Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)[C@H]1O[C@H:6]([O:8][C@:9]2(CO)[O:13][C@H:12](CO)[C@@H:11]([OH:16])[C@@H:10]2O)[C@H:5](O)[C@@H](O)[C@@H]1O.[CH3:24][C@H:25]([C@@H](O)C)C(OCC)=O.C[C@@H]([C@@H](O)C)C(OCC)=O>O.C(O)C.S(=O)(=O)(O)O.OP(O)=O.O[Mo](O)(=O)=O>[CH2:24]([C@H:10]([C@@H:11]([OH:16])[CH3:12])[C:9]([O:8][CH2:6][CH3:5])=[O:13])[CH3:25]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reactant: CCOC(=O)[C@H](C)[C@H](C)O
Agent: O=[Mo](=O)(O)O
Agent: CCOC(=O)[C@@H](C)[C@H](C)O
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@H](CC)[C@H](C)O
Temperature: 30 °C
Reaction time: 48 h

Procedure:
Twenty grams of bakers' yeast (Sigma Chemical Company, Saccharomyces cerevisiae, type II) was suspended in a solution of 30 grams of sucrose in water in a conical flask, and the mixture was placed in an orbital shaker chamber maintained at 220 rpm and 30° C. for 30 minutes to initiate fermentation. Two grams of ethyl 2-ethyl acetoacetate was dissolved in 2 ml of 95% ethanol, the resulting solution was added to the fermenting yeast, and shaking was resumed. The reaction was followed by TLC (staining with phosphomolybdic acid in ethanolic sulfuric acid) to monitor the consumption of starting material and the production of product alcohol. After approximately 48 hours the reaction was judged complete, and the reaction was terminated by removing the flask from the shaker and adding 20-30 grams of Celite to the reaction mixture. The resulting suspension was suction filtered through a pad of Celite, and the clear yellow filtrate was extracted with ethyl acetate (4×200 ml). The extracts were combined, dried over MgSO4, filtered, and rotary evaporated to leave 1.6 grams of a yellowish oil containing ethyl (2R,3S)-2-methyl-3-hydroxybutyrate as the major product (80%) and ethyl (2S,3S)-2-methyl-3-hydroxybutyrate (20%) as the minor product as judged by chiral chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([C:18](O)=[O:19])[CH:7]=[CH:6][C:5]2=1.C(Cl)CCl.O.ON1C2C=CC=CC=2N=N1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>C1COCC1.C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:14]=[C:13]([C:15]([NH2:16])=[O:17])[C:12]2[NH:11][C:10]3[C:5]([C:4]=2[CH:3]=1)=[CH:6][CH:7]=[C:8]([C:18]([N:40]1[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]1)=[O:19])[CH:9]=3
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(C(=O)O)ccc12
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)cc(Br)cc23)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 6-bromo-8-carbamoyl-9H-carbazole-2-carboxylic acid (8.47 g, 8.64 mmol), EDC (1.657 g, 8.64 mmol), and 1-hydroxybenzotriazole hydrate (1.324 g, 8.64 mmol) in THF/CH2Cl2 (5/1) (40 mL) was added 1-methylpiperazine (3.84 mL, 34.6 mmol). The reaction mixture turned into a dark pink suspension. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and partitioned between ethyl acetate and water/sat. NaHCO3. The aqueous phase was re-extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and concentrated to afford the crude product as a dark pink solid, which was purified by silica gel column chromatography (CH2Cl2/2M NH3 in MeOH=100/5-100/7). The product obtained was suspended in ethyl acetate and colorless solid was collected by filtration and air-dried to give 1.78 G of 3-bromo-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide. MS (ESI) m/z 415.1 (M+H). 1H NMR (DMSO-d6) δ ppm 11.68 (s, 1H) 8.60 (d, J=1.76 Hz, 1H) 8.28 (br. s., 1H 8.24 (d, J=8.13 Hz, 1H), 8.16 (d, J=1.76 Hz, 1H) 7.75 (s, 1H) 7.64 (br. s., 1H) 7.14-7.22 (m, 1H) 3.34-3.75 (m, 4H) 2.24-2.44 (m, 4H) 2.20 (s, 3H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:30])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=1.Br[C:32]1[CH:33]=[N:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[CH:37][CH:36]=2.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:30])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:32]2[CH:33]=[N:34][C:35]3[C:40]([CH:41]=2)=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:16]=1
Reactant: CC1(C)OB(c2cccc(OCC(O)CN3CCc4ccccc4C3)c2)OC1(C)C
Reactant: Brc1cnc2ccccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: OC(COc1cccc(-c2cnc3ccccc3c2)c1)CN1CCc2ccccc2C1
Temperature: 120 °C
Yield: 53.1 %

Procedure:
To a solution of 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propan-2-ol (250 mg, 0.61 mmol) in Dioxane (3 mL) was added 3-bromoquinoline (127 mg, 0.61 mmol), 2N K2CO3 (1 mL, 2 mmol) and PdCl2(dppf)2 (20 mg, 0.025 mmol). The reaction mixture was heated at 120° C. under microwave conditions for 30 min. the mixture was then concentrated to remove the solvents, the residue dissolved in ethyl acetate and washed with water. The separated organic layer dried and concentrated to yield the crude product which was purified HPLC separation to give the title compound (133 mg, 53.2%). 1HNMR (CH3OD, 400 MHz) δ: 9.39 (s, 1H), 9.12-9.08 (m, 1H), 8.28-8.19 (m, 2H), 8.06-8.00 (m, 1H), 7.90-7.84 (m, 1H), 7.88-7.46 (m, 3H), 7.36-7.20 (m, 4H), 7.18-7.12 (m, 1H), 4.78-4.40 (m, 3H), 4.23-4.16 (m, 2H), 4.02-4.80 (m, 1H), 3.65-3.40 (m, 3H), 3.40-3.20 (m, 2H). LCMS (m/z): 411.2 [M+H]
Reaction SMILES: FC(F)(F)C1NC2C([N+]([O-])=[O:13])=CC(C(F)(F)F)=CC=2N=1.[N+:21]([C:24]1[CH:29]=[C:28]([CH:30]([F:32])[F:31])[CH:27]=[C:26]([N+:33]([O-:35])=[O:34])[CH:25]=1)([O-:23])=[O:22].[N+](C1C=C(C=C([N+]([O-])=O)C=1O)C=O)([O-])=O>>[N+:21]([C:24]1[CH:29]=[C:28]([CH:30]([F:31])[F:32])[CH:27]=[C:26]([N+:33]([O-:35])=[O:34])[C:25]=1[OH:13])([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cc(C(F)F)cc([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc2nc(C(F)(F)F)[nH]c12
Agent: O=Cc1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cc(C(F)F)cc([N+](=O)[O-])c1O

Procedure:
Compounds in which the substituent in the 6(5) position of the benzene ring of the benzimidazole is difluoromethyl are prepared from 2,6-dinitro-4-difluoromethylbenzene according to the above procedure. This latter compound is prepared by the reaction of SF4 and 3,5-dinitro-4-hydroxybenzaldehyde to yield 2,6-dinitro-4-difluoromethylphenol which is converted to the corresponding chloride by conventional means. 2-Trifluoromethyl-4-nitro-6-difluoromethylbenzimidazole was prepared from the above diamine by the process of the above example and melted at about 132°-134° C. after recrystallization from benzene.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C@H:6]([NH:8][C:9]1[C:14]([C:15]2[N:20]=[CH:19][N:18]=[C:17]([O:21][C:22]3[C:27]4[N:28]=[C:29]([NH:31][C:32](=[O:34])[CH3:33])[S:30][C:26]=4[CH:25]=[CH:24][CH:23]=3)[CH:16]=2)=[CH:13][CH:12]=[C:11]([C:35]([F:38])([F:37])[F:36])[N:10]=1)[CH3:7].[CH3:39][C:40]([CH3:42])=O>>[CH:40]([N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C@H:6]([NH:8][C:9]1[C:14]([C:15]2[N:20]=[CH:19][N:18]=[C:17]([O:21][C:22]3[C:27]4[N:28]=[C:29]([NH:31][C:32](=[O:34])[CH3:33])[S:30][C:26]=4[CH:25]=[CH:24][CH:23]=3)[CH:16]=2)=[CH:13][CH:12]=[C:11]([C:35]([F:38])([F:36])[F:37])[N:10]=1)[CH3:7])([CH3:42])[CH3:39]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)nc4N[C@H](C)[C@H]4CCCN4)ncn3)cccc2s1
Reactant: CC(C)=O
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)nc4N[C@H](C)[C@H]4CCCN4C(C)C)ncn3)cccc2s1

Procedure:
N-(4-(6-(2-((R)-1-((R)-Pyrrolidin-2-yl)ethylamino)-6-(trifluoromethyl)pyridin-3-yl)-pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide, Example 12(d), (135 mg, 0.25 mmol) was reacted with acetone (56 μL, 0.75 mmol, Aldrich) under the conditions of Example 3(d) to give the title compound as a yellow solid. MS (ESI, pos. ion.) m/z: 586 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9]([C:11]1[N:12]=[CH:13][NH:14][CH:15]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:9][C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1c[nH]cn1
Reactant: Nc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Fc1ccc(NCc2c[nH]cn2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 15.5 %

Procedure:
To a solution of 4-fluoroaniline (0.60 g, 5.40 mmol) in 1,2-dichloroethane (5 ml) were added 4-formylimidazole (0.78 g, 8.10 mmol), sodium triacetoxyborohydride (2.29 g, 10.8 mmol) and acetic acid (0.06 ml). The reaction mixture was stirred at 50° C. for 4 h. The reaction mixture was then concentrated in vacuo and the residue was purified using flash chromatography (column: Isolute® Flash-NH2 (Separtis); eluent: methanol/dichloromethane gradient) to yield a white solid (160 mg, 16%); MS (ISP): 192.2 ((M+H)+.).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@H:8]([NH2:9])[CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1.ClC(Cl)Cl.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C(N(CC)CC)C>[CH3:1][O:2][C@H:3]1[C@H:8]([NH:9][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=2)[CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CO[C@@H]1CN(Cc2ccccc2)CC[C@H]1N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CO[C@@H]1CN(Cc2ccccc2)CC[C@H]1NC(=O)c1cccc(C(F)(F)F)c1
Reaction time: 20 h
Yield: 80.9 %

Procedure:
To a stirred solution of 10 parts of trans-3-methoxy-1-(phenylmethyl)-4-piperidinamine and 5.95 parts of N,N-diethylethanamine in 75 parts of trichloromethane was added dropwise a solution of 10.4 parts of 3-(trifluoromethyl)benzoyl chloride in 15 parts of N,N-diethylethanamine while cooling in an ice bath. Upon completion, stirring was continued for 20 hours at room temperature. The mixture was washed twice with a sodium hydroxide solution 5% and once with water and then dried, filtered and evaporated in vacuo. After crystallization of the residue from 27 parts of methylbenzene, the product was filtered off, washed with 45 parts of methylbenzene and dried, yielding 14.4 parts (80.9%) of trans-N-[3-methoxy-1-(phenylmethyl)-4-piperidinyl]-3-(trifluoromethyl)benzamide; mp. 135.2° C. (interm. 8).
Reaction SMILES: [F:1][C:2]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:3]=1[NH:4][CH:5]([CH3:9])[C:6]([OH:8])=[O:7].[C:16]1([C@H:22]([NH2:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[C:16]1([C@H:22]([NH2:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[F:1][C:2]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:3]=1[NH:4][C@@H:5]([CH3:9])[C:6]([OH:8])=[O:7]
Reactant: CC(Nc1ccc(F)c(F)c1F)C(=O)O
Agent: C[C@@H](N)c1ccccc1
Solvent: CO
Product: C[C@H](Nc1ccc(F)c(F)c1F)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(2,3,4-Trifluoroanilino)propionic acid (1.1 g) was dissolved in a solvent mixture (15 ml; methanol-IPE=1:20). At room temperature, a solution (15 ml) of (R)-1-phenylethylamine (333.2 mg) in a solvent mixture (methanol-IPE=1:20) was slowly added thereto. The obtained suspension was stirred at room temperature for additional 2 hours and then filtered while washing with IPE. Thus, the title compound was obtained as colorless crystals (802 mg). The optical purity of this product was 80% ee. Subsequently, chloroform was added to the obtained salt and the mixture was stirred at 50° C. for 18 hours. Then the suspension was filtered while washing with IPE to give 703 mg of the title compound as colorless crystals. The optical purity of this product was 99% ee.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][C:13]1[CH:14]=[C:15]([C:19]2([CH3:26])[NH:24][C:23](=O)[CH2:22][O:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][C:13]1[CH:14]=[C:15]([C:19]2([CH3:26])[NH:24][C:23](=[S:36])[CH2:22][O:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1
Reactant: CC1(c2cccc(Nc3cccc4cc(Cl)cnc34)c2)COCC(=O)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC1(c2cccc(Nc3cccc4cc(Cl)cnc34)c2)COCC(=S)N1
Yield: 71 %

Procedure:
A solution of (RS)-5-[3-(3-chloro-quinolin-8-ylamino)-phenyl]-5-methyl-morpholin-3-one (368 mg, 1.1 mmol) in tetrahydrofuran was treated with Lawesson's reagent (500 mg, 1.2 mmol) at room temperature during 3 hours. The progress of the reaction was checked by LC-MS. For the workup, the reaction mixture was evaporated at reduced pressure. The residue was partitioned between water (5 ml) and ethyl acetate (5 ml), then the organic layer separated, dried over sodium sulphate and evaporated. The crude product was purified by flash chromatography on silica gel using a gradient of cyclohexane/ethyl acetate as the eluent yielding 300 mg (71%) of (RS)-5-[3-(3-chloro-quinolin-8-ylamino)-phenyl]-5-methyl-morpholine-3-thione; (calculated) C20H18ClN3OS [383.90]; (found) [M+H]+=384.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][C@H:6]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].[N:23]([C:26]1[CH:27]=[C:28]([CH:32]([CH3:43])[C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH:29]=[CH:30][CH:31]=1)=[C:24]=[O:25]>O1CCCC1>[C:10]([O:9][C:7]([C@@H:6]1[CH2:14][CH2:15][C@H:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:5]1[C:3](=[O:4])[CH2:2][NH:1][C:24](=[O:25])[NH:23][C:26]1[CH:27]=[C:28]([CH:32]([CH3:43])[C:33]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[CH:29]=[CH:30][CH:31]=1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@H](c2ccccc2)N1C(=O)CN
Reactant: CC(C(=O)OCc1ccccc1)c1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: CC(C(=O)OCc1ccccc1)c1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)CC[C@H]2C(=O)OC(C)(C)C)c1
Yield: 59.2 %

Procedure:
Benzyl 2-{3-{3-[2-((2S,5R)-2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenyl}propionate (B form) may be obtained in a fashion similar to that described in Example 2, but starting from 0.79 g of tert-butyl (2S,5R)-1-(2-aminoacetyl)-5-phenylprolinate and 0.8 g of benzyl 2-(3-isocyanato-phenyl)propionate (B form) in 40 cm3 of tetrahydrofuran. After treatment, 0.9 g of benzyl 2-{3-{3-[2-((2S,5R)-2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenyl}propionate, melting at 75° C., is obtained.
Reaction SMILES: [OH:1][C:2]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8](O)=[O:9])=O.O.[NH2:17][NH2:18]>>[OH:1][C:2]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]1[CH2:6][CH2:7][C:8](=[O:9])[NH:17][N:18]=1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1cccc(O)c1O
Solvent: O
Product: O=C1CCC(c2cccc(O)c2O)=NN1

Procedure:
3-(2,3-Dihydroxybenzoyl)propionic acid was cyclised with hydrazine hydrate in a similar manner to that described in Example 3 (i) to give 6-(2,3-dihydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([Br:31])[N:14]=1)[N:11]([C@H:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])[C:10](=[O:23])[C:9]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[CH:8]2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2[C@@H](C)c2ccccc2)c1O
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2[C@@H](C)c2ccccc2)c1O
Yield: 65.1 %

Procedure:
A mixture of (5)-5-hydroxy-2-oxo-3-phenyl-1-(1-phenyl-ethyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (100 mg, 0.25 mmol) and N-bromosuccinimide (49 mg, 0.275 mmol) in CH2Cl2 (1 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-20% EtOAc/hexanes+1% AcOH) to give 78 mg of the title compound. MS: (−) m/z 477.19, 479.21 (M−1, 79/81Br).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][C:15]#[N:16])[CH:6]=1)[CH3:3].Cl.[C:18](=O)([O-])[O-:19].[K+].[K+]>CO.C(Cl)(Cl)Cl>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][C:15](=[NH:16])[O:19][CH3:18])[CH:6]=1)[CH3:3]
Reactant: CN(C)Cc1ccnc(CSCCC#N)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=N)CCSCc1cc(CN(C)C)ccn1
Temperature: -5 °C
Reaction time: 24 h
Yield: 90.7 %

Procedure:
3-(4-Dimethylaminomethyl-2-pyridylmethylthio)propionitrile (13.60 g) was dissolved in a mixture of dry methanol (70 ml) and dry chloroform (140 ml) and the stirred solution cooled to -5° C. under nitrogen. Dry hydrogen chloride gas was passed through the solution for 3.75 hours, keeping the temperature below 0° C. The solution was allowed to stand in a stoppered flask at ca. 4° C. for 24 hours and was added to a solution of potassium carbonate (45 g) in ice-water (500 ml). The chloroform layer was separated off and the aqueous layer extracted with chloroform (3×150 ml). The combined extracts were dried (K2CO3 and chloroform evaporated at reduced pressure to give methyl 3-(4-dimethylaminomethyl-2-pyridylmethylthio)propionimidate (14.02 g) as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:11]#[N:12])[C:6](=[CH:9][CH:10]=1)[C:7]#[N:8].[Cl:13][C:14]1[CH:15]=[CH:16][C:17](=[O:51])[N:18]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]3[N:28]=[CH:29][N:30](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:31]=3)=[CH:22][N:21]=2)[CH:19]=1>CC#N>[Cl:13][C:14]1[CH:15]=[CH:16][C:17](=[O:51])[N:18]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]3[N:28]([CH2:2][C:3]4[CH:4]=[C:5]([C:11]#[N:12])[C:6](=[CH:9][CH:10]=4)[C:7]#[N:8])[CH:29]=[N:30][CH:31]=3)=[CH:22][N:21]=2)[CH:19]=1
Reactant: N#Cc1ccc(CBr)cc1C#N
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Solvent: CC#N
Product: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1C#N
Temperature: 60 °C

Procedure:
4-Bromomethyl-phthalonitrile from step 3 (50 mg, 0.28 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (150 mg, 0.28 mmol) were dissolved in CH3CN (1.4 ml) and heated to 60° C. for 16 hours. The solvent was removed in vacuo and redissolved in MeOH (1.4 ml). The reaction mixture was heated to 60° C. for several hours. Solvent was removed in vacuo and the resulting residue was purified by flash chromatography [4% MeOH(5% NH4OH)/CH2Cl2 ] to yield the final product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20]C)[CH:3]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:33])[NH:28]2.B(Br)(Br)Br>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:8]([CH3:18])([CH3:19])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]2[NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][C:27](=[O:33])[NH:28]3)=[C:4]([OH:20])[CH:3]=1
Reactant: Nc1cccc2[nH]c(=O)ccc12
Reactant: COc1cc(Br)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: BrB(Br)Br
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3[nH]c(=O)ccc23)c2cc(Br)cc(O)c21

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 800 mg of 4-(4-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 348 mg of 5-amino-quinolin-2(1H)-one. 16 mg of diastereomer A of 5-{[7-bromo-2-, 5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one (fraction A) and 79 mg of diastereomer B of 5-{[7-bromo-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-quinolin-2(1H)-one are obtained by reaction of 800 mg of imine with 7.9 ml of boron tribromide solution (1H in dichloromethane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[N:7]=[C:6]2[CH2:25]O.S(Cl)([Cl:29])=O.C(OCC)(=O)C.CCCCCC>ClCCl>[Cl:29][CH2:25][C:6]1[C:5]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[N:7]=1
Reactant: COc1ccc(Cn2nc(CO)c3cc(OC)c(OC)cc32)cc1OC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(Cn2nc(CCl)c3cc(OC)c(OC)cc32)cc1OC
Temperature: 25 °C

Procedure:
In 1500 ml of dichloromethane was dissolved 184.0 g of 5,6-dimethoxy-1-(3,4-dimethoxybenzyl)-3-hydroxymethyl-1H-indazole at room temperature, followed by stirring under cooling with ice. To the solution was added dropwise 75.4 ml of thionyl chloride over 20 minutes. One minute later, the spot of the starting material on a thin layer chromatogram (ethyl acetate:hexane=2:1) disappeared. The reaction mixture was warmed to room temperature, and 3500 ml of dichloromethane was added thereto. The mixture was washed with 1000 ml of a saturated sodium Hydrogencarbonate aqueous solution, dried over sodium sulfate, filtered, and the evaporation of the solvent gave 189.7 g of a colorless solid. This solid was used in the subsequent reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][NH:13][CH2:14][CH2:15][CH2:16][CH:17]1[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:24]=[CH:25][C:26]4[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=4[CH:33]=3)[CH2:18]1)=[N:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2.[CH2:36]1[O:38][C@H:37]1[CH2:39][OH:40]>C1COCC1.CO>[OH:38][C@@H:37]([CH2:39][OH:40])[CH2:36][N:13]([CH2:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:34][CH3:35])[N:9]=2)[N:4]=[CH:3][C:2]=1[F:1])[CH2:14][CH2:15][CH2:16][CH:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:24]=[CH:25][C:26]3[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=3[CH:33]=2)[CH2:18]1
Reactant: COc1ccc2ncc(F)c(CNCCCC3CN(c4ccc5c(c4)NC(=O)CS5)C(=O)O3)c2n1
Reactant: OC[C@H]1CO1
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2ncc(F)c(CN(CCCC3CN(c4ccc5c(c4)NC(=O)CS5)C(=O)O3)C[C@@H](O)CO)c2n1
Temperature: 70 °C
Yield: 52 %

Procedure:
A solution of the compound of Example 78 (0.05 g, 0.1 mmol) in THF/MeOH (1:1, 0.5 mL) was treated with (S)-glycidol (0.06 mL, 5 eq.). The mixture was heated at 70° C. for 3 h, concentrated in vacuo and purified by FC (EA/MeOH 19:1+1% NH4OH) to give the title compound as a colourless solid (0.03 g, 52% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-])=O.P(OCC)(OCC)OCC>>[Cl:10][C:6]1[C:5]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:1][C:4]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1-c1ccccc1
Agent: CCOP(OCC)OCC
Product: Clc1cccc2[nH]c3ccccc3c12
Temperature: 140 °C
Yield: 36.4 %

Procedure:
In a stream of nitrogen, a 500 mL egg-plant flask was charged with 60.0 g (257.4 mmol) of 2-nitro-6-chlorobiphenyl, obtained in Synthesis Example 1. The content was heated to 140° C., and 106 g of triethyl phosphite was dropwise added over 2 hours. After the dropwise addition, the content was further heated at 140° C. for 2 hours. Then triethyl phosphite was distilled off under reduced pressure. Toluene was added to the residue, and the thus-deposited solid was filtered. The thus-obtained crude product was purified by silica gel column chromatography using toluene as a developing solvent to give 18.9 g (93.72 mmol) of 4-chlorocarbazole as a white powder (yield: 36%).