Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([CH2:16][CH2:17][O:18][CH2:19]CC)[C:6]1[C:11]([CH2:12]C)=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:14][CH3:15])=[O:4].Cl[C:23]1C=C(NC(=O)CC)C=CC=1Cl.ClC1C=C(NC(=O)C(C)=C)C=CC=1Cl.ClC1C=C(NC(=O)C(C)CCC)C=CC=1C.ClC1C=C(NC(=O)C(C)(C)C)C=CC=1Cl.ClC1C=C(NC(=O)C(C)(C)CCC)C=CC=1Cl.C(N(C1C=CC=CC=1)C(=O)CCl)(C)C.C(OCN(C1C(CC)=CC=CC=1CC)C(=O)CCl)CCC.COCN(C1C(CC)=CC=CC=1CC)C(=O)CCl>>[Cl:1][CH2:2][C:3]([N:5]([C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:14][CH3:15])[CH:16]([CH3:23])[CH2:17][O:18][CH3:19])=[O:4]
Reactant: CCC(=O)Nc1ccc(Cl)c(Cl)c1
Reactant: CCCOCCN(C(=O)CCl)c1c(CC)cccc1CC
Agent: C=C(C)C(=O)Nc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)C(=O)Nc1ccc(Cl)c(Cl)c1
Agent: CC(C)N(C(=O)CCl)c1ccccc1
Product: CCc1cccc(C)c1N(C(=O)CCl)C(C)COC

Procedure:
2-chloro-2',6'-diethyl-N-(2-propyloxyethyl)acetanilide; N-(3,4-dichlorophenyl)propionamide; N-(3,4-dichlorophenyl)methacrylamide; N-(3-chloro-4-methylphenyl)-2-methylpentanamide; N-(3,4-dichlorophenyl)trimethylacetamide; N-(3,4-dichlorophenyl)-alpha,alpha-dimethylvaleramide; N-isopropyl-N-phenylchloroacetamide; N-n-butoxymethyl-N-(2,6-diethylphenyl)chloroacetamide; N-methoxymethyl-N-(2,6-diethylphenyl)chloroacetamide.
Reaction SMILES: [C:1]1([S:7][CH:8]2[CH2:14][CH:13]3[CH:10]([C:11](=[O:15])[CH2:12]3)[CH:9]2[C:16]([O:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[C:1]1([S:7][C:8]2[CH2:14][CH:13]3[CH:10]([C:11](=[O:15])[CH2:12]3)[C:9]=2[C:16]([O:18][CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC2CC(Sc3ccccc3)C(C(=O)OC(c3ccccc3)c3ccccc3)C12
Solvent: c1ccncc1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(Sc2ccccc2)CC2CC(=O)C12

Procedure:
A 500 mL, 3-neck flask fitted with an argon inlet, septum cap, thermometer, and stir bar was charged with 7.2 g of 3-phenylthio-7-oxobicyclo[3.2.0]heptan-2-carboxylic acid, diphenylmethyl ester, prepared by the procedure of Paragraph A, dissolved in 200 mL of methylene chloride. To this rapidly stirred solution at -65° was added 5.7 mL of pyridine in one portion, then 1.85 mL of sulfonyl chloride dropwise, slowly. This solution was stirred between -60° and -55° C. for 30 min and then it was poured onto water. The organic phase was washed again with water, then with brine dried over sodium sulfate and evaporated to dryness. The two major components of this mixture was separated on a Waters prep LC/System 500 liquid chromatograph by elution on 2 silica gel cartridges with methylene chloride. The second major component to be eluted was 3-phenylthio-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmether ester, 3.46 g (48.3%) as a colorless solid: NMR (220 MHz; CDCl3): δ 2.27 (1 H, dd, J=17, 3.5), 2.6-3.0 (3H, m), 3.18 (1H, ddd, J=17, 8, 4), 4.57 (1H, m), 6.84 (1H, s), and 7.0-7.5 (15H, m). The analytical sample, mp 148° to 150°, was prepared by recrystallization from benzene-ether.
Reaction SMILES: [OH:1][C@H:2]([CH2:9][O:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4](OCC)=[O:5].[BH4-].[Na+].C(O)(=O)C>C(O)C.O>[C:11]([O:10][CH2:9][C@@H:2]([OH:1])[CH2:3][CH2:4][OH:5])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: OCC[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
In ethanol (10 ml) was dissolved (S)-ethyl 3-hydroxy-4-trityloxybutanoate (0.37 g, 0.975 mmol). Sodium borohydride (0.238 g, 6.29 mmol) was added to the solution and the solution was stirred at room temperature over night. Acetic acid was added to neutralize the solution. The solution was diluted with water (100 ml) and extracted with ethyl acetate. The extract was washed with saturated brine, dried on magnesium sulfate, filtered, and condensed in vacuo. The residue was subjected to silica gel chromatography to give (S)-1-trityloxy-2,4-butanediol (0.28 g, yield 82%).
Reaction SMILES: C([CH:6]([C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1)[CH:7]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[C:26]([O:34][CH:35]([F:37])[F:36])[CH:25]=1)[C:8]1[CH:9]=[N:10][C:11]([N:14]([CH3:23])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)(OCC)=O.[Li+].[OH-].Cl>C1COCC1.CO.O>[F:37][CH:35]([F:36])[O:34][C:26]1[CH:25]=[C:24]([CH:7]([C:8]2[CH:9]=[N:10][C:11]([N:14]([CH3:23])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)=[CH:12][CH:13]=2)[CH2:6][C:38]2[CH:39]=[CH:40][N:41]=[CH:42][CH:43]=2)[CH:29]=[CH:28][C:27]=1[O:30][CH:31]([F:33])[F:32]
Reactant: CCOC(=O)C(c1ccncc1)C(c1ccc(N(C)c2ccc(OC)cc2)nc1)c1ccc(OC(F)F)c(OC(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N(C)c2ccc(C(Cc3ccncc3)c3ccc(OC(F)F)c(OC(F)F)c3)cn2)cc1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a solution of the crude ester from Step 3 above in a mixture of THF/MeOH/water (4.5 mL/1.5 mL/1.5 mL), was added 1.6 mL (3.24 mmol) of a 2 N solution of LiOH. The resulting solution was stirred at 65 ° C. for 3 h, cooled down to room temperature followed by the addition of 3.4 mL of a 1.0 N HCl solution. The resulting mixture was rotovaped down to evaporate MeOH and the aqueous residue was diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layer were washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Gradient 70% Ethyl acetate/hexane to 100% ethyl acetate) to afford 67 mg (47%, 2 steps) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([C:10]([OH:12])=O)=[N:8][S:9][C:5]=2[CH:4]=1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24].CCN(CC)CC.CCCP(=O)=O>CN(C=O)C.CCOC(C)=O.O>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:10]([C:7]2[C:6]3[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[S:9][N:8]=2)=[O:12])=[CH:18][C:17]=1[C:23]([F:24])([F:25])[F:26]
Reactant: COc1ccc2c(C(=O)O)nsc2c1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: CCCP(=O)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(C(=O)Nc3ccc(F)c(C(F)(F)F)c3)nsc2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
209 mg (1.00 mMol) 6-methoxy-benzo[d]isothiazole-3-carboxylic acid (preparation see: WO 2004/029050, Procedure N), 269 mg (1.5 mMol) 4-fluoro-3-trifluoromethyl-aniline and 1.4 ml (10 mMol) Et3N are dissolved in 5 ml of dry DMF and cooled in an ice-bath. Then a solution of 1.17 ml (50% in DMF; 2.0 mMol) propylphosphonic anhydride is added. The mixture is stirred for 15 h at rt, when another 0.58 ml of propylphosphonic anhydride are added. After 2 h, the reaction mixture is poured into water and EtOAc, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed twice with water and brine, dried (Na2SO4) and partially concentrated. Addition of hexane precipitates the title compound: m.p.: 157° C.; MS: [M+1]+=371.
Reaction SMILES: [Li]CCCC.[N+:6]([CH2:9][CH2:10][CH3:11])([O-:8])=[O:7].[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>C1COCC1.C(Cl)Cl>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([CH:19]([OH:20])[CH:9]([N+:6]([O-:8])=[O:7])[CH2:10][CH3:11])=[CH:21][CH:22]=1)([O-:14])=[O:13]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCC[N+](=O)[O-]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC(C(O)c1ccc([N+](=O)[O-])cc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 71.6 %

Procedure:
n-BuLi (1.6 M in hexane, 6.24 mL) was added dropwise with stirring to a solution of nitropropane (0.9mL, 10mmol) in THF (12 mL) at -78° C. After 15 minutes a solution of TiCl3 (OPriso) (5 mmol) in THF (2 mL) and CH2Cl2 (3 mL) solution was added. After a further 15 minutes 4-nitrobenzaldehyde (0.75 mL, 5 mmol) in CH2Cl2 (4 mL) was added and the mixture allowed to warm up to room temperature (~30 min). Stirring was continued for a further 3.5 hours at room temperature and the mixture was quenched with an aqueous slurry of disodium EDTA (1.86 g, 5mmol) and extracted with Et2O (3×75 mL). The combined Et2O fractions were washed with dilute hydrochloric acid (2 M, 75 mL), aqueous sodium bicarbonate (75 mL) and water (75 mL), dried and evaporated in vacuo. Flash column chromatrography [Si2, hexane:Et2O, 3:1 v/v] gave 1-(4-nitrophenyl)-2-nitro-butan-1-ol (0.86 g, 72%) Erythro:threo ratio 7:1.
Reaction SMILES: [CH3:1][N:2]1[C:7](=O)[NH:6][C:5]([CH3:9])=[N:4][S:3]1(=[O:11])=[O:10].P(Cl)(Cl)(Cl)(Cl)[Cl:13].P(Cl)(Cl)(Cl)=O>>[Cl:13][C:7]1[N:2]([CH3:1])[S:3](=[O:11])(=[O:10])[N:4]=[C:5]([CH3:9])[N:6]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC1=NS(=O)(=O)N(C)C(=O)N1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=NS(=O)(=O)N(C)C(Cl)=N1
Temperature: 110 °C
Yield: 100 %

Procedure:
212 parts of 2,5-dimethyl-2H-1,2,4,6-thiatriazin-3-one-1,1-dioxide were introduced into a mixture of 292 parts of phosphorus pentachloride and 1,400 parts of phosphorus oxychloride at room temperature, while stirring. The reaction mixture was heated to 110° C. in the course of 30 minutes, stirred under reflux for 6 hours, and then concentrated under reduced pressure, giving 234 parts (100% of theory) of 3-chloro-2,5-dimethyl-2H-1,2,4,6-thiatriazine-1,1-dioxide of melting point 86°-90° C. (NMR (60 MHz, CDCl3): CH3 -C 2.4δ, CH3 -N 3.68δ).
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH:25][CH3:26])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([N:25]([CH3:26])[C:40]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:41])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)[CH2:14][CH2:15]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN[C@H](CC1CCCCC1)CN1CCN(c2cccc3[nH]ccc23)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)C1CCCCC1)[C@H](CC1CCCCC1)CN1CCN(c2cccc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.6 g (1.69 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(1H-indol-4-yl)-piperazin-1-yl]-ethyl}-methyl-amine and 0.5 mL (3.7 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.25 g (1.69 mmol) of cyclohexanecarboxylic acid chloride in dichloromethane. The reaction mixture was allowed to stir under nitrogen overnight at ambient temperature, and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H2O and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (ethyl acetate/hexanes) and converted to the hydrochloride.0.3 hydrate salt of the title compound with ethereal HCl yield 0.68 g (87%) as a white solid; mp=>260° C.; MS (+) ESI m/z=465 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH:33]=[CH:34][C:35]([N:41]1[CH2:46][C@H:45]([CH3:47])[NH:44][C@H:43]([CH3:48])[CH2:42]1)=[N:36]2>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:44]3[C@H:45]([CH3:47])[CH2:46][N:41]([C:35]4[CH:34]=[CH:33][C:32]5[C:37](=[CH:38][CH:39]=[CH:40][C:31]=5[Cl:30])[N:36]=4)[CH2:42][C@@H:43]3[CH3:48])[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN(c2ccc3c(Cl)cccc3n2)C[C@H](C)N1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: C[C@@H]1CN(c2ccc3c(Cl)cccc3n2)C[C@H](C)N1CCCCC1(C(=O)NCc2ccc(F)cc2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 5-chloro-2-(cis-3,5-dimethyl-piperazin-1-yl)-quinoline.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[CH2:12]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[CH2:12]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: BrCCCCCOCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CS(C)=O
Product: N#CC(C#N)(CCCCCOCc1ccccc1)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 9 h
Yield: 81.5 %

Procedure:
3.5 g of 2-(3,3,3-trifluoropropyl)malononitrile, 5.5 g of 5-bromopentyl benzyl ether and 0.70 g of potassium iodide were dissolved in 20 ml of dimethyl sulfoxide, 3.3 g of potassium carbonate was added, and the mixture was stirred at room temperature for 9 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 5.9 g of 2-(5-benzyloxypentyl)-2-(3,3,3-trifluoropropyl)malononitrile.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=O)[CH2:8]Br)=[CH:5][CH:4]=1)#[N:2].[CH3:13][NH:14][C:15]([NH2:17])=[S:16].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:13][NH:14][C:15]1[S:16][CH:8]=[C:7]([C:6]2[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:17]=1
Reactant: CNC(N)=S
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CNc1nc(-c2ccc(C#N)cc2)cs1
Temperature: 40 °C
Yield: 102.2 %

Procedure:
Slurry 4-cyanophenacyl bromide (1.12 g, 5 mmol) in absolute ethanol (25 mL). Heat to 40° C. to dissolve, then add N-methyl-thiourea (0.45 g, 5 mmol) and sodium bicarbonate (0.42 g, 5 mmol), and heat to reflux for 5 h. Cool to room temperature, filter the resulting off-white solid and wash with hexane (10 mL). Partition aqueous/ethanolic filtrate between water/EtOAc (4:1) and extract aqueous phase with EtOAc (2×25 mL). Dry the combined organic extracts over Na2SO4, concentrate in vacuo and combine with filtered solid from crude reaction mixture to obtain the desired intermediate (1.1 g, 99%) as an off-white solid suitable for use without additional purification. MS (ES+) m/z: 216 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.Cl.[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[O:25])[CH2:20][CH2:19]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)CC)C>[O:16]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:11]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](=[O:25])[C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)[CH2:20][CH2:19]2)=[O:13])=[CH:14][CH:15]=1
Reactant: Cc1ccc(C(=O)C2CCNCC2)cc1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)C2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
4-(1,1-Dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (253 mg) described in Preparation Example 16, (piperidin-4-yl) (p-tolyl)methanone hydrochloride (252 mg), 1-hydroxybenzotriazole 1 hydrate (142 mg) and triethylamine (0.15 mL) were dissolved in N,N-dimethylformamide (5 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (202 mg) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 5% aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (108 mg).
Reaction SMILES: [CH:1]([Mg]Br)([CH3:3])[CH3:2].Br[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:10][C:11]#[N:12].Cl>O1CCCC1.[Br-].[Zn+2].[Br-]>[CH:1]([C:7]1[CH:8]=[C:9]([CH2:10][C:11]#[N:12])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])([CH3:3])[CH3:2]
Reactant: COc1ccc(CC#N)cc1Br
Reactant: CC(C)[Mg]Br
Agent: Cl
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COc1ccc(CC#N)cc1C(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
An isopropylmagnesium bromide-0.63M tetrahydrofuran solution (3.2 ml, 2.0 mmol) was added dropwise to a solution of zinc bromide (473 mg, 2.1 mmol) in tetrahydrofuran (2 ml) under ice-cooling. After the mixture was stirred for 15 minutes, the reaction mixture was cooled to −78° C. After 3-bromo-4-methoxybenzyl cyanide (226 mg, 1.0 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)-dichloromethane adduct (32 mg, 0.04 mmol) were added to the mixture at −78° C., the temperature of the reaction mixture was raised to room temperature and the mixture was further stirred for 5 hours. 1N Hydrochloric acid was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was subjected to silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=8/1-6/1) to give crude (3-isopropyl-4-methoxyphenyl)acetonitrile (158 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl.Br[C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:36])[C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[OH:35])=[CH:22][C:21]=1[F:37]>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].O>[Cl:34][C:32]1[CH:31]=[CH:30][C:29]([OH:35])=[C:28]([CH:33]=1)[C:27]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[C:21]([F:37])[CH:22]=1)=[O:36]
Reactant: OB(O)c1ccncc1
Reactant: O=C(Nc1ccc(Br)c(F)c1)c1cc(Cl)ccc1O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(-c2ccncc2)c(F)c1)c1cc(Cl)ccc1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
4-Pyridineboronic acid (0.185 mg, 1.51 mmol), potassium carbonate (0.240 g, 1.74 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.189 g, 0.232 mmol) and water (0.5 ml) were added to a solution of N-(4-bromo-3-fluorophenyl)-5-chloro-2-hydroxybenzamide (compound of Reference Example 185; 0.400 g, 1.16 mmol) in dioxane (5 ml), and the mixture was stirred at 80° C. for 2 hours. Water was added to the reaction mixture, and the precipitated solid was collected by filtration and washed with acetone and dichloromethane to give the title compound (0.286 g, 72%) as a light grey solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[C@@H:6]1[CH2:25][N:9]2[C:10](=[O:24])[N:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[CH2:12][C@@H:8]2[CH2:7]1.O>CN(C=O)C>[N:1]([C@H:6]1[CH2:25][N:9]2[C:10](=[O:24])[N:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[CH2:12][C@@H:8]2[CH2:7]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@H](Br)CN12
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
Sodium azide (80 mg, 1.2 mmol) was added to a solution of (6S,7aS)-6-Bromo-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (350 mg, 1.0 mmol) in anhydrous DMF (10 mL), the mixture was heated to 70° C. and stirred for 2 hours. The mixture was cooled and poured into water (30 mL), extracted with ethyl acetate (3×20 mL), the organic layers was combined and washed with water (2×20 mL), brine (20 mL), dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with petroleum ether/ethyl acetate=10:1) to give 260 mg (83%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.59 (d, 2H, J=9.3 Hz), 7.19 (d, 2H, J=8.4 Hz), 4.33 (t, 1H, J=6.3 Hz), 4.13-3.98 (m, 3H), 3.75-3.72 (m, 1H), 3.15 (dd, 1H, J1=12.6 Hz, J2=2.1 Hz), 2.19 (dd, 1H, J1=13.2 Hz, J2=3.9 Hz), 1.73-1.63 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([CH:11]=1)[CH2:9][C:8]1[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:7]=1[N:6]=[C:5]2[N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]([CH3:30])([CH3:29])[C:25]([O:27][CH3:28])=[O:26])[CH2:19][CH2:18]1.N1C=CC=[CH:33][CH:32]=1.C(B1OB(C=C)OB(C=C)O1)=C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH2:32]([C:2]1[CH:3]=[C:4]2[N:10]([CH:11]=1)[CH2:9][C:8]1[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:7]=1[N:6]=[C:5]2[N:17]1[CH2:18][CH2:19][N:20]([CH2:23][C:24]([CH3:30])([CH3:29])[C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH2:22]1)[CH3:33]
Reactant: c1ccncc1
Reactant: COC(=O)C(C)(C)CN1CCN(C2=Nc3ccc(C)cc3Cn3cc(Br)cc32)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: C=CB1OB(C=C)OB(C=C)O1
Solvent: CO
Product: CCc1cc2n(c1)Cc1cc(C)ccc1N=C2N1CCN(CC(C)(C)C(=O)OC)CC1
Temperature: 140 °C

Procedure:
Mix methyl 3-[4-(2-bromo-7-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-2,2-dimethylpropanoate (1.00 equiv; 620.00 mg, 1.31 mmoles), triethenylboroxin pyridine (1.5 equiv; 472.79 mg, 1.96 mmoles;) in methanol (15 mL). Add a pre-blended mixture of 1.09 wt % tris(dibenzylideneacetonyl)bis-palladium (Pd2(dba)3), 1.16 wt % 1,1′-bis(di-tert-butylphosphino)ferrocene (dtbpf) and 97.75 wt % tripotassium phosphate (1.10 g) and heat at 140° C. for 25 mins in a microwave. Filter the reaction mixture through celite and dilute to 25 mL volume with methanol. Hydrogenate the methanolic solution by passing at 1 mL/min. through a H-Cube® flow hydrogenator using a 10% Pd/C catalytic cartridge at 50° C. Evaporate the solvent in vacuo to give methyl 3-[4-(2-ethyl-7-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-2,2-dimethylpropanoate. MS (m/z): 423.18 (M+1).
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.Cl.[Br:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2>>[Br:8][C:6]1[N:7]=[C:2]([N:25]2[C:26]3[C:22](=[CH:21][C:20]([O:27][CH3:28])=[CH:19][C:18]=3[Br:17])[CH2:23][CH2:24]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: COc1cc(Br)c2c(c1)CCN2
Reactant: CC[C@H](COC)n1cc(Br)nc(Br)c1=O
Agent: Cl
Product: CC[C@H](COC)n1cc(Br)nc(N2CCc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 122–123° C.; 1H NMR (300 MHz, CDCl3): δ 7.07 (s, 1 H), 6.92 (d, J=2.6 Hz, 1 H), 6.77 (d, J=2.2 Hz, 1 H), 4.95–4.80 (m, 1 H), 4.34 (t, J=7.7 Hz, 2 H), 3.78 (s, 3 H), 3.66 (dd, J=10.7, 5.5 Hz, 1 H), 3.56 (dd, J=10.3, 3.3 Hz, 1 H), 3.35 (s, 3 H), 3.10 (t, J=7.7 Hz, 2 H), 1.87–1.74 (m, 2 H), 0.93 (t, J=7.4 Hz, 3 H); HRMS (ESI) calcd for C18H22N3O3Br2 (M+H)+: 486.0028; found m/z 486.0018.