Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(OCOC)=C(C2OC3C=CC=C(C)C=3N=2)C=1.[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:42]=[CH:41][C:30]([CH:31]=[N:32][C:33]2[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][C:34]=2[OH:40])=[CH:29][CH:28]=1>>[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:42]=[CH:41][C:30]([C:31]2[O:40][C:34]3[CH:35]=[CH:36][CH:37]=[C:38]([CH3:39])[C:33]=3[N:32]=2)=[CH:29][CH:28]=1
Reactant: COCOc1ccc(C=Nc2c(C)cccc2O)cc1
Agent: COCOc1ccc(OC)cc1-c1nc2c(C)cccc2o1
Product: COCOc1ccc(-c2nc3c(C)cccc3o2)cc1

Procedure:
2-(4-methoxymethoxyphenyl)-4-methylbenzoxazole (F11) was prepared in a similar manner for the preparation of 2-(5-methoxy-2-methoxymethoxyphenyl)-4-methylbenzoxazole (F8) by using 2-[(4-methoxymethoxybenzylidene)amino]-3-methylphenol (F7) (5.43 g, 20 mmol) instead of 2-[(5-methoxy-2-methoxymethoxybenzylidene)amino]-3-methylphenol (F4) in 92% (4.92 g): 1H-NMR (500 MHz, CDCl3) δ3.53 (s, 3H), 5.24 (s, 3H), 7.17 (d, 1H, J=9.0 Hz), 7.35 (d, 1H, J=9.0 Hz), 10.52 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:5]=2[N:4]=1.S(=O)(=O)(O)O.N.O.[CH3:27]O>>[CH3:27][O:18][C:17]([C:15]1[CH:14]=[CH:13][C:6]2[N:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[C:3]([CH2:2][OH:1])=[N:4][C:5]=2[CH:16]=1)=[O:19]
Reactant: CO
Reactant: CC(C)CCn1c(CO)nc2cc(C(=O)O)ccc21
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc2c(c1)nc(CO)n2CCC(C)C
Temperature: 25 °C
Yield: 96 %

Procedure:
A mixture of 2-hydroxymethyl-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxylic acid (2.4 g, 9.1 mmol) and concentrated sulfuric acid (1.1 g, 10.9 mmol) in methanol (30 mL) was heated at reflux for 40 hrs. The solution was cooled to room temperature, the pH adjusted to 8-9 with concentrated ammonia, and water was added. A white precipitate formed that was collected by filtration and washed with water. The product was dried in vacuo to yield 2-hydroxymethyl-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxylic acid methyl ester (2.4 g, 96%) as a white solid.
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[S:7][N:6]=1)(=O)=O.[CH2:15]([OH:19])[C:16]#[C:17][CH3:18].[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH:10]1([C:8]2[S:7][N:6]=[C:5]([O:19][CH2:15][C:16]#[C:17][CH3:18])[N:9]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CS(=O)(=O)c1nsc(C2CCCC2)n1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1nsc(C2CCCC2)n1
Reaction time: 0.5 h
Yield: 54 %

Procedure:
300 mg of 3-methylsulfonyl-5-cyclopentyl-1,2,4-thiadiazole and 99 mg of 2-butyn-1-ol were dissolved in 3 g of N,N-dimethylformamide, 62 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 30 minutes under ice-cooling. Then, the reaction mixture was added to saturated brine, and extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to give 155 mg of 5-cyclopentyl-3-(2-butynyloxy)-1,2,4-thiadiazole (hereinafter referred to as the present invention compound (3)).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:21]([OH:24])(=[O:23])=[O:22])[C:5]([CH:8]=[CH:9][C:10]2[C:11]([S:17]([OH:20])(=[O:19])=[O:18])=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1.[N:25]1[C:32]([Cl:33])=[N:31][C:29]([Cl:30])=[N:28][C:26]=1Cl.[OH-].[Na+:35]>CC(C)=O>[Cl:30][C:29]1[N:31]=[C:32]([Cl:33])[N:25]=[C:26]([NH:1][C:2]2[CH:3]=[C:4]([S:21]([O-:24])(=[O:23])=[O:22])[C:5]([CH:8]=[CH:9][C:10]3[C:11]([S:17]([O-:20])(=[O:19])=[O:18])=[CH:12][C:13]([NH:16][C:26]4[N:25]=[C:32]([Cl:33])[N:31]=[C:29]([Cl:30])[N:28]=4)=[CH:14][CH:15]=3)=[CH:6][CH:7]=2)[N:28]=1.[Na+:35].[Na+:35]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(C=Cc2ccc(N)cc2S(=O)(=O)O)c(S(=O)(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=S(=O)([O-])c1cc(Nc2nc(Cl)nc(Cl)n2)ccc1C=Cc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1S(=O)(=O)[O-]
Temperature: 0 °C

Procedure:
Disodium 4,4'-bis(4,6-dichloro-s-triazin-2-ylamino)-2,2'-stilbenedisulfonate was prepared by interaction of 500 pounds of 4,4'-diamino-2,2'-stilbenedisulfonic acid with a solution of 500 pounds of cyanuric chloride in 2100 pounds of acetone in an aqueous reaction medium at pH 7-8 prepared by mixing 3200 pounds of crushed ice and approximately 2100 pounds of 10 percent aqueous sodium hydroxide solution. The disodium 4,4'-bis(4,6-dichloro-s-triazin-2-ylamino)-2,2'-stilbenedisulfonate thus obtained was mixed with 270 pounds of disodium phosphate and interacted at 15°-50° C with 625 pounds of aniline for thirty minutes and then the pH of the reaction mixture was adjusted to 6.7-6.8 by adding approximately 600 pounds of 10 percent aqueous sodium hydroxide solution during a period of one hour.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:34]3[CH2:37][C:36]([CH3:39])([CH3:38])[C:35]3=[O:40])[CH2:24][CH:23]2[OH:41])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:34]3[CH2:37][C:36]([CH3:38])([CH3:39])[C:35]3=[O:40])[CH2:24][C:23]2=[O:41])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: CC1(C)CN(c2ccccc2N2CCC(NC(=O)C3(NC(=O)c4cc5ccccc5o4)CCCCC3)C(O)C2)C1=O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)CN(c2ccccc2N2CCC(NC(=O)C3(NC(=O)c4cc5ccccc5o4)CCCCC3)C(=O)C2)C1=O
Temperature: 0 °C
Reaction time: 10 h
Yield: 86 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-[2-(3,3-dimethylazetidin-2-one-1-yl)phenyl]piperidin-3-ol (0.14 g) obtained in Step 4 in 3 ml of dimethylsulfoxide (DMSO), was added 0.16 ml of triethylamine. The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (0.15 g) was added slowly to the reaction mixture, which was stirred for about 10 hours at room temperature. The reaction mixture was diluted with 20 ml of ethyl acetate, washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was filtered and dried to give 120 mg of the titled compound as white color.
Reaction SMILES: [OH:1][P:2]([CH:16]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH2:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6](O)=[O:7])=[O:3].[NH2:35][C@H:36]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH3:37].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:3][P:2]([CH2:4][CH:5]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:6]([NH:35][C@H:36]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH3:37])=[O:7])([CH:16]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:1]
Reactant: O=C(NC(Cc1ccccc1)P(=O)(O)CC(Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C[C@H](NC(=O)C(Cc1ccccc1)CP(=O)(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Yield: 71.9 %

Procedure:
The process is performed according to the operating conditions described in 1.8, starting with 300 mg (0.62 mmol) of 3-[hydroxy[2-phenyl-1-[[(phenylmethoxy)carbonyl]amino]ethyl]phosphinyl]-2-(phenylmethyl)propanoic acid synthesized in 1.7., and 219 mg (0.62 mmol) of phenylmethyl alaninate in the form of the p-toluenesulphonic acid salt. 288 mg of product are recovered (yield=71.9%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](OB(O)O)[CH:5]=[CH:6][C:7]=1[F:8].Br[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[N:15][CH:16]=1
Reactant: OB(O)Oc1ccc(F)c(F)c1
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: Fc1ccc(-c2ccc(Br)cn2)cc1F

Procedure:
A mixture of 6.2 g of 3,4-difluorophenylboric acid, 8.5 g of 2,5-dibromopyridine, 0.31 g of tetrakistriphenylphosphine palladium, 60 ml of ethanol, 120 ml of benzene and 120 ml of 2N sodium carbonate solution is heated to boiling (66° C.) for 7 hours while stirring. After cooling the mixture is extracted with diethyl ether. The organic phase is washed with 100 ml of saturated sodium hydrogen carbonate solution and 100 ml of water, dried over sodium sulphite, filtered and concentrated. Purification of the residue by chromatography on silica gel with hexane/ethyl acetate 19:1 yields pure 5-bromo-2-(3,4-difluorophenyl)pyridine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[Cl:16].C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:31]2[CH:39]=[C:38]3[C:34]([C:35]([NH:48][C:49](=[O:53])[CH2:50][CH2:51][CH3:52])=[N:36][N:37]3[CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])=[CH:33][CH:32]=2)O1.C(OCC)(=O)C>O.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][C:3]1[CH:4]=[C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:2]=1[C:31]1[CH:39]=[C:38]2[C:34]([C:35]([NH:48][C:49](=[O:53])[CH2:50][CH2:51][CH3:52])=[N:36][N:37]2[CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:45])[CH3:46])=[CH:33][CH:32]=1
Reactant: Clc1cc(OCc2ccccc2)ccc1Br
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OCc4ccccc4)cc3Cl)ccc12
Yield: 56 %

Procedure:
1.95 g of 1-bromo-2-chloro-4-(phenylmethoxy)benzene, described previously, 1.11 g of sodium carbonate in 36 cm3 of water and 347 mg of tetrakis(triphenylphosphine)palladium are added to 2 g of N-[6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously in Example 56, in 180 cm3 of dioxane. The medium is then refluxed for 2 hours and the mixture is allowed to return to room temperature, 200 cm3 of ethyl acetate and 100 cm3 of water are added and the resulting mixture is filtered through a sinter funnel packed with Celite. The combined organic phases are washed with 100 cm3 of distilled water and then with 100 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (85/15 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). 1.34 g of N-[6-[2-chloro-4-(phenylmethoxy)phenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of a yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.C([Li])CCC.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>O1CCCC1.CCCCCC>[S:1]1[C:5]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][Br:15])=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: c1ccc2sccc2c1
Reactant: BrCCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: BrCCCCCCc1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of benzo[b]thiophene (1.92 g., 14.3 mmol) in 90 ml anhydrous tetrahydrofuran at -10° to 0° under argon was added n-butyllithium (7.8 ml of a 1.86M solution in hexane). After two hours, this solution was transferred dropwise into a stirred, 0° solution of 1,6-dibromohexane (6.5 ml, 0.043 mol) in 250 ml tetrahydrofuran. The solution was warmed to room temperature, stirred for 15 hours, quenched with water and concentrated. The residue was acidified and partitioned between ethyl ether and water. The aqueous portion was extracted twice with ether, and the combined organic portions were washed with water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a brown oil. Excess benzo[b]thiophene and 1,6-dibromohexane were removed by bulb to bulb distillation (85° to 90°/0.1 mm) to leave a dark brown syrup. This material was purified by flash chromatography (silica, hexane to 5% ethyl ether/hexane) to give the desired alkyl halide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[O:22])=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]([C:29]([O:31]CC)=[O:30])=[N:10][CH:9]=1.[Li+].[OH-]>C1COCC1.CO.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[O:22])=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]([C:29]([OH:31])=[O:30])=[N:10][CH:9]=1
Reactant: CCOC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Reaction time: 2 h
Yield: 68.9 %

Procedure:
To a yellow, homogeneous solution of ethyl 4-(2-fluorophenyl)-7-(morpholine-4-carbonyl)-9H-pyrido[3,4-b]indole-1-carboxylate (0.0592 g, 0.132 mmol) in THF (2.84 mL) and MeOH (0.945 mL) was added LiOH (0.022 g, 0.529 mmol) in water (0.5 mL). After 2 hr, the reaction mixture was concentrated in vacuo, and the residue was diluted with water and acidified with 1N aq. HCl to pH ˜4 by litmus paper. The mixture was extracted with EtOAc (3×), and the organic layers were combined, dried over Na2SO4, and concentrated in vacuo to give the desired product (0.0382 g, 0.091 mmol, 68.8% yield) as a yellow solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].C([N+](CCCC)(CCCC)CCCC)CCC.[CH:21]([C@@H:24]1[CH2:28][C@@H:27]([C@H:29](Br)[CH2:30][C@H:31]([C:35]([N:37]2[C@@H:41]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:40][O:39][C:38]2=[O:49])=[O:36])[CH:32]([CH3:34])[CH3:33])[O:26][C:25]1=[O:51])([CH3:23])[CH3:22].[N-]=[N+]=[N-]>C1(C)C=CC=CC=1>[CH:21]([C@@H:24]1[CH2:28][C@@H:27]([C@@H:29]([N:1]=[N+:2]=[N-:3])[CH2:30][C@H:31]([C:35]([N:37]2[C@@H:41]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:40][O:39][C:38]2=[O:49])=[O:36])[CH:32]([CH3:34])[CH3:33])[O:26][C:25]1=[O:51])([CH3:22])[CH3:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](Br)C[C@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)C(C)C)OC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)[C@@H]1C[C@@H]([C@H](C[C@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)C(C)C)N=[N+]=[N-])OC1=O
Temperature: 25 °C

Procedure:
13.6 g of freshly dried tetrabutylammonium azide are added to a solution, stirred at room temperature, of 17.8 g of 3(S)-isopropyl-5(S)-{1(R)-bromo-4-methyl-3(S)-[(4(S)-benzyloxazolidin-2-on-3-yl)-carbonyl]-pentyl}-tetrahydrofuran-2-one in 180 ml of toluene, and a further 10 g of the azide are added in the course of 160 hours' stirring at room temperature. The reaction mixture is then partitioned between ethyl acetate and water (2×) and saturated sodium chloride solution (1×). The organic phases are combined, dried over sodium sulfate and concentrated. The title compound is obtained from the evaporation residue by means of FC (hexane/ethyl acetate=8:2) and crystallisation from diethyl ether/hexane: m.p.=102°-103° C.; Rf (hexane/ethyl acetate=8:2)=0.2; HPLC Rt =18.55 minutes; FAB-MS (M+H)+ =457.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][CH2:13][C:4]=2[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[OH-].[K+].Cl.[OH-].[Na+]>C(O)CO>[Cl:1][C:2]1[C:3]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13][C:4]=2[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: CCOC(=O)N1CCc2cc3c(c(Cl)c2CC1)NC(=O)CC3
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: OCCO
Product: O=C1CCc2cc3c(c(Cl)c2N1)CCNCC3
Temperature: 120 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To 1.865 g of ethyl 11-chloro-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate were added 20 mL of ethylene glycol and 20 mL of a 40% aqueous potassium hydroxide solution, followed by heating to 120° C. for 18 hours. The reaction mixture was ice-cooled and adjusted to pH 1 by the addition of concentrated hydrochloric acid, followed by stirring for 1 hour. The reaction mixture was alkalified by the addition of a 1 M aqueous sodium hydroxide solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain 1.451 g of 11-chloro-1,3,4,6,7,8,9,10-octahydro-2H-azepino[4,5-g]quinolin-2-one as a brown solid. To 60 mg of 11-chloro-1,3,4,6,7,8,9,10-octahydro-2H-azepino[4,5-g]quinolin-2-one were added 1 ml of EtOAc and then EtOH, followed by dissolution under heating. The precipitated solid was collected by filtration to obtain 29.5 mg of 11-chloro-1,3,4,6,7,8,9,10-octahydro-2H-azepino[4,5-g]quinolin-2-one as a white solid.
Reaction SMILES: C[Al](C)C.[Br:5][C:6]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:7]=1[NH2:8].[N:14]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18][CH:17]=[C:16]([C:20](OC)=[O:21])[CH2:15]1>C(Cl)Cl>[Br:5][C:6]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:7]=1[NH:8][C:20]([C:16]1[CH2:15][N:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18][CH:17]=1)=[O:21]
Reactant: Nc1ccc(F)cc1Br
Reactant: COC(=O)C1=CCCN(C(=O)OC(C)(C)C)C1
Agent: C[Al](C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC=C(C(=O)Nc2ccc(F)cc2Br)C1
Temperature: 0 °C
Yield: 50.2 %

Procedure:
Trimethylaluminium (2.0 M in hexanes, 3.98 mL, 7.96 mmol) was added dropwise to a solution of 2-bromo-4-fluoroaniline (1.26 g, 6.63 mmol) in DCM (15 mL) under N2. After gas evolution ceased, 1-tert-butyl 3-methyl 5,6-dihydropyridine-1,3(2H)-dicarboxylate (1.60 g, 6.63 mmol) in DCM (10 mL) was added and the resulting mixture was refluxed overnight. After cooling to about 0° C., the reaction was quenched by the addition of saturated aqueous NaHCO3 solution. The organic layer was separated. The aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexanes:EtOAc, 6:1) to give tert-butyl 3-(2-bromo-4-fluorophenylcarbamoyl)-5,6-dihydropyridine-1(2H)-carboxylate (1.33 g, 50%) as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.36 (dd, J=9.2, 6.0 Hz, 1H), 7.87 (br s, 1H), 7.32 (dd, J=7.6, 2.8 Hz, 1H), 7.07 (ddd, J=9.2, 6.0, 2.8 Hz, 1H), 6.82 (br s, 1H), 4.27 (s, 2H), 3.54 (t, J=6.0 Hz, 2H), 2.38 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:11]3[C:25]([O-:27])=[O:26])=[CH:4][C:3]=2[O:2]1.[OH-].[K+]>CCO.C1COCC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:11]3[C:25]([OH:27])=[O:26])=[CH:4][C:3]=2[O:2]1
Reactant: O=C([O-])C1C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl (1RS, 2SR, 3SR)-1-(3,4-methylenedioxyphenyl)-3-phenylindane-2-carboxylate (650 mg, 1.68 mmol) in EtOH containing a few drops of THF was added 6M KOH (1.68 ml, 10.1 mmol). The resulting mixture was allowed to stir at room temperature overnight, then was concentrated under reduced pressure. The residue was partitioned between H2O and Et2O. The aqueous phase was acidified with 3M HCl and extracted several times with EtOAc. The combined EtOAc extracts were washed successively with H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to afford an oil, which was crystallized from EtOAc/hexanes. The title compound was obtained as a solid (305 mg, 51%); m.p. 186-187° C.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([OH:17])=O)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>ClCCl>[C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([Cl:20])=[O:17])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCCN(C(=O)c2ccccc2)C1
Solvent: ClCCl
Product: O=C(Cl)C1CCCN(C(=O)c2ccccc2)C1
Temperature: 25 °C
Yield: 100 %

Procedure:
1-benzoyl-3-piperidine carboxylic acid (1.01 g; 4.33 mmol) was suspended in dry dichloromethane (30 ml) under a nitrogen atmosphere. Thionyl chloride (3 ml; 41.3 mmol) was added and this mixture was heated to reflux for approximately 1 hour. It was then cooled to ambient temperature and evaporated under reduced pressure, giving 1-benzoyl-3-piperidinecarbonyl chloride (1.09 g) as a yellow oil. MS m/z (positive ion; run in CH3CN) 503 (dimer+; 30), 254 ([M+2]H+; 35), 252 (MH+; 100), 248 (50), 234 (60), 216 (25), 102 (30).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([O:22]CC)=[O:21])[C:11]3[CH:16]=[N:15][N:14]([CH:17]([CH3:19])[CH3:18])[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][NH:36][CH:37]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:19][CH:17]([N:14]1[C:12]2[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:33]4[CH:34]=[N:35][NH:36][CH:37]=4)=[CH:3][CH:4]=3)[CH:9]=[C:10]([C:20]([OH:22])=[O:21])[C:11]=2[CH:16]=[N:15]1)[CH3:18]
Reactant: CCOC(=O)c1cc(-c2ccc(Br)cc2)nc2c1cnn2C(C)C
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)n1ncc2c(C(=O)O)cc(-c3ccc(-c4cn[nH]c4)cc3)nc21
Yield: 34.9 %

Procedure:
To a 5-mL microwave vial were added ethyl 6-(4-bromophenyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (80 mg, 0.206 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (56.0 mg, 0.288 mmol), 1,4-dioxane (2 mL) and sodium carbonate (0.206 mL, 0.412 mmol), and the mixture was degassed with nitrogen for 10 min. Next added PdP(Ph3)4 (19.05 mg, 0.016 mmol) and the vial was sealed. The reaction mixture was irradiated (microwave) at 120° C. overnight. The reaction mixture was filtered and concentrated in vacuo. The residue was purified using reverse-phase HPLC to give 25 mg (35%) of product. LCMS E-S (M+H)=348.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (d, J=6.8 Hz, 6 H), 5.38 (quin, J=6.6 Hz, 1 H), 7.81 (d, J=8.3 Hz, 2 H), 8.14-8.30 (m, 4H), 8.36 (s, 1 H).