Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br.C(OCC)(=O)C>CS(C)=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:8]([N:6]1[CH:5]=[N:4][N:3]=[CH:7]1)[C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: BrCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(CCCCCCCCCCBr)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 240 mg, 6.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMSO (25 mL) at r.t. The mixture was stirred for 1 hour at this temperature and 1,10-dibromodecane (5 mL) was added. The reaction mixture was stirred overnight and ethyl acetate (100 mL) was added. The mixture was transferred into a separation funnel and extracted with water (twice 100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure (water bath temperature <30° C.). The resulting orange oil was mixed with diethyl ether (100 mL) and filtered through a layer of silica (ca. 5 cm). The silica was washed with more diethyl ether (ca. 100 mL) to remove the excess of 1,10-dibromodecane. The crude product was washed from the silica with acetone (120 mL). The acetone solution was concentrated under reduced pressure and the residue was purified by column-chromatography (eluent: ethyl acetate) to give the title compound as a pale yellow solid. Yield: 1.32 g (65%). 1H-NMR (400 MHz, d6-DMSO) δ=1.16-1.40 (m, 14H), 1.76 (tt, J=7.0, 7.0 Hz, 2H), 3.50 (t, J=6.6 Hz, 2H), 3.79 (t, J=7.0 Hz, 2H), 6.61 (d, J=9.0 Hz, 2H), 7.70 (d, J=9.0 Hz, 2H), 8.95 (s, 2H). 4-{[10-(4-Hydroxy-phenylsulfanyl)-decyl]-[1,2,4]triazol-4-yl-amino}-benzonitrile (CAB03011, STX625)
Reaction SMILES: [N+]([O-])(O)=O.CC(O)=O.[CH2:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)[CH3:10].[Br:20]Br>O.[N+]([O-])([O-])=O.[Ag+]>[Br:20][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:11]=1[CH2:9][CH3:10])[C:15]([OH:17])=[O:16]
Reactant: BrBr
Reactant: CCc1ccc(C(=O)O)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCc1ccc(C(=O)O)cc1Br

Procedure:
To a mixture of conc. HNO3 (66 mL), glacial AcOH (300 mL) and water (50 mL), 4-ethyl-benzoic acid (15 g) was added, stirring vigorously, before treating with bromine (5.67 mL). Finally a solution of AgNO3 (16.97 g) in water (50 mL) was added dropwise and the mixture was stirred vigorously for 2 h. The precipitate was collected by filtration, washed well with water, before being extracted with hot, saturated K2CO3 solution, and then treated with charcoal. The hot solution was filtered through kieselguhr and the solution was acidified to pH1 using conc. HCl. The resulting white precipitate was collected by filtration and dried in the vacuum oven overnight at 60° C. to afford the title compound (19.46 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[C:17](OC(=O)C)(=[O:19])[CH3:18].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([C:11]([F:13])([F:14])[F:12])=[CH:6][C:5]=1[NH:15][C:17](=[O:19])[CH3:18]
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(I)c(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A solution of 2-amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (42.0 g, 122 mmol) in toluene (400 mL) was treated with acetic anhydride (12.8 mL, 135 mmol) and the mixture was heated to reflux for 16 h under nitrogen. It was then allowed to cool to r.t. and diluted with water. The mixture was rendered neutral by adding small portions of sodium hydrogencarbonate, and the organic layer was separated. The aqueous phase was extracted with EtOAc, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was recrystallized in hexanes to give 2-acetylamino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (43.4 g, 112 mmol, 92%) as a white powder, m.p. 96-98° C., ESI-MS: m/z 388 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:16]([CH2:24]O)[O:15][C:14]3=[O:26])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([N:31](CC)CC)C.S(Cl)(C)(=O)=O.[N-]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:16]([CH2:24][NH2:31])[O:15][C:14]3=[O:26])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C1O[C@@H](CO)[C@H](c2ccccc2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: CS(=O)(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Product: NC[C@@H]1OC(=O)N(c2ccc(Oc3ccc(Cl)cc3)cc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-(hydroxymethyl)-4-phenyloxazolidin-2-one (44 mg, 0.11 mmol) and triethylamine (0.046 mL, 0.33 mmol) in dichloromethane (1.5 mL) at 0° C. was added mesyl chloride (0.012 mL, 0.15 mmol). The reaction mixture was stirred at this temperature for 20 min until reaction complete as judged by TLC, and then was quenched with NaHCO3 aqueous solution. The aqueous layer was extracted (2× dichloromethane) and the organics combined, dried (MgSO4), and concentrated. The oil was taken up in 2 mL DMF and treated with NaN3 (14 mg, 0.2 mmol) at 70° C. for 5 h (monitored by analytical LC/MS). The reaction was cooled to room temperature, and then quenched with water. Ethyl acetate was added and the organic was washed with brine, dried (MgSO4), and concentrated. The oil was re-dissolved in THF/water (10:1, 1 mL) and treated with triphenylphosphine (34 mg, 0.12 mmol). The reaction was stirred at room temperature overnight and then concentrated. Flash chromatography (0-5% MeOH/dichloromethane) gave 35 mg (80%, 3 steps) of a the title compound as colorless oil that crystallized on standing. 1H NMR (acetone-d6) δ (ppm) 7.49-7.53 (m, 2H), 7.30-7.46 (m, 7H), 6.92-6.97 (m, 4H), 5.48 (d, 1H, J=4.8 Hz), 4.55 (dd, 1H, J=9.5, 4.7 Hz), 3.64 (dd, 2H, J=4.9, 1.6 Hz). HPLC-MS calculated C22H19ClN2O3 (M+H+): 395.1, found: 395.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]([NH:8]C(=O)OC(C)(C)C)[CH:7]=1.Br[C:26]1[C:27]([C:32]#[N:33])=[N:28][CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO.ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:26]3[C:27](=[C:32]([NH2:33])[N:8]=[C:6]2[CH:7]=1)[N:28]=[CH:29][CH:30]=[CH:31]3
Reactant: N#Cc1ncccc1Br
Reactant: CC(C)(C)OC(=O)Nc1cc(F)ccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1nc2cc(F)ccc2c2cccnc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from step 2) (1.0 eq.) and 3-bromopicolino-nitrile (1.0 eq.) in toluene (0.24 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (4.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-40% ethyl acetate in toluene to give a solid which was then triturated in 10% ethyl acetate in hexane to give 8-fluorobenzo[f][1,7]naphthyridin-5-amine. 1H NMR (acetone d-6): δ 9.00 (d, 1H), 8.90 (d, 1H), 8.46-8.50 (dd, 1H), 7.83-7.87 (dd, 1H), 7.26 (d, 1H), 7.15 (t, 1H), 6.9 (br, 2H). LRMS [M+H]=214.1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[C:20]([O:22][CH3:23])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)C(N)c1cccs1
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1cccs1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(2-thienyl)acetate (prepared from L-α-2-thienylglycine (Sigma) using General Procedure G), the title compound was prepared as a solid (mp=161-162° C.). The product was purified by preparative LC 2000 chromatography using 1:4 EtOAc/hexanes.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11]1[S:15][C:14]2=[N:16][CH:17]=[C:18](I)[N:13]2[N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>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.C(COC)OC>[CH2:3]([NH:10][C:11]1[S:15][C:14]2=[N:16][CH:17]=[C:18]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[C:27]([O:28][CH3:29])[CH:26]=3)[N:13]2[N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Ic1cnc2sc(NCc3ccccc3)nn12
Reactant: COc1ccc(B(O)O)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: COc1ccc(-c2cnc3sc(NCc4ccccc4)nn23)cc1OC
Temperature: 90 °C
Yield: 52.8 %

Procedure:
An aqueous solution of NaOH (1.00 ml) was added to a mixture of benzyl-(5-iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-amine (250.00 mg; 0.70 mmol; 1.00 eq.), 3,4-dimethoxyphenylboronic acid (191.59 mg; 1.05 mmol; 1.50 eq.), Pd(PPh3)4 and dimethoxyethane (5.00 ml) under N2. The resulting suspension was heated in the microwave at 90° C. for 30 minutes under N2. The reaction was filtered, washed with dimethoxyethane, water and dried at 40° C. for 18 h. 135.5 mg of the desired product were obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:18]=[C:19](C)[CH:20]=[CH:21][CH:22]=3)[C:3]=12.[F:25]C1C=CC=CC=1C=O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[F:25])[C:3]=12
Reactant: O=Cc1ccccc1F
Reactant: Cc1cccc(-c2nn(C)c3nnc(-c4ccccc4)c(Cl)c23)c1
Product: Cn1nc(-c2ccccc2F)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound 22 was synthesised following similar procedures outlined in Example 24 (Compound 19), using 2-fluorobenzaldehyde instead of 3-methylbenzaldehyde in Step 1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[C:17]([CH3:23])[N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:24]=1.[F:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[F:25][C:26]1[N:31]=[CH:30][C:29]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]5[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[C:17]([CH3:23])[N:16]=5)[N:14]=[C:7]4[C:6]=3[CH:24]=2)=[CH:28][CH:27]=1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)n(C(C)C)n1
Reactant: OB(O)c1ccc(F)nc1
Product: Cc1nc(-c2cn3c(n2)-c2cc(-c4ccc(F)nc4)ccc2OCC3)n(C(C)C)n1
Yield: 39 %

Procedure:
10-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine was reacted with 6-fluoropyridin-3-ylboronic acid to give 10-(6-fluoropyridin-3-yl)-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.121 g, 39%). 1H NMR (500 MHz, DMSO) δ 8.67 (d, J=2.4, 1H), 8.52 (d, J=2.6, 1H), 8.25 (td, J=8.2, 2.7, 1H), 7.92 (s, 1H), 7.68 (dd, J=8.5, 2.5, 1H), 7.31 (dd, J=8.4, 2.8, 1H), 7.19 (d, J=8.5, 1H), 5.69 (dt, J=13.3, 6.6, 1H), 4.56 (s, 4H), 2.26 (s, 3H), 1.47 (d, J=6.6, 6H). MS(ESI(+)): m/z 405.2 (M+H)
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[N:9]([Si](C(C)C)(C(C)C)C(C)C)[CH:10]=[CH:11][C:4]=12.C([Li])(CC)C.C(Br)(Br)(Br)[Br:30]>O1CCCC1>[Br:30][C:8]1[C:3]([C:2]([F:23])([F:22])[F:1])=[C:4]2[CH:11]=[CH:10][NH:9][C:5]2=[N:6][CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(F)(F)F)ccnc21
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: FC(F)(F)c1c(Br)cnc2[nH]ccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
4-Trifluoromethyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (1.54 g, 4.5 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to −78° C. Sec-butyllithium (1.4 M in cyclohexane, 10 mL, 14 mmol) was added dropwise and the mixture was stirred at −78° C. for 1 h. A solution of carbontetrabromide (4.5 g, 13.5 mmol) in tetrahydrofuran (20 mL) was added quickly at −78° C. and the mixture was stirred for 15 min. The reaction was quenched with saturated ammonium chloride solution. The mixture was warmed to ambient temperature and the layers were separated. The organic layer was dried with magnesium and concentrated. Purification by flash silica gel chromatography using a gradient of (ethyl acetate and methanol 9:1) in hexanes afforded 5-Bromo-4-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (170 mg, 0.64 mmol, 9% yield). 1H NMR (500 MHz, DMSO-d6) δ 12.49 (bs, 1H), 8.54 (s, 1H), 7.82 (m, 1H), 6.61 (m, 1H). MS: m/z 264.9/266.9 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9])#[CH:2].[F:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][C:13]=1[OH:19].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(NCC)C>O1CCOCC1.C(OCC)C.[Cu]I>[OH:19][C:13]1[CH:14]=[C:15]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=2)[C:8]#[N:9])[CH:16]=[CH:17][C:12]=1[F:11]
Reactant: Oc1cc(I)ccc1F
Reactant: C#Cc1cncc(C#N)c1
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: CCNCC
Solvent: CCOCC
Product: N#Cc1cncc(C#Cc2ccc(F)c(O)c2)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 42 %

Procedure:
Add bis(phenylnitrile)palladium (II) chloride (115 mg, 0.3 mmol) to a suspension of copper (I) iodide (38 mg, 0.2 mmol) in anhydrous 1,4-dioxane (1 mL) under nitrogen and stir for 10 min. Sequentially add 5-ethynyl-nicotinonitrile (1.28 g, 10 mmol), (prepared essentially as described in PREPARATION 4), 2-fluoro-5-iodophenol, (prepared essentially as described in PREPARATION 15), (2.37 g, 10 mmol) and tri-tert-butylphosphine (121 mg, 0.6 mmol) in 1,4-dioxane (5 mL) and diethylamine (2.1 mL, 12 mmol) to the reaction mixture and heat at 60° C. for 16 h. Cool to room temperature, dilute with diethyl ether, stir for 10 min and filter through diatomaceous earth. Wash the filtrate sequentially with water and an aqueous saturated solution of sodium chloride. Dry (magnesium sulfate), concentrate and purify by silica gel chromatography, eluting with 0:100 to 35:100 ethyl acetate:hexanes, to give the title compound (1.0 g, 42%) as a yellow solid.
Reaction SMILES: C([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][C@H:9]1[CH2:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[C:13]1([C@@H:12]2[NH:8][C@H:9]([CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=3)[CH2:10][CH2:11]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2)cc1
Reaction time: 0.75 h
Yield: 37.5 %

Procedure:
To a stirred solution of methyl 4-[N-Boc-5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoate (1.28 g, 3.11 mmol) in CH2Cl2 (30 ml) was added trifluoroacetic acid (10 ml) at rt, and the resulting mixture was stirred for 45 min. The mixture was concentrated in vacuo and poured into aq.NaHCO3, then extracted with CHCl3. The organic layer was washed with water, drying over anhydrous Na2SO4, and concentrated in vacuo to give methyl 4-[5-(R)-phenyl-2-(S)-pirrolidinyl methoxy]benzate (363 mg, quant.) as yellowish oil. The product was used for next reactions without further purification. 1H-NMR (CDCl3) δ 1.71–1.83 (m, 2 H), 2.03–2.10 (m, 1 H), 2.15–2.24 (m, 1 H), 3.68–3.74 (m, 1 H), 3.89 (s, 3 H), 4.01–4.09 (m, 2 H), 4.28 (t, J=7.2 Hz, 1 H), 6.95 (d, J=8.8 Hz, 2 H), 7.22–7.27 (m, 1 H), 7.33 (t, J=8.0 Hz, 2 H), 7.42 (d, J=7.6 Hz, 2 H), 8.00 (d, J=8.8 Hz, 2 H); MS (ESI) m/z, 312 (M++H) 353 (M++CH3CN).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([O:17][CH2:18][CH3:19])[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([OH:16])=[CH:8][CH:7]=1.[CH3:21][C:22]1[S:26][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH2:37]CO.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[CH:4]([O:17][CH2:18][CH3:19])[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([O:16][CH2:21][C:22]2[S:26][C:25]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)=[N:24][C:23]=2[CH3:37])=[CH:8][CH:7]=1
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCO
Reactant: CCOC(Cc1ccc(O)c2c1CCCC2)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)c2c1CCCC2)C(=O)OC

Procedure:
In analogy to the procedure described in example 14 b], [rac]-2-ethoxy-3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid methyl ester (example 2 c]) was reacted with 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole [PCT Int. Appl. (2001), WO 01/00603 A1] in N,N-dimethylformamide in the presence of cesium carbonate to give [rac]-2-ethoxy-3-{4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 1 e], to yield [rac]-2-ethoxy-3-{4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-5,6,7,8-tetrahydro-naphthalen-1-yl}-propionic acid as colorless solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:12]=[C:11]([C:13]3[CH:27]=[C:26]([CH3:28])[C:16]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:15]([CH3:29])[CH:14]=3)[O:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.[CH2:30]([Mg]Br)[CH:31]([CH3:33])[CH3:32]>>[CH2:30]([C:2]1[C:3]2[N:12]=[C:11]([C:13]3[CH:27]=[C:26]([CH3:28])[C:16]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:15]([CH3:29])[CH:14]=3)[O:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1)[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)C[Mg]Br
Reactant: CSc1nc(Cl)c2nc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)oc2n1
Product: CSc1nc(CC(C)C)c2nc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)oc2n1
Yield: 20 %

Procedure:
Analogously to example 1 (g), the reaction of 1.50 g of tert-butyl [4-(7-chloro-5-methylsulfanyloxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenoxy]acetate with isobutylmagnesium bromide gave 0.31 g (20%) of the title compound.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C@H:13]3[CH2:16][C@H:15]([CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CC(N(C)C)=O>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C@H:13]3[CH2:14][C@H:15]([CH2:17][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH2:16]3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](c3ccc(CN4CCCC4)cc3)C2)cc1
Solvent: CC(=O)N(C)C
Product: c1cc([C@H]2C[C@H](CN3CCCC3)C2)ccc1CN1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of Example 48 (trans-toluene-4-sulfonic acid 3-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutylmethyl ester) (200 mg, 0.5 mmol) in DMA (1.5 mL) was added the appropriate amine, for example pyrollidine (84 uL, 1.0 mmol). The reaction was then heated to 110 □C (oil bath). After 12 hr the reaction was cooled to rt and concentrated under reduced pressure. This material was free based by stirring in solid K2CO3 and MeOH for 2 hours. After 2 hr of stirring silica gel was added to the vessel (dry pack) and the methanolic slurry was concentrated. Purfication of this material was accomplished by flash column chromatography using a 12 g ISCO column, eluting with a gradient of 5%–10% MeOH/CH2Cl2 with 0.2% NH4OH. The product containing fractions were collected and concentrated to give the title compound as a colorless oil. The HCl salt was made by taken the freebase up in EtOAc and then adding a solution of HCl (2 eq, 1 M HCl, THF) to give a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:22])[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2.C[O:24][C:25](=[O:48])[C@H:26]([C@@H:45]([CH3:47])O)[NH:27]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([O:22][C@H:45]([CH3:47])[C@@H:26]([C:25]([OH:48])=[O:24])[NH2:27])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:16]2[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: COc1ccccc1C1(O)c2ccccc2-c2ccccc21
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Product: COc1ccccc1C1(O[C@H](C)[C@H](N)C(=O)O)c2ccccc2-c2ccccc21

Procedure:
from 9-(2-methoxyphenyl)-9H-fluoren-9-ol (Example 3k) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
Reaction SMILES: ClC1C=C2C(=CC=1)N(C1C=CC(F)=CC=1)C=C2.N1CCC(=O)CC1.[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[CH:30]=[C:29]2[C:42]1[CH2:43][CH2:44][NH:45][CH2:46][CH:47]=1>>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:35]1[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=1)[CH:30]=[C:29]2[CH:42]1[CH2:43][CH2:44][NH:45][CH2:46][CH2:47]1
Reactant: Fc1ccc(-n2cc(C3=CCNCC3)c3cc(Cl)ccc32)cc1
Agent: Fc1ccc(-n2ccc3cc(Cl)ccc32)cc1
Agent: O=C1CCNCC1
Product: Fc1ccc(-n2cc(C3CCNCC3)c3cc(Cl)ccc32)cc1

Procedure:
The intermediate may be worked up in a conventional manner. The further process leading to sertindole comprises cyclization of N-(4-fluorophenyl)-N-(2-carboxy-4-chlorophenyl)glycine to the corresponding 3-acetoxy-indole using eg. acetic anhydride in the presence of alkalimetal acetate such as sodium acetate. 5-chloro-1-(4-fluoro)indole is then obtained from the 3-acetoxy-indole by reduction and subsequent elimination of H2O. The resulting 5-chloro-1-(4-fluorophenyl)indole is reacted with 4-piperidone according to the above procedure, the resulting 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole is reduced in order to obtain 5-chloro-1-(4-fluorophenyl)-3-(piperidin-4-yl)indole which in turn is reacted with 1-(2-chloroethyl)-2-imidazolidinon to obtain sertindole. Alternatively, the 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole may first be reacted with 1-(2-chloroethyl)-2-imidazolidinon followed by reduction, thereby obtaining sertindole, which may be isolated as an acid addition salt, e.g. the tartrate, or as the free base.