Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4](I)[CH:3]=1.[Li]CCCC.[F:15][CH2:16][C:17](OCC)=[O:18]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C:17](=[O:18])[CH2:16][F:15])[CH:3]=1
Reactant: CCOC(=O)CF
Reactant: Fc1ccc(Br)cc1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CF)c1cc(Br)ccc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A solution of 4-bromo-1-fluoro-2-iodobenzene (5.0 g, 116 mmol, (1), Aldrich) in THF (60 ml) under nitrogen atmosphere was cooled to −78° C. A solution of n-BuLi (2.5M in hexanes; 7.31 ml, 18.28 mmol, Aldrich) was added drop wise and the reaction was stirred at −78° C. for one hour. Ethyl monofluoroacetate (2.1 g, 19.94 mmol, Aldrich) was added drop wise and the reaction was stirred at −78° C. for one hour. The reaction was quenched with aqueous saturated ammonium chloride solution and allowed to warm to RT. The reaction was diluted with water and EtOAc. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The material was purified via silica gel flash chromatography using a gradient of 0-20% EtOAc in Hexanes to afford the title compound as an off white solid. (2.45 g, 10.42 mmol, 63% yield). MS m/z=234.9 M+. Calculated for C8H5BrF2O: 235.03
Reaction SMILES: [Cl:1][C:2]1[C:39]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:37]=[CH:36][C:3]=1[CH2:4][N:5]([CH2:22][CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:11]=1.IC.[CH:46](N(C(C)C)CC)(C)C.[CH3:55][S:56]([OH:59])(=[O:58])=[O:57]>CN(C=O)C.C(Cl)Cl>[CH3:55][S:56]([OH:59])(=[O:58])=[O:57].[Cl:1][C:2]1[C:39]([C:40]([F:41])([F:43])[F:42])=[CH:38][CH:37]=[CH:36][C:3]=1[CH2:4][N:5]([CH2:22][CH:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH2:17][CH2:18][N:19]([CH3:46])[CH2:20][CH2:21]2)[CH:11]=1
Reactant: FC(F)(F)c1cccc(CN(CCCOc2cccc(N3CCNCC3)c2)CC(c2ccccc2)c2ccccc2)c1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)O
Solvent: CN(C)C=O
Solvent: CI
Solvent: ClCCl
Product: CN1CCN(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)c2)CC1
Temperature: 50 °C

Procedure:
To a stirring solution of (2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-piperazin-1-yl-phenoxy)-propyl]-amine (150 mg, 2.46 mmol) in anhydrous DMF (20 ml) was added iodomethane (16.8 uL, 2.71 mmol) and diisopropylethylamine (86 uL, 4.93 mmol). The resulting solution was heated at 50° C. for 4 hours and then concentrated. Purification by flash silica gel chromatography (silica gel 60, EM science; 3% MeOH and 0.5% NH2OH in CH2Cl2) afforded the N-methylated product. The amine was dissolved in CH2Cl2 and methansulfonic acid (2 equivalents) was added. The methylene chloride solution was concentrated and the resulting bis-methanesulfonate salt was dried under vacuum to yield the title compound as a solid, 56 mg (37%). MS(ES) m/e 622.4 (M+).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:4]=[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>CC(C)=O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:12][S:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:13])[CH3:1])[CH:4]=2)(=[O:11])=[O:10])=[O:25])=[CH:19][CH:18]=1
Reactant: CN(C)c1cccc(S(N)(=O)=O)c1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CN(C)c1cccc(S(=O)(=O)NC(=O)Nc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The 3-(dimethylamino)benzenesulfonamide was dissolved in acetone (9.1 ml) to which was added 9.3 ml of 1N sodium hydroxide. To this mixture was added 4-chlorophenylisocyanate (1.43 g, 9.3 mmoles) dissolved in 9.1 ml of acetone. This mixture was stirred for 45 minutes at room temperature and then filtered. The filtrate was acidified using 1N hydrochloric acid (9.3 ml) and stirred for 2 hours, resulting in a precipitate. The solid was collected, washed thrice with water, and recrystallized using heated toluene (150 ml) and ethyl acetate (25 ml), followed by filtration and cooling.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[CH2:12]([O:14][C:15](=[O:27])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[CH:25]=[O:26])[CH3:13].[NH4+].[Cl-]>C1COCC1.CCOCC>[CH2:12]([O:14][C:15](=[O:27])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[CH:25]([OH:26])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH3:13]
Reactant: CCOC(=O)COc1ccc(Br)cc1C=O
Reactant: C#C[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Br)cc1C(O)C#C[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
To a cooled (−78° C.) solution of (trimethylsilyl)acetylene (3.93 g, 40.0 mmol) in dry THF (40 mL) was slowly added a 2.5 M solution of butyllithium in hexanes (14.54 mL, 36.36 mmol). After stirring for 30 minutes at −78° C., the mixture was transferred to a cooled (−78° C.) solution of (4-bromo-2-formylphenoxy)acetic acid ethyl ester (10.44 g, 36.36 mmol) in dry THF (120 mL). Upon completion, the reaction mixture was stirred at −78° C. for 45 minutes. Saturated aq. NH4Cl (40 mL) was slowly added to the reaction mixture followed by Et2O (40 mL). The quenched reaction mixture was allowed to warm up to room temperature. The phases were separated and the aqueous phase was extracted with Et2O (2×). The combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude oil was purified by column chromatography (SiO2), then was stirred for 90 min with polystyrene-supported trisamine (PS-Trisamine, 4.17 mmol/g, 8 g) in CH2Cl2 (160 mL). The resin was filtered off and the filtrate was concentrated in vacuo to give the title compound as pale yellow oil (7.6 g, 19.7 mmol, 54%). LC/MS (an10p8) Rt 4.30 min, m/z 408 [M+Na]+; 1H NMR (CDCl3): δ 0.24 (s, 9H), 1.31 (t, 3H), 4.27 (q, 2H), 4.71 (s, 2H), 5.79 (s, 1H), 6.74 (d, 1H), 7.39 (dd, 1H), 7.79 (d, 1H).
Reaction SMILES: CO[C:3](=[O:26])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:27][NH:28][C:29]([NH2:31])=[O:30].C[O-].[Mg+2].C[O-].CO>>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[CH:20]4)=[CH:13][CH:12]=2)[C:3]([NH:31][C:29]([NH:28][CH3:27])=[O:30])=[O:26])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(-c2ccc3[nH]ccc3c2)cc1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(-c2ccc3[nH]ccc3c2)cc1
Temperature: 25 °C
Yield: 28.6 %

Procedure:
A mixture of 3-cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-propionic acid methyl ester (245 mg, 0.71 mmol) and methyl urea (131 mg, 1.76 mmol) was treated with a solution of magnesium methoxide in methanol (7.4 wt. %, 5.5 mL, 2.12 mmol). The reaction mixture was then concentrated in vacuo to approximately one-half the volume of methanol. The resulting reaction mixture was then heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C. and then partitioned between water (20 mL) and ethyl acetate (50 mL). The layers were separated, and the aqueous layer was further extracted with ethyl acetate (1×25 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 1-{3-cyclopentyl-2-[4-(1H-indol-5-yl)-phenyl]-propionyl}-3-methyl-urea (79 mg, 29%) as a white foam: mp 91-95° C. (foam to gel); FAB-HRMS m/e calcd for C24H27N3O2 (M+H)+ 390.2181, found 390.2192.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(O[N:13]([CH2:17][C:18]1[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:26]([C:27]([O:29][CH3:30])=[O:28])[C:20]=2[N:19]=1)[CH:14]=C=O)(C)(C)C>C(Cl)Cl>[CH3:14][NH:13][CH2:17][C:18]1[NH:19][C:20]2[C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1
Reactant: COC(=O)c1cccc2[nH]c(CN(C=C=O)OC(C)(C)C)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1nc2cccc(C(=O)OC)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (15 ml) was added to a cooled solution (0° C.) of methyl 2-((tert-butoxy-carbonyl(methyl)amino)methyl)-1H-benzo[d]imidazole-4-carboxylate (12.54 mmol) in methylene chloride (60 ml) and the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated off completely, in vacuo, and the residue was co-distilled 2× with methylene chloride and employed in the next stage.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:8])=[CH:4][N:5]=[N:6][CH:7]=1.[F:9][C:10]1([F:22])[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:11]1>CN1C(=O)CCC1>[F:22][C:10]1([F:9])[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:2]3[C:3]([NH2:8])=[CH:4][N:5]=[N:6][CH:7]=3)[CH2:18][CH2:17]2)[CH2:11]1
Reactant: Nc1cnncc1Cl
Reactant: FC1(F)CCN(CC2CCNCC2)C1
Solvent: CN1CCCC1=O
Product: Nc1cnncc1N1CCC(CN2CCC(F)(F)C2)CC1
Temperature: 170 °C
Yield: 23.5 %

Procedure:
A mixture of 5-chloropyridazin-4-amine (50 mg, 0.3860 mmol), 4-[(3,3-difluoropyrrolidin-1-yl)methyl]piperidine (197.1 mg, 0.9650 mmol) in NMP (10 mL) were heated under microwave conditions at 170° C. for 7 hours. The reaction was passed through a 10 g SCX-2 cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with 2M NH3 in MeOH/DCM mixtures. The solvent was removed in vacuo and the residue was purified by column chromatography (ISCO Companion, 12 g column, eluting with 0 to 10% MeOH/DCM, loaded in DCM) to give the sub-title product as a beige solid (27 mg, 23% Yield). 1H NMR (500 MHz, DMSO) δ 8.46 (d, 1H), 8.41 (s, 1H), 5.85 (s, 2H), 3.20 (d, 2H), 2.87 (t, 2H), 2.69 (t, 2H), 2.59 (td, 2H), 2.34 (d, 2H), 2.24 (tt, 2H), 1.83-1.74 (m, 2H), 1.65-1.53 (m, 1H), 1.43-1.30 (m, 2H); 19F NMR (471 MHz, DMSO) δ −90.81; LC-MS ES+: 298.1, ES−: 296.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15](=[O:24])(=[O:23])[CH2:14][CH2:13]1)[NH:6][C:5]2=O.[NH2:26][C@H:27]1[C@H:31]([F:32])[CH2:30][N:29](C(OCC2C=CC=CC=2)=O)[CH2:28]1>>[F:32][C@@H:31]1[CH2:30][NH:29][CH2:28][C@H:27]1[NH:26][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=2)[N:8]=[C:7]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15](=[O:23])(=[O:24])[CH2:14][CH2:13]2)[N:6]=1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)[nH]c(=O)c2c1
Reactant: N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc(N[C@@H]3CNC[C@H]3F)c2c1

Procedure:
The title compound was prepared in analogy to Example 92-1 in Scheme 44 by using 6-methyl-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one (prepared in analogy to 6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one in Example 91) and benzyl trans-3-amino-4-fluoropyrrolidine-1-carboxylate. MS obsd. (ESI+) [(M+H)+] 442, 1H NMR (400 MHz, CDCl3) δ ppm 8.40-8.02 (d, J=7.6 Hz, 1 H), 7.83-7.81 (d, J=7.2 Hz, 1 H), 7.52-7.49 (m, 1 H), 7.37-7.35 (d, J=10.8 Hz, 3 H), 7.22 (s, 1 H), 5.41 (s, 1 H), 5.30-5.00 (brs, 2 H), 4.90-4.55 (brs, 2 H), 3.70-3.68 (d, J=5.2 Hz, 1 H), 3.48 (s, 2 H), 3.31-3.25 (brs, 2 H) 2.95 (s, 1 H), 2.38 (s, 3 H), 2.20-2.18 (d, J=8.8 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[S:23][C:24]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)=[CH:25][C:26]=3[C:27]#[C:28][Si](C)(C)C)=[O:21])=[CH:15][C:14]=2[O:40][CH3:41])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:28]=[CH:27][C:26]4[CH:25]=[C:24]([C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=5)[S:23][C:22]=4[C:20]3=[O:21])=[CH:15][C:14]=2[O:40][CH3:41])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)cc2C#C[Si](C)(C)C)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
Dissolve 3-(4-{[5-(4-chloro-phenyl)-3-trimethylsilanylethynyl-thiophene-2-carbonyl]-amino}-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (420 mg, 0.69 mmol) in THF (11 mL) and add 1 M tetrabutylammonium fluoride (1.50 mL, 1.50 mmol, solution in THF). Stir the solution at RT overnight. Dilute the solution with EtOAc (100 mL) and wash with water (3×50 mL) and brine (50 mL). Dry the organic solution, filter, and concentrate the filtrate. Purify the crude material by flash chromatography, using a linear gradiant of 30-70% EtOAc/hexanes, to give 280 mg (75%) of the title compound. LC-MS/ES m/z (35Cl) 483.0 [M−t-butyl+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SC)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH3:31][O:32][NH:33][CH3:34]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]([O:32][CH3:31])[CH3:34])=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:29])[F:30])[CH:3]=1
Reactant: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNOC
Product: CON(C)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(methoxy-methyl-amino)-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one and O,N-Dimethyl-hydroxylamine following General Procedure B.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C@H:13]([C:16]([NH2:18])=[O:17])[CH2:14][CH3:15])[C:9](=[O:19])[CH2:8]1)(=O)=O.[I-:20].[Na+]>C1COCC1>[I:20][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C@@H:13]([CH2:14][CH3:15])[C:16]([NH2:18])=[O:17])[C:9](=[O:19])[CH2:8]1
Reactant: [I-]
Reactant: CC[C@@H](C(N)=O)N1CCC(COS(C)(=O)=O)CC1=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H](C(N)=O)N1CCC(CI)CC1=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 65636364 %

Procedure:
In a 150 ml three necked flask fitted with magnetic stirrer and reflux condenser, under inert atmosphere, 6.88 g (23.5 nmoles) of {1-[(1S)-1-(aminocarbonyl)propyl]-6-oxo-3-piperidinyl}methyl methanesulfonate 24 were dissolved in 86 ml of THF. 3.9 g (25.9 mmoles, 1.1 eq) of sodium iodide were added in one portion and the mixture was brought to reflux. After 5 hours, 780 mg (5.2 mmoles, 0.22 eq) of sodium iodide were added and reflux continued for a total of 10 hours. After cooling down to 0° C., the mixture was filtered, the precipitate washed with THF, the combined organic fractions concentrated to dryness and purified by PrepLC (800 g SiO2, CH2Cl2/MeOH, 95/5) to give 7.21 g of crude compound. It was crystallised from 80 ml ethanol to give 5 g of pure iodide 13, 66% yield.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.C(O)C.O>O1CCCC1.C(OCC)C>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[OH:13])=[CH:10][CH:9]=1
Reactant: Cc1cscn1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: Cc1csc(C(O)c2ccc(Cl)cc2)n1
Temperature: -60 °C
Reaction time: 1.5 h
Yield: 73.7 %

Procedure:
A solution of 5.949 g of 4-methyithiazole in 5 mL of tetrahydrofuran was added dropwise to 38 mL of a 1.6-M n-butyllithium/n-hexane solution in 6 mL of tetrahydrofuran under cooling at −60° C. After the mixture was stirred for 1.5 hours, a solution of 8.434 g of 4-chlorobenzaldehyde in 20 mL of tetrahydrofuran was added dropwise thereto. After the mixture was stirred at the same temperature for 1.8 hours, it took 2 hours to bring back to a room temperature, and then 15 mL of 50% ethanol aqueous solution was added to the mixture. The reaction solution was poured into water, and diethyl ether was added thereto, and the resulting mixture was subjected to extraction. The extract was washed with a saturated saline solution and then dried over magnesium sulfate. The solvent was distilled off, and then the raw product was purified by silica gel column chromatography (hexane/ethyl acetate (volume ratio)=2:1 to 1:1) to give the title compound (10.602 g (74%)).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[C:38]2=[N:49][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:54][CH2:53][C:16]([CH3:55])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:52])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:51])=[CH:28][C:29]=2[C:30]2[CH:50]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[C:38]2=[N:49][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:55])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:52])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:51])=[CH:28][C:29]=2[C:30]2[CH:50]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:53][CH2:54]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(-c2ccc(F)cc2)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc3c1-c1ccc(F)cc1)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 5.1 %

Procedure:
Prepared in 5.1% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-5-(4-fluorophenyl)-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.12 (s, 1H), 8.05 (s, 1H), 7.88 (d, J=7.7 Hz, 1H), 7.48-7.41 (m, 3H), 7.36-7.29 (m, 3H), 7.22-7.12 (m, 3H), 5.98 (br. s., 1H), 4.61 (br. s., 1H), 3.93-3.81 (m, 1H), 3.66 (t, J=11.0 Hz, 1H), 3.38 (br. s., 4H), 2.18 (s, 3H), 1.95-1.63 (m, 9H), 1.55 (br. s., 1H), 1.22 (s, 3H), 1.19 (s, 9H), 1.07 (d, J=5.9 Hz, 3H). LCMS (ESI, M): 737.4.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:17][CH3:18])[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)=[O:4]>FC(F)(F)C(O)=O.ClCCl>[CH3:1][O:2][C:3]([C:5]1([S:17][CH3:18])[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(SC)CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(SC)CCNC1
Reaction time: 2 h
Yield: 217.2 %

Procedure:
3-Methylsulfanyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2.15 gm, 8.8 mmol) was dissolved in 20 ml of 50% trifluoroacetic acid/dichloromethane and stirred for 2 hrs. The reaction mixture was evaporated to give 3.35 g of 3-Methylsulfanyl-pyrrolidine-3-carboxylic acid methyl ester 4BP as a gummy solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[C:18]3[CH2:24][CH:23]4[N:25]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH:20]([CH2:21][CH2:22]4)[CH2:19]3)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=3.C(N(CC)C(C1C=CC2C(=C3CC4NC(CC4)C3)C3C(OC=2C=1)=CC=CC=3)=O)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]([CH:18]3[CH2:19][CH:20]4[N:25]([C:26](=[O:31])[C:27]([F:28])([F:29])[F:30])[CH:23]([CH2:22][CH2:21]4)[CH2:24]3)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=3
Reactant: COc1cccc2c1Oc1cc(Br)ccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Agent: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2
Product: COc1cccc2c1Oc1cc(Br)ccc1C2C1CC2CCC(C1)N2C(=O)C(F)(F)F

Procedure:
Using an adaptation of the method described in Procedure 4, substituting 1-[3-(3-bromo-5-methoxy-xanthen-9-ylidene)-8-aza-bicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoro-ethanone, 4k for 9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic acid diethylamide, 8a, the title compound 1-[3-(3-bromo-5-methoxy-9H-xanthen-9-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoro-ethanone, 5k was obtained
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([C:17](OC)=[O:18])=[CH:13][C:11]=2[N:12]=1.O.[OH-].[Na+]>C1COCC1>[CH3:7][C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:11]=2[N:12]=1
Reactant: COC(=O)c1ccc2sc(C)nc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2cc(CO)ccc2s1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
A cooled (−10° C.) suspension of LiAlH4 (207 mg; 5.47 mmol) in anh. THF (40 ml) was treated with a solution of methyl 2-methylbenzo[d]thiazole-5-carboxylate (1.032 g; 4.97 mmol) in anh. THF (20 ml). The mixture was further stirred at −10° C. for 20 min. Water (0.20 ml), 15% aq. NaOH (0.20 ml), and water (0.60 ml) were then successively added, and the resulting mixture was further stirred at rt for 1 h. Filtration, concentration to dryness under reduced pressure, and additional drying under HV afforded (2-methylbenzo[d]thiazol-5-yl)methanol as a yellow oil. LC-MS (conditions A): tR=0.48 min.; [M+H]+: 180.19 g/mol.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:8]1.C([O:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([CH2:32]Br)[CH:29]=[CH:28][C:27]=1[O:34][CH3:35])C>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:32][C:30]3[CH:29]=[CH:28][C:27]([O:34][CH3:35])=[C:26]([CH:31]=3)[C:25]([OH:36])=[O:24])[CH2:18][CH2:17]2)=[CH:8]1
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Reactant: c1coc(Cn2cc(C3CCNCC3)c3ccccc32)c1
Product: COc1ccc(CN2CCC(c3cn(Cc4ccco4)c4ccccc34)CC2)cc1C(=O)O

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 1.9 g (6.5 mmol) of 1-furan-2-ylmethyl-3-piperidin-4-yl-1H-indole (example 83, part B) and 1.9 g (7.1 mmol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. After standard work-up and recrystallisation with ethanol, 0.5 g (16% of yield) of the expected acid were obtained.
Reaction SMILES: [CH2:1]([CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=1>O1CCCC1>[N+:31]([C:30]1[C:25]([C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:1][CH3:2])=[N:26][CH:27]=[CH:28][CH:29]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)C(CC)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)(C(=O)OCC)c1ncccc1[N+](=O)[O-]

Procedure:
Diethyl ethylmalonate is dissolved in tetrahydrofuran and treated with one equivalent of sodium bis(trimethylsilyl)amide followed by 2-chloro-3-nitropyridine to give the title compound.