Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[F:16])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[F:17][C:18]([F:22])([F:21])[CH2:19][NH2:20]>C1COCC1>[F:16][C:15]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH2:2][NH:20][CH2:19][C:18]([F:22])([F:21])[F:17]
Reactant: CC(C)(C)OC(=O)c1ccc(F)c(CBr)c1
Reactant: NCC(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(F)c(CNCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 72 %

Procedure:
A mixture of tert-butyl 3-bromomethyl-4-fluorobenzoate (14 g, 48 mmol) and 2,2,2-trifluoroethylamine (25 g, 250 mmol) in THF (300 mL) was stirred under argon at RT for 4 d, concentrated, and the residue partitioned between Et2O and 10% K2CO3. The organic phase was washed with 10% K2CO3 and brine, dried, and concentrated. The residue was purified by chromatography (silica gel, step gradient, 0-8% ethyl acetate/hexane) to give the title compound as a pale yellow oil (10.7, 72%): MS (ES) m/e 308.3[M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][N:10]([C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=1)[S:29]([C:20]1[CH:21]=[CH:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=1)(=[O:31])=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNc1cncc(Br)c1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCN(c1cncc(Br)c1)S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of Example 386A (50 mg, 0.158 mmol) in pyridine (2 mL) was added 2-naphthalenesulfonyl chloride (72 mg, 0.316 mmol) at rt. The formed yellow solution was stirred at rt for 15 h. Pyridine was removed by blowing with nitrogen and the residual yellow solid was purified by flash chromatography (30-60% EtOAc in hexane) to the desired product (81 mg, 100%). MS (DCI) m/z 506, 508 (M+1)+.
Reaction SMILES: [CH:1]([CH:4]([CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].[C:17]([CH:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)#[N:18]>>[CH:1]([CH:4]([CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:5]([O:7][CH:19]([C:17]#[N:18])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:21]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C=Cc1ccc(F)cc1)C(=O)O
Product: CC(C)C(C=Cc1ccc(F)cc1)C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1

Procedure:
2-Isopropyl-4-(4-fluorophenyl)-3-butenoic acid (1.12 mmol) is reacted via the acid chloride with α-cyano-m-phenoxybenzyl alcohol (1.86 mmol) to yield α-cyano-m-phenoxybenzyl 2-isopropyl-4-(4-fluorophenyl)-3-butenoate, MS m/e 429 (M+).
Reaction SMILES: [NH2:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[S:12][CH:13]=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.[F:21][C:22]([F:30])([F:29])[S:23]([CH2:25][C:26](Cl)=[O:27])=[O:24].[OH-].[Na+]>C(=O)(O)[O-].[Na+].CC(C)=O>[F:21][C:22]([F:30])([F:29])[S:23]([CH2:25][C:26]([NH:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[S:12][CH:13]=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12)=[O:27])=[O:24]
Reactant: O=C(Cl)CS(=O)C(F)(F)F
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(CS(=O)C(F)(F)F)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Reaction time: 0.5 h

Procedure:
To a solution of 3.1 g (0.009 mol) of 7-amino-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid in 60 ml of 3 percent aqueous sodium bicarbonate is added 60 ml of acetone. The solution is cooled to -15° and 1.94 g (0.010 mol) of trifluoromethylsulfinylacetyl chloride in 20 ml of acetone is added over a 10-minute period. The reaction mixture is stirred at -15° for 30 minutes while maintaining the pH at 7.6-8.0 by addition of 10 percent sodium hydroxide, then at 25° for one hour. The reaction mixture is extracted once with ether and the aqueous phase is acidified to pH 2.5 with dilute hydrochloric acid and extracted with ethyl acetate. The organic extracts are dried (MgSO4) and concentrated in vacuo to give the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH2:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[C:3]1=[O:25].C(N(CC)CC)C.Cl[C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([C:44]([F:47])([F:46])[F:45])[CH:42]=2)[N:37]=[CH:36][N:35]=1>CCO>[CH:15]([N:13]([CH3:14])[C@@H:10]1[CH2:11][CH2:12][C@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[C:41]([C:44]([F:46])([F:47])[F:45])[CH:42]=4)[N:37]=[CH:36][N:35]=3)[C:3]2=[O:25])[C@H:8]([CH2:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:9]1)([CH3:17])[CH3:16]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](Nc3ncnc4ccc(C(F)(F)F)cc34)C2=O)[C@H](CS(=O)(=O)C(C)C)C1
Temperature: 80 °C
Yield: 43.9 %

Procedure:
To a solution of (S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(isopropylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one (75 mg, 0.14 mmol) in EtOH (2 mL) was added triethylamine (0.12 mL, 0.84 mmol) and 4-chloro-6-(trifluoromethyl)quinazoline (39 mg, 0.16 mmol). The mixture was heated at 80° C. for 14 h and then concentrated in vacuo. The residue was pjurified by HPLC to provide the title compound, (S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(isopropylsulfonylmethyl)cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one (35 mg, 44% yield). MS found: (M+H)+=570.
Reaction SMILES: Cl.C(N[C:6](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[C:7]([OH:9])=[O:8])(=O)C.[OH2:19].C1(C)C=CC=CC=1>CN1CCCC1=O>[Cl:18][C:13]1[CH:12]=[C:11]([CH2:10][C:6](=[O:19])[C:7]([OH:9])=[O:8])[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: CC(=O)NC(=Cc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: O
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: O=C(O)C(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 125 °C

Procedure:
140 mL 4 M HCl were added to a suspension of 21.0 g (76.6 mmol) 2-acetylamino-3-(3,4-dichloro-phenyl)-acrylic acid in 100 mL N-methyl-2-pyrrolidinone and the reaction mixture was then heated for 4 h at an oil bath temperature of 125° C. The cooled reaction solution was poured onto a cooled mixture of 350 mL water and 120 mL toluene. The phases were separated, the aqueous phase was again extracted with toluene, the combined organic phases were extracted with water, filtered through Na2SO4 and evaporated down i. vac. The residue was taken up in 1 M NaOH and washed twice with diethyl ether. The aqueous phase was acidified with 2 M HCl and extracted three times with EtOAc. The combined organic phases were filtered through Na2SO4 and evaporated down i. vac. The residue was combined with diethyl ether, suction filtered and dried in the vacuum drying cupboard.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:2]2[S:6][C:5]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])=[CH:4][CH:3]=2)[CH:21]=1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)s1
Reactant: OB(O)c1cccnc1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2cccnc2)s1

Procedure:
The title compound was prepared by a method analogous to that described in Example 1 from (R)-3′-(5-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and pyridine-3-boronic acid. The title compound (24 mg) was isolated as the hydrochloride salt which was an off-white solid, m/z 342 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1Cl.[CH3:11][C:12]1[NH:13][CH:14]=[CH:15][N:16]=1>O1CCOCC1>[Cl:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1[N:13]1[CH:14]=[CH:15][N:16]=[C:12]1[CH3:11]
Reactant: Cc1ncc[nH]1
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Solvent: C1COCCO1
Product: Cc1nccn1-c1cnn(C)c(=O)c1Cl
Yield: 27.3 %

Procedure:
A solution of 10.0 g (54.2 mmol) of 4,5-Dichloro-2-methyl-2H-pyridazin-3-one (CAS: [933-76-6]) and 8.90 g (108.4 mmol) of 2-methylimidazole in 50 ml of dioxane was stirred for 16 h at 100° C. The solution was concentrated in vaccuo and the residue was purified by flash chromatography over silicagel using a 95:5 mixture of methylene chloride and methanol as eluant to yield 3.33 g (14.82 mmol, 27%) of the title compound as a white crystalline solid, MS: m/e=225.1, 227.1 (M+H+).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:24])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][CH2:22][CH3:23])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH2:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH:25](/[C:2]1[N:3]=[C:4]([NH2:24])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][CH2:22][CH3:23])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])=[CH:26]\[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: C=CCCCC
Reactant: CCCNc1nc2c(N)nc(I)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: CCCC/C=C/c1nc(N)c2nc(NCCC)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reaction time: 0.58 h

Procedure:
The reaction was performed with 2-iodo-8-propylaminoadenosine (9, 400 mg, 0.89 mmol) and (E)-1-borocatechol)-1-hexene (2.67 mmol). The mixture was purified by column chromatography (10% MeOH in CH2Cl2). Yield 43 mg (0.11 mmol, 12%), mp 170–172÷C; Rƒ 0.41 (10% MeOH in CH2Cl2); 1H NMR (MeOD-d4) δ 6.93–6.82 (m, 1H, ═CHCH2), 6.29 (d, 1H, J=15.48 Hz, ═CH), 6.04 (d, 1H, J=7.65 Hz, H-1′), 4.79–4.74 (m, 1H, H-2′), 4.29–4.26 (m, 1H, H-3′), 4.13–4.12 (m, 1H, H-4′), 3.81 (q, 2H, J=8.24 Hz, H-5′), 3.37–3.32 (m, 2H, NHCH2), 2.24 (q, 21H, J=7.16 Hz, ═CHCH2), 1.89–1.66 (m, 2H, NHCH2CH2), 1.51–1.35 (m, 4H, CH2CH2), 1.02–0.91 (m, 6H, 2×CH3); MS m/z 407 (M+H)+; HPLC, System A: 20–100% CH3CN in H2O in 35 min., retention time=8.10 min.; System B: 30–100% CH3OH in H2O in 40 min., retention time=20.25 min.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:24])=[C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)(=[O:13])=[O:12])[CH:9]=1)(=[O:3])[CH3:2].C[Li].[CH3:27]COCC>C1COCC1>[Cl:24][C:7]1[CH:6]=[CH:5][C:4]([C:1]([OH:3])([CH3:27])[CH3:2])=[CH:9][C:8]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)(=[O:13])=[O:12]
Reactant: CCOCC
Reactant: COc1ccc(S(=O)(=O)Nc2cc(C(C)=O)ccc2Cl)cc1OC
Agent: [Li]C
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)Nc2cc(C(C)(C)O)ccc2Cl)cc1OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of N-(5-acetyl-2-chloro-phenyl)-3,4-dimethoxy-benzenesulfonamide (1.4 g, 3.8 mmol) in THF (16 mL) at −78° C. was added dropwise a solution of methyl lithium in ether (1.6 M, 6.5 mL, 2.75 eq). The mixture was stirred at −78° C. for 30 min and then allowed to warm to RT. The mixture was partitioned between EA and NH4Cl solution, the aqueous phase was once more extracted with EA and the combined organic layers were dried over MgSO4 and concentrated. The residue was purified by chromatography on SiO2 (hex/EA 2:1, 1:1) to give the desired product (0.97 g, 67%) as a yellowish foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:21][CH2:22][C:23]#[N:24])[C:9](=O)[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.CO>C1COCC1>[NH2:24][CH2:23][CH2:22][CH2:21][N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:9][CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16]
Reactant: CN(CC(=O)N(CCC#N)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CN(CCN(CCCN)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 104465.6 %

Procedure:
tert-butyl 2-((3-chlorophenyl)(2-cyanoethyl)amino)-2-oxoethyl(methyl)carbamate (500 mg, 1.4 mmol) was dissolved in anhydrous THF (10 mL) and heated to reflux under nitrogen atmosphere. A solution of BH3.MeS in THF was added drop wise and stirring was continued under reflux overnight. The resulting solution was cooled to room temperature. Methanol was added drop wise to quench the reaction. After evaporation of the solution, the crude product was purified by column chromatography to afford the pure product tert-butyl 2-((3-aminopropyl)(3-chlorophenyl)amino)ethyl(methyl)carbamate (500 g, yield 99%).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([NH2:21])=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[NH:21][C:25]([CH:22]3[CH2:24][CH2:23]3)=[O:26])[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Product: O=C(Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12)C1CC1

Procedure:
The title compound, MS: m/e=344.3 (M+H+), was prepared in accordance with the general method of example 18 from (R)—N2-indan-1-yl-quinoline-2,5-diamine and cyclopropane carbonyl chloride.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH:11](O)[CH2:10][CH2:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=[O:18]>>[C:1]1([C:7]2[CH2:12][CH2:11][C:10](=[O:18])[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(O)CC1c1ccccc1
Reactant: O=C(O)C(F)(F)F
Product: O=C1CC=C(c2ccccc2)CC1

Procedure:
The phenyl-4-hydroxycyclohexanone produced in step (2), on mixing with a strong acid such as trifluoroacetic acid at moderate (room) temperature, yields 4-phenyl-3-cyclohexen-1-one. The thus produced compound (without isolation) is reduced at the 3-position of the cyclohexane ring, (e.g., with hydrogen in the presence of a catalyst such as palladium on charcoal) to yield 4-phenylcyclohexanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:26](=[O:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[N:8]1[C:13]2=[N:14][C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([CH:22]([OH:25])[CH2:23][CH3:24])[C:16]=3[N:12]2[CH2:11][CH2:10][CH2:9]1.[O:29]1CC[CH2:31][CH2:30]1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:30]([O:25][CH:22]([C:17]1[C:16]2[N:12]3[CH2:11][CH2:10][CH2:9][N:8]([C:7]4[CH:6]=[CH:5][C:4]([C:26](=[O:28])[CH3:27])=[CH:3][C:2]=4[Cl:1])[C:13]3=[N:14][C:15]=2[C:20]([Cl:21])=[CH:19][CH:18]=1)[CH2:23][CH3:24])(=[O:29])[CH3:31]
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(C(C)=O)cc1Cl
Reactant: C1CCOC1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCC(OC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(C(C)=O)cc1Cl
Temperature: 25 °C
Reaction time: 7 h
Yield: 70 %

Procedure:
To a solution of 1-{3-Chloro-4-[9-chloro-6-(1-hydroxypropyl)-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl]phenyl}ethanone (120.0 mg, 0.287 mmol) in pyridine (0.2 mL)/tetrahydrofuran (0.5 mL) was added acetic anhydride (0.5 mL) at 0° C. The reaction mixture was stirred at room temperature for 7 hrs. The mixture was concentrated. The residue was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-40% ethyl acetate/n-hexane gradient mixture. The residue was recrystallized from ethanol/n-hexane to give the title compound as a colorless powder (92.5 mg, 0.201 mmol, 70%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[CH:12]=2)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31][CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1>>[F:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]([C:19]3[CH:20]=[CH:21][C:22]4[C:23]5[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31][CH2:30][CH2:29][C:24]=5[N:25]([CH3:28])[C:26]=4[CH:27]=3)[C:13](=[O:17])[CH:12]=2)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Reactant: O=c1cc(OCc2ncc(F)cc2F)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ncc(F)cc5F)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Yield: 52.2 %

Procedure:
4-((3,5-Difluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (206 mg, 0.544 mmol) and tert-butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (100 mg, 0.418 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (117 mg, 50%) as a yellow oil; ESI MS m/z 537 [M+H]+;
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:13][N:12]([C:14]2[C:15]3[N:16]([N:20]=[N:21][N:22]=3)[CH:17]=[CH:18][N:19]=2)[CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].CN(C=O)C.[Br:28]N1C(=O)CCC1=O>O>[Br:28][C:17]1[N:16]2[N:20]=[N:21][N:22]=[C:15]2[C:14]([N:12]2[CH2:13][CH:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7])[CH2:11]2)=[N:19][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C(=O)OC(C)(C)C)C1CN(c2nccn3nnnc23)C1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CN(c2ncc(Br)n3nnnc23)C1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
A 3 L round bottom flask was charged with tert-butyl methyl(1-(tetrazolo[1,5-a]pyrazin-8-yl)azetidin-3-yl)carbamate (200 g, 0.66 mol) and DMF (1 L). To the above was added N-bromosuccinimide (117 g, 0.66 mol) in portions at 10° C. The resulting mixture was stirred at 10° C. for 0.5 h. Work-up: the reaction mixture was poured into water (3 L). The resulting crystalline solid was collected by filtration, washed with water (500 mL), and dried to afford 200 g (79%) of the product as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([C@@H:12]([NH2:14])[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([CH:12]([NH:14][S:2]([CH3:1])(=[O:4])=[O:3])[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CS(=O)(=O)Cl
Product: CC(NS(C)(=O)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
TEA (2.90 mL, 20.9 mmol) and methanesulfonylchloride (2.0 g, 17.46 mmol). were added to a solution of (S)-1-phenyl-ethylamine Compound 3h1 (2.13 g, 17.46 mmol) at 0° C., under a N2 atmosphere. The mixture was stirred for 3 hrs, while warming to r.t. The reaction was quenched with water (20 mL) and the organic layer was diluted with CH2Cl2 (100 mL), washed with water and brine, separated and dried with anhydrous sodium sulfate, then filtered and concentrated in vacuo to yield N-(1-phenyl-ethyl)-methanesulfonamide Compound 3h2 as an oil.
Reaction SMILES: O=[C:2]([NH:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27])[C:3](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10])=[O:5].C(Cl)(=O)C(Cl)=O>C1C=CC=CC=1.CN(C=O)C>[CH:20]1[CH:19]=[CH:18][C:17]([CH:16]=[C:3]([C:4]2[O:5][C:9](=[O:10])[C:8]3[C:7](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:6]=2)[C:2]2[O:27][C:26](=[O:28])[C:25]3[C:24](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:23]=2)=[CH:22][CH:21]=1
Reactant: O=C(Nc1ccccc1C(=O)O)C(=Cc1ccccc1)C(=O)Nc1ccccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=c1oc(C(=Cc2ccccc2)c2nc3ccccc3c(=O)o2)nc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The Compound 11 (4 g, 9.28 mmol) was suspended in dry benzene (100 ml) and oxalyl chloride (3.2 ml, 37.18 mmol) was added dropwise under ice cooling. Then, with addition cf 8 drops of dry DMF, the mixture was stirred at room temperature for 2 hours. After the reaction, the solvent was removed and the residue was extracted with chloroform. The organic layer was washed with 1N.HCl, saturated brine, 4% NaHCO3 aqueous solution, and saturated brine and dried over magnesium sulfate. The solvent was evaporated. The residue was dissolved in chlcroform and applied on silica gel column for chromatography (benzene ethyl acetate=4:1). Recrystallization from isopropyl ether gave the desired compound 52 in crystal (3.26 g, yield, 89%). m.p., IR, and NMR pectra of the product fully agreed with those of the one obtained in Example 19.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[C:12](Br)[CH:13]=[CH:14][CH:15]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1>>[CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[C:12]([C:33]3[C:28]([F:27])=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccnc1F
Reactant: Brc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CC2
Product: Fc1ncccc1-c1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CC2
Yield: 75 %

Procedure:
The title compound was synthesized as described for Intermediate example I-4 in 75% yield, starting from (2R)-N,N-dibenzyl-8-bromo-1,2,3,4-tetrahydronaphthalen-2-amine and 2-fluoropyridine-3-boronic acid; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.29-8.34 (m, 1 H), 7.78-7.89 (m, 1 H), 7.41-7.52 (m, 1 H), 7.21-7.30 (m, 8 H), 7.11-7.21 (m, 4 H), 7.01 (dd, 1 H), 3.51-3.61 (m, 4 H), 2.89-3.00 (m, 1 H), 2.83 (br. s., 1 H), 2.59-2.78 (m, 2 H), 2.34-2.46 (m, 1 H), 2.00-2.12 (m, 1 H), 1.64-1.79 (m, 1 H); MS (ESI) m/z 424[M+H+].
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1>CS(C)=O.C(#N)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:32][CH2:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:23][CH:24]=1
Reactant: NCCc1ccc(O)cc1
Reactant: O=C(COc1ccc(Cl)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Solvent: CC#N
Solvent: CS(C)=O
Product: O=C(NCCc1ccc(O)cc1)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2

Procedure:
A solution of 2,2,2-trichloro-1-{10-[(4-chlorophenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 67 (0.3 mmol) and tyramine (0.62 mmol) in dimethylsulfoxide (0.2 mL) and acetonitrile (4 mL) was stirred at 80° C. for 18 hours. The solvents were evaporated and the residue was dissolved in dichloromethane, washed with water, dried over anhydrous sodium sulfate and evaporated. The compound was purified by HPLC (normal phase, Luna® CN bonded packing) and crystallized from ethyl acetate/hexane (0.12 g), m.p. 206-207 ° C. MS [(+)ESI, m/z]: 516 [M+H]+ Anal. Calcd for C29H26CIN3O4: C, 67.50; H, 5.08; N, 8.14. Found: C, 67.35; H, 5.07; N, 8.08.