Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)C.B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:14][O:13][C:9]1[CH:10]=[CH:11][C:12]2[CH:4]=[CH:5][S:6][C:7]=2[CH:8]=1
Reactant: CCOC(CSc1cccc(OC)c1)OCC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc2ccsc2c1
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
A solution of 1-[(2,2-diethoxy)ethylthio]-3-methoxybenzene (13.0 g, 0.051 mol) in CH2Cl2 (100 ml) was added dropwise to a solution of BF3.Et2O (6.7 ml, 0.054 mol) in CH2Cl2 (1000 ml) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 0.5 hours, treated with aqueous NaHCO3 solution, and stirred until both phases were clear. The CH2Cl2 layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give 8.68 g of an approximately 10:1 mixture of 6- and 4-methoxybenzo[b]thiophene as a dark brown oil. Purification by vacuum distillation (bp=65°-7° C. at 0.3 mmHg) gave 5.58 g of pale yellow oil. Major isomer: 'H NMR, δ: (CDCl3): 3.85 (3H, s, --OCH3); 6.98 (1H, dd, J=4.5, H5); 7.23 (2H, s, H2, H3); 7.35 (1H, d, J=1.5, H7); 7.68 (1H, d, J=4.5, H4).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C(O)=O.[NH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])C2>O1CCCC1.N1CCCCC1>[O:7]=[C:5]1[CH2:6][C:20]2[C:12](=[CH:13][CH:14]=[C:18]([NH:17][CH:16]=[O:21])[CH:19]=2)[NH:11]1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: CC(=O)OC(C)=O
Solvent: C1CCNCC1
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CNc1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
A solution of acetic anhydride (1.6 ml) and formic acid (1.2 ml) was stirred for 1 hour at room temperature, and added with 5-amino-1,3-dihydro-indol-2-one (3.56 g, 24 mmol, prepared according to U.S. Pat. No. 6,114,371) in 60 ml of tetrahydrofuran and piperidine (0.04 ml). The resulting mixture was stirred for 3 hours at room temperature until a precipitate was formed. The solid was filtered and recrystallized from methanol to give N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-formamide (3.6 g, 85%) as a white solid.
Reaction SMILES: [O:1]1[CH2:24][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:23])[NH:10]2.[H-].[Na+].[CH3:27]I.[Cl-].[NH4+]>CS(C)=O>[CH3:27][N:10]1[C:11]2[C:6](=[C:5]([O:4][CH2:3][CH:2]3[O:1][CH2:24]3)[CH:14]=[CH:13][C:12]=2[O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:7][CH2:8][C:9]1=[O:23]
Reactant: CI
Reactant: O=C1CCc2c(OCC3CO3)ccc(OCc3ccccc3)c2N1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CN1C(=O)CCc2c(OCC3CO3)ccc(OCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
3.3 g of 5-(2,3-epoxypropoxy)-8-benzyloxy-3,4-dihydrocarbostyril was dissolved in 50 ml of dimethyl sulfoxide, and 1.3 g of 50% sodium hydride was added to the solution followed by stirring at room temperature for 30 minutes. 2.9 g of methyl iodide dissolved in 10 ml of dimethyl sulfoxide was added dropwise thereto, and the resulting mixture was stirred at room temperature for 2 hours. 200 ml of a saturated aqueous solution of ammonium chloride was added to the reaction mixture followed by extracting with chloroform. The chloroform layer was washed with water and then dried over anhydrous sodium sulfate. The chloroform was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallized from ethanol to obtain 1.7 g of 1-methyl-5-(2,3-epoxypropoxy)-8-benzyloxy-3,4-dihydrocarbostyril as yellow needle-like crystals having a melting point of 111°-112.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH3:27])[CH:22]=3)[CH:17]=2)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH3:27])[CH:22]=3)[CH:17]=2)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:10]=2)[CH:8]=1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(-c2cccc(O)c2)c1
Reactant: ClCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(-c2cccc(OCCN3CCCCC3)c2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
Synthesized from 2-(3′-benzyloxy-5-methoxybiphenyl-2-yl)-6-methoxynaphthalene (205 mg) according to an analogous synthetic method to Example 22, 5′-methoxy-2′-(6-methoxynaphthalen-2-yl)biphenyl-3-ol (176 mg) was obtained. To a solution of 5′-methoxy-2′-(6-methoxynaphthalen-2-yl)biphenyl-3-ol (276 mg) in N,N-dimethylformamide (7 ml) were sequentially added potassium carbonate (220 mg) and 1-(2-chloroethyl)piperidine (280 mg), and the solution was stirred for 2 hours at 60° C. Water was added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (319 mg).
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[N:6][CH:7]=[C:8]([C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)[CH:9]=1.[Li]CCCC.CN([CH:24]=[O:25])C.[NH4+].[Cl-]>CCOCC.CCCCCC>[CH3:15][C:10]1([C:8]2[CH:9]=[C:4]([CH:24]=[O:25])[CH:5]=[N:6][CH:7]=2)[O:14][CH2:13][CH2:12][O:11]1
Reactant: CC1(c2cncc(Br)c2)OCCO1
Reactant: CN(C)C=O
Agent: N#N
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(c2cncc(C=O)c2)OCCO1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 3-bromo-5-(2-methyl-[1,3]dioxolan-2-yl)-pyridine (450 mg, 1.84 mmol) in Et2O (40.0 mL) at −78° C. was added dropwise n-BuLi (0.72 mL of a 2.5M solution in hexane, 1.88 mmol). The reaction mixture was then stirred at −78° C. for 30 min before DMF (0.17 mL, 2.24 mmol) was added dropwise. The reaction mixture was allowed to warm to rt over 1 h. Sat. aq NH4Cl was added and the mixture was extracted three times with Et2O. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (10:1 hept-EA to 1:2) gave the title compound as a pale yellow oil. TLC: rf (50:50 hept-EA)=0.21.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[C:15](Cl)([N:17]=[C:18]=[O:19])=[O:16]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[O:14][C:18](=[O:19])[NH:17][C:15](=[O:16])[C:10]=3[CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1c1ccc(F)cc1
Reactant: O=C=NC(=O)Cl
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccc(F)cc1)CCC2
Yield: 19.62 %

Procedure:
2-(4-fluorophenyl)cyclohexanone and carbonisocyanatidic chloride (0.966 mL, 12 mmol) was reacted as in Intermediate AC(1) to provide 8-(4-fluorophenyl)-5,6,7,8-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (415.0 mg, 1.689 mmol, 19.62% yield) as white solid and 4a-(4-fluorophenyl)-4-a,5,6,7-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (746.4 mg, 3.04 mmol, 35.3% yield) as white solid.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][CH:9]2[CH2:11][N:10]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:5][CH:4]=1)#[N:2].C([C@H]1OC1)Cl>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][C@@H:9]2[CH2:11][N:10]2[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:19][CH:20]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC1COc1ccc(C#N)cc1
Agent: ClC[C@@H]1CO1
Product: CC(C)(C)OC(=O)N1C[C@H]1COc1ccc(C#N)cc1

Procedure:
The sub-title compound was prepared according to the procedures described in steps (a) to (e) above for the synthesis of tert-butyl 2-[(4-cyanophenoxy)-methyl]-1-aziridinecarboxylate, but using (S)-(+)-epichlorohydrin in place of epichlorohydrin in step (a).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([C:16]([O:18]CC)=[O:17])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH3:21].Cl>C(O)C>[C:16]([C:13]1[CH:14]=[CH:15][C:10]2[N:9]=[C:8]([CH3:21])[N:7]([CH2:6][C:5]3[CH:22]=[CH:23][CH:24]=[CH:25][C:4]=3[Cl:3])[C:11]=2[CH:12]=1)([OH:18])=[O:17]
Reactant: CCOC(=O)c1ccc2nc(C)n(Cc3ccccc3Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Yield: 90.7 %

Procedure:
Eighty milliliters of ethanol and 37 g of a 10% sodium hydroxide aqueous solution were added to 10.0 g of 1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole, and the mixture was refluxed for 4 hours. The reaction solution was cooled, and was then adjusted to a pH of 6 with 10% hydrochloric acid. The precipitate was collected, washed with water, and dried under reduced pressure to give 8.30 g of 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (121).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>C([O-])([O-])=O.[Na+].[Na+].C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([O:19][CH3:18])[CH:25]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Yield: 66.1 %

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (150 mg), 66 mg of 3-methoxyphenylboronic acid and 14 mg of bis(triphenylphosphine)palladium(II) dichloride in 1 mL of 1M Na2CO3 aqueous solution and 1 mL of acetonitrile was heated to 100° C. in a sealed microwave reactor for 20 min. The reaction mixture was evaporated. The crude product was purified by flash chromatography eluting with 0-50% EtOAc/hexane to yield 2-chloro-6-(3-methoxyphenyl)-4-morpholinothieno[3,2-d]pyrimidine (94 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[N:17]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[F:27])[N:18]=[CH:19][C:11]=2[CH:10]=1.[Cu][C:29]#[N:30]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:29]#[N:30])=[CH:4][C:3]=1[C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[N:17]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[F:27])[N:18]=[CH:19][C:11]=2[CH:10]=1
Reactant: N#C[Cu]
Reactant: Cn1c(=O)c(-c2cc(I)ccc2Cl)cc2cnn(-c3c(F)cccc3F)c21
Solvent: CN(C)C=O
Product: Cn1c(=O)c(-c2cc(C#N)ccc2Cl)cc2cnn(-c3c(F)cccc3F)c21
Temperature: 140 °C

Procedure:
A mixture of 5-(2-chloro-5-iodophenyl)-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (60 mg, 0.12 mmol) and copper(I) cyanide (54 mg, 0.6 mmol) in DMF (1.5 mL) were heated in a microwave at 140° C. for 1 h. LC-MS indicates ˜60% conversion to the desired product. Additional copper(I) cyanide (100 mg) was added and the reaction mixture was heated for another 1 h in the microwave at 140° C. The reaction mixture was diluted in DCM (20 mL), washed with brine (2×15 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified on the ISCO 12 g column (15-50% EtOAc in hexanes) affording the title compound as a white amorphous solid. MS (ESI, pos.ion) m/z: 397.0 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:5]=[C:4]([O:17][C:18]2[C:25]([CH3:26])=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=2[CH3:27])[CH:3]=1.O1CCOCC1.O.[NH3:35]>C1(C)C=CC=CC=1>[NH2:35][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:5]=[C:4]([O:17][C:18]2[C:25]([CH3:26])=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=2[CH3:27])[CH:3]=1
Reactant: N
Reactant: Cc1cc(C#N)cc(C)c1Oc1cc(Cl)nc(Nc2ccc(C#N)cc2)n1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C#N)cc(C)c1Oc1cc(N)nc(Nc2ccc(C#N)cc2)n1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
4-[[6-chloro-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethyl-benzonitrile (24 gm) was dissolved in aqueous ammonia (240 ml) and 1,4-dioxane (274 ml) at room temperature. The contents were heated to 120° C. and maintained for 12 hours at 120° C. To the reaction mass was added water (360 ml) and the reaction mass was slowly cooled to 50 to 60° C. The reaction mass was further cooled to 0 to 5° C. and stirred for 1 hour at 0 to 5° C., filtered. The wet solid obtained was dissolved in toluene (150 ml) under stirring. The separated solid was filtered and dried at 50° C. to obtain 10 gm of 4-[[6-amino-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:20]=[N:21][C:22]([N:25]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34]([N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)=[O:35])[CH:32]=4)[C:27]([S:41][CH3:42])=[CH:26]3)=[N:23][CH:24]=2)[CH:14]=1>ClCCl>[CH3:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:24]=[N:23][C:22]([N:25]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34]([N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)=[O:35])[CH:32]=4)[C:27]([S:41]([CH3:42])=[O:6])=[CH:26]3)=[N:21][CH:20]=2)[CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cn(-c2ncc(-c3cc(C)ccn3)cn2)c2cc(C(=O)N3CCCC3)ccc12
Solvent: ClCCl
Product: Cc1ccnc(-c2cnc(-n3cc(S(C)=O)c4ccc(C(=O)N5CCCC5)cc43)nc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
m-Chloroperoxybenzoic acid (77%, 0.14 g, 0.62 mmol) in dichloromethane (10 mL) was added at 0° C. to a solution of 269c) (0.33 g, 0.77 mmol) in dichloromethane (40 mL) and the reaction mixture was stirred at room temperature for 3 h. The mixture was then washed successively with saturated sodium hydrogen carbonate solution (2×20 mL) and brine (1×30 mL), dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography [silica gel; dichloromethane with 2% methanol]. White solid. Yield: 0.215 g (63% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]#[CH:13].CON(C)[C:17]([C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[C:24]([O:29][CH3:30])[CH:23]=2)=[O:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[C:12]#[C:13][C:17]([C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[C:24]([O:29][CH3:30])[CH:23]=2)=[O:18]
Reactant: COc1ccc2cc(C(=O)N(C)OC)cnc2c1
Reactant: C#Cc1cc(C(F)(F)F)ccc1Cl
Product: COc1ccc2cc(C(=O)C#Cc3cc(C(F)(F)F)ccc3Cl)cnc2c1

Procedure:
The title compound was prepared with the alkyne from step B and N,7-dimethoxy-N-methylquinoline-3-carboxamide the intermediate from example 2 step E following the procedure described in example 2 step F. 1H NMR (CDCl3, 500 MHz): 9.62 (d, J=2.1 Hz, 1H), 8.97 (d, J=2.1 Hz, 1H), 8.03 (s, 1H), 7.87 (d, J=8.9 Hz, 1H), 7.69 (d, J=3.0 Hz, 2H), 7.51 (d, J=2.3 Hz, 1H), 7.31 (dd, J=2.3, 8.9 Hz, 1H), 4.03 (s, 3H). LC-MS: 3.85 min. (M+H)=389.9.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6]2.[H-].[Na+].I[CH3:18]>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[N:6]2[CH3:18]
Reactant: COC(=O)c1cc2c(Br)cccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2c(Br)cccc2n1C

Procedure:
The preparation is carried out as in Example 1.1, from 20 g (79 mmol) of methyl 4-bromo-1H-indole-2-carboxylate, from 3.8 g of 60% sodium hydride and from 6 ml of iodomethane. After reaction, the solvent is evaporated under reduced pressure and the residue is taken up in water. The mixture is extracted with ethyl acetate. The organic phase is dried and the solvent is evaporated under reduced pressure. The product is dried under reduced pressure. 20.6 g (77 mmol) of solid are obtained.
Reaction SMILES: Cl.C(OCC)(=O)C.[CH2:8]([O:10][C:11]([C@:13]1([NH:35]C(OC(C)(C)C)=O)[C@H:18]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:17][C@@H:16]2[C@H:14]1[C@@:15]2([F:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:12])[CH3:9].C(=O)([O-])O.[Na+]>>[CH2:8]([O:10][C:11]([C@:13]1([NH2:35])[C@H:18]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:17][C@@H:16]2[C@H:14]1[C@@:15]2([F:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:12])[CH3:9]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](NCc3ccc(Cl)c(Cl)c3)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@H]1NCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)OCC
Reaction time: 6 h
Yield: 92.3 %

Procedure:
2.8 mL of a 4N hydrogen chloride/ethyl acetate solution was added to 28 mg of (1R,2R,3R,5R,6R)-2-t-butoxycarbonylamino-3-(3,4-dichlorobenzylamino)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester, and the mixture was stirred for 6 hours at ice-cooling, and further stirred for 18 hours at room temperature. The reaction solution was ice-cooled, and then neutralized with a saturated aqueous solution of sodium hydrogen carbonate, followed by separation. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, thereby yielding 21 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylamino)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[H-].[Na+].Br[CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4[CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2noc(-c3cccc4[nH]ccc34)n2)cc1Cl
Reactant: CC(C)(C)OC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2noc(-c3cccc4c3ccn4CCCC(=O)OC(C)(C)C)n2)cc1Cl
Temperature: 50 °C
Yield: 96.2 %

Procedure:
To a solution of 3-(3-chloro-4-isopropoxyphenyl)-5-(1H-indol-4-yl)-1,2,4-oxadiazole (0.100 g, 0.283 mmol) in DMF (0.999 ml) was added NaH (0.012 g, 0.311 mmol). After about 15 min tert-butyl 4-bromobutanoate (0.095 g, 0.424 mmol) was added and the reaction mixture was heated to about 50° C. After about 24 h the reaction mixture was cooled to ambient temperature, concentrated in vacuo and purified by chromatography on silica gel (eluting with EtOAc/Hep) to provide tert-butyl 4-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-1H-indol-1-yl)butanoate (0.135 g, 93%) as a colorless oil that solidified on standing.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.[BrH:24]>>[BrH:24].[C:14]1([C:5]2[CH:4]=[C:3]([OH:2])[C:8]([OH:9])=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][N:15]=1
Reactant: COc1cc(C2=NCCc3ccccc32)cc([N+](=O)[O-])c1OC
Agent: Br
Product: O=[N+]([O-])c1cc(C2=NCCc3ccccc32)cc(O)c1O

Procedure:
1.4 g of 1-(3,4-dimethoxy-5-nitrophenyl)-3,4-dihydroisoquinoline are treated with 15 ml of constant-boiling hydrobromic acid and heated to boiling under reflux under a nitrogen atmosphere for 1.5 hours. After distilling the hydrobromic acid in a water-jet vacuum, the crystalline residue is recrystallized from acetone. There is obtained 5-(3,4-dihydro-1-isoquinolinyl)-3-nitropyrocatechol hydrobromide in the form of yellow crystals of m.p. >250° (decomposition).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][C:8]([C:12]#[N:13])=[N:9]2)=[CH:4][CH:3]=1.[CH2:20]([Sn](CCCC)(CCCC)CCCC)[CH:21]=[CH2:22]>O1CCOCC1>[CH2:22]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][C:8]([C:12]#[N:13])=[N:9]2)=[CH:4][CH:3]=1)[CH:21]=[CH2:20]
Reactant: N#Cc1cc(-c2ccccc2)c2ccc(Cl)cc2n1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Solvent: C1COCCO1
Product: C=CCc1ccc2c(-c3ccccc3)cc(C#N)nc2c1

Procedure:
To a solution of 7-chloro-4-phenylquinoline-2-carbonitrile (3.3 g, 12.5 mmol) in dioxane (120 mL) was added tetrakistriphenylphosphine (3.6 g, 3.1 mmol) and allyltributyltin (11.5 mL, 38 mmol). The mixture was refluxed for 10 h, concentrated and purified on silica gel (eluting with dichloromethane/hexanes, 3:1) to give the title compound. MS (+ESI): 271 (M+H)+.
Reaction SMILES: [Br:1]Br.[N:3]1([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1>Br.C(O)(=O)C>[BrH:1].[Br:1][CH2:15][C:14]([C:11]1[CH:10]=[CH:9][C:8]([N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[CH:13][CH:12]=1)=[O:16]
Reactant: CC(=O)c1ccc(-n2ccnc2)cc1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc(-n2ccnc2)cc1
Reaction time: 8 h

Procedure:
Add bromine (5.71 mL, 0.111 mol) to a solution of 4'-(1H-imidazol-1-yl)acetophenone (20.75 g, 0.111 mol) in 30-32% HBr in acetic acid. Stir the mixture overnight and collect the crystals. Wash the crystals with ethanol (3×50 mL) and air dry for 2h at room temperature to afford the title compound.
Reaction SMILES: C([O:8][C:9]1[C:17]([Cl:18])=[C:16]([CH3:19])[C:15]([CH3:20])=[C:11]([C:12]([OH:14])=[O:13])[C:10]=1[NH2:21])C1C=CC=CC=1>CCO.[Pd]>[Cl:18][C:17]1[C:9]([OH:8])=[C:10]([NH2:21])[C:11](=[C:15]([CH3:20])[C:16]=1[CH3:19])[C:12]([OH:14])=[O:13]
Reactant: Cc1c(C)c(C(=O)O)c(N)c(OCc2ccccc2)c1Cl
Agent: [Pd]
Solvent: CCO
Product: Cc1c(C)c(C(=O)O)c(N)c(O)c1Cl
Reaction time: 5 h
Yield: 46.4 %

Procedure:
3-Benzyloxy-4-chloro-5,6-dimethylanthranilic acid (10 mg, 0.03 mmol) was dissolved in EtOH (1.5 mL) and 10% Pd/C (2 mg) was added. Hydrogenation at room temperature and atmospheric pressure for 5 h, filtration, evaporation yielded 7 mg of crude product. Purification by preparative HPLC (Lichrosorb-C18, MeOH-Phosphate buffer (pH3) 50:50) adjusting the pH to 5 with NaHCO3 (aq), concentrating by a stream of N2, extracting with EtOAc (3×5 mL), washing the organic phase with brine, drying (MgSO4) and evaporating afforded the title compound (3 mg). 1H NMR (DMSO-d6): δ 3.3 (br, OH), 3.16 (s, 2H), 2.16 (s, 3H), 2.15 (s, 3H); 13C NMR (DMSO-d6): δ 169.92, 137.87, 135.16, 126.38, 123.51, 121.39, 117.31, 17.72, 15.95; MS (EI, 70 eV): m/z (rel.int.) 217/215 (M+, 21/63), 199/197 (20/59), 171/169 (37/100).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1.[OH:14][CH:15]([CH3:19])[C:16](=[O:18])[CH3:17].N1C=CC=CC=1.CCN=C=NCCCN(C)C.Cl.Cl>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:19][CH:15]([O:14][C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:13])=[CH:12][CH:11]=1)[C:16](=[O:18])[CH3:17]
Reactant: CC(=O)C(C)O
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)OC(C)C(C)=O)cc1

Procedure:
A mixture of terphthalic acid monomethyl ester (1.0 g, 5 mmol), 3-hydroxy-butane-2-one (0.531 g, 6.8 mmol), 4-dimethylamino pyridine (1.27 g, 10 mmol), pyridine (0.79 g, 10 mmol) and EDCl.HCl (1.6 g, 8 mmol) was stirred in dry DMF (10 mL) over night under nitrogen atmosphere. The reaction mixture was poured into ice cold water and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with water (50 mL×2) and with brine, then dried over anhydrous sodium sulphate and concentrated. the obtained residue was purified by column chromatography using 3% ethyl acetate in hexane to obtain the title compound.