Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](OP(N3CCOCC3)(N3CCOCC3)=O)[CH2:9][N:8]=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:33]=1.[SH2:34]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:34])[CH2:9][N:8]=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:33]=1
Reactant: S
Reactant: O=P(OC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)(N1CCOCC1)N1CCOCC1
Solvent: C1CCOC1
Product: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1

Procedure:
To a stirred solution of 245 mg. (0.5 mmole) of 7-chloro-2-di-(morpholino)phosphinyloxy-5-phenyl-3H-1,4-benzodiazepine in 10 ml. of tetrahydrofuran containing 0.5 ml. of triethylimine at room temperature was introduced a stream of hydrogen sulfide gas until tlc indicated that all the starting material was consumed (15 minutes). Tetrahydrofuran was evaporated. The residue was partitioned between methylene chloride and water. The methylene chloride layer was dried and evaporated. Crystallization of the residue from methanol yielded, in two crops, a product having a melting point of 243°-245°.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Br:10])[N:4]=1.[O:11]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12]1>>[Br:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][O:17][CH2:16][CH:13]2[CH2:14][CH2:15][O:11][CH2:12]2)[N:4]=1
Reactant: OCC1CCOC1
Reactant: BrCc1cccc(CBr)n1
Product: BrCc1cccc(COCC2CCOC2)n1
Yield: 37 %

Procedure:
Prepared from 2,6-bis(bromomethyl)pyridine and (RS)-tetrahydrofuran-3-methanol by the alkylation method described for the final step of Example 32 to give the title compound (37%); NMR δH (400 MHz, CDCl3) 7.70 (1H, t, J 8.0 Hz), 7.37-7.33 (2H, m), 4.63 (2H, s), 4.53 (2H, s), 3.89-3.82 (2H, m), 3.77-3.72 (1H, m), 3.65-3.61 (1H, m), 3.56-3.46 (1H, m), 2.66-2.56 (1H, m), 2.09-1.99 (1H, m), 1.69-1.60 (1H, m); (M+H)+ 286, 288.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH:10]1([CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[C:18](Cl)=[O:19])[CH2:12][CH2:11]1>>[CH:10]1([CH2:13][O:14][C:15]2[CH:16]=[C:17](/[C:18](/[O:19][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:15]([O:14][CH2:13][CH:10]4[CH2:12][CH2:11]4)[CH:16]=3)=[CH:8]/[C:7]3[C:6]([Cl:9])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:12][CH2:11]1
Reactant: COc1ccc(C(=O)Cl)cc1OCC1CC1
Reactant: Cc1c(Cl)cncc1Cl
Product: COc1ccc(C(=O)O/C(=C\c2c(Cl)cncc2Cl)c2ccc(OC)c(OCC3CC3)c2)cc1OCC1CC1

Procedure:
The compound was obtained starting from 3,5-dichloro-4-methyl-pyridine and 3-(cyclopropylmethoxy)-4-methoxy-benzoyl chloride, following the procedure of Example 31.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[CH:22][C:21]=3[Cl:34])[C:15]2=[O:35])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>C(Cl)Cl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:34][C:21]1[CH:22]=[C:23]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[CH:24]=[C:25]([Cl:26])[C:20]=1[CH2:19][C@@H:16]1[CH2:17][CH2:18][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15]1=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(F)cc4)cc3Cl)C2=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1[C@H](Cc2c(Cl)cc(-c3ccc(F)cc3)cc2Cl)CCN1C1CCNCC1
Yield: 85 %

Procedure:
Treat a solution of 4-[(R)-3-(3,5-Dichloro-4′-fluoro-biphenyl-4-ylmethyl)-2-oxo-pyrrolidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Preparation 17) (0.85 g, 0.18 mmol) in CH2Cl2 (10 mL) with Trifluoroacetic acid (2 mL). Stir the reaction 1 hr at room temperature. Concentrate the reaction in vacuo. Purify the crude on a SCX column using 2M NH4 in MeOH to elute the pure product. Remove the solvent to afford 0.59 g (85%) of product. MS (m/e): 421 (M+1).
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6]([O:8]CC)=O.[Cl:15][C:16]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][C:17]=1[C:18]([O:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:19].Cl>C(OCC)C.CN(C)C=O>[Cl:15][C:16]1[CH:32]=[CH:31][C:30]([N:33]2[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:34]2=[O:35])=[CH:29][C:17]=1[C:18]([O:20][C:21]([CH3:27])([CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:19]
Reactant: CCOC(=O)C(C)(C)OC(=O)c1cc(N=C=O)ccc1Cl
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)ccc1Cl
Temperature: -5 °C

Procedure:
4.9 g of sodium hydride (50% dispersion in white oil) are added to 120 ml of dimethylformamide while stirring and the mixture is cooled to -5° C. At this temperature a solution of 22.4 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 180 ml of diethyl ether is added dropwise during 30 minutes. The reaction mixture is stirred at room temperature for one hour and thereafter cooled to -65° C. A solution of 28 g of ethyl 2-(2-chloro-5-isocyanato-benzoyloxy)-2-methylpropionate in 100 ml of dimethylformamide is now added dropwise during 30 minutes. The reaction mixture is stirred at -65° C. for 2 hours; thereafter it is left to warm to room temperature. The reaction mixture is introduced into 300 ml of 1N hydrochloric acid at 0° C. The mixture is extracted twice with 300 ml of ethyl acetate each time. The organic phases are back-washed once with 200 ml of water and once with 200 ml of saturated sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate/n-hexane. There is obtained ethyl 2-{2-chloro-5-[3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-benzoyloxy}-2-methylpropionate, m.p. 176°-177° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:28][O:29][CH3:30])[C:9]([C:11]3[S:12][C:13]4[C:19]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)=[CH:18][CH:17]=[C:16]([O:26][CH3:27])[C:14]=4[N:15]=3)=[N:10][C:5]2=[CH:4][CH:3]=1>N1CCOCC1>[CH3:30][O:29][CH2:28][N:8]1[C:6]2=[N:7][C:2]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:3][CH:4]=[C:5]2[N:10]=[C:9]1[C:11]1[S:12][C:13]2[C:19]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:18][CH:17]=[C:16]([O:26][CH3:27])[C:14]=2[N:15]=1
Reactant: COCn1c(-c2nc3c(OC)ccc(N4CCOCC4)c3s2)nc2ccc(Cl)nc21
Solvent: C1COCCN1
Product: COCn1c(-c2nc3c(OC)ccc(N4CCOCC4)c3s2)nc2ccc(N3CCOCC3)nc21
Temperature: 150 °C
Yield: 135.5 %

Procedure:
g 5-Chloro-3-methoxymethyl-2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3H-imidazo[4,5-b]pyridine (0.22 mmol) were dissolved in morpholine (5 ml) in an autoclave and heated to 150° C. for 16 h. The residue was triturated in water whereupon a precipitate formed, which was isolated and dried in vacuo. 0.074 g 3-methoxymethyl-2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-5-morpholin-4-yl-3H-imidazo[4,5-b]pyridine (66%) were obtained as a yellow solid; M.p.: 126–128° C.
Reaction SMILES: [F:1][C:2]([F:31])=[CH:3][C@@:4]12[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([O:22]C)[CH:16]=[CH:15][C:14]=3[C:13]1=[CH:12][CH2:11][C@@:9]1([CH3:10])[C@H:5]2[CH2:6][CH2:7][C@@H:8]1[O:24]C1CCCCO1.CC(C[AlH]CC(C)C)C>CCOCC>[F:1][C:2]([F:31])=[CH:3][C@@:4]12[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[C:13]1=[CH:12][CH2:11][C@@:9]1([CH3:10])[C@H:5]2[CH2:6][CH2:7][C@@H:8]1[OH:24]
Reactant: COc1ccc2c(c1)CC[C@]1(C=C(F)F)C2=CC[C@]2(C)[C@@H](OC3CCCCO3)CC[C@H]21
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOCC
Product: C[C@]12CC=C3c4ccc(O)cc4CC[C@@]3(C=C(F)F)[C@@H]1CC[C@@H]2O

Procedure:
105 mg of 8β-(2,2-difluorovinyl)-3-methoxy-17β-(tetrahydropyran-2-yloxy)-estra-1,3,5(10),9(11)-tetraene was reacted according to general operating instructions 19 for ether cleavage with DIBAH/acid. The yield of colorless crystals with a melting point of 103-106° C. was 75 mg (93%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.O.O.Cl.Cl.[NH2:20][CH:21]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=[CH:35][CH:34]=2)=[CH:28][CH:27]=1)[C:22]([OH:24])=[O:23].C([O-])([O-])=O.[K+].[K+].Cl>CS(C)=O.O>[C:22]([CH:21]([NH:20][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=[CH:35][CH:34]=2)=[CH:28][CH:27]=1)([OH:24])=[O:23]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(Cc1ccc(Nc2ccnc3ccccc23)cc1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccc(Nc2ccnc3ccccc23)cc1)C(=O)O
Temperature: 110 °C
Reaction time: 24 h
Yield: 83.6 %

Procedure:
A mixture of 2,6-dichloro-quinoline-3-carboxylic acid (0.17 g, 0.7 mmol), 2-amino-3-[4-(quinolin-4-ylamino)-phenyl]propionic acid dihydrochloride dihydrate (0.291 g, 0.7 mmol) and K2CO3 (0.507 g, 3.7 mmol) in DMSO (1.5 mL) is stirred at 110° C. temperature for 24 h in a Pierce reaction vial. After cooling the reaction mixture is diluted with water (10 mL) and acidified with 2N aqueous HCl till pH ˜3. The precipitated solid is collected on filter and washed with water to give the title compound (0.3 g, 84%) as yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[Li]CCCC.C([O:16][C:17](=O)[CH:18]([F:20])[F:19])C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:17](=[O:16])[CH:18]([F:20])[F:19])[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(I)c1
Reactant: CCOC(=O)C(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1cccc(Br)c1)C(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1-Bromo-3-iodo-benzene (22.5 g, 90 mmol, Aldrich) was dissolved in THF and cooled to −78° C. nBuLi (69.8 ml, 90 mmol) was added over 15 minutes and the reaction was stirred for 30 min. at −78° C. Difluoro-acetic acid ethyl ester (16.59 ml, 153 mmol, Aldrich) was added dropwise and stirring was continued for 3 hrs. After completion the reaction was quenched by the addition of 329 ml 2 M HCl solution and reaction was warmed to r.t. The phases were separated and the aqueous phases was extracted with Et2O. The organic phases were washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by automated column chromatography (cyclohexane/ethyl acetate) to yield the title compound as a yellow oil. 1H-NMR (360 MHz, DMSO-d6): 8.18 (s, 1H), 8.02 (m, 2H), 7.61 (t, 1H), 7.21 (t, 1H, CHF2); GC/MS: 234 [(M+H)+].
Reaction SMILES: [Cl:1][CH2:2]CO.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]#N)=[CH:8][CH:7]=1.C(P(CC)CC)C.C(OCC)C>CC(C)=O.O>[Cl:1][CH2:2][CH2:13][S:12][C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=1
Reactant: OCCCl
Reactant: N#CSc1ccc(O)cc1
Agent: CCP(CC)CC
Solvent: O
Solvent: CCOCC
Solvent: CC(C)=O
Product: Oc1ccc(SCCCl)cc1

Procedure:
2-chloro-ethanol (3.9 g, 0.049 mole) was added to a solution of the product of Example 35 (7.4 g, 0.049 mole) in acetone (50 ml). After cooling with an ice bath triethylphosphine (5.6 g, 0.047 mole) was added dropwise over 25 minutes. Ethyl ether (200 ml) and water (75 ml) were added and the layers separated. The organic layer was washed with water (4×50 ml) and saturated sodium chloride (2×25 ml) dried over magnesium sulfate, filtered and concentrated to give a yellow oil. The structure was confirmed by its NMR spectrum.
Reaction SMILES: C1O[C:4]([CH:7]2[C:12](=[O:13])[CH:11]([CH3:14])[CH2:10][N:9]([C:15]([O:17][CH3:18])=[O:16])[CH2:8]2)([NH:5]O)[O:3]C1.OS(O)(=O)=O.[OH-].[Na+]>O>[OH:3][C:4]1[C:7]2[CH2:8][N:9]([C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH:11]([CH3:14])[C:12]=2[O:13][N:5]=1
Reactant: COC(=O)N1CC(C)C(=O)C(C2(NO)OCCO2)C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N1Cc2c(O)noc2C(C)C1
Reaction time: 0.5 h

Procedure:
(RS)-1-Methoxycarbonyl-4-oxo-5-methylpiperidine-3-carbohydroxamic acid ethylene ketal (3.95 g; 14.4 mmol) was at 5° C. added in small portions to a mixture of 96% H2SO4 (9 ml) and water (1 ml). The mixture was then kept at 50° C. for 30 min. and poured on ice. The pH was adjusted to 3 with 9N sodium hydroxide and the mixture was extracted three times with methylene chloride (75 ml). Evaporation in vacuo yielded 2.23 g of crude product. To obtain an analytically pure sample the crude product was purified by CC (eluent: ethyl acetate containing 2% methanol and 2% glacial acetic acid). Recrystallization from toluene yielded the pure title compound, M.P. 128°-129° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]1[CH2:11][C:12](=[O:15])[CH2:13][CH2:14][C:8]1=[C:7]2[CH2:16][C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18].[CH3:23][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]1[CH:11]([CH3:23])[C:12](=[O:15])[CH2:13][CH2:14][C:8]1=[C:7]2[CH2:16][C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCCOC(=O)Cc1c2n(c3c(F)cccc13)CC(=O)CC2
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCCOC(=O)Cc1c2n(c3c(F)cccc13)C(C)C(=O)CC2
Reaction time: 0.17 h

Procedure:
A solution of propyl (4-fluoro-7-oxo-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate in THF (0.17 M) was treated at −78° C. with a 1.0 M solution of NaHMDS in THF (1.2 eq.). After stirring for 10 min, MeI (2.0 eq.) was added. The cooling bath was removed and the mixture stirred for 1 hour, concentrated to dryness and the residue purified by chromatography on SiO2 (0-100% EtOAc/hexanes).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][CH:28]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:33]([C:30]5[CH:31]=[CH:32][C:27]([C:36]6[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=6)=[CH:28][CH:29]=5)=[O:34])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(-c2ccccc2)cc1

Procedure:
The title compound, white solid (112 mg, 88%), MS (ISP) m/z=509.5 [(M+H)+], mp 241° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and biphenyl-4-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:21]>CN1C(=O)CCC1.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[O:21])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(=O)c2ccc(F)cc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 11.1 %

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (7 g, 0.032 mol) in 3 mL of NMP, KOH (12.7 g, 0.226 mol) was added at RT. The reaction mixture was stirred well at RT for 20 min. Then a solution of 2-bromo-1-(4-fluorophenyl)ethanone (6.5 g, 0.032 mol) in 2 mL NMP was added dropwise into the reaction mixture at RT over 2-4 h. The reaction was monitored by LCMS and TLC. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by column chromatography, providing the desired product (1.2 g, 11.02%). 1HNMR (CDCl3, TFA salt) d (ppm): 8.18-8.01 (m, 2H), 7.71 (s, 1H), 7.30 (s, 1H), 7.22-7.10 (m, 2H), 7.00 (d, 1H), 3.60-3.31 (m, 4H), 3.20-3.06 (m, 2H), 2.85-2.70 (m, 2H), 2.45 (s, 6H).
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[CH3:23].[CH3:24][N:25]1C=CN=C1>[Fe-4](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].[K+].[Cu]I>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:24]#[N:25])=[C:3]([CH3:23])[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: Cn1ccnc1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(Br)sc2n1
Agent: N#C[Fe-4](C#N)(C#N)(C#N)(C#N)C#N
Agent: [Cu]I
Agent: [K+]
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(C#N)sc2n1
Temperature: 160 °C
Reaction time: 16 h
Yield: 28.6 %

Procedure:
To a solution of N-(2-bromo-3,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 77) (100 mg, 0.232 mmol) in 1-methylimidazole (1.5 mL, 18.82 mmol) was added potassium ferrocyanide (17.06 mg, 0.046 mmol) and copper(I) iodide (4.41 mg, 0.023 mmol) and the reaction stirred at 160° C. for 16 h. The reaction mixture was then cooled to RT before directly purifying on silica, eluting with a gradient of 0-20% 2M NH3 in MeOH in DCM. Further purification by MDAP (acidic conditions), afforded the title compound (25.1 mg). LCMS (A) m/z: 378 [M+1]+, Rt 1.10 min (acidic).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[N:11]1[C:15](=[O:16])[CH2:14][S:13]/[C:12]/1=[N:17]\[C:18]([NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[CH:32][N:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=3)[N:30]=2)=[CH:25][CH:24]=1)=[O:19])([CH3:3])[CH3:2].[Br:45]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:45][CH:22]([C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:33]=[CH:32][N:31]([C:34]3[CH:35]=[CH:36][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:38][CH:39]=3)[N:30]=2)=[CH:27][CH:28]=1)[CH2:21][NH:20][C:18](/[N:17]=[C:12]1\[S:13][CH2:14][C:15](=[O:16])[N:11]\1[C:5]1[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])=[O:19]
Reactant: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NCC(Br)c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Yield: 21.8 %

Procedure:
To a dry round-bottomed flask (20 mL) equipped with a magnetic stirrer and a reflux condenser were added (Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea (F5) (0.20 g, 0.32 mmol), carbon tetrachloride (1 mL), N-bromosuccinimide (0.057 g, 0.32 mmol), and azobisisobutyronitrile (0.0053 g, 0.032 mmol). The reaction was heated to reflux for 2 hours. The reaction was cooled. Purification by flash column chromatography using 0-100% ethyl acetate/hexanes as eluent provided the title compound as a yellow oil (0.049 g, 21%).
Reaction SMILES: C(O)(C(F)(F)F)=O.O1CCCCC1[O:14][NH:15][C:16]([C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:27][CH:26]([NH:28][S:29]([C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=3)(=[O:31])=[O:30])[CH2:25]2)=[N:22][CH:23]=1)=[O:17]>C(Cl)Cl.CO>[OH:14][NH:15][C:16]([C:18]1[CH:23]=[N:22][C:21]([N:24]2[CH2:27][CH:26]([NH:28][S:29]([C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=3)(=[O:31])=[O:30])[CH2:25]2)=[N:20][CH:19]=1)=[O:17]
Reactant: O=C(NOC1CCCCO1)c1cnc(N2CC(NS(=O)(=O)c3ccc4ccccc4c3)C2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: O=C(NO)c1cnc(N2CC(NS(=O)(=O)c3ccc4ccccc4c3)C2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.2 %

Procedure:
TFA (0.60 ml) was added to a solution of N-(tetrahydro-2H-pyran-2-yloxy) 2-{3-[(2-napthylsulfonyl)amino]azetidin-1-yl}pyrimidine-5-carboxamide (156 mg, 0.32 mmol) in DCM (10 ml) and MeOH (10 ml) at r.t. and the solution stirred at r.t. for 24 h. Further TFA (0.40 ml) was added and stirring continued for a further 18 h. The reaction mixture was concentrated in vacuo and the TFA was removed by azeotroping with DCM to yield a white foam. Trituration in hot DCM (15 ml) and MeOH (1 ml) gave a white precipitate which upon cooling to r.t. was isolated by filtration affording the title compound as a white solid (82 mg, 50%). LCMS purity 100%, m/z 400 [M+H]+, 1H NMR (400 MHz, d5-DMSO) δ: 3.64 (2H, m), 4.12 (2H, t), 4.31 (1H, br s), 7.71-7.76 (2H, m), 7.84 (1H, d), 8.09 (1H, d), 8.18-8.22 (2H, m), 8.49 (1H, s), 8.57 (3H, s), 9.01 (1H, s), 11.07 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:13]I>>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CI
Reactant: COC(=O)c1cc(O)cc(Br)c1
Product: COC(=O)c1cc(Br)cc(OC)c1

Procedure:
Methyl 3-bromo-5-hydroxybenzoate (O6.032; 2.52 g) was alkylated with methyl iodide and worked up analogously to the conditions of O5.043. 2.5 g of the title compound were obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:7]([C:8](O)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[CH3:11][N:5]1[CH:6]=[C:7]([C:8]([Cl:17])=[O:9])[C:3]([C:2]([F:13])([F:12])[F:1])=[N:4]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1cc(C(=O)O)c(C(F)(F)F)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
To 3-(Trifluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (3.00 g, 15.5 mmol) suspended in dichloromethane was added oxalyl chloride (2.24 g, 17.8 mmol) and dimethylformamide (one drop). The reaction mixture was stirred at room temperature until bubbling stopped at which point the organic solution was evaporated in vacuo to obtain 3.25 g (99%) of the title compound.
Reaction SMILES: [H-].[Na+].[C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]2[NH:14][C:13](=[O:15])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.CC(O)=O>CN(C)C=O>[C:3]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:4]=[CH:5][C:6]([CH2:9][C@H:10]2[N:14]([CH2:28][C:27]3[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[C:13](=[O:15])[CH2:12][CH2:11]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)CC[C@H]2Cc2ccc(-c3ccccc3)cc2)cc1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
Under N2, sodium hydride (55%, 6.9 g, 158 mmol) is added to the mixture of (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (3a, R1=H) (36 g, 143 mmol) in 400 mL dry dimethylformamide at r.t., then 4-methoxybenzyl chloride (24.7 g, 158 mmol) is added. The reaction mixture is heated to 55° C. and stirred for 3 h. Cooled to r.t., 5 mL AcOH is added, and stirred for another 15 min, then dimethylformamide is removed, the residue is redissolved in 400 mL ethyl acetate, washed with water, dried with sodium sulfate. The solvent is removed, the residue is redissolved in 100 mL tert-butylmethylether, cooled to 0° C. and stirred for 5 h, filtered, and dried to afford (S)-5-biphenyl-4-ylmethyl-1-(4-methoxy-benzyl)-pyrrolidin-2-one (3a, R1=p-methoxybenzyl). 1HNMR (400 MHz, CDCl3): 1.78 (m, 1H, 3-CHH), 1.90 (m, 1H, 3-CHH), 2.28 (m, 2H, 2-CH2), 2.59 (dd, 1H, 5-CHH), 3.05 (dd, 1H, 5-CHH), 3.80 (s, 3H, OCH3), 3.98 (d, 1H, CHH), 5.05 (d, 1H, CHH), 6.80˜7.40 (13H, m, aromatic).