Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[C:9]([N:11]1[C:19]2[CH:18]=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[C:13]2[CH2:21][N:22]([CH3:25])[CH2:23][CH2:24][C:12]1=2)#[CH:10].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[CH3:25][N:22]1[CH2:23][CH2:24][C:12]2[N:11]([C:9]#[C:10][C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=3)[C:19]3[CH:18]=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[C:13]=2[CH2:21]1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: Cc1ccc(Br)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc(C#Cn2c3c(c4cc(C)ccc42)CN(C)CC3)nc1

Procedure:
A mixture of 2-bromo-5-methyl-pyridine (250 mg, 1.45 mmol), 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (391 mg, 1.74 mmol), TBAF.3H2O (1.374 g, 4.36 mmol) and dichloro bistriphenylphosphine palladium(II) (51 mg, 0.072 mmol) was stirred at 85° C. for 10 min. The reaction mixture was poured into water and extracted with EtOAc (3×100 mL). The organic layer was washed with water (3×100 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (neutral alumina, eluent-0.5% MeOH in DCM) to yield 2,8-dimethyl-5-(5-methyl-pyridin-2-ylethynyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, freebase) δ (ppm): 8.41 (s, 1H), 7.5 (m, 2H), 7.4 (d, 1H), 7.18 (s, 1H), 7.08 (d, 1H), 3.6 (s, 2H), 3.0 (t, 2H), 2.83 (t, 2H), 2.58 (s, 3H), 2.42 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH2:26][CH2:25][C:24](=[O:27])[NH:23][N:22]=3)=[C:17]([F:28])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[NH:23][N:22]=3)=[C:17]([F:28])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C3=NNC(=O)CC3)c(F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-c3ccc(=O)[nH]n3)c(F)c2)CC1

Procedure:
In a 10 mL round bottom flask, 4-[3-fluoro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (525 mg, 1.34 mmol), and cesium carbonate (874 mg, 2.68 mmol), in dimethylsulfoxide (5 mL) was heated to 135° C. 3 h. The reaction was cooled and the slurry was partitioned between methylene chloride and water extracted three times, and then dried over MgSO4. Purification with silica gel chromatography eluting with methylene chloride/methanol (95:5) produced 500 mg (93%). Mp 117-119° C. MS m/z 390 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][O:9][S:11]([CH3:10])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccncc1F
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccncc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C. TEA (44 μl, 0.314 mmol, 2 eq.) was added to (3-fluoro-pyridin-4-yl)-methanol (20 mg, 0.157 mmol, 1 eq.) in 1 mL DCM, followed by MsCl (15 μl, 0.188 mmol, 1.2 eq.) The reaction was stirred at 0° C. for 30 minutes. HPLC and LC-MS showed reaction complete. The reaction crude was concentrated down. Ethyl acetate was added and washed with saturated NAHCO3 aqueous solution. The Ethyl acetate layer was concentrated after dried over Na2SO4 to give color oil which was used directly in next step. LC-MS shows 206.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:17])([S:6][C:7]1[CH:16]=[CH:15][C:10]([NH:11]C(=O)C)=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].Cl>O>[F:17][C:2]([F:1])([S:6][C:7]1[CH:16]=[CH:15][C:10]([NH2:11])=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4]
Reactant: CC(=O)Nc1ccc(SC(F)(F)C(F)F)cc1
Agent: Cl
Solvent: O
Product: Nc1ccc(SC(F)(F)C(F)F)cc1

Procedure:
A mixture of 5 g of XI and 40 ml of 6 N hydrochloric acid was heated under reflux for 4 hours. The mixture was diluted with 200 ml of water and filtered. The filtrate was concentrated to dryness and the solid residue was triturated with ether and filtered to give 4-(1,1,2,2-tetrafluoroethylthio)aniline (XII) as a hydrochloride salt.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH:33]([OH:40])[CH2:34][CH2:35][NH:36][CH:37]([CH3:39])[CH3:38]>>[Cl:24][C:20]1[CH:19]=[C:18]([F:25])[C:17]([CH2:16][O:15][C:12]2[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH:33]([OH:40])[CH2:34][CH2:35][NH:36][CH:37]([CH3:38])[CH3:39])=[O:29])[S:14][N:13]=2)=[C:22]([F:23])[CH:21]=1
Reactant: CC(C)NCCC(O)CCN
Reactant: NC(=O)c1c(OCc2c(F)cc(Cl)cc2F)nsc1NC(=O)Oc1ccccc1
Product: CC(C)NCCC(O)CCNC(=O)Nc1snc(OCc2c(F)cc(Cl)cc2F)c1C(N)=O

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-chloro- benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 1-amino-5-isopropylamino-pentan-3-ol by the procedure analogous to Example 6. HPLC ret. time: 3.2 minutes. 1H NMR (400 MHz, CD3OD) δ7.17 (d, 1H, J=7.6 Hz), 5.52 (s, 2H), 3.69 (m, 1H), 3.34 (t, 2H, J=6.4 Hz), 2.80 (s, 1H, J=6.0 Hz), 2.73 (m, 2H), 1.68-1.58 (m, 4H), 1.06 (d, 6H, J=6.0 Hz) ppm; MS (APCI, m/z): 506 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>>[CH2:28]([O:27][C:25]([CH:24]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccsc2)SCC(N)C1=O
Reactant: O=C(OCc1ccccc1)C(Br)CCc1ccccc1
Product: CC(C)(C)OC(=O)CN1CC(c2ccsc2)SCC(NC(CCc2ccccc2)C(=O)OCc2ccccc2)C1=O

Procedure:
0.3 g of t-butyl α-[6-amino-5-oxo-2-(3-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [synthesized as described in Example 42(g)], was N-alkylated using 0.6 g of benzyl 2-bromo-4-phenylbutyrate by the procedure described in Example 42(h). The reaction product was chromatographed on a silica gel column eluted with a 1:40 by volume mixture of ethyl acetate and methylene chloride, to give two isomers, A and B (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([OH:22])=O)=[CH:14][CH:13]=3)=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[S:8][C:7]=2[CH:31]=1.[F:32][C:33]([F:38])([F:37])[CH2:34][CH2:35][NH2:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([NH:36][CH2:35][CH2:34][C:33]([F:38])([F:37])[F:32])=[O:22])=[CH:14][CH:13]=3)=[C:9]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[S:8][C:7]=2[CH:31]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(=O)O)cc2)cc1
Reactant: NCCC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(=O)NCCC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a 30 mL vial containing (E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (41 mg, 0.10 mmol) was added DMF (3 mL), followed by 3,3,3-trifluoropropan-1-amine (13.94 mg, 0.12 mmol), HATU (54.1 mg, 0.14 mmol), and DIEA (0.050 mL, 0.28 mmol). The mixture was stirred at room temperature for 30 min after which the reaction was quenched with sat. aq. NH4Cl and diluted with DCM. The organic phase was collected (phase separator) and concentrated in vacuo onto silica gel. The crude material was purified by column chromatography (SiO2, 0-30% EtOAc/heptane) to afford (E)-3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-N-(3,3,3-trifluoropropyl)acrylamide (38 mg, 0.07 mmol, 72% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm=7.64 (d, J=9.09 Hz, 2H), 7.45-7.56 (m, 3H), 7.42 (d, J=2.02 Hz, 1H), 7.25 (d, J=8.59 Hz, 1H), 6.90-7.02 (m, 5H), 6.47 (d, J=15.66 Hz, 1H), 3.88 (s, 3H), 3.74-3.85 (m, 3H), 3.54 (t, J=7.07 Hz, 2H), 2.34-2.56 (m, 2H). LC/MS (m/z, MH+): 528.3.
Reaction SMILES: [Cl-].[NH4+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[C@@:13]12[N:22]=[C:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[S:20][CH2:19][C@@H:18]1[CH2:17][C@H:16]([CH2:31][OH:32])[O:15][CH2:14]2>C(O)C.[Fe]>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([F:3])=[C:5]([C@@:13]23[N:22]=[C:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:29])[CH3:27])[S:20][CH2:19][C@@H:18]2[CH2:17][C@H:16]([CH2:31][OH:32])[O:15][CH2:14]3)[CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc([N+](=O)[O-])ccc3F)CO[C@@H](CO)C[C@H]2CS1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@@H](CO)C[C@H]2CS1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
Iron powder (121 mg) and a saturated ammonium chloride solution (1 ml) were added to a solution of tert-butyl [(4aR,6R,8aS)-8a-(2-fluoro-5-nitrophenyl)-6-hydroxymethyl-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl]carbamate (120 mg) in ethanol (20 ml). The reaction solution was heated under reflux for 40 minutes and then cooled to room temperature. The insoluble matter was filtered off through celite, and the filtrate was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (67 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25].[H-].[Na+].[C:32](Cl)(=[O:34])[CH3:33]>O1CCCC1>[C:32]([N:23]([C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:7][C:2]=1[Cl:1])[C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25])(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCNC(=O)N(C(C)=O)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26 %

Procedure:
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-phenyl}-N′-propylurea 100 mg) was dissolved in anhydrous tetrahydrofuran (30 ml), and sodium hydride (60 wt %, 88 mg) was added to the solution. The mixture was stirred at room temperature for 15 min. Next, acetyl chloride (63 μl) was added to the reaction solution, and the mixture was stirred at room temperature for additional 2 hr. The solvent was removed by distillation under the reduced pressure, and water was added to the residue. The mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/acetone to give 27 mg (yield 26%) of the title compound.
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4][C@@H:3]2[CH2:7][NH:8][CH2:9][C@H:2]12.Br[C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[N:22][CH:23]=1>>[Cl:24][C:21]1[N:22]=[CH:23][C:18]([N:8]2[CH2:7][C@@H:3]3[C@@H:2]([N:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4]3)[CH2:9]2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]2CNC[C@@H]21
Reactant: Clc1ccc(Br)cn1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]2CN(c3ccc(Cl)nc3)C[C@@H]21
Yield: 49 %

Procedure:
tert-Butyl cis-octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (374 mg, 1.65 mmol), prepared as described in (EP0603887A2) and 5-bromo-2-chloropyridine (314 mg, 1.65 mmol), prepared as described in (Tetrahedron Lett. (1998), 39, 2059-2062) were processed as described in Example 1E to provide the title compound (273 mg, 49% yield). MS (DCI/NH3) m/z 338/340 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][N:22]3[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]3)=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(N2CCOCC2)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
A 100 mL round-bottom flask was charged with 4-(morpholin-4-yl)-2(trifluoromethyl)benzaldehyde (1.00 g, 3.86 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (0.720 g, 3.86 mmol, 1.00 equiv), 1,2-dichloroethane (15 mL). The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.40 g, 11.3 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (10 mL), extracted with dichloromethane (3×10 mL). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (25/75) to provide 1.60 g (97% yield) of tert-butyl 4-[[4-(morpholin-4-yl)-2(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 430 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[NH:23][CH:22]=4)[C:18]([Cl:30])=[CH:17][N:16]=3)=[C:10]([O:31][CH3:32])[CH:9]=2)[CH2:4][C@H:3]1F.COC1C=[C:41]([N:43]2[CH2:48]CC(N3CCN(C)CC3)[CH2:45][CH2:44]2)[CH:40]=CC=1N.CCN(C(C)C)C(C)C>C(O)CCCC.C(Cl)Cl.CO>[Cl:30][C:18]1[C:19]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)=[N:20][C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([N:1]4[CH2:45][CH2:44][N:43]([CH3:48])[CH2:41][CH2:40]4)[CH2:3][CH2:4]3)=[CH:9][C:10]=2[O:31][CH3:32])=[N:16][CH:17]=1
Reactant: COc1cc(N2CC[C@@H](N)[C@H](F)C2)ccc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Temperature: 25 °C
Yield: 52.8 %

Procedure:
As an alternate procedure to the compound described in Example 10, a solution of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) (3.67 g, 13.89 mmol), 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 27) (4.23 g, 13.89 mmol), and PTSA monohydrate (6.6 g, 34.7 mmol) in n-pentanol (56 mL) was heated in an oil bath at 140° C. overnight. The reaction mixture was cooled to RT. Hunig's base (10 mL) was added. Concentration in vacuo removed the solvent, and the residue was loaded to silica gel column and eluted with 10% MeOH, 1% NH4OH in CH2Cl2. The collected fractions were concentrated and the residue was triturated with diethyl ether. Filtration afforded the solid and it was dissolved in a mixture of CH2Cl2 (100 mL) and MeOH (500 mL). Concentration in vacuo reduced the solvent volume to 70 mL and filtration yielded the solid as the title compound (3.9 g, 53% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH2:13])[S:11][CH:12]=1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23](Cl)(=[O:25])=[O:24]>>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23]([NH:13][C:10]1[S:11][CH:12]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=1)(=[O:25])=[O:24]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: Nc1nc(-c2ccccc2Cl)cs1
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1nc(-c2ccccc2Cl)cs1

Procedure:
The title compound was prepared from 4-(2-chlorophenyl)-1,3-thiazol-2-amine and 2,4 -dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (40.3 mg) with purity >90%. MS (pos) m/z 435.0, 437.0.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5]([O:34][CH3:35])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:33])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH3:35][O:34][CH:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)[C:18](=[O:32])[N:17]2[CH3:33])=[CH:11][CH:12]=1)[C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)C(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
A solution of 2-methoxy-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester (0.040 g, 0.079 mmol) in ethanol (5 mL) was treated with aqueous 5 N NaOH (0.5 mL) and stirred at room temperature for 2 h. The solvent removed in vacuo. The resultant residue was acidified with aqueous 1 N HCl (10 mL) and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford 0.026 g (68%) 2-methoxy-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)- propionic acid. 1H NMR. MS (ES+) m/z calc'd for C24H28N2O5F3 (M+1) 481. Found m/z 481.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][N:22]2C(=O)C3=CC=CC=C3C2=O)=[N:19][N:18]=[C:17]1[CH2:33][N:34]([CH3:36])[CH3:35].O.NN>C(O)C>[F:15][C:13]1[CH:12]=[CH:11][C:10]2[N:16]3[C:17]([CH2:33][N:34]([CH3:35])[CH3:36])=[N:18][N:19]=[C:20]3[CH2:21][N:22]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[CH:14]=1
Reactant: CN(C)Cc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(F)cc1C(=O)c1ccccc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(C)Cc1nnc2n1-c1ccc(F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 27, 2'-chloro-5-fluoro-2-[3[(dimethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to give 8-fluoro-1[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([CH:17]([CH3:39])[C:18](=[O:38])[NH:19][CH2:20][C:21]2[C:22]([C:31]3[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=3)=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)[CH:14]=[CH:13][C:3]=1[CH2:4][NH:5]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[NH2:5][CH2:4][C:3]1[CH:13]=[CH:14][C:15]([CH:17]([CH3:39])[C:18]([NH:19][CH2:20][C:21]2[C:22]([C:31]3[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=3)=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=2)=[O:38])=[CH:16][C:2]=1[Cl:1]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CNC(=O)OC(C)(C)C)c(Cl)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CN)c(Cl)c2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a stirred solution of tert-butyl 2-chloro-4-(1-oxo-1-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methylamino)propan-2-yl)benzylcarbamate (132 mg, 0.234 mmol) in dichloromethane (4 mL), cooled to 0° C., were added trifluoroacetic acid (2 ml). The resulting reaction mixture was stirred for 1 h at 0° C. and 1 hour at room temperature, then basified to pH 8-9 with aq. NaHCO3. The mixture was filtered using celite pad. The filtrate dissolved in dichloromethane and extracted with NaHCO3. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(4-(aminomethyl)-3-chlorophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (90 mg) was obtained as 83% yield.
Reaction SMILES: [N:1]1([C:6]([S-:8])=[S:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([NH+](CC)CC)C.[Cl-].[Li+].O1CCCC1.O(P(O[C:40]1[C@H:41]([CH3:64])[C@H:42]2[C@@H:59]([C@H:60]([OH:62])[CH3:61])[C:58](=[O:63])[N:43]2[C:44]=1[C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([N+:55]([O-:57])=[O:56])=[CH:51][CH:50]=1)=[O:46])(OC1C=CC=CC=1)=O)C1C=CC=CC=1>O.C(OCC)(=O)C>[OH:62][C@@H:60]([C@H:59]1[C:58](=[O:63])[N:43]2[C:44]([C:45]([O:47][CH2:48][C:49]3[CH:50]=[CH:51][C:52]([N+:55]([O-:57])=[O:56])=[CH:53][CH:54]=3)=[O:46])=[C:40]([S:7][C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[S:8])[C@H:41]([CH3:64])[C@H:42]12)[CH3:61]
Reactant: S=C([S-])N1CCCC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC(=S)N3CCCC3)[C@H](C)[C@H]12
Reaction time: 8 h
Yield: 73.3 %

Procedure:
Triethylammonium 1-pyrrolidinyldithiocarboxylate (1.0 g, 4.03 mmol) and lithium chloride (171 mg, 4.03 mmol) were added to a tetrahydrofuran solution (50 ml) of p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (2.0 g, 3.36 mmol) at room temperature. The mixture was stirred at that temperature overnight in a nitrogen stream, and poured in a mixed liquid of ethyl acetate and water. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (Wakogel™ C-300, n-heptane-ethyl acetate 1:1→2:3) to give p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-2-[(1-pyrrolidinyl)thiocarbonylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (1.21 g, yield: 74%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>ClCCl>[CH2:22]([O:21][C:19](=[O:20])[NH:7][C:4]1[CH:5]=[CH:6][C:1]([NH2:8])=[CH:2][CH:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccc(N)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Yield: 68.8 %

Procedure:
1,4-Phenylenediamine (10 g, 0.093 mol) was stirred rapidly in dichloromethane (800 mL) with diisopropylethylamine (16 mL, 0.093 mol) and the solution cooled to 0° C. A solution of benzyl chloroformate (13 mL, 0.093 mol) in dichloromethane (100 mL) was added very slowly via a dropping funnel. The reaction was left to warm to room temperature over 16 h and concentrated in vacuo. The remaining residue was purified by column chromatography on silica eluting with ethyl acetate/petroleum ether (using a gradient from 25% to 80%) to give 1 as a cream solid (15.5 g, 69.6%). 1H NMR (CDCl3, 400 MHz) δ 3.56 (s(br), 2H, NH2), 5.18 (s, 2H, CH2), 6.45 (s(br), 1H, NH), 6.64 (d, 2H, J=8.8 Hz, ArH), 7.15 (d, 2H, J=6.9 Hz, ArH), 7.36 (m, 5H, ArH).