Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:11]([N:14]2[C:22]3[C:17](=[C:18]([NH2:23])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]Cl.C(N(C(C)C)CC)(C)C>ClC1C=CC=CC=1>[C:1]1([S:11]([N:14]2[C:22]3[C:17](=[C:18]([N:23]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc2c1ccn2S(=O)(=O)c1cccc2ccccc12
Reactant: ClCCNCCCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Clc1ccccc1
Product: O=S(=O)(c1cccc2ccccc12)n1ccc2c(N3CCNCC3)cccc21
Reaction time: 4 h

Procedure:
A mixture of 461 mg (1.43 mmole) 1-(naphthalene-1-sulfonyl)-1H-indol-4-ylamine, 255 mg (1.43 mmole) bis(2-chloroethyl)amine hydrochloride, and 0.5 mL diisopropylethylamine in 5 mL chlorobenzene was heated under reflux. After 4 hours, 0.25 mL diisopropylethylamine was added and heating under reflux was continued for 15 hours. The mixture was partitioned between 25 mL ethyl acetate and 10 mL 5% sodium hydroxide. The organic phase was washed with 5 mL saturated sodium chloride solution, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was subjected to low pressure column chromatography over silica gel 230-400 mesh eluting with 8% methanol in chloroform. 1-(Naphthalene-1-sulfonyl)-4-piperazin-1-yl-1H-indole (1) was isolated as the hydrochloride salt from ethyl acetate/ether, 54 mg, M+H=392.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]3O)[C:6]=2[N:7]=1.O.CC#N.[C:25](OC(C)(C)C(Br)=O)(=[O:27])C.C([O-])(O)=O.[Na+]>C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([O:27][CH3:25])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@H:14]4[O:15][C@@H:12]34)[C:6]=2[N:7]=1
Reactant: CC(=O)OC(C)(C)C(=O)Br
Reactant: Nc1nc(Cl)c2ccn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1nc(N)nc2c1ccn2[C@@H]1O[C@H](CO)[C@H]2O[C@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 115 %

Procedure:
To a mixture of 2-amino-7-(β-D-ribofuranosyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.8 g, 6.0 mmol) in acetonitrile (80 mL) were added a solution of H2O/CH3CN (1:9, 1.08 mL) and then α-acetoxyisobutyryl bromide (3.5 mL, 24 mmol). After 2 h stirring at room temperature, saturated aqueous NaHCO3 (170 mL) was added and the mixture was extracted with EtOAc (300+200 mL). The combined organic phase was washed with brine (100 mL), dried (Na2SO4) and evaporated to a pale yellow foamy residue. This was suspended in anhydrous MeOH (80 mL) and stirred overnight with 25 mL of DOWEX OH resin (previously washed with anhydrous MeOH). The resin was filtered, washed thoroughly with MeOH and the combined filtrate evaporated to give a pale yellow foam (1.92 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:4]=1[C:5]#[N:6].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23]Cl.C(N(CC)CC)C>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23][N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][O:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:3]([F:2])[C:4]=2[C:5]#[N:6])[CH2:14][CH2:15]1
Reactant: N#Cc1c(F)cccc1OCC1CCNCC1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: N#Cc1c(F)cccc1OCC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Yield: 73 %

Procedure:
A mixture of 2-fluoro-6-(piperidin-4-ylmethoxy)-benzonitrile hydrochloride (240 mg; 0.89 mmol) (Example 126, Step 3) was heated with 3,4-dichlorobenzyl chloride (0.15 mL; 2.0 mmol) and triethylamine (0.3 mL; 2.0 mmol) to 50° C. for 16 hours. Reaction was cooled and quenched with dilute HCl and mixture extracted with ethyl acetate (2×20 mL). Combined organics washed with water, saturated sodium bicarbonate, brine and dried over Na2SO4. Crude material was purified by chromatography using 0.5-2% methanol/DCM gradient to afford 2-[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethoxy]-6-fluoro-benzonitrile as a yellow oil. (280 mg; 73% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18](=[O:20])[CH3:19])[N:13]=[C:12]2[CH2:21][CH:22](O)[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.[NH4+].[Cl-].[N-:39]=[N+:40]=[N-:41].[Na+]>C(Cl)Cl.CCOCC.O.C(OCC)(=O)C>[N:39]([CH:22]([CH3:23])[CH2:21][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[N:14]([C:18](=[O:20])[CH3:19])[N:13]=1)=[N+:40]=[N-:41]
Reactant: CC(=O)n1nc(CC(C)O)c2cc(OCc3ccccc3)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)n1nc(CC(C)N=[N+]=[N-])c2cc(OCc3ccccc3)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.8 %

Procedure:
A solution of the product from Step B (0.12 g, 0.37 mmol) and methanesulfonyl chloride (0.04 ml, 0.48 mmol) in CH2Cl2 (5 ml) and under nitrogen was cooled to 0° C. and triethylamine (0.07 ml, 0.48 mmol) was added. The resulting mixture was stirred at 0° C. for 10 min followed by the addition of a saturated aqueous solution of NH4Cl (20 ml) and ethyl acetate (20 ml). The aqueous layer was separated and extracted with ethyl acetate (2×5 ml). The combined extracts were washed with a saturated aqueous solution of NaCl (2×15 ml), dried (MgSO4), and evaporated to a residue which was dissolved in DMF (3 ml). Sodium azide (0.08 g, 1.2 mmol) was added and the mixture was stirred at 70° C. for 18 h. After cooling, water (20 ml) and ether (20 ml) were added and the aqueous layer was separated and further extracted with ether (3×20 ml). The combined extracts were washed with a saturated aqueous solution of NaCl (3×15 ml), dried (MgSO4), and evaporated to a residue that was purified by chromatography (silica, 10% ethyl acetate in hexane) to give a yellow oil (0.12 g). MS(ES) m/z 350 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([F:15])[C:12]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]2=[O:28])=[CH:11][C:3]=1[O:4][C:5]1[C:9]([OH:10])=[N:8][S:7][N:6]=1.Br[CH:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:14]=[C:13]([F:15])[C:12]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[N:18]([CH3:27])[C:17]2=[O:28])=[CH:11][C:3]=1[O:4][C:5]1[C:9]([O:10][CH:30]([C:31]([O:33][CH3:34])=[O:32])[CH3:35])=[N:8][S:7][N:6]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3nsnc3O)c(Cl)cc2F)c1=O
Reactant: COC(=O)C(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1nsnc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
200 mg of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-hydroxy-1,2,5-thiadiazole and 150 mg of methyl 2-bromopropionate were dissolved in 10 ml of N,N-dimethylformamide, to this was added 100 mg of potassium carbonate, and the mixture was stirred for 3 hours at room temperature. This reaction solution was poured into dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, then, saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.17 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-[1-(methoxycarbonyl)ethoxyl]-1,2,5-thiadiazole [present compound 10-2].
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:12](Br)[C:13]#[CH:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:14]([O:11][C:1]1[CH:2]=[CH:3][CH:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2)[C:13]#[CH:12]
Reactant: Oc1cccc2c1CCCC2
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1cccc2c1CCCC2

Procedure:
5,6,7,8-Tetrahydronaphthalen-1-ol (Aldrich, 3.93 g, 26.5 mmol), propargyl bromide (80% in toluene, 3.9 ml, 35 mmol), and potassium carbonate (4.83 g, 35 mmol) were stirred together in acetonitrile (75 mL) for 6 days at ambient temperature. The solvent was removed under reduced pressure, and the residue taken into water and extracted with diethyl ether. The organic layers were combined, dried with magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.76 (m, 4H), 2.49 (t, J=2.37 Hz, 1H), 2.68 (t, J=5.59 Hz, 2H), 2.75 (t, J=5.59, 2H), 4.69 (d, J=2.37 Hz, 2H), 6.74 (dd, J=7.80, 3.73 Hz, 2H), 7.06 (t, J=7.80 Hz, 1H). MS (DCI) m/z 187.06 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[F:29][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[C:15]2[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4ccccc4F)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(F)cc(-c3ccccc3F)c2O1

Procedure:
The title compound was prepared (0.060 g, 40%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.2 g, 0.48 mmol) and methylamine (0.149 g, 4.80 mmol). mp 140-141° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]([O-:18])=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]([OH:18])=[O:17])=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccc(Br)cc1COc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(Br)cc1COc1ccccc1
Yield: 94.3 %

Procedure:
Add 13.33 gm. (0.0415 mole) of 5-bromo-α-phenoxy-o-toluate to a solution of 3.32 gm. (0.0830 mole) of sodium hydroxide in 23 ml. of water and 200 ml. of methanol and heat at reflux for 1 hour. Remove the methanol under vacuum. Dissolve the residue in 200 ml. of water and acidify with concentrated hydrochloric acid to the Congo Red end point. Remove the solids by filtration and dry to obtain the title product (yield 12.02 gm. m.p. 160°-163° C.).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[S:18][CH:17]([CH2:25][O:26][CH3:27])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH3:27][O:26][CH2:25][CH:17]1[CH2:16][NH:15][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[S:18]1
Reactant: COCC1CN(C(=O)OC(C)(C)C)c2ccccc2S1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCC1CNc2ccccc2S1
Reaction time: 3 h

Procedure:
3 ml of a 25% trifluoroacetic acid solution in methylene chloride are added to 435 mg of 4-tert-butoxycarbonyl-2(R,S)-methoxymethyl-3,4-dihydro-2H1,4-benzothiazine at 0° C. and the mixture is stirred for 3 h. The reaction mixture is concentrated and the residue is chromatographed over 30 g of silica gel with a 99:1 mixture of methylene chloride and methanol, This gives the title compound: Rf (99:1 mixture of methylene chloride/methanol)=0.67.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]1[S:11][CH:10]=[N:9][CH:8]=1.[CH2:12]([O:19][C:20]1[N:25]=[C:24]([C:26](OC)=[O:27])[CH:23]=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C1COCC1>[CH2:12]([O:19][C:20]1[N:25]=[C:24]([C:26]([C:10]2[S:11][C:7]([CH3:6])=[CH:8][N:9]=2)=[O:27])[CH:23]=[CH:22][CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cncs1
Reactant: COC(=O)c1cccc(OCc2ccccc2)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cnc(C(=O)c2cccc(OCc3ccccc3)n2)s1
Temperature: -78 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of n-BuLi (2.5 M in hexane, 16 mL, 40 mmol) in dry THF (120 mL) at −78° C. was added 5-methylthiazole (4.17 g, 40 mmol) drop wise over 20 minutes under nitrogen atmosphere. The mixture was stirred at −78° C. for 2 hrs and a solution of methyl 6-(benzyloxy)picolinate (4.7 g, 20 mmol) in THF (30 mL) was added drop wise over 20 minutes. After being stirred at −78° C. for 1 hr, the mixture was acidified with HCl (1N) to pH around 6 and extracted with ethyl acetate. The organic layer was concentrated and then diluted with MTBE. The white precipitate was collected by filtration to give A030-4. The remaining filtrate was concentrated. The residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (10/1) to afford A030-4. Total 6.2 g of (6-(benzyloxy)pyridin-2-yl)(5-methylthiazol-2-yl)methanone (85% yield) was obtained as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[Na+].[I-].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH:41]([Si:34]([CH:35]([CH3:37])[CH3:36])([CH:38]([CH3:40])[CH3:39])[O:33][CH2:32][CH2:31][N:28]1[CH2:27][CH2:26][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:30][CH2:29]1)([CH3:42])[CH3:43]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)[Si](OCCN1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](OCCN1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68 %

Procedure:
To a solution of Intermediate A (102 mg, 0.63 mmol) in DMF (1.5 mL) was added NaI (60% dispersion in oil, 68 mg, 1.71 mmol). The mixture was stirred at RT for 5 min, then a solution of Intermediate 94b (240 mg, 0.57 mmol) in DMF (1.5 mL) was added and the mixture stirred at 60° C. for 1.25 h. The cooled mixture was diluted with water and extracted with DCM (4×25 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-10% (2M NH3 in MeOH) in DCM, to give the title compound as a pale brown gum (219 mg, 68%). LCMS (Method 3): Rt 2.65 min, m/z 565 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7](N)[C:6]=2[CH:5]=[CH:4][N:3]=1.[N+]([O-])([O-])=O.[Na+].NC(N)=O.[N+]([O-])([O-])=O.[BrH:26]>O.[Cu]Br>[Br:26][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]=[C:2]2[Cl:1]
Reactant: Nc1cccc2c(Cl)nccc12
Reactant: Br
Agent: [Cu]Br
Agent: NC(N)=O
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: Clc1nccc2c(Br)cccc12
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
To a 500 mL round-bottomed flask containing 1-chloroisoquinolin-5-amine (Step 2, 5.8 g, 32.5 mmol) in H2O (33 mL) and 40% HBr (14 mL) chilled to −50 C in an ice bath, was added a freshly prepared solution of (Sodium nitrate (2.47 g, 35.7 mmol) in 8 mL of H2O) drop-wise over 15 minutes. After the addition, the mixture was kept at 2° C., while stirred an additional 20 minutes. Then urea (0.192 g, 3.2 mmol) was added in order to decompose excess nitrate in the reaction mixture. After an additional 5 minutes of stirring the diazonium salt mixture was transferred into a dropping funnel. The diazonium salt was added drop-wise into a heated (70° C.) solution of Copper (1) Bromide (4.66 g, 32.5 mmol) in 40% HBr (30 mL)). After the addition, the mixture was heated to 80° C. for 1.5 hours. Then the mixture was allowed to cool to ambient temperature. The solid, which had formed in the reaction mixture, was collected by filtration. Then recrystallized from hot EtOAc and Hexanes, after drying, gave a brown crystalline solid, which was titled product (4.576 g; 18.9 mmol). MS (ESI pos. ion) m/z: 243 (M+H). Calc'd Exact Mass for C9H5BrCl: 242.5
Reaction SMILES: [OH-].[K+].[ClH:3].C[O:5][C:6](=[O:23])[CH:7]=[C:8]1[CH2:13][CH2:12][C:11]([N:20]([CH3:22])[CH3:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.CCOCC.Cl>C(O)C>[ClH:3].[CH3:22][N:20]([CH3:21])[C:11]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13][C:8](=[CH:7][C:6]([OH:23])=[O:5])[CH2:9][CH2:10]1
Reactant: COC(=O)C=C1CCC(c2ccccc2)(N(C)C)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CN(C)C1(c2ccccc2)CCC(=CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
1.7 M KOH (70.5 ml, 120 mmol) was added to a solution of (4-dimethylamino-4-phenylcyclohexylidene)acetic acid methyl ester hydrochloride (1.8 g, 5.8 mmol) in ethanol (200 ml) and the mixture was stirred at RT for 16 h. The reaction mixture was concentrated and the residue was taken up in water (40 ml). The aqueous phase was extracted by shaking with ether (2×40 ml), and 5.5 M hydrochloric acid (23.6 ml, 130 mmol) was added. After the aqueous phase had been concentrated, the residue was extracted with ethanol (2×40 ml), the potassium chloride which remained was separated off and the filtrate was concentrated. The hydrochloride of the acid was thereby obtained as a colourless solid in a yield of 98% (1.67 g).
Reaction SMILES: [Cl-:1].C(=[N:9][N+:10]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)[C:11]=1[CH2:28][CH3:29])C1C=CC=CC=1.Cl>O>[Cl-:1].[NH2:9][N+:10]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)[C:11]=1[CH2:28][CH3:29]
Reactant: CCc1n(Cc2cc(OC)c(OC)c(OC)c2)cc[n+]1N=Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: CCc1n(Cc2cc(OC)c(OC)c(OC)c2)cc[n+]1N

Procedure:
3.1 g (7.45 mmol) of 1-benzylideneamino-2-ethyl-3-(3,4,5-trimethoxybenzyl)imidazolium chloride are dissolved in 70 ml of water, whereupon the solution is treated with 8 ml of 25 percent hydrochloric acid. The resulting benzaldehyde is removed by steam distillation. After evaporation the product is recrystallized from ethanol/ether. There is obtained 1-amino-2-ethyl-3-(3,4,5-trimethoxybenzyl)-imidazolium chloride of melting point 174°.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4]>C(O)C>[OH:4][CH2:3][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(-c2cccc(C=O)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(-c2cccc(CO)c2)cc1
Reaction time: 0.83 h
Yield: 71.9 %

Procedure:
Sodium borohydride (132 mg) was added to a solution of methyl 3′-formylbiphenyl-4-carboxylate (720 mg), which is the product of Reference example 14(a), in ethanol (50 ml) at ambient temperature. The mixture was stirred under an atmosphere of nitrogen for 50 minutes. The reaction mixture was quenched with 50% acetic acid and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the layers were separated. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to afford the desired compound (522 mg) as colorless crystals.
Reaction SMILES: 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.CC(C)([O-])C.[Na+].[Br:53][C:54]1[CH:63]=[CH:62][CH:61]=[C:60](Br)[C:55]=1[O:56][CH2:57][CH2:58][NH2:59]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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]>[Br:53][C:54]1[C:55]2[O:56][CH2:57][CH2:58][NH:59][C:60]=2[CH:61]=[CH:62][CH:63]=1
Reactant: NCCOc1c(Br)cccc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Brc1cccc2c1OCCN2
Temperature: 95 °C
Reaction time: 12 h
Yield: 6.4 %

Procedure:
A three neck flask was charge with tris(dibenzylideneacetone)dipalladium(0) (0.37 g, 0.0004 mol, 2 mol % Pd), (±) racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.64 g, 0.001 mol, 5 mol % Pd), and sodium tert-butoxide (2.7 g, 0.028 mol) and flushed with nitrogen. A solution of 2-(2,6-dibromo-phenoxy)ethylamine (6 g, 0.02 mol) in toluene (50 mL) was added. The mixture was heated to 95° C. and was stirred for 12 h. The mixture was cooled to room temperature, taken up in ethyl acetate, filtered and concentrated. The crude material was purified by flash chromatography on silica gel (eluting with hexane-ethyl acetate; 7:3, v/v) to give 8-bromo-3,4-dihydro-2H-benzo[1,4]oxazine as an oil (275 mg, 48%). The hydrochloride salt was prepared from ethanol-hydrogen chloride. MS: MH+=214. M.p. 184.1-195.4° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[CH2:23][CH2:22]3)[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9].Cl.[CH3:30][N:31](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.CN>ClCCl.O>[CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[CH2:23][CH2:22]3)[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8]([NH:31][CH3:30])=[O:9]
Reactant: COc1ccc(-c2ccc3c(c2)CCC3=O)c(OCC(C)(C)C(=O)O)c1OC
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)C(C)(C)COc1c(-c2ccc3c(c2)CCC3=O)ccc(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 3-[2,3-Dimethoxy-6-(1-oxo-indan-5-yl)-phenoxy]-2,2-dimethyl-propionic acid (Compound 205) (100 mg, 0.260 mmol) in dichloromethane, were added 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) (75 mg, 3.90 mmol), 1-Hydroxybenzotriazole hydrate (HOBT) (80 mg, 0.520 mmol) and triethylamine (0.1 mL, 0.9814 mmol) and 1M methylamine solution (0.4 mL, 0.520 mmol) and the resultant reaction mixture was stirred at 16 h at room temperature. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined dichloromethane layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) afforded the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CCN(CC)CC.[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:27](=[O:28])[CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Br)ccc1NC(=O)Cc1ccccc1
Reaction time: 27 h

Procedure:
To a mixture of methyl 2-amino-5-bromobenzoate (9.00 g, 39.1 mmol) and Et3N (7.6 mL, 54.8 mmol) in CH2Cl2 (90 mL) at 4° C. was added 2-phenylacetyl chloride (7.26 g, 46.9 mmol) dropwise. After completion of the addition, the cooling bath was removed and the mixture was stirred for 27 hours. TLC showed that some of the starting material methyl 2-amino-5-bromobenzoate still remained. More 2-phenylacetyl chloride (1.88 g, 12.2 mmol) and Et3N (2.2 mL, 15.9 mmol) were added, and the mixture was stirred overnight. K2CO3 (aqueous) was added, the organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, dried (Na2SO4), filtered, and concentrated in vacuo. CH3CN (100 mL) was added, and the precipitated solid was filtered, washed with Et2O, and dried to afford the title compound. The filtrate was concentrated in vacuo, and the solid was filtered, washed with Et2O, and dried to provide additional title compound.