Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19].O>C(Cl)Cl>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[N:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)[S@](N)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)N=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.9 %

Procedure:
To a mixture of 3,5-bis(trifluoromethyl)benzaldehyde (5 g, 20.7 mmol) and (R)-2-methylpropane-2-sulfinamide (3.3 g, 26.9 mmol) in DCM (50 ml) at 0° C., was drop wise added Ti(O-iPr)4 (5.9 g, 24.8 mmol) under N2 atmosphere. After stirring for 20 h at room temperature, the reaction mixture was poured into water (100 mL) with vigorous stirring. The precipitate was filtered off and the filtrate was extracted with DCM (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous MgSO4, and then concentrated. The residue was purified by silica gel chromatography (PE/EtOAc=5/1 to 2/1) to give the title compound (5.5 g, yield: 78%); m/z (ES+): 346 [M+H]+.
Reaction SMILES: [CH3:1][Mg]Cl.CON(C)[C:7](=[O:22])[CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1>C1COCC1>[O:22]=[C:7]([CH3:1])[CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH2:14]1
Reactant: CON(C)C(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.1 %

Procedure:
Added dropwise 3.0 M methylmagnesium chloride in THF (8.63 mL, 25.9 mmol) to a solution of tert-butyl 4-(2-(methoxy(methyl)amino)-2-oxoethyl)piperidine-1-carboxylate (5.93 g, 20.7 mmol) in THF (100 mL) at 0° C. Warmed to ambient temperature and stirred for 90 minutes. Partitioned between ether and 2N HCl, washed the organic layer twice with water, brine, dried, and concentrated to afford the title compound (4.95 g, 99.1% yield) as a clear oil.
Reaction SMILES: [C:1](=[O:17])([O:14][CH2:15]Cl)[O:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[I-:18].[Na+].O>C(#N)C>[C:1](=[O:17])([O:14][CH2:15][I:18])[O:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(OCCl)OCCCOCc1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(OCI)OCCCOCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
[3-(Benzyloxy)propyl] chloromethyl carbonate (2.0 g) was dissolved in acetonitrile (3 ml), and sodium iodide (4.6 g) was added. The mixture was stirred under a nitrogen atmosphere at 60° C. for 2 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml). The ethyl acetate layer was washed with an aqueous 5% sodium thiosulfate solution (50 ml×2), water (50 ml×2), and a saturated sodium chloride aqueous solution (50 ml). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain [3-(benzyloxy)propyl] iodomethyl carbonate (2.5 g) as a pale yellow liquid.
Reaction SMILES: COC(=O)COC1C=C(Cl)C(SC#N)=CC=1C.C[O:19][C:20](=[O:49])[CH2:21][O:22][C:23]1[CH:28]=[C:27]([Cl:29])[C:26]([S:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=3)=[CH:34][CH:33]=2)=[CH:25][C:24]=1[CH3:48]>>[Cl:29][C:27]1[C:26]([S:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]3[CH:39]=[CH:40][C:41]([C:44]([F:45])([F:46])[F:47])=[CH:42][CH:43]=3)=[CH:36][CH:37]=2)=[CH:25][C:24]([CH3:48])=[C:23]([CH:28]=1)[O:22][CH2:21][C:20]([OH:49])=[O:19]
Reactant: COC(=O)COc1cc(Cl)c(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1C
Agent: COC(=O)COc1cc(Cl)c(SC#N)cc1C
Product: Cc1cc(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c(Cl)cc1OCC(=O)O

Procedure:
Preparation of 5-Chloro-2-methyl-4-thiocyanato-phenol (compound 20A) The title compound was prepared in a manner analogous to Example 1B from 5-chloro-2-methyl-phenol. 400 MHz 1H NMR (DMSO-d6) δ 10.60 (s, 1H), 7.54 (s, 1H), 6.98 (s, 1H), 2.07 (s, 3H). Step 2. Preparation of (5-Chloro-2-methyl-4-thiocyanato-phenoxy)-acetic acid methyl ester(compound 20B) The title compound was prepared from the product of Example 20A in a manner analogous to Example 1C. 400 MHz 1H NMR (DMSO-d6) δ 7.62 (s, 1H), 7.40 (s, 1H), 4.94 (s, 2H), 3.65 (s, 3H), 2.15 (s, 3H). Step 3. Preparation of (5-Chloro-4-mercapto-2-methyl-phenoxy)-acetic acid methyl ester (compound 20C) The title compound was prepared from (5-chloro-2-methyl-4-thiocyanato-phenoxy)-acetic acid methyl ester in a manner analogous to Example 1D. 400 MHz 1H NMR (DMSO-d6) δ 7.27 (s, 1H), 6.97 (s, 1H), 5.31 (s, 1H), 4.79 (s, 2H), 3.64 (s, 3H), 2.07 (s, 3H). Step 4. Preparation of [5-Chloro-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)phenoxy]-acetic acid methyl ester (compound 20D) The title compound was prepared in the manner analogous to Example 1F using 3B and 20C. 400 MHz 1H NMR (DMSO-d6) δ 7.82 (d, 2H, J=8.3 Hz), 7.74 (d, 2H, J=8.3 Hz), 7.62 (d, 2H, J=8.3 Hz), 7.39 (d, 2H, J=8.3 Hz), 7.27 (s, 1H), 7.00 (s, 1H), 4.82 (s, 2H), 4.20 (s, 2H), 3.64 (s, 3H), 2.09 (s, 3H); MS m/z 480 (M+). Step 5. Preparation of [5-Chloro-2-methyl-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid (compound 20) The title compound was prepared in the manner analogous to Example 1 using 20D. mp 161-162° C.; 400 MHz 1H NMR (DMSO-d6) δ 7.83 (d, 2H, J=8.3 Hz), 7.74 (d, 2H, J=8.3 Hz), 7.62 (d, 2H, J=8.3 Hz), 7.51 (d, 2H, J=8.3 Hz), 7.26 (s, 1H), 6.95 (s, 1H), 4.69 (s, 2H), 4.20 (s, 2H), 2.08 (s, 3H); MS m/z 467 (M+1).
Reaction SMILES: [Na].C[O:3][C:4](=O)/[C:5](/[CH3:14])=[C:6](\[NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])/[CH3:7]>CO>[CH3:13][O:12][C:10]([C:9]1[NH:8][C:6]([CH3:7])=[C:5]([CH3:14])[C:4]=1[OH:3])=[O:11]
Reactant: COC(=O)CN/C(C)=C(/C)C(=O)OC
Agent: [Na]
Solvent: CO
Product: COC(=O)c1[nH]c(C)c(C)c1O
Yield: 83.6 %

Procedure:
Using the method described in Example 1, 5.7 g of sodium in 250 ml of methanol, and 40 g of 3-(methoxycarbonylmethylamino)-2-methylcrotonic acid methyl ester in 90 ml of methanol, give 28.1 g of 3-hydroxy-4,5-dimethyl-pyrrole-2-carboxylic acid methyl ester, of melting point 170°-172° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:5])[CH3:2].[O:20]=[S:21]1(=[O:35])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24][C:23]([CH2:31][C:32](O)=[O:33])=[N:22]1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[N:11]([C:32](=[O:33])[CH2:31][C:23]1[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:21](=[O:20])(=[O:35])[N:22]=1)[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCC1NCc1ccc(F)cc1
Reactant: O=C(O)CC1=NS(=O)(=O)c2ccccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCC1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2ccccc2N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(4-Fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (prepared as described in Example 11, 133.5 mg, 0.503 mmol) was mixed with (1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (132.9 mg, 0.554 mmol) in N,N-dimethylformamide (4.6 mL). N-methylmorpholine (122 μL, 1.11 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (106.2 mg, 0.554 mmol). The reaction mixture was shaken at 25° C. for 16 h. A 1.0 M aqueous hydrochloric acid solution (4.6 mL) was added at 25° C., and the aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with saturated aqueous brine solution (10 mL). The organic layer was dried over sodium sulfate, filtered, concentrated and dried in vacuo to afford the crude product, 2-[[2-(1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(4-fluoro-benzyl)-amino]-cyclopentanecarboxylic acid ethyl ester, as a pale yellow oil, which was directly used in the next step without further purification. LC-MS (ESI) calcd for C24H26FN3O5S 487.16, found 488.3 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([NH2:21])=[O:20])=[CH:5]2.[NH2:22][C:23]1[CH:28]=[C:27](Br)[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>[Cu](I)I.O.O1CCOCC1>[NH2:22][C:23]1[CH:28]=[C:27]([NH:21][C:19]([C:6]2[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[O:20])[CH:26]=[CH:25][N:24]=1
Reactant: Nc1cc(Br)ccn1
Reactant: NC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)ccn1
Temperature: 170 °C
Yield: 53.5 %

Procedure:
0.2 g (1.05 mmol) of copper iodide, 0.6 g (2.10 mmol) of 5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 1.2, 0.4 g (2.31 mmol) of 2-amino-4-bromopyridine, 1.16 g (8.40 mmol) of potassium carbonate and 15 mL of anhydrous dioxane are placed in a 10 mL pressure tube specific for microwave reactors. The suspension is degassed for a few minutes and 0.14 mL (1.15 mmol) of trans-1,2-cyclohexanediamine is then added. The tube is then sealed and heated in the microwave reactor at 170° C. for two 1-hour cycles, After this time, the suspension cooled to room temperature is poured into 50 mL of water and then extracted with 2×75 mL of dichlororomethane. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The crude reaction product is then purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 0.425 g of the expected product is thus obtained in the form of a beige-coloured solid.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([NH:22][CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:41][NH2:42].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([NH:22][CH3:23])=[O:21])[N:16]=2)[CH2:11][C:12]([NH:42][OH:41])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Reactant: C[Si](C)(C)ON
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: CNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-{3-[(methylamino)carbonyl]-1,2,4-oxadiazol-5-yl}hexanoic acid (Preparation 8) (285 mg, 0.88 mmol) and N-methylmorpholine (110 μl, 1.00 mmol) in anhydrous tetrahydrofuran (10 ml) was cooled to 0° C., treated with isobutyl chloroformate (130 μl, 1.00 mmol) and stirred under a nitrogen atmosphere for 1 hour. O-(Trimethylsilyl)hydroxylamine (130 μl, 1.06 mmol) was added and the mixture was stirred for 18 hours, being allowed to warm to room temperature over this time. The mixture was then treated with aqueous citric acid solution (10% w/v, 10 ml) and stirred for 2 hours. This mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layers were washed sequentially with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The solid was then recrystallised from hexane:ethyl acetate to afford the title compound as a white solid (130 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:23][C:24]3[CH:25]=[C:26]([Cl:30])[CH:27]=[N:28][CH:29]=3)=[C:16]([CH:22]=2)[C:17]([O:19]CC)=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Li+].[OH-]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:23][C:24]3[CH:25]=[C:26]([Cl:30])[CH:27]=[N:28][CH:29]=3)=[C:16]([CH:22]=2)[C:17]([OH:19])=[O:18])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2)ccc1Oc1cncc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2)ccc1Oc1cncc(Cl)c1
Reaction time: 8 h

Procedure:
To a stirred solution of the product of Example 8 (81 mg, 0.170 mmol) in MeOH (3 mL) and water (1.0 mL) was added LiOH (89.6 mg, 3.74 mmol). The solution was stirred overnight and the solvent was evaporated to yield a white solid which was recrystallized from chloroform/ethanol. Isolated yield of the title compound: 46.5 mg, 61%.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].Cl.CN.C(=O)(O)[O-].[Na+].[CH3:23][N:24](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([NH:24][CH3:23])=[O:11])[CH:6]=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: COc1nc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Product: CNC(=O)c1ccc([N+](=O)[O-])c(OC)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 85 %

Procedure:
The suspension of 6-methoxy-5-nitropicolinic acid (1 equiv), methylamine hydrochloride (2 equiv), sodium bicarbonate (2 equiv), HATU (2 equiv) in DMSO (1 M) was stirred at 25° C. for 15 h. The reaction mixture was quenched with saturated aqueous sodium chloride and then washed with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (anhydrous sodium sulfate), filtered, and concentrated. The crude product was purified by silica gel column chromatography (0-90% ethyl acetate (with 1% 1N ammonia in MeOH) in hexane). Concentration of the desired fractions under reduced pressure afforded the title compound (85%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.86 (d, J=4.73 Hz, 3H) 4.17 (s, 3H) 7.77 (dd, J=8.04, 0.79 Hz, 1H) 8.54-8.60 (m, 1H) 8.77 (m, J=4.10 Hz, 1H); MS (ESI) m/z 212.2 [M+1]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:7]([N+:20]([O-])=O)[CH:6]=1)[CH3:2]>CCOC(C)=O.[Pd]>[NH2:20][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[NH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:4]([N:3]([CH2:24][CH3:25])[CH2:1][CH3:2])=[O:23]
Reactant: CCN(CC)C(=O)c1ccc(NCCN2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)c1ccc(NCCN2CCCCC2)c(N)c1
Reaction time: 24 h
Yield: 98.8 %

Procedure:
Following general procedure 2C: A mixture of N,N-diethyl-3-nitro-4-{[2-(1-piperidinyl)ethyl]amino}benzamide (0.800 g, 2.30 mmol) and 10% Pd/C in EtOAc (30 mL) was hydrogenated for 24 hours at 30 psi. Usual work-up provided the title compound (0.724 g, 99%) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH3:17][O:18][C:19]1[N:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21](O)=O>>[CH3:17][O:18][C:19]1[C:20]([C:21]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[CH:24][CH:25]=[C:26]([O:28][CH3:29])[N:27]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: COc1ccc(C(=O)O)c(OC)n1
Product: COc1ccc(-c2nnc(-c3c(-c4ccccc4)noc3C)o2)c(OC)n1
Yield: 24 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (500 mg, 2.30 mmol) was converted using 2,6-dimethoxynicotinic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate=80:20 to 40:60, 204 mg, 24%) which was obtained as a white solid. MS: m/e=365.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2]
Reactant: [H][H]
Reactant: CCN1CCc2ccc([N+](=O)[O-])cc2CC1
Agent: [Pd]
Solvent: CO
Product: CCN1CCc2ccc(N)cc2CC1

Procedure:
3-Ethyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (740 mg/3.4 mmol) was dissolved in anhydrous methanol (ca. 10 mL) and the solution added to a Parr flask. Palladium (10% on charcoal) was added carefully (WARNING: this addition should be done under a atmosphere of nitrogen to avoid ignition of methanol vapor in flask) and the mixture shaken under 40 psi of hydrogen for 2 hours. The mixture was then filtered and the colorless filtrate concentrated to afford 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (yellows upon standing). The material was typically used without further purification (680 mg/quantitative). 1H NMR (400 MHz, CDCl3) δ 6.9 (d, J=7.6 Hz, 1H), 6.4 (m, 2H), 2.9 (m, 4H), 2.7 (m, 6H), 1.1 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([C:11]2[S:15][C:14]([NH2:16])=[N:13][N:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>>[CH:5]1([C:11]2[S:15][C:14]([N:16]=[C:1]=[O:2])=[N:13][N:12]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: Nc1nnc(C2CCCCC2)s1
Reactant: O=C(Cl)Cl
Product: O=C=Nc1nnc(C2CCCCC2)s1

Procedure:
A saturated solution of phosgene in ethyl acetae (500 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. 5-Cyclohexyl-2-amino-1,3,4-thiadiazole (6 grams) is added to the reaction vessel, and the resulting mixture is stirred and heated at reflux for a period of about 4 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized from a dimethyl formamide-water mixture to yield the desired product 5-cyclohexyl-1,3,4-thiadiazol-2-yl isocyanate dimer having a melting point of 237° to 239° C.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[F:16][C:17]([F:41])([F:40])[CH2:18][NH:19][C:20]([C:22]1([CH2:35][CH2:36][CH2:37][CH2:38]Br)[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21]>>[F:16][C:17]([F:40])([F:41])[CH2:18][NH:19][C:20]([C:22]1([CH2:35][CH2:36][CH2:37][CH2:38][N:13]2[CH2:14][CH2:15][N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=3)[CH2:11][CH2:12]2)[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: Cl
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cccc(Cl)c3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(3-chlorophenyl)-piperazine dihydrochloride and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[S:4][N:3]=1.[Br:12][CH2:13][CH2:14][CH:15](Br)[CH3:16]>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([CH3:1])=[N:3][S:4][C:5]=2[CH:10]=1
Reactant: Cc1nsc2cc(O)ccc12
Reactant: CC(Br)CCBr
Product: Cc1nsc2cc(OCCCCBr)ccc12

Procedure:
In analogy to example 2.1, 3-Methyl-benzo[d]isothiazol-6-ol and 1,3-dibromobutane were converted to yield 6-(4-Bromo-butoxy)-3-methyl-benzo[d]isothiazole as brown oil, MS: 300 (MH+, 1 Br).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:24]=[O:25]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([Cl:16])=[C:11]([C:12]([F:15])=[CH:13][CH:14]=1)[CH:24]=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(OCc2ccccc2)c(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c(F)ccc(OCc2ccccc2)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
To a solution of 1-benzyloxy-2-chloro-4-fluoro-benzene (618, 5.8 g, 0.024 mol) in tetrahydrofuran (100 mL) was added 2.50 M of n-butyllithium (2.7 mL, 2.50 M in hexane, 0.029 mol) slowly at −78° C. over 15 minutes under nitrogen. The reaction mixture was stirred at −78° C. for 30 minutes. To the reaction mixture was then added N,N-dimethylformamide (4.2 mL, 0.054 mol). The reaction was allowed to warm to room temperature and was continued at room temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with hydrochloric acid (10%), water, brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a white solid (619, 2.1 g, 32%). MS (ESI) [M+H+]+=265.08.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][C@H:3]2[CH2:6][NH:7][CH2:8][C@@H:2]12.[Br:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21](Br)[CH:22]=1.CC(C)([O-])C.[Na+].C(OCC)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:16][C:17]1[CH:22]=[C:21]([N:7]2[CH2:6][C@H:3]3[C@H:2]([N:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]3)[CH2:8]2)[CH:20]=[N:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2CNC[C@H]21
Reactant: Brc1cncc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC[C@H]2CN(c3cncc(Br)c3)C[C@H]21
Temperature: 80 °C
Yield: 47.3 %

Procedure:
The product from Example 15E (0.56 g, 2.70 mmol) in toluene (27 mL) was treated with tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, available from Alfa Aesar) (50 mg, 0.10 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, available from Strem Chemicals) (68 mg, 0.10 mmol), 3,5-dibromopyridine (available from Aldrich Chemical Co.,) (0.69 g, 2.90 mmol) and sodium tert-butoxide (available from Aldrich Chemical Co.,) (0.44 g, 4.60 mmol). After heating at 80° C. for 16 hours, the reaction mixture was poured into diethyl ether (100 mL), washed with brine (100 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, 5% MeOH/CH2Cl2) to provide the title compound as a yellow oil (0.47 g, 47% yield). MS (DCI/NH3) m/z 368/370 (M+H)+.