Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[S:3][C:4](=[O:7])[NH:5][N:6]=1.C([O-])(O)=O.[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].CCOCC>CN(P(N(C)C)(N(C)C)=O)C.[Na+].[I-]>[C:23]([O:22][C:20](=[O:21])[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15][CH2:14][N:6]1[NH:5][C:4](=[O:7])[S:3][C:2]1=[O:1])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)CCCCCCBr
Reactant: O=c1[nH]nc(O)s1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)OC(=O)C=CCCCCn1[nH]c(=O)sc1=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 21.9 %

Procedure:
A solution of 11.8 g (0.1 mole) of 1,3,4-thiadiazoline-2,5-dione (1) (Example 1A) in 75 ml of HMPA was stirred with 9.24 g (0.11 mole) of NaHCO3 at room temperature for 18 hrs and then 0.3 g NaI was added followed by 26.5 g (0.1 mole) of tert-butyl 7-bromoheptanoate which was added dropwise over a period of 2 hr. The reaction mixture was stirred at room temperature for 5 days then poured with stirring into 500 ml of ice-cold 5% HCl topped with 200 ml of ether. The ether phase was washed with water and then with three 100-ml portions of 2.5% NaHCO3. The combined NaHCO3 solutions were washed with fresh ether, topped with 200 ml of fresh ether, and while being cooled in ice, acidified by dropwise addition of conc. HCl to pH 2-3. The ether layer was drawn off, two more ether extractions of the aqueous layer were made, and the combined ether extract was washed once with satd. NaCl, dried over Na2SO4, and evaporated. 2,5-Dioxo-1,3,4-thiadiazoline-3-heptanoic acid tert-butyl ester (6.58 g, 22%) was obtained as an oil, IR, (neat) νmax 1735 and 1725 (CO2 t-Bu), and 1675 cm-1 (amide), pmr, (CDCl3, TMS) δ 8.70 (s,1H,OH,NH), 3.75 (t, 2H, NCH2), 2.22 (t, 2H, CH2CO2), and 1.45 ppm (s, 9H C(CH3)3).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=O)[NH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:19][CH3:20])(=[O:3])[CH3:2].CN(C=O)C.S(Cl)([Cl:36])=O>>[C:1]([O:4][CH:5]([CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([Cl:36])=[N:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:19][CH3:20])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCC(CN1CCN(C)CC1)OC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCC(CN1CCN(C)CC1)OC(C)=O
Temperature: 80 °C
Yield: 88 %

Procedure:
A solution of 7-[2-acetoxy-3-(4-methylpiperazin-1-yl) propoxy]-6-methoxyquinazolin-4-one (930 mg, 2.4 mmol) in thionyl chloride (10 ml) containing DMF (150 μl) was heated at 80° C. for 5 hours. The volatiles were removed under vacuum and the residue azeotroped with toluene. The solid was partitioned between methylene chloride and water and the pH of the aqueous layer was adjusted to 7 with solid sodium bicarbonate. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol saturated with ammonia (95/5). The fractions containing the expected product were combined and the volatiles were removed under vacuum to give 7-[2-acetoxy-3-(4-methylpiperazin-1-yl)propoxy]-6-methoxy-4-chloroquinazoline (859 mg, 88%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:37])[C:14]2[O:20][C:19]3[C:21]([Cl:33])=[CH:22][C:23]([NH:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:35])(=[O:34])[C:15]=2[CH:36]=1)=[O:10].CO>O>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:37])[C:14]2[O:20][C:19]3[C:21]([Cl:33])=[CH:22][C:23]([N:25]([C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:34])(=[O:35])[C:15]=2[CH:36]=1)=[O:10]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCCC3)cc(Cl)c1O2
Reactant: COCC(=O)Cl
Solvent: CO
Solvent: O
Product: COCC(=O)N(CCN1CCCC1)c1cc(Cl)c2c(c1)CS(=O)(=O)c1cc(C(=O)OC)cc(C)c1O2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Methoxy-acetyl chloride (0.6 mL, 6.4 mmol) was added to a solution of Example 72k (0.3 g, 0.64 mmol) with stirring. The temperature was raised to 80° C. and stirring continued for 2 h. The reaction mixture was treated with methanol (1 mL), water and extracted with chloroform. The organic layer was washed with water, brine, dried and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.260 g (75.14%); 1H NMR (DMSO-d6): δ 0.71 (bs, 4H, 2CH2), 2.60 (bs, 4H, 2CH2), 2.70 (s, 3H, CH3), 3.20 (s, 3H, OCH3), 3.70 (s, 3H, CH3), 3.80 (bs, 4H, 2CH2), 4.00 (s, 3H, OCH3), 5.40 (s, 2H, CH2), 7.65 (s, 1H, Ar), 7.80 (s, 1H, Ar), 8.19 (s, 1H, Ar). 8.22 (s, 1H, Ar); MS: m/e (CI+) 533 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[CH:23]([Si:26]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[N:27]1[C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:30]2[C:29]([CH:36]=[O:37])=[CH:28]1)([CH3:25])[CH3:24].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH:36]([OH:37])[C:29]3[C:30]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[N:27]([Si:26]([CH:38]([CH3:40])[CH3:39])([CH:41]([CH3:43])[CH3:42])[CH:23]([CH3:24])[CH3:25])[CH:28]=3)=[CH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1ccc(Br)cn1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C=O)c2cccnc21
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(C(=O)Nc3ccc(Cl)cc3)nc2)c2cccnc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 14.4 %

Procedure:
To 5-Bromo-pyridine-2-carboxylic acid (4-chloro-phenyl)-amide (70, 0.50 g, 1.60 mmol) in tetrahydrofuran (20.0 mL), under an atmosphere of nitrogen at −78° C., tert-butyllithium (3.02 mL, 1.70 M in Hexane) was added. After 20 minutes, 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (47, 0.39 g, 1.3 mmol, prepared as described in Example 18) in tetrahydrofuran (10.0 mL) was added to the reaction. The reaction was stirred at −78° C. for 1 hour, then allowed to warm to room temperature for 10 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the compound as colorless oil (71, 100 mg, 14%). MS (ESI) [M+H+]+=535.3.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[CH:19][C:20]4[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=4)[N:22]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[C:30]([C:32]1[CH:33]=[N:34][NH:35][CH:36]=1)#[N:31]>>[F:27][C:26]([F:29])([F:28])[C:23]1[N:21]2[N:22]=[C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:34]5[CH:33]=[C:32]([C:30]#[N:31])[CH:36]=[N:35]5)=[CH:6][CH:7]=4)[CH2:12][CH2:13]3)[CH:18]=[CH:19][C:20]2=[N:25][N:24]=1
Reactant: N#Cc1cn[nH]c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCN(c4ccc(OCCBr)cc4)CC3)nn12
Product: N#Cc1cnn(CCOc2ccc(N3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)c1
Yield: 75 %

Procedure:
Obtained in 75% yield by an analogous method to Example 847, starting from 6-[4-[4-(2-bromoethoxy)phenyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine and 4-cyanopyrazole.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[C@H:11]1([NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH2:17].[BH4-].[Na+]>O>[CH2:1]([NH:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@@H:11]1[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@H]1CCCC[C@@H]1N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N[C@H]1CCCC[C@@H]1NCc1ccccc1
Temperature: 25 °C
Yield: 48 %

Procedure:
Benzaldehyde (3.05 mL, 30.0 mmol) was added to a methanol (300 mL) solution of (1S,2S)-cyclohexane-1,2-diamine (3.43 g, 30.0 mmol) with stirring at room temperature, and the mixture was stirred overnight at the same temperature. The reaction mixture was cooled to 0° C. Sodium borohydride (2.27 g, 60.0 mmol) was added thereto, and the mixture was stirred at 0° C. for 2 hours. To the reaction mixture, water (30 mL) was added, and the product was extracted twice with methylene chloride (50 mL). The organic layers were combined and dried over magnesium sulfate, and the solvent was then distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane) to obtain (1S,2S)-N-benzylcyclohexane-1,2-diamine (cas no. 207450-11-1) (2.95 g, yield: 48%) in a pale yellow oil form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].Cl.[NH2:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36][CH2:35]1.C(N(CC)CC)C>C1COCC1>[OH:40][C@H:37]1[CH2:38][CH2:39][C@H:34]([NH:33][C:16]2[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]3[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[C:14]=3[N:15]=2)[CH2:35][CH2:36]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(N[C@H]2CC[C@H](O)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 48 h

Procedure:
The product of Example 48 (300 mg, 0.67 mmol), trans-4-aminocyclohexanol hydrochloride (226 mg, 1.5 mmol), and triethylamine (0.42 mL, 3 mmol) were combined in THF (15 mL) and stirred under Ar at 500 for 2 days. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography with 0-20% EtOAc/CH2Cl2 followed by recrystallization from CH2Cl2/hexane gave the product as a white-crystalline solid. mp 158-160°, LC MS m/z=481 (MH+). Retention time=2.08 min.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([C:11](=[O:18])[CH2:12][NH:13][CH:14]([CH2:16][CH3:17])[CH3:15])=[CH:5][C:4]=1[C:19]#[N:20]>>[NH2:2][C:3]1[C:4]([C:19]#[N:20])=[CH:5][C:6]([CH:11]([OH:18])[CH2:12][NH:13][CH:14]([CH2:16][CH3:17])[CH3:15])=[CH:7][C:8]=1[C:9]#[N:10]
Reactant: CCC(C)NCC(=O)c1cc(C#N)c(N)c(C#N)c1
Agent: Cl
Product: CCC(C)NCC(O)c1cc(C#N)c(N)c(C#N)c1

Procedure:
m.p. of the hydrochloride: 197°-199° C., was prepared from 4'-amino-2-sec.butylamino-3',5'-dicyano-acetophenone analogous to Example 48.
Reaction SMILES: [F:1][C:2]1[CH:41]=[CH:40][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:27]=[CH:26][C:25]([CH2:28][O:29][Si](C(C)C)(C(C)C)C(C)C)=[CH:24][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:40][CH:41]=1
Reactant: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc32)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
cis-Methyl 4-((E)-2-(4-fluorobenzoylimino)-6-((triisopropylsilyloxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate (0.61 g, 1.048 mmol) was suspended in 2.1 mL of THF and cooled to 0° C. under nitrogen. To this mixture was added TBAF (1 M in THF) (1.573 mL, 1.573 mmol) dropwise via syringe, and the resulting mixture was stirred for 30 minutes at 0° C. The ice bath was removed, and the mixture was stirred for another 30 minutes at RT. The resulting mixture was diluted with DCM and washed with water. The organic layer was collected, dried over sodium sulfate, and concentrated, and the residue was purified by silica gel chromatography (30-50% EtOAc/Hexanes) to provide the title compound (190 mg, 42.6% yield). MS m/z=426.2 [M+H]. Calc'd for C23H24FN3O4: 425.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.63-1.92 (m, 4H) 2.15-2.30 (m, 2H) 2.53-2.74 (m, 2H) 2.78-2.94 (m, 1H) 3.76 (s, 3H) 4.58 (d, J=5.58 Hz, 2H) 4.62-4.82 (m, 1H) 5.24 (t, J=5.58 Hz, 1H) 7.11-7.20 (m, 1H) 7.20-7.33 (m, 2H) 7.35-7.66 (m, 2H) 7.84-8.46 (m, 2H) 12.78 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[O:4].[CH3:6][N:7]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[N:8]([CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].N1C=CC=CC=1>C1C=CC=CC=1>[CH3:6][N:7]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[N:8]([CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](=[O:25])[NH:5][C:3]([NH:2][CH3:1])=[O:4])=[CH:22][CH:21]=1)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: CNC(N)=O
Reactant: CN(C(=O)OCc1ccccc1)N(Cc1ccc(C(=O)Cl)cc1)C(=O)OCc1ccccc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CNC(=O)NC(=O)c1ccc(CN(C(=O)OCc2ccccc2)N(C)C(=O)OCc2ccccc2)cc1

Procedure:
7.4 g. of methyl urea, 46.7 g. of 4-[(2-methyl-1,2-dicarbobenzoxy-hydrazino)-methyl]-benzoyl chloride, 8 g. of pyridine and 200 ml. of benzene were mixed and refluxed for 8 hours. After cooling down, the mixture was poured onto water and extracted with an ether/methylene chloride mixture. The extract was washed with water, with 1 N hydrochloric acid and again with water, dried over sodium sulfate and freed of the solvent by distillation. The residue crystallized upon triturating with methanol. The crystals were filtered off and dried, yielding 1-methyl-2-[4-(4-methyl-allophanoyl)-benzyl]-1,2-dicarbobenzoxy-hydrazine melting at 141°-142°. 25 g. thereof were dissolved in 50 ml. of glacial acetic acid and to it were added 100 ml. of a 33% solution of hydrobromic acid in glacial acetic acid. After 4 hours standing, the crystals formed were filtered off, washed with glacial acetic acid and ether, and recrystallized from methanol, yielding 1-methyl-2-[4-(4-methyl-allphanoyl)benzyl]-hydrazine hydrobromide of melting point 183°-183.5°.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[O:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[CH:19]=2)[N:8]([CH3:27])[N:7]=1)=[O:5])C.[OH-].[Na+]>CS(C)=O.O>[O:22]1[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[CH:19]=[C:18]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[N:8]([CH3:27])[N:7]=[C:6]([C:4]([OH:5])=[O:3])[C:10]=1[CH3:11]
Reactant: CCOC(=O)c1nn(C)c(-c2ccccc2-c2cc3ccccc3o2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(C(=O)O)nn(C)c1-c1ccccc1-c1cc2ccccc2o1
Temperature: 45 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
A suspension of 0.615 g (1.71 mmol) of 5-(3-benzofuran-2-yl-phenyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid ethyl ester in 5.50 ml of DMSO was treated at RT with 0.85 ml (3.41 mmol) of aqueous 1N NaOH. After 2 h, reaction was heated at 45° C. for 30 min. Then it was diluted with chilled water and extracted with Et2O. The water phase was acidified with aqueous 10% KHSO4 and extracted with Et2O (2×). These organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated to give 0.481 g (84%) of 5-(3-benzofuran-2-yl-phenyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid as light brown powder. MS: 331.4 (M−H−).
Reaction SMILES: C(OC([N:8]1[CH2:26][CH2:25][C@@H:11]2[N:12]([CH3:24])[C:13]3[C:14]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[Br-].[CH2:28]([Zn+])[CH2:29][CH2:30][CH3:31]>>[CH2:28]([C:16]1[CH:15]=[C:14]([C:20]([F:21])([F:23])[F:22])[C:13]2[N:12]([CH3:24])[C@H:11]3[CH2:25][CH2:26][NH:8][CH2:9][C@H:10]3[C:18]=2[CH:17]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CN1c2c(cc(Br)cc2C(F)(F)F)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Reactant: CCCC[Zn+]
Agent: [Br-]
Product: CCCCc1cc2c(c(C(F)(F)F)c1)N(C)[C@H]1CCNC[C@@H]21

Procedure:
The title compound was prepared by following the general coupling procedure as a colorless oil from (4aS,9bR)-8-bromo-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 45) and n-butyl zinc bromide. MS (ES+): 313 (base, M+H).
Reaction SMILES: [NH2:1][C@@H:2]([C@@H:38]([C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=1)[C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([F:46])[CH:40]=1)[C:3]([NH:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([F:37])[C:11]=1[CH2:12][CH2:13][C@H:14]1[O:19][CH2:18][C@H:17]([CH2:20][O:21][C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[N:16]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:15]1)=[O:4].C(N(CC)CC)C.Cl[C:62]([O:64][CH3:65])=[O:63]>C(Cl)Cl>[CH3:65][O:64][C:62]([NH:1][C@@H:2]([C@@H:38]([C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=1)[C:39]1[CH:40]=[C:41]([F:46])[CH:42]=[C:43]([F:45])[CH:44]=1)[C:3]([NH:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([F:37])[C:11]=1[CH2:12][CH2:13][C@H:14]1[O:19][CH2:18][C@H:17]([CH2:20][O:21][C:22]([NH:24][CH2:25][C:26]([F:29])([F:27])[F:28])=[O:23])[N:16]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:15]1)=[O:4])=[O:63]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N)[C@@H](c2ccc(F)cc2)c2cc(F)cc(F)c2)OC[C@@H]1COC(=O)NCC(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H](C(=O)Nc1cncc(F)c1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(F)cc1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2S,3S)-2-amino-3-(4-fluorophenyl)-3-(3,5-difluorophenyl)-N-(5-fluoro-4-(2-((2R,5R)-4-(tert-butyloxycarbonyl)-5-(2,2,2-trifluoroethylaminocarbonyloxymethyl)morpholine-2-yl)ethyl)pyridin-3-yl)propanamide (Example 90, step 5) (64 mg, 0.084 mmol) in 1 mL of CH2Cl2 was added triethylamine (0.047 mL, 0.34 mmol) and methyl chloroformate (0.013 mL, 0.17 mmol). The mixture was stirred at ambient temperature for 1 h, then diluted with CH2Cl2 and washed with aqueous NaHCO3 and brine. The organic phase was dried (MgSO4), filtered, and the solvents were removed in vacuo. The residue was chromatographed on a 12 g SiO2 column using a gradient elution of 0-100% EtOc in hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give a gum. LC MS: RT=1.38 min, M+H=816 (2 min gradient)
Reaction SMILES: C([O:5][C:6](=[O:39])[C@@H:7]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:11][CH:10]=1)(C)(C)C>FC(F)(F)C(O)=O.O>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([S:29]([NH:28][C@@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]3[NH:26][CH2:25][CH2:24][CH2:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]([OH:39])=[O:5])(=[O:30])=[O:31])=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(CCCOc1ccc(C[C@H](NS(=O)(=O)c2ccc(Cl)cc2)C(=O)O)cc1)NC1=NCCCN1
Reaction time: 2 h

Procedure:
35.7 mg of (2S)-2-(4-chlorobenzenesulfonylamino)-3-{4-[3-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-propoxy]-phenyl}-propionic acid tert-butyl ester were dissolved in trifluoroacetic acid/water (95/5) and stirred for 2 hours. The solvent was removed in vacuo. The residue was dissolved in acetic acid/water and lyophilized. Yield 20.2 mg. MS (ES+): m/e=523.1 (M)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[C:22](Cl)=[N:23][C:24]([S:27][CH3:28])=[N:25][CH:26]=2)=[O:20])=[CH:14][CH:13]=1.O>CO>[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[C:22]([NH:1][CH2:2][CH:3]([OH:4])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[N:23][C:24]([S:27][CH3:28])=[N:25][CH:26]=2)=[O:20])=[CH:14][CH:13]=1
Reactant: NCC(O)c1ccccc1
Reactant: CSc1ncc(C(=O)Nc2ccc(F)cc2)c(Cl)n1
Solvent: O
Solvent: CO
Product: CSc1ncc(C(=O)Nc2ccc(F)cc2)c(NCC(O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.5 %

Procedure:
To a solution of 2-amino-1-phenyl-ethanol (140 mg, 1.01 mmol) in methanol (5 mL) was added 4-chloro-2-methylsulfanylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (100 mg, 0.34 mmol). The mixture was stirred for 16 h at an ambient temperature and the resulting mixture was poured into water. Solids were collected by filtration and were dried in vacuo to afford 103.7 mg (0.26 mmol, 78% yield) of the titled compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.22(s, 1H), 8.85 (m, 1H), 8.60 (s, 1H), 7.65(m, 2H), 7.40–7.05 (m, 7H), 5.67 (m, 1H), 4.78 (m, 1H), 3.78 (m, 1H), 3.41 (m, 1H), 2.44 (s, 31H); MS (EI) m/z 397.18 (M−H)−.
Reaction SMILES: [Cl:1][C:2]([F:13])([F:12])[CH2:3][CH:4]1[CH2:8][N:7]([CH2:9]Cl)[C:6](=[O:11])[CH2:5]1.C([O:21][CH2:22][C:23]1[S:27][C:26]2=[N:28][C:29]([C:31]([F:34])([F:33])[F:32])=[CH:30][N:25]2[N:24]=1)C1C=CC=CC=1>O1CCOCC1.FC(F)(F)C(O)=O.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]([F:13])([F:12])[CH2:3][CH:4]1[CH2:8][N:7]([CH2:9][C:30]2[N:25]3[C:26]([S:27][C:23]([CH2:22][OH:21])=[N:24]3)=[N:28][C:29]=2[C:31]([F:33])([F:34])[F:32])[C:6](=[O:11])[CH2:5]1
Reactant: O=C1CC(CC(F)(F)Cl)CN1CCl
Reactant: FC(F)(F)c1cn2nc(COCc3ccccc3)sc2n1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: O=C1CC(CC(F)(F)Cl)CN1Cc1c(C(F)(F)F)nc2sc(CO)nn12
Temperature: 90 °C
Yield: 36 %

Procedure:
A solution of 4-(2-chloro-2,2-difluoroethyl)-1-(chloromethyl)pyrrolidin-2-one a18 in dioxane (5 ml) is added to a hot solution (90° C.) of dry ZnCl2 (0.272 g, 2 mmol, 0.5 eq) and 2-[(benzyloxy)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole a29 (1.3 g, 4 mmol, 1 eq) in dioxane (5 ml). The reaction mixture is heated at 90° C. for 3 days and 1,4-dioxane is removed under reduced pressure. The crude reaction mixture is taken up in trifluoroacetic acid (20 ml) and heated at 60° C. for 2 hours. After cooling, the trifluoro-acetic acid is removed under reduced pressure. The residue is purified by chromatography on silicagel (MeOH/CH2Cl2) and pure 4-(2-chloro-2,2-difluoroethyl)-1-{[2-(hydroxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one 7 (573 mg) is obtained after re-crystallization from ethyl acetate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:15]2[C:7](=[CH:8][C:9]([F:16])=[C:10]3[C:14]=2[CH2:13][CH2:12][O:11]3)[NH:6][C:5]=1C(O)=O.Cl.[OH-].[Na+]>>[F:16][C:9]1[CH:8]=[C:7]2[C:15]([C:4]([CH2:3][CH2:2][NH2:1])=[CH:5][NH:6]2)=[C:14]2[C:10]=1[O:11][CH2:12][CH2:13]2
Reactant: NCCc1c(C(=O)O)[nH]c2cc(F)c3c(c12)CCO3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NCCc1c[nH]c2cc(F)c3c(c12)CCO3
Yield: 50.2 %

Procedure:
Compound 11 (55 mg, 0.208 mmol) was refluxed with 10% HCl for 2 h. After cooling the resulting solution was made alkaline with 30% NaOH. It was extracted with ethyl acetate. The organic layer was concentrated to yield the desired compound, 2-(4-fluoro-1,6-dihydro-2H-3-oxa-6-aza-as-indacen-8-yl)-ethylamine (XII, R1═R2═R3═H, X═F, 23 mg, yield 50%).