Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O.C([Cl:19])(=O)C>>[Cl-:19].[CH3:6][O:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[N+:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: CC(=O)Cl
Reactant: COc1ccccc1C=O
Product: COc1ccccc1C=[N+]1CCCC1
Product: [Cl-]

Procedure:
The reaction of 6.9 ml (0.084 mol) pyrrolidine and 4.8 g (0.035 mol) 2-methoxybenzaldehyde in accordance with general synthesis instructions 2 and subsequent reaction with 2.1 ml (0.035 mol) acetyl chloride in accordance with general synthesis instructions 3 gave 6.2 g (corresponding to 78% of the yield calculated by theory) 1-(2-methoxy-benzylidene)-pyrrolidinium chloride.
Reaction SMILES: C[C:2]([CH:6](O)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:3][CH2:4]C.CCCCCC([OH:24])/C(/C)=C/CC>>[CH2:4]([OH:24])[CH:3]=[CH:2][CH2:6][CH2:7][CH:8]=[CH:9][CH2:10][CH3:11]
Reactant: CC/C=C(\C)C(O)CCCCC
Reactant: CCC=C(C)C(O)CCCCC
Product: CCC=CCCC=CCO

Procedure:
4-methyl-3-decen-5-ol (UNDECAVERTOL, Givaudan-Roure)*
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[N:8][C:6]=2[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:19]3[CH2:24][CH2:23][CH:22]([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:21][CH2:20]3)=[N:8][C:6]=2[N:7]=1
Reactant: CC(C)(O)C1CCNCC1
Reactant: O=Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(O)C1CCN(Cc2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.6 %

Procedure:
A mixture of 5-chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidine-2-carbaldehyde (400 mg, 1.4 mmol), 2-piperidin-4-yl-propan-2-ol (242 mg, 1.7 mmol), and 4 Å molecular sieves (1.5 g) in 1,2-dichloroethane (20 mL) was stirred at RT for 6 h. Sodium triacetoxyborohydride (593 mg, 2.8 mmol) was added and the resulting reaction mixture was stirred at RT under nitrogen atmosphere for 18 h. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (Si—PPC, (10% MeOH in EtOAc): EtOAc, gradient 0:100 to 20:80) to afford the title compound as an orange solid (344 mg, 60%). 1H NMR (400 MHz, CDCl3): δ 3.98-3.93 (6 H, m), 3.85 (5 H, m), 3.08 (2 H, m), 2.28 (2 H, m), 1.79 (2 H, m), 1.48 (3 H, m), 1.23-1.21 (6 H, m).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[BrH:18].C(O)(=O)C.BrBr>C(O)(=O)C>[Br:18][CH2:16][C:15]([C:12]1[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][CH:13]=1)=[O:17]
Reactant: CCCCCCCCc1ccc(C(C)=O)cc1
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: CCCCCCCCc1ccc(C(=O)CBr)cc1
Temperature: 30 °C
Reaction time: 3 h

Procedure:
To a solution of 4′-octylacetophenone (18′) (23.9 g) in acetic acid (100 ml) is added hydrogen bromide-acetic acid solution (25%, 34 ml) under ice-cooling, which is followed by dropwise addition of bromine (5.3 ml). The mixture is heated to 30° C. and stirred for 3 hr. The solvent is distilled away and the mixture is purified by silica gel column chromatography to give 2-bromo-4′-octylacetophenone as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH2:19][CH3:20])[CH3:18].O>ClCCl>[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH2:19][CH3:20])[CH3:18]
Reactant: COC(=O)c1sccc1N
Reactant: CCC(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCC(C)c1ccc(S(=O)(=O)Nc2ccsc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.3 %

Procedure:
To a solution of methyl 3-aminothiophene-2-carboxylate (0.68 g; 4.3 mmol) in pyridine (0.52 mL; 6.4 mmol) and anhydrous dichloromethane (15 mL), was added a solution of 51 (1.0 g; 4.3 mmol) in dichloromethane (3 mL). After stirring 16 hours at room temperature, the reaction was mixed with water (50 mL), and the organic phase was separated. The aqueous phase was extracted with dichloromethane (2×10 mL), and the combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexanes (0 to 25% v/v gradient elution) to yield the title product as a white solid (0.75 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][C:18]1[CH:19]=[C:20]([CH:30]=[CH:31][CH:32]=1)[CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][NH:16][CH2:17][C:18]3[CH:19]=[C:20]([CH:30]=[CH:31][CH:32]=3)[CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc(CNCc2ccc(-c3ccc(F)cc3)cc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
4′-Fluorobiphenyl-4-carbaldehyde (1.0 g, 5 mmol, 1.0 eq) and tert-butyl 3-(amino methyl)benzylcarbamate (1.18 g, 5 mmol, 1 eq) were dissolved in dry methanol under nitrogen and refluxed for 4 h. The reaction mass was cooled to 0° C. and sodium borohydride (570 mg, 15 mmol, 3 eq) was added portionwise at 0° C. over 20-30 minutes. The mixture was stirred for 1 h at 0° C. and then the reaction was quenched with 10% aq. sodium bicarbonate solution. The mixture was stirred at room temperature for 1 h. The resulting solution was completely evaporated under vacuum and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by silica gel (60-120) column chromatography using 5-10% methanol dichloromethane as the eluent to afford the desired compound (1.8 g, 85%) as a light yellow liquid. 1H NMR (400 MHz, DMSO-d6) δ 1.30-1.37 (d, 9H), 3.66-3.69 (d, 4H), 4.09-4.11 (d, 2H), 7.07-7.09 (d, 1H), 7.18-7.29 (m, 6H), 7.36-7.42 (m, 1H), 7.56-7.59 (m, 2H), 7.65-7.67 (d, 2H), 7.68-7.70 (m, 2H). MS (ESI): 421.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:5][CH2:6][CH:7]=[CH2:8])[CH2:3][OH:4].Cl[C:11](Cl)([O:13]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C.[OH-].[Na+].[NH2:33][C@H:34]([C:39]([OH:41])=[O:40])[C:35]([CH3:38])([CH3:37])[CH3:36]>O1CCOCC1>[CH3:1][C:2]([CH3:9])([CH2:5][CH2:6][CH:7]=[CH2:8])[CH2:3][O:4][C:11]([NH:33][C@H:34]([C:39]([OH:41])=[O:40])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:13]
Reactant: C=CCCC(C)(C)CO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(C)(C)COC(=O)N[C@H](C(=O)O)C(C)(C)C
Temperature: 22 °C
Reaction time: 1 h
Yield: 153.9 %

Procedure:
To a stirred solution of 2,2-dimethylhex-5-en-1-ol (10.75 g, 83.85 mmol) in anhydrous 1,4-dioxane (100 mL), at 0° C. and under nitrogen, was added triphosgene (13.69 g, 46.12 mmol) and then DIPEA (14.61 mL, 83.85 mmol) cautiously. This reaction solution was stirred at 22° C. for 1 hour, cooled to 0° C. and added slowly 1N NaOH (83.85 mL, 83.85 mmol) and L-tert-leucine (11.00 g, 83.85 mmol), then stirred at 22° C. for 20 hours. The reaction solution was basified to pH 10 with 1N NaOH, washed with CH2Cl2 (3×100 mL), acidified to pH 5 with 1N HCl and extracted with CH2C]2 (3×150 mL). The combined CH2Cl2 layer was washed with water (100 mL), dried over Na2SO4, filtered and concentrated to give the title product (20.26 g, 84.66%). 1H NMR (500 MHz, CDCl3) δ 5.85-5.77 (m, 1 H); 5.24 (d, 1 H); 5.01 (d, 1 H); 4.93 (d, 1 H); 4.20 (d, 1 H); 3.86 (d, 1 H); 3.79 (d, 1 H); 2.01 (m, 2 H); 1.36 (m, 2 H); 1.04 (s, 9 H); 0.92 (m, 6 H) ppm. LRMS (ESI) m/z 286 [(M+H)+; calcd for C15H28NO4: 286].
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][OH:6])=[O:4].[F:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(C(C)C)C(C)C)C>ClCCl>[F:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][CH2:2][C:3]([NH:5][OH:6])=[O:4])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(OCCCCF)cc1
Reactant: NCC(=O)NO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNS(=O)(=O)c1ccc(OCCCCF)cc1)NO
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To the resin from stage 58.1 (350 mg, ˜0.3 mmol) are added successively 4-(4-fluorobutoxy)-benzenesulfonyl chloride (306 mg, 1.15 mmol) in dry dichloromethane (4 ml), and N-ethyldiisopropylamine (0.24 ml, 1.40 mmol) in dry dichloromethane (4 ml). After stirring for 15 h at r.t. the suspension is filtered and the resin washed with dichloromethane (22×), DMF (2×), alternating with H2O and DMF (3×), alternating with THF and 2-propanol (3×), dichloromethane (3×). The resin is dried under reduced pressure to provide polymer-bound 2-[4-(4-fluoro-butoxy)-benzenesulfonylamino]-N-hydroxy-acetamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[CH:5]=[CH:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:47][CH:48]([O:50]C(/N=N/C(OC(C)C)=O)=O)C.C(O)(=O)C>C1COCC1>[C:48]([O:13][C@@H:11]1[CH2:10][N:9]([C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:12]1)(=[O:50])[CH3:47]
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: CCOC(=O)c1cnn2ccc(N3C[C@H](O)C[C@@H]3c3cccc(F)c3)nc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2ccc(N3C[C@@H](OC(C)=O)C[C@@H]3c3cccc(F)c3)nc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.8 %

Procedure:
To a mixture of ethyl 5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (Example 41, Step E, 260 mg, 0.702 mmol) and PPh3 (460 mg, 1.75 mmol) in THF (10.0 mL) was added DIAD (276 μL, 1.40 mmol) followed by acetic acid (80.4 μL, 1.40 mmol). The reaction was stirred at ambient temperature for 48 hours and then concentrated. The residue was purified by reverse phase column chromatography (0-70% acetonitrile/water) to afford ethyl 5-((2R,4S)-4-acetoxy-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (228 mg, 79% yield). MS (apci) m/z=413.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1.[C:12](Cl)(=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16].C(O)(=O)CCC=C.S(Cl)(Cl)=O>C(Cl)Cl.N1C=CC=CC=1>[C:12]([NH:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([O:2][CH3:1])=[O:11])(=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16]
Reactant: C=CCCC(=O)Cl
Reactant: COC(=O)c1cccc(N)c1
Agent: C=CCCC(=O)O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: C=CCCC(=O)Nc1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
Methyl(3-amino)benzoate (4.5 g, 29.8 mmol) was taken up in DCM (10 ml) and pyridine (1 ml) at 0° C. 4-Pentenoyl chloride (freshly prepared from 4-pentenoic acid (3.0 g, 29.97 mmol) and thionyl chloride (6.6 ml) at r.t. for 1 h, evaporated and azeotroped with DCM) was added dropwise in DCM (3 ml). The mixture was allowed to warm to r.t. and stirred overnight. The mixture was evaporated and partitioned between EtOAc and 1M HCl. The organic portion was washed with 5% KHCO3 and brine, filtered (Whatman® 1PS, phase separator), and evaporated. The residue was chromatographed (eluant 30% EtOAc in hexanes) to provide a colourless oil (2.20 g, 32%).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([N:18]=[C:19]=[S:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>>[CH2:11]([N:18]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][N:10]=[C:19]1[S:20][CH2:26][C:25]1[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: S=C=NCc1ccccc1
Reactant: NNC(=O)c1ccccc1
Reactant: Clc1ccc(CBr)cc1
Product: Clc1ccc(CSc2nnc(-c3ccccc3)n2Cc2ccccc2)cc1

Procedure:
This compound was synthesized using the same methodology as described in Example 1 above, using benzoic acid hydrazide, benzyl isothiocyanate and 4-chlorobenzyl bromide as the starting materials.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=[O:20])[C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)[CH3:2].[CH2:22](O[Si](C)(C)C)[CH2:23][CH2:24][CH3:25].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C([SiH](CC)CC)C.Cl>C(Cl)Cl.O>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:20][CH2:22][CH2:23][CH2:24][CH3:25])[C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:16])([CH3:17])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCCCO[Si](C)(C)C
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCCOC(C(=O)OCC)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 56.8 %

Procedure:
6 g of oxo-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetic acid ethyl ester and 2.6 g of butoxytrimethylsilane were dissolved in 200 ml of methylene chloride. The solution was cooled to 0° C., treated with 400 mg of trimethylsilyl triflate and stirred at 0° C. for 1.5 hours. After the dropwise addition of 2 g of triethylsilane, the reaction mixture was stirred at room temperature for 26 hours, then diluted with 500 ml of water, acidified with 2N hydrochloric acid and extracted with ether. The organic phase was washed with water, dried (Na2SO4) and the solvent evaporated. The oily residue was purified with flash chromatography (silica gel, eluent hexane/tert.butyl methyl ether 3%) and preparative HPLC (YMC CN 60 Å5-15 μm, hexane) to give 3.5 g of the title product as colorless oil.
Reaction SMILES: [OH-:1].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#N)=[C:6]([O:13][CH3:14])[CH:5]=1.[OH2:15]>CO>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:15])=[O:1])=[C:6]([O:13][CH3:14])[CH:5]=1
Reactant: COc1cc(Br)ccc1CC#N
Reactant: O
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)ccc1CC(=O)O
Yield: 86 %

Procedure:
A solution of NaOH (5.72 g, 143 mmol) in water (29 mL) was added to a solution of (4-bromo-2-methoxy-phenyl)-acetonitrile (10.2 g, 45.1 mmol) in MeOH (100 mL). The reaction mixture was heated at reflux for 18 hours. The solvent was evaporated under reduced pressure and water was added. The aqueous mixture was washed with diethyl ether, and the aqueous layer was acidified by addition of aqueous HCl (2 M) to pH 1. The aqueous mixture was then extracted with EtOAc, and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure to give 9.49 g (86% yield) of (4-bromo-2-methoxy-phenyl)-acetic acid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].N1C=CC=CC=1.[C:22](Cl)(=[O:26])[C:23]([CH3:25])=[CH2:24]>O1CCCC1>[C:22]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:26])[C:23]([CH3:25])=[CH2:24]
Reactant: O=C(O)CCCCCCCCCCCO
Reactant: C=C(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCCCCCCCCCCC(=O)O
Temperature: 0 °C
Yield: 53 %

Procedure:
To a solution of 2.16 g of 12-hydroxydodecanoic acid in 30 ml of tetrahydrofuran (THF) is added 1.09 g of pyridine. The mixture is cooled to 0° C. and a solution of 1.04 g of methacryloyl chloride in 15 ml of THF is added dropwise. The mixture is allowed to warm to room temperature while stirring and is then stirred at ambient temperature for 12 hours. The solvent is then removed under reduced pressure and the residual solid is dissolved in 25 ml of diethylether. The solution is washed with distilled water, dried over magnesium sulfate and then evaporated to dryness. The product is purified by chromatography, using a 1:2 mixture of ethylacetate and hexane to give 1.5 g (53% yield) of 12-methacryloyloxydodecanoic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:9]=[N:10][C:11](Cl)=[N:12][CH:13]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:7][C:8]1[CH:9]=[N:10][C:11]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:12][CH:13]=1
Reactant: C1CCNCC1
Reactant: Clc1ncc(Br)cn1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Brc1cnc(N2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Piperidine (5.1 ml, 51.6 mmol) was added to a stirred solution of 5-bromo-2-chloropyrimidine (5 g, 25.8 mmol) and triethylamine (9.0 ml, 64.5 mmol) in toluene (30 ml). After stirring at room temperature for 24 hours the reaction mixture was diluted with ethyl acetate and washed with 2N hydrochloric acid, brine and dried (magnesium sulfate). The organic layer was filtered, concentrated in vacuo and the resulting residue was purified by column chromatography eluting with ethyl acetate to afford the title compound (D32).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH3:22]>CO.C(OCC)C>[CH2:19]([O:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCBr
Reactant: COC(=O)Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: CCCCOc1ccccc1CC(=O)OC
Yield: 65.3 %

Procedure:
16.6 g of methyl 2-hydroxyphenyl acetate are dissolved in 100 ml of methanol. 15 g of potassium carbonate and 18 g of n-butyl bromide are added. After 24 hours of refluxing followed by filtration, the solution is concentrated under reduced pressure. The oil obtained is taken up in diethyl ether and washed with NaHCO3 and H2O. Drying over sodium sulfate and removal of the solvent leaves 14.5 g (65%) of a yellow oil which can be purified by distillation.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:22]=1[CH3:23])[C:7]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([O:18][CH3:19])[C:10]=1[O:20][CH3:21])=[O:8].[F:26][C:27]([F:32])([F:31])C([O-])=O.[Na+].CN1CCCC1=O>CCOCC.O.[Cu]I>[CH3:23][C:22]1[C:6]([C:7]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([O:18][CH3:19])[C:10]=2[O:20][CH3:21])=[O:8])=[C:5]([O:24][CH3:25])[CH:4]=[CH:3][C:2]=1[C:27]([F:32])([F:31])[F:26]
Reactant: COc1cc(C)c(C(=O)c2c(OC)ccc(Br)c2C)c(OC)c1OC
Reactant: O=C([O-])C(F)(F)F
Agent: [Cu]I
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOCC
Product: COc1cc(C)c(C(=O)c2c(OC)ccc(C(F)(F)F)c2C)c(OC)c1OC
Temperature: 160 °C

Procedure:
A mixture of 63C (6.15 g, 0.015 mol), sodium trifluoroacetate (9.52 g, 0.07 mol), copper-(I)iodide (13.37 g, 0.07 mol) and 1-N-methyl-2-pyrrolidinone (100 ml) is heated to 160° C. for 118 hours. The reaction mixture is cooled to room temperature and diluted with ether and water. The organic phase is separated and concentrated and the residue is purified by column chromatography (petrol ether:ethyl acetate, 95:5 v/v) yielding the pure product as white crystals, 1.3 g, (22%) having a melting point of 95-96° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](=[O:22])[NH:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:9]=2)[N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:3]=1[C:30]1[C:31]([O:36][CH3:37])=[N:32][CH:33]=[CH:34][CH:35]=1.[C:38]1(B(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:37][O:36][C:31]1[C:30]([C:3]2[N:4]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[C:5]3[C:10]([C:2]=2[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:9][C:8]([C:11](=[O:22])[NH:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[CH:7][CH:6]=3)=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: COc1ncccc1-c1c(Br)c2cc(C(=O)NCCCN3CCOCC3)ccc2n1C(=O)OC(C)(C)C
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncccc1-c1c(-c2ccccc2)c2cc(C(=O)NCCCN3CCOCC3)ccc2n1C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
To a solution of tert-butyl 3-bromo-2-(2-methoxypyridin-3-yl)-5-(3-morpholinopropylcarbamoyl)-1H-indole-1-carboxylate (0.38 mmol), phenylboronic acid (69 mg, 0.57 mmol), Cs2CO3 (0.18 g, 0.57 mmol) in dioxane (3 ml) and water (1 ml) was added Pd(PPh3)4 (43 mg, 0.038 mmol). The reaction mixture was heated at 100° C. for up to 3 h. The reaction mixture was quenched by adding ethyl acetate (15 ml) and saturated NaHCO3 (10 ml). The ethyl acetate layer was separated and washed with brine (10 ml), dried with Na2SO4, filtered and concentrated to give a crude product. The crude product was purified using flash column chromatography (SiO2, 5% EtOAc in hexanes to 10% EtOAc in hexanes). The desired product, tert-butyl 2-(2-methoxypyridin-3-yl)-5-(3-morpholinopropylcarbamoyl)-3-phenyl-1H-indole-1-carboxylate was obtained as a light yellow solid (0.017 g, 47%); 400 MHz 1H NMR (DMSO-d6) δ: 8.57 (t, J=5.2 Hz, 1H), 8.24 (d, J=8.8 Hz, 1H), 8.17 (dd, J=1.2 Hz, 4.4 Hz, 1H), 8.10-7.98 (m, 1H), 7.92 (dd, J=1.2 Hz, 8.4 Hz, 1H), 7.45 (dd, J=1.6 Hz, 7.6 Hz, 1H), 7.40-7.23 (m, 3H), 7.23-7.19 (m, 1H), 6.94-6.89 (m, 1H), 3.87 (s, 3H), 3.57-3.50 (m, 4H), 3.34-3.25 (m, 2H), 2.35-2.28 (m, 6H), 1.71-1.62 (m, 2H), 1.24 (s, 9H); LCMS: 571 [M+H]. Hydrolysis as described in example 33 provides compound 1 in Table 2.
Reaction SMILES: [C:1]1([CH:7]([N:14]2[CH2:17][CH:16]([OH:18])[CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl>CS(C)=O.[OH-].[Na+]>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:14]2[CH2:17][CH:16]([O:18][CH2:19][CH:21]3[O:23][CH2:22]3)[CH2:15]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: c1ccc(C(c2ccccc2)N2CC(OCC3CO3)C2)cc1
Reaction time: 72 h

Procedure:
37.5 g of diphenylmethylazetidin-3-ol are dissolved at room temperature in a mixture of 250 ml of dimethyl sulphoxide and 150 ml of 5% strength sodium hydroxide solution, 65 ml of epichlorohydrin are added and the mixture is allowed to stand for 3 days at room temperature. The reaction mixture is extracted using 300 ml of methylene chloride, and the organic phase is dried over sodium sulphate and evaporated. The crude product is distilled in vacuo.