Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][C:5]([NH2:7])=[NH:6].[CH:8]1[C:20]2[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[CH:10][C:9]=1[C:21](OC)=[O:22]>CN(C=O)C>[NH2:6][C:5]([NH2:7])=[N:4][C:21]([C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:19][C:20]=2[CH:8]=1)=[O:22]
Reactant: COC(=O)c1ccc2c(c1)[nH]c1ccccc12
Reactant: N=C(N)N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(N)=NC(=O)c1ccc2c(c1)[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A 192 mg portion of sodium hydride (60%) was added to 6.5 ml DMF solution of 573 mg guanidine hydrochloride and stirred at room temperature for 1 hour. A 6.5 ml DMF solution of 270 mg methyl 9H-carbazole-2-carboxylate was added to this solution, followed by stirring at 70° C. for 2.5 hours. After spontaneous cooling to room temperature and subsequent evaporation of the solvent, water was added thereto and the thus precipitated solid was purified by Chromatorex (methanol/chloroform) to obtain 236 mg of N-(diaminomethylene)-9H-carbazole-2-carboxamide as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:24][CH3:25])=[CH:11][C:12]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:28])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]([O:24][CH3:25])=[CH:11][C:12]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[C:13]([CH:17]=1)[C:14]([Cl:28])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2noc(C)n2)c(C(=O)O)cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(-c2noc(C)n2)c(C(=O)Cl)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzoic acid (reference example 5-1) (817 mg), thionyl chloride (0.53 mL), N,N-dimethylformamide (1 drop) and toluene (10 mL) was stirred at 80° C. for 30 minutes. The mixture was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated under reduced pressure to give 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzoyl chloride.
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].O[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[CH:22][CH:21]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:1]([CH:3]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[CH:22][CH:21]=2)=[CH:14][CH:15]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)Cc1ccc(O)cc1
Reactant: CC(C)C(=O)Nc1ccc(CCO)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(C#N)Cc1ccc(OCCc2ccc(NC(=O)C(C)C)cc2)cc1
Reaction time: 8 h
Yield: 26.8 %

Procedure:
Ethyl 2-cyano-3-(4-hydroxyphenyl)propanoate (1 g, 4.56 mmol) and N-[4-(2-hydroxyethyl)phenyl]-2-methylpropanamide (1.42 g, 6.85 mmol) were mixed in dichloromethane (40 ml). 1,1′-(Azodicarbonyl)dipiperidine (2.3 g, 9.12 mmol) and triphenylphosphine (2.4 g, 9.15 mmol) were then added respectively. The mixture was stirred overnight and filtered. The filtrate was evaporated to dry in vacuum. Column chromatography of the residue on silica gel using ethyl acetate/heptane as eluant gave 0.5 g desired product, yield 27%.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[Cl:40])=[O:12])=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C@@:15]2([C:23]#[N:24])[C@H:16]([CH2:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:17][N:13]([C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:41])=[O:2])=[CH:5][CH:6]=3)=[O:12])[C@@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[Cl:40])=[C:26]([F:32])[CH:27]=1
Reactant: COC(=O)c1ccc(NC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C[C@@H]1CN(C(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2Cl)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a mixture of rac-4-{[(2S,3S,4S)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,3-dichloro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid methyl ester (85.0 mg, 0.14 mmol) in THF/MeOH (0.6 mL/0.2 mL) was added 4 N LiOH (0.2 mL), and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated and quenched with 2 NH2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-4-{[(2S,3S,4S)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,3-dichloro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid (54.3 mg, 65.4%). LC-MS (ES+) m/z Calcd for C30H27Cl3FN3O3+H [(M+H): 604; Found: 604.
Reaction SMILES: Cl.[F:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([CH2:7][CH2:8][NH:9]2)=[CH:5][CH:4]=1.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>CN1CCCC1=O>[ClH:13].[F:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:5][CH:4]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Cc1c(F)ccc2c1NCC2
Agent: Cl
Solvent: CN1CCCC1=O
Product: COc1cc2ncnc(N3CCc4ccc(F)c(C)c43)c2cc1OC
Yield: 58 %

Procedure:
Utilizing a procedure analogous to that described in Example 47 (with conversion to the HCl salt analogous to Example 2), this product was prepared in 58% yield from 6-fluoro-7-methyl-indoline (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in N-methyl-pyrrolidinone. (M.P. 220°-225° C.; LC-MS: 340 (MH+); anal. RP18-HPLC RT: 4.63 min.).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C@H:31]1([NH2:41])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1>C(Cl)Cl.CN(C=O)C>[C@H:31]1([NH:41][C:6]([C:3]2[CH2:2][O:1][CH2:5][CH:4]=2)=[O:8])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)c1ccoc1
Reactant: N[C@@H]1CCCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(N[C@@H]1CCCc2ccccc21)C1=CCOC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of furan-3-carboxylic acid (100 mg, 0.68 mmol), HOBt (240 mg, 1.78 mmol) and EDCI.HCl (196 mg, 1.03 mmol) in CH2Cl2 (8 mL) and DMF (1.5 mL) at 0° C., was added (R)-1,2,3,4-tetrahydronaphthalen-1-amine (160 μL, 1.06 mmol). The reaction was stirred at rt for 24 h, after which CH2Cl2 was added. The resulting solution was washed with saturated NaHCO3, H2O, brine, dried over MgSO4 and concentrated in vacuo. Recrystallization from EtOH/H2O afforded (R)—N-(1,2,3,4-tetrahydronaphthalen-1-yl)-2,5-dihydrofuran-3-carboxamide. 1H NMR (500 MHz, CDCl3): δ 1.89 (m, 3H), 2.12 (m, 1H), 2.84 (m, 2H), 5.35 (m, 1H), 5.96 (br d, 1H, J=7.75 Hz), 6.59 (dd, 1H, J=1.90, 0.86 Hz), 7.13 (m, 1H), 7.19 (m, 2H), 7.32 (m, 1H), 7.43 (t, 1H, J=1.73 Hz), 7.93 (m, 1H). MS(M+H, 242).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:5][O:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:18]([O:20][C:21](=[O:35])[CH2:22][NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[O:33][CH3:34])[CH3:19].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[CH3:34][O:33][C:26]1[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:25]=1[CH2:24][N:23]([CH2:2][C:3]1[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:5][O:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:35]
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Reactant: CCOC(=O)c1onc(-c2cccs2)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(-c2cccs2)noc1C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.3 %

Procedure:
Ethyl 4-(bromomethyl)-3-(thiophen-2-yl)isoxazole-5-carboxylate (16.5 mmol) was dissolved in 35 mL of DMF. N-(2,4-dimethoxybenzyl)glycine ethyl ester (4.2 g, 16.5 mmol) and potassium carbonate (4.5 g, 32.9 mmol) were added, and the mixture was stirred at room temperature for 16 h. EtOAc (100 mL) and water (100 mL) were added and the aqueous layer was extracted with additional EtOAc. The combined organic layer was washed with water and brine, and dried over MgSO4. After solvent was removed in vacuo, the crude was purified by flash chromatography (0-40% EtOAc/hexanes) to give 2.2 g of the title compound. MS: (+) m/z 489.44 (M+1).
Reaction SMILES: [NH2:1][C:2](=[O:15])[C@H:3]([NH:7]C(=O)OC(C)(C)C)[CH:4]1[CH2:6][CH2:5]1.[ClH:16]>O1CCOCC1>[ClH:16].[NH2:7][C@H:3]([CH:4]1[CH2:6][CH2:5]1)[C:2]([NH2:1])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(N)=O)C1CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)[C@H](N)C1CC1

Procedure:
A solution of (R)-tert-butyl 2-amino-1-cyclopropyl-2-oxoethylcarbamate (300 mg, 1.40 mmol) in 4N HCl in dioxane (8 mL) was stirred at room temperature for 20 min. It was then concentrated in vacuo to give (R)-2-amino-2-cyclopropylacetamide hydrochloride (225 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)#[N:21]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]#[N:21])[CH2:33][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Reactant: N#Cc1ccccc1N1CCNCC1
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2ccccc2C#N)CC1
Yield: 91 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(2-cyanophenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 91%). 1H NMR (300 MHz, CDCl3): δ 2.46 (s, 3H), 3.28 (s, 4H), 3.86 (s, 3H), 4.08-4.19 (m, 4H), 7.01-7.08 (m, 3H), 7.17-7.37 (m, 1H), 7.49-7.61 (m, 4H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH2:11][C:10](=[O:12])[CH:9]=[CH:8][CH2:7]1)(=[O:3])[CH3:2].C(O[CH2:18][N:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:20][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl>[C:1]([O:4][CH2:5][CH:6]1[CH2:7][CH:8]2[CH:9]([CH2:18][N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:20]2)[C:10](=[O:12])[CH2:11]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1CC=CC(=O)C1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OCC1CC(=O)C2CN(Cc3ccccc3)CC2C1
Reaction time: 1 h
Yield: 70.4 %

Procedure:
Two drops of trifluoroacetic acid are added to a solution of 6.5 g of 5-acetoxymethylcyclohex-2-en-1-one and 14 g of N-butoxymethyl-N-trimethylsilylmethylbenzylamine [prepared according to the method described by Y. Tarao et al., Chem. Pharm. Bull., 33., 2762 (1985)] in 60 cm3 of dry dichloromethane. On reaching reflux, the reaction mixture is maintained at the same temperature for 30 minutes and then left at 20° C. for one hour. After addition of 1.0 g of potassium carbonate, the suspension obtained is filtered, and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The oily residue obtained is chromatographed on a silica gel column (particle size 0.06-0.2 mm, height 42 cm) in a mixture of cyclohexane and ethyl acetate (40:60 by volume) and then in ethyl acetate. 8.2 g of (3aRS,6SR,7aSR)-6-acetoxymethyl-2-benzylperhydroisoindol-4-one are obtained in the form of a yellowish oil.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:5]2[CH:12]=[C:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[S:14][C:4]=2[C:3]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[CH:28]([C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=1B(O)O)=[O:29].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:22]1([C:3]2[C:4]3[S:14][C:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:12][C:5]=3[N:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]=2[C:31]2[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:30]=2[CH:28]=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)Cn1c(Br)c(C2CCCCC2)c2sc(C(=O)OC(C)(C)C)cc21
Reactant: COc1ccc(B(O)O)c(C=O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)Cn1c(-c2ccc(OC)cc2C=O)c(C2CCCCC2)c2sc(C(=O)OC(C)(C)C)cc21
Temperature: 25 °C
Yield: 57 %

Procedure:
tert-Butyl 5-bromo-6-cyclohexyl-4-(2-methoxy-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (1 eq., prepared as described in Example 1, Step 3) and 2-formyl-4-methoxyphenylboronic acid (1.5 eq.) were dissolved in dioxane (0.1 M) and treated with 2 M Na2CO3 solution (2 eq.). The solution was degassed by bubbling argon through it and Pd(PPh3)2Cl2 (0.1 eq.) was added. The reaction mixture was heated to reflux for 20 min. After cooling down to RT, the mixture was diluted with EtOAc and washed with 1 N hydrochloric acid and with brine. The organic layer was dried over sodium sulfate and evaporated in vacuo and the residue purified by chromatography (PE:EtOAc, 9:1) to afford the pure title compound (57%) as a solid. 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 9.64 (s, 1H), 7.89 (s, 1H), 7.43 (s, 1H), 7.41-7.38 (m, 2H), 4.92 (d, J 18.0, 1H), 4.73 (d, J 18.0, 1H), 3.90 (s, 3H), 3.50 (s, 3H), 2.14-2.09 (m, 1H), 1.73-1.19 (m, 10H), 1.54 (s, 9H). MS (ES+) m/z: 534 [M+Na]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[N+:19]([O-])=O)[CH3:3].Cl[Sn]Cl>>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[NH2:19])[CH3:1]
Reactant: CN(C)Cc1ccccc1Sc1ccc(F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Product: CN(C)Cc1ccccc1Sc1ccc(F)cc1N

Procedure:
The authentic sample, N,N-dimethyl-2-(2-amino-4-fluorophenylthio)benzylamine (12) vas also synthesized in multisteps. Reaction of 2-chloro-5-fluoronitrobenzene with 2-thio-N,N-dimethylbenzamide gave N,N-dimethyl-2-(2-nitro-4-fluorophenylthio)-benzamide (9). Reduction of compound 9 with BH3 gave N,N-dimethyl-2-(2-nitro-4-fluorophenylthio)benzylamine (10) and its amine borane (11) in a ratio of ˜1:1 (Scheme 1). Compound 10 was reduced further with SnCl2 to give the final product (12).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:15]([CH3:29])[C:16](=[O:28])[CH2:17][N:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH3:19])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[NH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O)=[O:32].C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>CN(C=O)C.O.[Cl-].[Na+].O.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]>[Cl:27][C:22]1[CH:21]=[C:20]([N:18]([CH3:19])[CH2:17][C:16]([N:15]([CH3:29])[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]3[C:33]([C:31]([NH2:30])=[O:32])=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:3][CH:4]=2)[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:28])[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: NC(=O)c1ccccc1B(O)O
Reactant: CN(CC(=O)N(C)C(CN1CCCC1)c1ccc(Br)cc1)c1ccc(Cl)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CC(=O)N(C)C(CN1CCCC1)c1ccc(-c2ccccc2C(N)=O)cc1)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 47.3 %

Procedure:
N1-[1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethyl]-N2-(3,4-dichlorophenyl)-N1,N2-dimethylglycinamide (100 mg, 0.200 mmol) was dissolved in 1.5 mL of DMF and combined with [2-(aminocarbonyl)phenyl]boronic acid (40 mg, 0.240 mmol), Pd(dppf)2Cl2 (8 mg, 0.01 mmol), and 400 uL of 2M Na2CO3 in water. The reaction mixture was heated to at 80° C. and stirred for 18 h. Ethyl acetate (4 mL) and brine (4 mL) were added and the reaction mixture was filtered. The organic layer was separated and the solvent was removed under reduced pressure. The residue was dissolved in 1.0 mL DMSO and purified by preparative HPLC (Phenomenex 75×30 mm column, 40 mL/min flow rate, A: 0.1% TFA in acetonitrile B: 0.1% TFA in water, A: 10 to 100% over 15 min, UV detection at 215 nm) to give 51 mg (47%) of the title compound as a yellow solid. MS (ES) m/e 539/541 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH:5]=[CH:6][CH:7]([N:21]([C:23](=[O:38])[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[CH3:22])[CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].[H][H]>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH:7]([N:21]([C:23](=[O:38])[C:24]1[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[C:26]([C:34]([F:36])([F:37])[F:35])[CH:25]=1)[CH3:22])[CH:8]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=CC(C(c1ccccc1)c1ccccc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCC(C(c1ccccc1)c1ccccc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A solution of 15.0 g (27.3 mmol) of 4-[N-(3,5-bistrifluoromethyl-benzoyl)-N-methylamino]-5,5-diphenyl-pent-2-enoic acid ethyl ester in 400 ml of tetrahydrofuran is hydrogenated with 1.5 g of 10% palladium on activated carbon under 1 atm. of hydrogen. After 4 hours the suspension is filtered over Hyflo and washed with tetrahydrofuran, and the filtrate is concentrated by evaporation. The title compound is obtained in the form of a yellow oil. TLC: ethyl acetate/hexane (1:2) Rf =0.50; Rt (HPLC)=22.4 min; 1H-NMR (400 MHz, d6 -DMSO, 120° C.) d 7.96 (br, 1H), 7.48-7.18 (m, 12H), 5.44 (br, 1H), 4.31 (d, 1H), 4.05 (q, 2H), 2.56 (br s, 3H), 2.44-2.27 (m, 2H), 1.93 (m, 1H), 1.76 (m, 1H), 1.17 (t, 3H); FAB-MS (M+H)+ =552.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.[CH3:13][NH2+:14][CH3:15].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.O>C1COCC1>[CH3:13][N:14]([CH3:15])[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)=[O:12]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: C[NH2+]C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
1H-indazole-3-carboxylic acid (45.2 g, 279 mmol) was suspended in THF (500 mL), and to the suspension were added 1-hydroxybenzotriazole dimethylammonium salt (55.7 g, 308 mmol) obtained in a similar manner to the known method [for example, Synthesis, page 285 (1992)] and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58.9 g, 307 mmol), followed by stirring at room temperature overnight. The reaction mixture was added with water, was extracted with ethyl acetate, and the organic layer was sequentially washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from mixed solvent of acetone/water to obtain N,N-dimethyl-1H-indazole-3-carboxamide (37.7 g, 71%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:23])[CH2:9][C:10]2[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=2)[O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:23])[CH2:9][C:10]2[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=2)[O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COc1cccc(CC(=O)c2cccc(O)c2)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(CC(=O)c2cccc(OCc3ccc4ccccc4n3)c2)c1
Temperature: 60 °C

Procedure:
A mixture of ethyl 2-(3-(2-(3-hydroxyphenyl)2-oxoethyl)phenoxy)acetate (0.01 mol), 2-chloromethylquinoline (0.01 mol), and K2CO3 (0.01 mol) in 20 mL of DMF are heated at 60° C. overnight. After work-up, the crude product is purified by flash chromatography to give ethyl 2-(3-(2-(3-(2-quinolinylmethyloxy)phenyl)-2-oxoethyl)phenoxy)acetate.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][S:11]([C:14]2[CH:15]=[N:16][C:17](Cl)=[C:18]([Cl:20])[CH:19]=2)(=[O:13])=[O:12])=[O:9])=[N:4][CH:3]=1.[CH3:22][CH:23]1[CH2:27][CH2:26][CH2:25][NH:24]1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][S:11]([C:14]2[CH:15]=[N:16][C:17]([N:24]3[CH2:25][CH2:26][CH2:27][CH:23]3[CH3:22])=[C:18]([Cl:20])[CH:19]=2)(=[O:13])=[O:12])=[O:9])=[N:4][CH:3]=1
Reactant: O=C(Nc1ncc(Br)s1)NS(=O)(=O)c1cnc(Cl)c(Cl)c1
Reactant: CC1CCCN1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1CCCN1c1ncc(S(=O)(=O)NC(=O)Nc2ncc(Br)s2)cc1Cl

Procedure:
N-[(5-Bromo-1,3-thiazol-2-yl)carbamoyl]-5,6-dichloropyridine-3-sulfonamide (20 mg, 0.05 mmol) was dissolved in DMF (1 ml) and reacted with 2-methylpyrrolidine (0.10 ml, 1 mmol) at 50° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with water, NaHCO3 (half sat. 3×), 5% KHSO4/10% K2SO4, NaCl sat., dried (MgSO4.2H2O), filtered and concentrated under reduced pressure. The crude was purified by preparative RP-HPLC: 6 mg, MS: m/e 477.9 (MH−).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[C:8]3[C:13]4[C:14]([O:18]C)=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.C(S)(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)[C:8]3[C:13]4[C:14]([OH:18])=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[CH:3]=1
Reactant: COc1cccc2sc3c(c12)C(N1CCN(C)CC1)=Nc1ccc(F)cc1N3
Agent: CC(S)S
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CN1CCN(C2=Nc3ccc(F)cc3Nc3sc4cccc(O)c4c32)CC1

Procedure:
In the same manner as in Example 62 and using 8-fluoro-1-methoxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine, dichloromethane, ethanedithiol and aluminium chloride, 8-fluoro-1-hydroxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is obtained.