:19]2=O.C(N(CC)CC)C>CC(C)=O>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1([CH2:14][OH:15])[CH2:16][O:17][C:18]([CH3:24])([CH3:19])[O:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: OCC(CO)(CO)CCOCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC1(C)OCC(CO)(CCOCc2ccccc2)CO1
Yield: 164 %

Procedure:
543 mg of the crude 4-benzyloxy-2,2-dihydroxymethylbutanol product was dissolved in 3 mL of acetone, 232 mg (1.0 mmol equivalents) of 10-camphorsulfonic acid was added thereto, and a reaction was carried out at room temperature (25° C.) overnight. After completion of the reaction, triethylamine was added dropwise, and the mixture was concentrated under vacuum. The crude product thus obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=4/1) to give 459 mg (1.64 mmol equivalents) of 5-benzyloxyethyl-2,2-dimethyl-5-hydroxymethyl-1,3-dioxane.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[N+:16]([O-])([OH:18])=[O:17].O.[K+].[Br-]>C(O)(=O)C>[OH:1][C:2]1[C:11]([N+:16]([O-:18])=[O:17])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(O)c(C(=O)OC)c1
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(C(=O)OC)c(O)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 88 %

Procedure:
Into a 250 mL three-necked round-bottom flask equipped with a magnetic stirrer, a condenser, and nitrogen inlet, dimethyl 4-hydroxyisophthalate (15.0 g, 71.4 mmol) was dissolved in acetic acid (150 mL). Nitric acid (10 ml) was then added dropwise. The mixture was warmed at 60° C. for 12 h. Then, the cool mixture was poured into water. The light yellow precipitate was collected, air-dried and recrystallized from ethanol to give 16.0 g (88% yield) of light yellow crystals: mp=74-76° C. Anal. Calcd. for C10H9NO7: C, 47.07%; H, 3.55%; N, 5.49%; O, 43.89%. Found: C, 47.75%; H, 4.01%; N, 5.44%; O, 43.51%: FT-IR (KBr, cm−1): 3076, 2992, 1722, 1690. Mass spectrum (m/e): 255 (M+, 100% relative abundance), 241, 237. 1H-NMR (DMSO-d6, ppm) δ 3.89 (s, 3H, CH3), 3.97 (s, 3H, CH3), 8.46-8.47 (d, 1H, Ar), 8.55-8.56 (d, 1H, Ar). 13C-NMR (CDCl3, ppm) δ 52.72, 53.38, 117.60, 120.19, 130.61, 135.31, 138.50, 156.13, 163.70, 166.87.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][C:48]1[CH:49]=[C:50]2[C:55](=[CH:56][CH:57]=1)[NH:54][CH2:53][CH2:52][CH2:51]2>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:54]4[C:55]5[C:50](=[CH:49][C:48]([CH3:47])=[CH:57][CH:56]=5)[CH2:51][CH2:52][CH2:53]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: Cc1ccc2c(c1)CCCN2
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCCc3cc(C)ccc32)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 6-methyl-1,2,3,4-tetrahydroquinoline (Alfa) to give the title product. LC-MS (ES+) 794 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[N:7]([CH2:27][CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([N:38]=[C:39]=[O:40])[CH:36]=2)[NH:31][C:30]=1[C:41]1[CH:46]=[C:45]([CH3:47])[CH:44]=[C:43]([CH3:48])[CH:42]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([S:19]([CH3:22])(=[O:21])=[O:20])[C:13]=1[S:23]([CH3:26])(=[O:25])=[O:24])([CH3:4])([CH3:3])[CH3:2].[N:50]([CH2:53][C:54]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=O)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:1]([O:5][C:6](=[O:49])[N:7]([CH2:27][CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([NH:38][C:39]3[O:40][C:54]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[CH:53][N:50]=3)[CH:36]=2)[NH:31][C:30]=1[C:41]1[CH:42]=[C:43]([CH3:48])[CH:44]=[C:45]([CH3:47])[CH:46]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([S:19]([CH3:22])(=[O:21])=[O:20])[C:13]=1[S:23]([CH3:26])(=[O:25])=[O:24])([CH3:3])([CH3:2])[CH3:4]
Reactant: [N-]=[N+]=NCC(=O)c1ccccc1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(N=C=O)cc3c2CCN(CCCCc2ccc(N)c(S(C)(=O)=O)c2S(C)(=O)=O)C(=O)OC(C)(C)C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(Nc4ncc(-c5ccccc5)o4)cc3c2CCN(CCCCc2ccc(N)c(S(C)(=O)=O)c2S(C)(=O)=O)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.2 %

Procedure:
To a solution of {2-[2-(3,5-dimethylphenyl)-5-isocyanato-1H-indol-3-yl]ethyl}-[4-(4-amino(dimethanesulfonyl)phenyl)butyl] carbamic acid tert-butyl ester (30 mg in 0.50 mL dry methylene chloride) was added 9 mg of 2-azido-1-phenyl-ethanone followed by 14 mg triphenylphosphine and the mixture stirred at room temperature. After 4 hours, the mixture was applied to a silica gel column for purification by flash chromatography (hexane:ethyl acetate, 3:2; then 1:1; then 2:3; then 1:3) to give the title compound (13 mg).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@@H:16]([NH2:20])([CH2:18][CH3:19])[CH3:17].C([BH3-])#N.[Na+]>CO>[C@@H:16]([NH:20][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)([CH2:18][CH3:19])[CH3:17]
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: CC[C@H](C)N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC[C@H](C)NCc1ccc(Oc2ccccc2)cc1
Reaction time: 18 h
Yield: 69.2 %

Procedure:
4-Phenoxybenzaldehyde (8.13 g, 41 mmol) and (S)-sec-butylamine (3 g, 41 mmol) were dissolved in methanol (137 mL) under a nitrogen at room temperature. Sodium cyanoborohydride (2.58 g) was added, and stirring was continued for 18 hours. The solvent was removed, and the residue was suspended in ether, washed with brine and dried over Na2SO4. The ether was evaporated, and the crude product was chromatographed on silica gel eluting with 3% methanol in methylene chloride to provide 7.24 g (77%) of the title compound as a colorless oil.
Reaction SMILES: O=[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][C:4]2[CH:12]=[N:13][NH:14][C:3]1=2.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[CH:12]=[N:13][NH:14][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1c2c([nH]c3cn[nH]c13)CCCC2
Product: Clc1c2c(nc3cn[nH]c13)CCCC2
Yield: 88 %

Procedure:
4,5,6,7,8,9-Hexahydro-9-oxo-1H-pyrazolo[4,3-b]quinoline (5.0 g, 0.026 mole) was treated with phosphoryl chloride (40 ml) and the mixture heated under reflux for 30 minutes. The excess reagent was evaporated off and the residue treated with water (30 ml) and then made basic by the addition of sodium carbonate solution. The solid was filtered off, washed with water, dried and recrystallised from ethyl acetate to give the title compound as a yellow solid (4.85 g, 88%), m.p. 190°-193° C. Found: C, 57.85; H, 4.95; N, 20.00; Cl, 16.95% C10H10ClN3 requires C, 57.85; H, 4.85; N, 20.25; Cl, 17.20%
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][C:3]1([C:11]([CH3:13])=[CH2:12])[CH:9]=[O:10].[CH2:14]([Mg]Cl)[CH:15]=[CH2:16]>>[CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][C:3]1([CH:9]([OH:10])[CH2:16][CH:15]=[CH2:14])[C:11]([CH3:13])=[CH2:12]
Reactant: C=C(C)C1(C=O)CCC(C)=CC1C
Reactant: C=CC[Mg]Cl
Product: C=CCC(O)C1(C(=C)C)CCC(C)=CC1C

Procedure:
In analogy to Example 3,1-(2,4-dimethyl-1-(prop-1-en-2-yl)cyclohex-3-enyl)but-3-en-1-ol (91% yield) was prepared starting from 2,4-dimethyl-1-(prop-1-en-2-yl)cyclohex-3-enecarbaldehyde and allylmagnesium chloride
Reaction SMILES: CS[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.ClCl.[C:15](Cl)([Cl:18])([Cl:17])[Cl:16]>>[Cl:16][C:15]([Cl:18])([Cl:17])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CSc1cccc2ccccc12
Reactant: ClC(Cl)(Cl)Cl
Agent: ClCl
Product: ClC(Cl)(Cl)c1cccc2ccccc12

Procedure:
100 g of 1-naphthyl methyl sulphide are dissolved in 250 ml of carbon tetrachloride. Chlorine is introduced into the solution at 75° to 80° C., until the solution is saturated. The solvent and the resulting sulphur chloride are then distilled off. 30 g of 1-trichloromethylnaphthalene of boiling point 124° to 128° C./0.3 mm are obtained, after fractional distillation, from the reaction product which remains as a residue.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][O:12][CH3:13].C([Mg]Br)(C)C.C([O:21][C:22](=O)[C:23]([F:26])([F:25])[F:24])C>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:22](=[O:21])[C:23]([F:26])([F:25])[F:24])=[C:3]([O:9][CH2:10][CH2:11][O:12][CH3:13])[CH:4]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: COCCOc1cc(Cl)ccc1Br
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: COCCOc1cc(Cl)ccc1C(=O)C(F)(F)F
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
1-Bromo-4-chloro-2-(2-methoxy-ethoxy)-benzene (CAS#1245563-20-5) (5.00 g, 18.8 mmol) was dissolved in THF (30 mL) and cooled to 0° C. i-Propylmagnesium bromide (11.3 mL, 2.0 M in THF, 22.6 mmol) was added dropwise, and the reaction was stirred at 10° C. for 30 min, then warmed to RT for 16 h. The reaction was then cooled to −15° C. and trifluoroacetic acid ethyl ester (3.37 mL, 28.2 mmol) was added. The reaction was stirred at 10° C. for 1 h. The reaction was quenched with HCl (2 N, 38 mL) at 0° C. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, then concentrated in vacuo. Purification by normal phase silica gel column chromatography (EtOAc/heptane) provided 1-(4-chloro-2-(2-methoxyethoxy)phenyl)-2,2,2-trifluoroethanone.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=O>C(O)(=O)C.[Pd]>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH2:7]2
Reactant: COc1cc2c(c(Cl)c1Cl)CCCC2=O
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc2c(c(Cl)c1Cl)CCCC2
Yield: 91.9 %

Procedure:
5,6-Dichloro-7-methoxy-1-tetralone (20 g., 0.08 mole) dissolved in acetic acid (300 ml.) is hydrogenated over 5% palladium on carbon (12 g.). The catalyst is removed and washed well with acetic acid. The combined acetic acid fractions are evaporated to dryness and the residue is crystallized from hexane to obtain 5,6-dichloro-7-methoxytetralin (17 g.), melting point 67°-68.5° C.