Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Sn](Cl)Cl.[N:4]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[C@@H:6]([NH:12][C:13]([C:15]1[O:16][C:17]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:18]=3[CH:19]=1)=[O:14])[CH2:5]2.O.[OH-].[Na+]>CN(C=O)C>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11]1)[C@@H:6]([NH:12][C:13]([C:15]1[O:16][C:17]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:18]=3[CH:19]=1)=[O:14])[CH2:5]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc([N+](=O)[O-])ccc2o1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc2oc(C(=O)N[C@H]3CN4CCC3CC4)cc2c1
Reaction time: 8 h

Procedure:
2.0 ml (4 mmol) of a 2 M tin(II) chloride solution in DMF are added to N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-nitro-1-benzofuran-2-carboxamide (100 mg, 0.32 mmol). The mixture is stirred overnight. The reaction mixture is poured into water and made basic using 1N aqueous sodium hydroxide solution. The aqueous phase is extracted six times with ethyl acetate. The combined organic phases are dried over magnesium sulfate, and the solvent is removed under reduced pressure using a rotary evaporator. The crude product is taken up in methanol and shaken together with acidic ion exchange resin (Dowex WX2-200) for about 20 min. The loaded ion exchanger is washed three times with in each ase 30 ml of methanol, then with water/methanol 8:2, again with methanol, with dichloromethane and finally again with methanol. The product is eluted using methanol/triethylamine 95:5. The solvent is removed under reduced pressure using a rotary evaporator. 52 mg (58% of theory) of the title compound are isolated.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH:10][O:11][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[Br:18]Br>O.CC(O)=O>[NH2:1][C:2]1[C:3]([C:8]([NH:10][O:11][CH3:12])=[O:9])=[N:4][C:5]([Br:18])=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CONC(=O)c1ncccc1N
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CONC(=O)c1nc(Br)ccc1N
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
A suspension of 3-amino-N-methoxypyridine-2-carboxamide (Compound 46E, 0.275 g, 1.64 mmol) in H2O (4.5 mL) was treated with a drop of Sulfuric acid and 0.6 mL of AcOH. After about 10 min of vigorous stirring, a solution of Bromine (84.7 uL, 1.64 mmol) in 0.4 mL of AcOH was cautiously added. After an additional 15-20 min of stirring the texture of the reaction mixture/suspension changed to become a more coarse orange ppt. This material was collected by filtration and dried to afford 240 mg of the title compound as an orange solid (59%). 1H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 6.91 (br. s., 2H), 3.66 (s, 3H); MS (ESI): m/z=245.98, 247.98 [M+H]+; UPLC: tR=0.67 min (UPLC-TOF: polar—2 min)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.N1CCC[C@H]1C(O)=O.I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Cu]I.CS(C)=O>[C:15]1([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Ic1ccccc1
Reactant: C1CCNC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Product: c1ccc(N2CCCC2)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 59.6 %

Procedure:
Pyrrolidine (21.6 g, 304.23 mmol), L-proline (1.12 g, 9.74 mmol), and CuI (960 mg, 5.05 mmol) were added sequentially to 1-iodobenzene (10.0 g, 49.02 mmol). DMSO (40 mL) was then added, and the resulting solution was stirred at 60° C. for 20 hours. The reaction mixture was then quenched by adding 400 mL of iced water. The resulting solution was extracted with ethyl acetate (3×150 mL), and the organic layers were combined, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using a 1:100 ethyl acetate/petroleum ether solvent system to afford 4.3 g (57%) of 1-phenylpyrrolidine as brown oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:22]=1[NH:23][C:24]1[C:33]2[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([CH2:55]O)[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([CH2:55][O:36][C:30]2[CH:29]=[C:28]3[C:33]([C:24]([NH:23][C:22]4[CH:37]=[CH:38][C:39]([CH3:41])=[CH:40][C:21]=4[F:20])=[N:25][CH:26]=[N:27]3)=[CH:32][C:31]=2[O:34][CH3:35])[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: COc1cc2c(Nc3ccc(C)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(C)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
Triphenylphosphine (2.19 g, 8.36 mmol) was added to a suspension of 4-(2-fluoro-4-methylanilino)-7-hydroxy-6-methoxyquinazoline (1 g, 3.34 mmol) in methylene chloride (10 ml) cooled at 0° C., followed by 1-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine (1.08 g, 5.01 mmol), (prepared as described for the starting material in Example 1), and diethyl azodicarboxylate (1.31 ml, 8.36 mmol). After stirring for 2 hours at ambient temperature, the volatiles were removed under vacuum. The residue was purified by column chromatography eluting with methylene chloride/methanol (2/98). After removal of the solvent by evaporation, the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-4-(2-fluoro-4-methylanilino)-6-methoxyquinazoline (327 mg, 20%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][S:6][CH2:5][C:4]1=[O:9].I[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1>[Cu]Br.CN(C=O)C>[Cl:17][C:14]1[CH:15]=[C:16]([N:3]2[CH2:8][CH2:7][S:6][CH2:5][C:4]2=[O:9])[CH:11]=[CH:12][C:13]=1[Cl:18]
Reactant: O=C1CSCCN1
Reactant: Clc1ccc(I)cc1Cl
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CSCCN1c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 81 %

Procedure:
Under a nitrogen atmosphere in a flame-dried flask, sodium hydride (72 mg, 1.79 mmol, 60% oil dispersion) was washed with hexanes and then treated with 6 mL of anhydrous DMF, and cooled to 0° C. Thiomorpholin-3-one (200 mg, 1.71 mmol) was added in one portion with stirring. After gas evolution had stopped (ca. 30 min), 4-iodo-1,2-dichlorobenzene (700 mg, 2.56 mmol) was added, followed after 5 minutes by copper (I) bromide (490 mg, 3.42 mmol). After heating at 75° C. overnight, the mixture was partitioned between ethyl acetate and 1N lithium chloride, filtered through diatomaceous earth and combined with additional ethyl acetate washes of the diatomaceous earth filter cake. The organic layers were washed with additional 1N lithium chloride, brine (saturated sodium chloride) and dried over calcium sulfate (CaSO4). Concentration in vacuo gave 363 mg of light brown oil which was flash chromatographed (30-50% ethyl acetate in hexanes) to give a white solid, 108 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:5](F)=[N:6][CH:7]=1.C(O)C.[NH2:24][NH2:25]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)=[N:25][NH:24][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)c1ccc(CC(=O)c2cc(Br)cnc2F)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CN(C)c1ccc(Cc2n[nH]c3ncc(Br)cc23)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.2 %

Procedure:
1-(5-Bromo-2-fluoro-pyridin-3-yl)-2-(4-dimethylamino-phenyl)-ethanone (890 mg, 2.64 mmol), ethanol (100 ml), and anhydrous hydrazine (0.4 ml, 12.74 mmol) were combined and stirred for 18 hours at room temperature. The reaction was diluted with water and the precipitate filtered and dried to obtain 500 mg (57%) of [4-(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-ylmethyl)-phenyl]-dimethyl-amine. MS m/z 331.1+333.1 (M+H+).
Reaction SMILES: [OH-].[K+].[CH2:3]([N:10]1[C:20]2[C:15](=[C:16]([OH:21])[CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][C:11]1=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:22]1[O:24][CH:23]1[CH2:25][OH:26]>CO>[CH2:3]([N:10]1[C:20]2[C:15](=[C:16]([O:21][CH2:22][CH:23]([OH:24])[CH2:25][OH:26])[CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][C:11]1=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCc2c(O)cccc2N1Cc1ccccc1
Reactant: OCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCc2c(OCC(O)CO)cccc2N1Cc1ccccc1
Yield: 43.3 %

Procedure:
0.7 g of potassium hydroxide was dissolved in 30 ml of methanol, and 2.5 g of 1-benzyl-5-hydroxy-3,4-dihydrocarbostyril and 0.9 g of glycidol were added to the resulting solution followed by refluxing the mixture for 4 hours. After the mixture was concentrated to dryness, the residue was extracted with 50 ml of chloroform, and the extract was washed with a 5% aqueous potassium hydroxide and then water and then dried over anhydrous sodium sulfate. The chloroform was then removed by distillation and the resulting residue was recrystallized from ethyl acetate to give 1.4 g of 1-benzyl-5-(2,3-dihydroxy)propoxy-3,4-dihydrocarbostyril as colorless needle-like crystals having a melting point of 154° - 155° C.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[N:17]1C=CC=C[CH:18]=1>C(Cl)Cl>[CH:5]1[C:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][CH2:9][CH2:8][C:7]=2[C:2]([C:18]#[N:17])=[CH:3][CH:4]=1
Reactant: Clc1cccc2c1CCCc1ccccc1-2
Reactant: c1ccncc1
Solvent: ClCCl
Product: N#Cc1cccc2c1CCCc1ccccc1-2

Procedure:
Under a dry nitrogen atmosphere a mixture of 4-chloro-6,7-dihydro-5H-dibenzo[a,c]cycloheptene (1.6 grams, 0.007 mole), cuprous cyanide (0.95 gram, 0.011 mole), and pyridine (0.8 gram, 0.01 mole) was stirred and heated at 195° for approximately 16 hours. The mixture was cooled, dissolved in methylene chloride (150 ml), and the resultant solution was washed with three 70 ml portions of concentrated ammonium hydroxide. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to give a brown solid. Recrystallization from n-hexane give 6,7-dihydro-5H-dibenzo[a,c]cycloheptene-4-carbonitrile (mp 109°-111°).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C:19](=[O:21])[CH3:20])=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: NCCCc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCCCc1ccc(F)cc1
Reaction time: 0.33 h
Yield: 86.3 %

Procedure:
1-(para-fluorophenyl)-3-aminopropane (1.00 g, 6.53 mmol, 1 eq.) and triethylamine (0.91 mL, 6.53 mmol, 1 eq.) were dissoved in THF (10 mL) at 25° C. under N2. Then a THF solution (5 mL) of acetyl chloride (0.46 mL, 6.53 mmol, 1 eq.) was added dropwise via an addition funnel over 10 minutes. Worked up after 20 minutes by filtering off the solids then stripping the filtrate to obtain an amber oil. The oil was purified over silica gel in 1:1 Hexanes/EtOAc to 100% EtOAc to 4:1 EtOAc/MeOH. Obtained 1.10 g of an amber oil as product. MS (ESI) detects (M+H)+=196.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH:11]1([C:14]2[C:15]([CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([N:35]4[C:39]([CH3:40])=[CH:38][C:37]([CH3:41])=[N:36]4)=[CH:31][C:30]=3[CH3:42])=[C:16]([N:20]3[C:24](=[O:25])[N:23]([CH3:26])[N:22]=[N:21]3)[CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:12]1>O>[CH:11]1([C:14]2[C:15]([CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([N:35]4[C:39]([CH3:40])=[C:38]([CH:3]=[O:4])[C:37]([CH3:41])=[N:36]4)=[CH:31][C:30]=3[CH3:42])=[C:16]([N:20]3[C:24](=[O:25])[N:23]([CH3:26])[N:22]=[N:21]3)[CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:12]1
Reactant: CN(C)C=O
Reactant: Cc1cc(C)n(-c2ccc(OCc3c(C4CC4)cccc3-n3nnn(C)c3=O)c(C)c2)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc(-n2nc(C)c(C=O)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Reaction time: 1 h

Procedure:
At room temperature, a mixture of N,N-dimethylformamide 20 ml and phosphorus oxychloride 0.85 ml was stirred for one hour. To the above-mentioned mixture was added 1-{3-cyclopropyl-2-[2-methyl-4-(3,5-dimethyl-pyrazol-1-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (Present compound 3) 2.0 g and was stirred at 100° C. for three hours. At room temperature, to the resulting mixture was added water 10 ml. The mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-{3-cyclopropyl-2-[2-methyl-4-(3,5-dimethyl-4-formyl-pyrazol-1-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (hereinafter, referred to as “Present compound 51”) 1.7 g.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26][NH2:27])=[CH:23][CH:22]=1>>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:27][CH2:26][CH2:25][C:24]2[CH:28]=[CH:29][C:21]([F:20])=[CH:22][CH:23]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NCCc1ccc(F)cc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3ccc(F)cc3)cc2F)cn1
Yield: 39.1 %

Procedure:
Using a method similar to Example 405, using 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.040 g, 0.154 mmol) and 4-fluorophenethylamine (0.021 g, 0.154 mmol) gives the title compound (0.0231 g, 39.2%): TOF MS ES+ 384.2 (M+H)+, HRMS calcd for C21H20N3O2F, 384.1524 (M+H)+, found 384.1509, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=7.8 min, 100% purity.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:11][CH3:12])[CH:3]1O.CS(Cl)(=O)=O.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][C:2]1([CH3:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:11][CH3:12])[CH:3]1[N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNCC1
Reactant: COc1cccc2c1CC(C)(C)C2O
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c1CC(C)(C)C2N1CCCCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Triethylamine (10 ml) is added to a stirred solution of the 1-hydroxy indane of Step 2. above (8.4 g) in methylene chloride (190 ml) at RT under nitrogen; the mixture is cooled to 0° C. and methanesulfonyl chloride (4 ml) is added. The mixture is stirred for three hours at RT, cooled to 0° C., piperidine (128 ml) added and stirred at RT overnight. Sat'd aq. sodium bicarbonate is added to the mixture and the organic phase separated, washed with aq. sodium bicarbonate, sat'd NaCl, dried, filtered and the filtrate evaporated in vacuo affording the desired product as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:8]([OH:10])=O.[NH2:17][C@H:18]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19]1>>[C:25]1([CH2:24][CH2:23][N:20]2[CH2:21][CH2:22][C@H:18]([NH:17][C:8](=[O:10])[CH:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH2:19]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)C(c1ccccn1)c1ccccn1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Product: O=C(N[C@H]1CCN(CCc2ccccc2)C1)C(c1ccccn1)c1ccccn1

Procedure:
Bis(2-pyridyl)acetic acid and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)bis(2-pyridyl)acetamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].I[CH3:19]>C(Cl)(Cl)Cl.[Ag]=O>[CH3:19][O:17][CH2:16][C:12]1[C:9]2[C:10]([CH3:11])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[O:7][C:8]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1oc2cccc(CO)c2c1C
Reactant: CI
Agent: O=[Ag]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1oc2cccc(COC)c2c1C
Temperature: 55 °C
Yield: 93.8 %

Procedure:
To a solution of 0.19 g (0.81 mmole) of ethyl 4-(hydroxymethyl)-3-methyl-1-benzofuran-2-carboxylate (Example 92, Step 2) in 2 mL of chloroform was added silver (II) oxide (0.34 g, 1.46 mmol, 1.8 eq) and 2 mL of iodomethane and the mixture was heated in sealed tube at ˜55° C. for 4.5 days. The reaction was filtered and concentrated in vacuo to provide 0.20 g of ethyl 4-(methoxymethyl)-3-methyl-1-benzofuran-2-carboxylate. Yield: ˜93.8% m.p. 45-47° C.; MS: 249.1(M+H)+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([C:13]1[C:14]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=2[Cl:31])=[C:15]([Cl:22])[C:16]2[N:17]([CH:19]=[CH:20][N:21]=2)[CH:18]=1)=[O:12]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:9][O:10][C:11]([C:13]1[C:14]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=2[Cl:31])=[C:15]([Cl:22])[C:16]2[N:17]([C:19]([Br:1])=[CH:20][N:21]=2)[CH:18]=1)=[O:12]
Reactant: COC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cn2c(Br)cnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Reaction time: 5 h

Procedure:
N-bromosuccinimide (14 mg, 0.080 mmol) was added to a solution of 7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (30 mg, 0.072 mmol) in chloroform (1.0 mL). After stirring for five hours the reaction was diluted with ethyl acetate, washed with NaHSO3, brine, dried over Na2SO4, and concentrated to a yellow solid (33 mg, 92%). MS APCI (+) m/z 494, 496, 498 (M+, Cl, Br pattern) detected. 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 8.65 (s, 1H), 7.67 (s, 1H), 7.55 (dd, 1H), 7.22 (dd, 1H), 6.53 (d, 1H), 3.98 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[Cl:16]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Cl:16][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][C:6]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2ccc(F)cc2c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.5 %

Procedure:
Ethyl 5-fluoroindole-2-carboxylate (2.0 g) was dissolved in N,N-dimethylformamide (20 ml), and a solution of N-chlorosuccinimide (1.4 g) in N,N-dimethylformamide (10 ml) was added dropwise to the solution under ice cooling. The mixture was stirred at room temperature for 18 hours, and the reaction mixture was diluted with ethyl acetate and successively washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride. The resultant organic layer was then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to obtain the title compound (1.9 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[N:10]=[C:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[N:8]=[C:7](C(Cl)(Cl)Cl)[N:6]=1.[NH3:19].O>O1CCCC1>[NH2:19][C:7]1[N:6]=[C:5]([CH2:4][CH2:3][CH2:2][Cl:1])[N:10]=[C:9]([C:11]([Cl:12])([Cl:13])[Cl:14])[N:8]=1
Reactant: N
Reactant: ClCCCc1nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n1
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(CCCCl)nc(C(Cl)(Cl)Cl)n1
Reaction time: 0.5 h

Procedure:
102.3 g of 2-(3-chloro-n-propyl)-4,6-bis-(trichloromethyl)-1,3,5-triazine are dissolved in 100 ml of tetrahydrofuran, and to this solution are added at room temperature, with stirring, 400 ml of concentrated aqueous ammonia solution. After 30 minutes, 500 ml of water are addded, and the reaction mixture is extracted twice with 100 ml of ether each time. The ether phases are dried over magnesium sulfate, filtered, and concentrated by evaporation to leave 68.3 g of title product in the form of light-brown oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH2:12][O:13][CH3:14])[CH2:3][CH2:2]1.[CH3:18][C:19]([CH3:27])([C:21]1[N:25]=[C:24]([CH3:26])[O:23][N:22]=1)[NH2:20]>>[CH3:18][C:19]([NH:20][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH2:12][O:13][CH3:14])[N:8]=1)=[O:17])([C:21]1[N:25]=[C:24]([CH3:26])[O:23][N:22]=1)[CH3:27]
Reactant: Cc1nc(C(C)(C)N)no1
Reactant: COCCOc1nc(C(=O)O)ccc1C1CC1
Product: COCCOc1nc(C(=O)NC(C)(C)c2noc(C)n2)ccc1C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(2-methoxyethoxy)-pyridine-2-carboxylic acid (Example 142 d) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=361.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])\[CH3:7])[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])\[CH2:7][Br:18])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C(\C)Oc1ccc(Cl)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1ccc(Cl)cc1Cl
Yield: 65.2 %

Procedure:
To a stirred mixture of (E)-3-(2,4-dichloro-phenoxy)-but-2-enoic acid ethyl ester (4.00 g, 0.015 mol) in carbon tetrachloride (25 mL) under a nitrogen atmosphere was added N-bromosuccinimide (2.32 g, 0.013 mol) and benzoyl peroxide (280 mg, 0.001 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(2,4-dichloro-phenoxy)-but-2-enoic acid ethyl ester (3.00 g, 58%) as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([O:18]C)=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1)#[N:2].[Li+].[OH-:34]>O1CCCC1.CO>[NH2:2][C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH3:32])[CH:26]=3)=[C:8]([CH:15]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])[C:16]([OH:18])=[O:17])[N:9]([CH3:14])[C:10]2=[O:13])=[CH:5][CH:4]=1)=[O:34]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(C#N)cc2c(=O)n1C
Reactant: [OH-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3cc(C(N)=O)ccc23)cc1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
A solution of methyl [7-cyano-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetate (17 mg, 0.039 mmol) in tetrahydrofuran (THF) (0.600 mL) and methanol (0.6 mL) was treated with LiOH (0.118 mL, 0.236 mmol) and stirred at 50° C. for 2 hours. Additional LiOH (300 uL) was added and the reaction was stirred at 50° C. for 4 h, and then cooled to rt overnight. The mixture was concentrated and purified with reverse phase chromatography (20-100% MeCN/H2O-0.1% TFA, 12 min) to afford [7-(aminocarbonyl)-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetic acid (9.6 mg, 0.022 mmol, 56.0% yield) as white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.02 (s, 1 H), 8.22-8.10 (m, 1 H), 7.39-7.28 (m, 4 H), 7.25-7.15 (m, 1 H), 7.09-6.99 (m, 1 H), 5.39 (d, J=1.2 Hz, 1 H), 3.76 (s, 3 H), 2.38 (s, 3 H), 2.33 (s, 3 H), 1.08 (s, 4.5 H), 1.06 (s, 4.5 H); LCMS (m/z) ES+=437 (M+1).