Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)[Cl:14].[CH3:16][O:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25].CCCCCC>CCOC(C)=O>[CH3:16][O:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22]([Cl:14])=[CH:21][C:20]=1[NH:25][C:8](=[O:10])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:11]
Reactant: COC(=O)c1ccccc1N
Reactant: CC(C(=O)O)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1ccc(Cl)cc1NC(=O)C(C)c1ccccc1
Yield: 82.1 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-phenyl-propionic acid (2.00 g, 13.3 mmol), SOCl2 (2.88 mL, 40.0 mmol) and 2-amino benzoic acid methyl ester (1.72 g, 9.31 mmol). After normal workup, the pure objective compound (2.43 g, 82%) was obtained as a pale yellow syrup by a flash column chromatography (n-hexane:EtOAc=20:1): 1H-NMR (200 MHz, CDCl3) δ 1.61 (d, J=6.92 Hz, 3H, CH3), 3.72-3.85 (m, 4H, OCH3, CH), 6.95 (d, J=2.03 Hz, 1H, ArH), 6.99 (d, J=2.03 Hz, 1H, ArH), 7.24-7.45 (m, 5H, ArH), 7.84 (d, J=8.55 Hz, 1H, ArH), 8.84 (d, J=2.03 Hz, 1H, ArH), 11.15 (br s, 1H, NH).
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[CH2:13]([NH:15][CH:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]1)[CH3:14].[C@H:23]1([NH:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([NH2:43])[CH:39]=3)[N:34]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1>>[CH2:13]([N:15]([CH:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]1)[C:1]([NH:43][C:38]1[CH:39]=[C:40]2[C:35](=[CH:36][CH:37]=1)[N:34]=[C:33]([NH:32][C@H:23]1[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24]1)[CH:42]=[CH:41]2)=[O:12])[CH3:14]
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: CCNC1CCC(O)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CCN(C(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)C1CCC(O)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 4-ethylamino-cyclohexanol and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=445.7 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]([C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)[C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=2)=[O:7])=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.B(Br)(Br)Br.O.CCOC(C)=O>C(Cl)Cl>[F:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:7])=[C:4]([C:27]([F:28])([F:29])[F:30])[CH:3]=1
Reactant: COc1ccc(N(C(=O)c2ccc(F)cc2C(F)(F)F)c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc(F)cc1C(F)(F)F)N(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
Compound 4-fluoro-N,N-bis(4-methoxyphenyl)-2-(trifluoromethyl)benzamide (2e′) (1.00 g, 2.38 mmol) was dissolved in dry CH2Cl2 (30 mL) at room temperature. BBr3 (10 mL of 1.0 M CH2Cl2 solution, 10.0 mmol) was added dropwise with stifling via a syringe at room temperature. The reaction solution was allowed to stir overnight at room temperature. The mixture was cooled to 0° C. in an ice bath and hydrolyzed by adding water. EtOAc was added to partition the solution. The organic layer was separated; the aqueous layer was extracted with EtOAc twice. The organic layers were combined, washed with brine and dried over anhydrous MgSO4. The solvent was removed under vacuum. The residue was purified by flash column chromatography using silica-gel with CH3OH/CH2Cl2 (1/9 v/v) to afford the pure desired phenolic compound as a white solid, 0.86 g, 92.5% yield. 1H NMR (DMSO-d6, 300 MHz) δ 9.55 (s, 1H), 9.53 (s, 1H), 7.69-7.58 (m, 2H), 7.46-7.39 (m, 1H), 7.18 (d, 2H, J=8.7 Hz), 6.93 (d, 4H, J=8.7 Hz), 7.03 (d, 2H, J=8.4 Hz), 6.78 (d, 2H, J=8.7 Hz), 6.57 (d, 2H, J=8.7 Hz). MS m/z 392.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:10]([C:12]3[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH:13]=3)=[CH:11][C:3]=12.[F:32][C:33]1[CH:34]=[CH:35][C:36]([O:42][CH3:43])=[C:37](B(O)O)[CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.C(OCC)(=O)C>[F:8][C:7]1[C:2]([C:35]2[CH:34]=[C:33]([F:32])[CH:38]=[CH:37][C:36]=2[O:42][CH3:43])=[C:3]2[CH:11]=[C:10]([C:12]3[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH:13]=3)[N:9]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:4]2=[N:5][CH:6]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: CCOC(=O)C1CC=C(c2cc3c(Cl)c(F)cnc3n2S(=O)(=O)c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1CC=C(c2cc3c(-c4cc(F)ccc4OC)c(F)cnc3n2S(=O)(=O)c2ccccc2)CC1
Temperature: 75 °C

Procedure:
To a solution of Example 279A (1250 mg, 2.86 mmol) in 13.3 mL tetrahydrofuran/water (3:1) was added 5-fluoro-2-methoxyphenylboronic acid (1043 mg, 3.72 mmol), sodium carbonate (1214 mg, 11.45 mmol) and phenylallylchloro[1,3-bix(diisopropylphenyl)-2-imidazol-2-ylidene]palladium(II) (60.3 mg, 0.086 mmol) and the mixture was heated at 75° C. for 2 hours. The mixture was cooled to room temperature, and diluted with ethyl acetate, and the organics washed with saturated sodium bicarbonate, water, and brine, dried over magnesium sulfate, filtered, and concentrated. Purification by flash chromatography (Analogix280, SF 40-80 column, 10-60% ethyl acetate/hexane gradient) gave the title compound. MS (ESI): 553.1 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][N:7]([CH3:28])[CH2:8][C:9]1[C:13]2[CH:14]=[CH:15][C:16]([O:18][C:19]3[S:20][C:21]4[C:22]([N:27]=3)=[N:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][C:12]=2[O:11][CH:10]=1)C.[Li+].[OH-]>C1COCC1>[CH:4]([OH:29])=[O:3].[CH3:28][N:7]([CH2:8][C:9]1[C:13]2[CH:14]=[CH:15][C:16]([O:18][C:19]3[S:20][C:21]4[C:22]([N:27]=3)=[N:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][C:12]=2[O:11][CH:10]=1)[CH2:6][CH2:5][C:4]([OH:29])=[O:3]
Reactant: CCOC(=O)CCN(C)Cc1coc2cc(Oc3nc4ncccc4s3)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(CCC(=O)O)Cc1coc2cc(Oc3nc4ncccc4s3)ccc12
Product: O=CO
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 46.6 %

Procedure:
To a solution of 3-{methyl-[6-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-3-ylmethyl]-amino}-propionic acid ethyl ester (30 mg, 0.07 mmol) in THF (0.75 mL) was added 4 N LiOH (0.1 mL). The mixture was stirred (rt, 6.5 h). Purification by reverse phase HPLC provided the title compound as a white solid (7 mg, 21%). MS (ESI): mass calcd. for C19H17N3O4S, 383.09; m/z found, 384.9 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.49 (dd, J=4.9, 1.6, 1H), 8.32 (dd, J=8.0, 1.6, 1H), 8.15 (s, 1H), 7.97-7.92 (m, 1H), 7.80 (d, J=2.1, 1H), 7.44 (dd, J=8.6, 2.1, 1H), 7.38-7.32 (m, 1H), 4.48 (s, 2H), 3.35 (t, J=6.5, 2H), 2.80 (s, 3H), 2.66 (t, J=6.5, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:11][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)cccc1[N+](=O)[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(Cl)c1CBr
Temperature: 25 °C

Procedure:
To a solution of the 1-chloro-2-methyl-3-nitrobenzene (2.0 g, 11.66 mmol) in anhydrous carbon tetrachloride 50 mL, NBS (2.07 g, 11.66 mmol) and benzoyl peroxide (0.141 g, 0.583 mmol) was added. The reaction mixture was heated to reflux overnight. Then, the reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated to provide crude 2-(bromomethyl)-1-chloro-3-nitrobenzene, which was used for the next step without any further purification (2.93 g); 1H NMR (400 MHz, DMSO-d6): δ 4.77 (s, 2H), 7.60 (t, J=6.2, 8.2 Hz, 1H), 7.90 (d, J=8.2 Hz, 1H), 8.00 (d, J=8.2 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[CH:12]12[NH:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][CH:14]([OH:20])[CH2:13]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C.ClCCl>[Br:1][C:2]1[C:10]2[C:9]([N:19]3[CH:12]4[CH2:18][CH2:17][CH:16]3[CH2:15][CH:14]([OH:20])[CH2:13]4)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: Clc1ncnc2scc(Br)c12
Reactant: OC1CC2CCC(C1)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: OC1CC2CCC(C1)N2c1ncnc2scc(Br)c12
Yield: 100 %

Procedure:
5-Bromo-4-chlorothieno[2,3-d]pyrimidine (2.11 g, 8.5 mmol) in dry acetonitrile (100 mL) was treated with 8-azabicyclo[3.2.1]octan3-ol (1.34 g, 10.6 mmol) and potassium carbonate (3.519 g, 25.5 mmol) and stirred and heated at reflux for 4 h. The reaction was diluted with ethyl acetate (200 mL) and dichloromethane (100 mL) and washed with water (100 mL). The organic layer was separated, dried over sodium sulphate and concentrated in vacuum to give 8-(5-bromothieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-ol as a yellow solid (2.890 g, 8.5 mmol, 100%). This was used directly in the next step without further purification. 1H NMR (CDCl3) δ: 1.83 (2H, d, J=12 Hz), 2.0 (2H, br s) 2.28 (2H, d, J=6 Hz), 2.45 (2H, d, J=8 Hz), 4.15 (1H, br s), 4.7 (2H, br s), 7.35 (1H, s), 8.45 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:40]#[C:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[C:44]([F:50])[CH:43]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:40]#[C:41][C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[C:44]([F:50])[CH:43]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: COc1ccc(C#CBr)cc1F
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: COc1ccc(C#Cn2c3c(c4cc(Cl)ccc42)CCN(C)CC3)cc1F
Temperature: 80 °C

Procedure:
9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.42 mmol), CuSO4.5H2O (21 mg, 0.085 mmol), 1,10-Phenanthroline (30 mg, 0.17 mmol) and K3PO4 (180 mg, 0.85 mmol) and 4-(bromoethynyl)-2-fluoro-1-methoxybenzene (131 mg, 0.46 mmol) in toluene (5 mL) were charged and flushed with nitrogen. The reaction mixture was heated at 80° C. for 16 h. The reaction was monitored by LCMS. The reaction mixture was filtered through Celite, washed with DCM. The organic layer was concentrated and purified by column chromatography (100-200 mesh size silica gel, 60-80% ethyl acetate in hexane) to get 9-chloro-6-((3-fluoro-4-methoxyphenyl)ethynyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole which was further purified by prep TLC to get 24 mg of product. 1HNMR (CDCl3, freebase) δ (ppm): 7.40 (d, 2H), 7.30 (m, 2H), 7.20 (d, 1H), 6.95 (t, 1H), 3.90 (s, 3H), 3.10 (m, 2H), 2.90 (m, 6H), 2.50 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1.C([BH3-])#[N:18].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:18])[CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: C[C@H](c1ccc(Br)cc1)N1CCC(=O)CC1
Agent: [Na+]
Product: C[C@H](c1ccc(Br)cc1)N1CCC(N)CC1
Yield: 106.5 %

Procedure:
Prepared following the general method of Example 370 step (i) (R)-1-[1-(4-bromophenyl)ethyl]-4-piperidinone (420 mg) ammonium acetate (0.80 g) and sodium cyanoborohydride (120 mg) to give the subtitle compound (449 mg).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([CH:11]2[NH:15][CH:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:23][C:24]1[CH:25]=[C:26]([NH:30][C:31](=[O:37])[NH:32][CH2:33][C:34](O)=[O:35])[CH:27]=[CH:28][CH:29]=1.C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:23][C:24]1[CH:25]=[C:26]([NH:30][C:31](=[O:37])[NH:32][CH2:33][C:34]([N:15]2[CH:11]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:12][CH2:13][CH:14]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:35])[CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CCC2c2ccccc2)c1
Yield: 18.3 %

Procedure:
0.9 cm3 of sulphinyl chloride is added slowly to a suspension of 3.1 g of tert-butyl (2RS,5SR)-5-phenylprolinate and 2.6 g of 2-[3-(3-methylphenyl)ureido]acetic acid in 100 cm3 of anhydrous 1,2-dichloroethane heated to reflux. The reaction mixture is then heated under reflux for 15 minutes, then cooled to 50° C. and neutralized to a pH of 7-8 by addition of a 10% aqueous sodium bicarbonate solution. The organic phase is washed with 3 times 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. The crude product obtained is purified by chromatography on silica [eluent: dichloromethane/methanol (98/2 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at a temperature in the vicinity of 45° C. After recrystallization in acetonitrile, 1 g of tert-butyl (2RS,5SR)-1-{2-[3-(3-methylphenyl)ureido]acetyl}-5-phenylprolinate, melting at 156° C., is obtained.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([O:11][CH:8]2[CH2:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:9]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CC(C)(C)C1CCC(O)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCC(C(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Into a one liter, four-necked, round bottom flask equipped with stirrer, condenser, and thermometer, 200.0 parts of pyridine and 31.75 parts of 4-t-butylcyclohexanol were mixed under a nitrogen blanket and chilled to 0° C. with an ice water bath. To this solution 47.75 parts of p-toluenesulfonyl chloride were added in portions over thirty minutes. The solution was stirred for one hour at 0° C. and then allowed to stand for twenty-four hours at 15° C. The mixture was poured into one liter of ice water and subsequently extracted with 700 parts of methylene chloride. The organic layer was washed successively with cold 6 N sulfuric acid (until the water layer was acidic to pH paper), dilute sodium bicarbonate (three times with 500 part-portions), and water (twice with 500 part-portions). It was then dried over sodium sulfate, filtered, and the solvent removed in vacuo to yield the 4-t-butylcyclohexyl para-toluenesulfonate as a pale yellow liquid which solidified on standing.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][N:5]1[C:29](=[O:30])[N:8]2[CH:9]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[C:10]3[NH:11][C:12]4[C:17]([C:18]=3[CH2:19][C:7]2([CH3:31])[C:6]1=[O:32])=[CH:16][C:15]([O:20]C)=[CH:14][CH:13]=4.C(=O)(O)[O-].[Na+]>ClCCl>[NH3:2].[CH3:33][N:2]([CH3:1])[CH2:3][CH2:4][N:5]1[C:29](=[O:30])[N:8]2[CH:9]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[C:10]3[NH:11][C:12]4[C:17]([C:18]=3[CH2:19][C:7]2([CH3:31])[C:6]1=[O:32])=[CH:16][C:15]([OH:20])=[CH:14][CH:13]=4
Reactant: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCN(C)C)C(=O)N1C3c1cccc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)CCN1C(=O)N2C(c3cccc(O)c3)c3[nH]c4ccc(O)cc4c3CC2(C)C1=O
Product: N
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
A solution of 150 mg (3aSR,10RS)-2-(2-dimethylamino-ethyl)-10-(3-hydroxy-phenyl)-6-methoxy-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]fluorene-1,3-dione (example 7) in 5 ml dichloromethane is cooled to −78° C. 20 ml bor tribromide are added drop wise. The suspension is stirred for 30 min at −78° C. and allowed to warm up to room temperature. After stirring for 1 h at room temperature, the mixture is cooled to 0° C. and an aqueous solution of sodium bicarbonate is added. The organic layer is separated and dried with magnesium sulfate. The solvent is removed at reduced pressure. After column chromatography (silica gel, ethyl acetate, methanol, ammonia 10:0.3:0.2), 49 mg of the title compound are obtained as a colourless foam. MS: m/z (MH+)=435.2
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:3]1=[O:24].[C:25]([O:29][C:30]([NH:32][C@H:33]([CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([CH:47]([CH3:49])[CH3:48])[CH:39]=1)[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH:47]([N:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38]([CH2:37][C@@H:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:26])([CH3:28])[CH3:27])[C:34](=[O:35])[NH:1][CH:2]2[CH2:11][C:10]3[C:5](=[C:6]([N:12]4[CH2:16][CH2:15][CH2:14][C:13]4=[O:17])[CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:18][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[C:3]2=[O:24])=[CH:39]1)([CH3:49])[CH3:48]
Reactant: NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Reactant: CC(C)n1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Product: CC(C)n1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC2Cc3cccc(N4CCCC4=O)c3N(Cc3ccsc3)C2=O)c2ccccc21
Yield: 114.2 %

Procedure:
The procedure of Example 14(a) was repeated, except that (−)-3-amino-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-3,4-dihydroquinolin-2(1H)-one (500 mg) and (R)-2-(tert-butoxycarbonylamino)-3-(1-isopropyl-1H-indol-3-yl)propanoic acid (609 mg) synthesized in Referential Example 1(e) were used, whereby the title compound (1.12 g) was yielded.
Reaction SMILES: C[O:2][C:3](=[O:37])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:36])(=[O:35])[NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].[Li+].[OH-].CO>C1COCC1.O>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=1[C:6]([NH:5][C@H:4]([C:3]([OH:37])=[O:2])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:36])(=[O:35])[NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:21][CH:22]=1)=[O:15]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
N-(2,6-Dichlorobenzoyl)-4-[2-[N-(tert-butyl)sulfamoyl]phenyl]-L-phenylalanine methyl ester (75 mg) was dissolved in THF (5 mL) and to this solution was added a solution of LiOH (monohydrate, 10 mg) in water (0.4 mL). Few drops of MeOH were added and the mixture was stirred at room temperature overnight. The mixture was evaporated, water was added to the residue and the mixture was acidified with 10% citric acid. The separated solid was collected by filtration, washed with water and dried to give 60 mg of the title compound. ESMS: m/z 549 (MH+), 547 ((M−H]−).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:17]3[CH:22]=[CH:21][N:20]=[N:19][CH:18]=3)=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[CH:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:25])[CH3:24].Cl>C(O)CCCC>[C:11]1([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([N:29]4[CH2:30][CH2:31][N:26]([CH:23]([CH3:25])[CH3:24])[CH2:27][CH2:28]4)=[N:7][N:6]3[C:8]=2[C:17]2[CH:22]=[CH:21][N:20]=[N:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ccc2nc(-c3ccccc3)c(-c3ccnnc3)n2n1
Reactant: CC(C)N1CCNCC1
Agent: Cl
Solvent: CCCCCO
Product: CC(C)N1CCN(c2ccc3nc(-c4ccccc4)c(-c4ccnnc4)n3n2)CC1
Temperature: 150 °C
Yield: 83.4 %

Procedure:
The mixture of 0.45 g (1.5 mmol) of 6-chloro-2-phenyl-3-(pyridazin-4-yl)imidazo[1,2-b]pyridazine and 0.38 g (2.9 mmol) of 1-isopropylpiperazine in 6 ml of pentanol is heated in a sealed tube at 150° C. for 2 days. The mixture is cooled and poured into a 1N aqueous solution of hydrochloric acid. This solution is washed with diethyl ether and then basified using an aqueous solution of sodium hydroxide. The product is finally extracted with dichloromethane, and the organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. A brown oil is obtained, which is chromatographed on silica gel, elution being carried out with a mixture of aqueous ammonia, methanol and dichloromethane (0.4/4/96), to give 0.50 g of a solid.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Mg]Br)C.[Cl:21][C:22]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25].O>C1COCC1>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:14][C:24](=[NH:25])[C:23]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:22]=2[Cl:21])=[CH:15][CH:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: N#Cc1ccc(Cl)cc1Cl
Agent: CC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: N=C(Nc1ccc(OCc2ccccc2)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.8 %

Procedure:
4-Benzyloxyaniline hydrochloride (5.0 g, 21.2 mmol) was dropwise added to a solution of ethylmagnesium bromide (44.5 ml, 1M in THF, 44.5 mmol) in 25 ml dry TIHF under nitrogen atmosphere. After stirring for 20 minutes a solution of 2,4-dichlorobenzonitrile (3.65 g, 21.2 mmol) in 25 ml THF was added. The reaction mixture was stirred for 20 hours at room temperature. Water (50 ml) was carefully added. Extraction with EtOAc (2×100 ml), drying (Na2SO4), filtration and evaporation to dryness afforded 7.7 g (98%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([O:30][CH3:31])[CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=3)[N:3]=2)=[C:23]([O:30][CH3:31])[CH:22]=1
Reactant: COc1cc(F)ccc1B(O)O
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: COc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Example 3 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and (4-fluoro-2-methoxyphenyl)boronic acid (Aldrich Chemical Company Inc.). The batch was purified by preparative HPLC:
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]1=O.[BH4-].[Na+].Cl>C1COCC1.CO>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC1Cc2c(cccc2-c2ccccc2)C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1=Cc2cccc(-c3ccccc3)c2C1
Yield: 90090.4 %

Procedure:
50 g (0.226 mmol) of 2 were dissolved in 450 cm3 of THF/MeOH (2:1), and 12.8 g (0.34 mol) of sodium borohydride were added in portions at 0° C. with stirring. The reaction mixture was stirred for a further 18 hours and poured into ice, concentrated HCl was added to pH 1 and the mixture was extracted a number of times with Et2O. The combined organic phases were washed with saturated aqueous NaHCO3 solution and NaCl solution and then dried (MgSO4). The solvent was removed in vacuo, and the crude product, without further purification, was taken up in 1 dm3 of toluene, 2 g of p-toluene sulfonic acid were added, and the mixture was refluxed for 2 hours. The reaction mixture was washed with 200 cm3 of saturated aqueous NaHCO3 solution, and the solvent was removed in vacuo. The crude product was purified by filtration through 500 g of silica gel (hexane/CH2Cl2), giving 42 g (90%) of 3 as a colorless oil.