Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: NC(=O)c1cc(F)ccc1N
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc(F)cc4C(N)=O)nc(Cl)nc32)cc1

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 8.8 mmol) and 2-amino-5-fluorobenzamide (4.0 g, 26 mmol), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-5-fluorobenzamide was isolated as a white solid (3.05 g, 76% Yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3 H), 6.68 (d, J=4.03 Hz, 1 H), 7.42-7.50 (m, 3 H), 7.65 (dd, J=9.51, 3.11 Hz, 1 H), 7.72 (d, J=3.84 Hz, 1 H), 7.83 (s, 1 H), 7.97 (dt, J=8.65, 1.90 Hz, 2 H), 8.26 (s, 1 H), 8.30 (dd, J=9.15, 5.12 Hz, 1 H), 11.81 (s, 1 H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:21]([O-])(O)=O.[Na+].CI.C(OCC)(=O)C>CN(C=O)C>[CH3:21][O:19][C:18](=[O:20])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([I:17])=[CH:15][CH:16]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](Cc1ccc(I)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 40 h
Yield: 111.8 %

Procedure:
To a solution of 5.02 g (12.8 mmol) of N-Boc-4-iodophenylalanine in 60 mL of DMF was added NaHCO3 (1.42 g, 16.9 mmol) followed by methyl iodide (3.0 mL, 48.2 mmol). The mixture was stirred under argon for 40 h at room temperature. After this time, 150 mL of ethyl acetate was added, and the mixture was washed with 3×100 mL of deionized water. The organic layer was separated, dried over Na2SO4, and concentrated under vacuum to yield 5.80 g of a yellow oily solid. The crude product was purified by flash chromatography (1:5 ethyl acetate:hexanes) to afford a white solid (4.72 g, 91%). mp 79-80° C.; 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9 H), 3.04 (2 dd, J=4.8 Hz, 12.8 Hz), 3.72 (s, 3 H), 4.58 (m, 1 H), 4.97 (brs, NH, 1 H), 6.88 (d, J=7.8 Hz, 2 H), 7.62 (d, J=7.8 Hz, 2 H); HRMS (ESI, M+1) calcd for C15H21INO4406.0510, found 406.0515.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][C:7]2=O)([O-])=O.[C:20](OC(=O)C)(=[O:22])[CH3:21]>[Pd]>[C:20]([NH:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:8][CH2:7]2)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cc(=O)c2cc([N+](=O)[O-])ccc2o1
Agent: [Pd]
Product: CCOC(=O)C1CCc2cc(NC(C)=O)ccc2O1
Temperature: 80 °C

Procedure:
A hydrogenation apparatus is charged with 6 g of ethyl 6-nitrochromone-2-carboxylate (Example 10), 3.5 mL of acetic anhydride, 1 g of 10% palladium on carbon, 4.0 g of dry, powdered 3A molecular sieves, and 30 mL of glacial acetic acid. After purging several times with nitrogen, the apparatus is purged several times with hydrogen. Under continuous stirring, the apparatus is maintained at about 70 psi with hydrogen and about 80° C. for about 10-12 h. The apparatus is then cooled to about 50° C., evacuated of hydrogen, and purged several times with nitrogen. Trifluororoacetic acid (3.5 mL) is added to the mixture, then the apparatus is resealed, purged several times with hydrogen, and pressurized to 70 psi with hydrogen. The stirred reaction mixture is heated to 80° C. until the reaction is complete by HPLC (intermediate:product≦3%), then cooled to room temperature. After filtering the mixture through Celite, the catalyst and molecular sieves are washed with 10 mL aliquots of glacial acetic acid, and the washes combined with the filtrate. These combined filtrates are concentrated by mild distillation to an oil, which is dissolved in ethyl acetate and washed with saturated NaHCO3. The aqueous fraction is extracted with ethyl acetate, then made strongly acidic with concentrated HCl and extracted several times with ethyl acetate. The combined ethyl acetate fractions are combined and concentrated to a solid. The solid is washed with acetonitrile, filtered, and dried to afford about 3.5-4.0 g of ethyl 6-acetamidochromane-2-carboxylate as a white solid.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:4][CH2:3]2.[CH:49]1([CH2:54][C:55]([OH:57])=O)[CH2:53][CH2:52][CH2:51][CH2:50]1>>[CH:49]1([CH2:54][C:55]([N:46]2[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][NH:40][C@:5]34[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:6]3[C@@H:7]3[C@@:2]([CH3:1])([CH2:3][CH2:4]4)[C@@:19]4([CH3:20])[C@@H:10]([C@:11]5([CH3:33])[C@@H:16]([CH2:17][CH2:18]4)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]4[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=4)=[CH:13][CH2:12]5)[CH2:9][CH2:8]3)[CH2:44][CH2:45]2)=[O:57])[CH2:50][CH2:51][CH2:52][CH2:53]1
Reactant: O=C(O)CC1CCCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)CC4CCCC4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound (3.1 mg) was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure as described above using cyclopentylacetic acid as the acylating agent. LCMS: m/e 752.9 (M+H)+, 3.93 min (method 14). 1H NMR (500 MHz, METHANOL-d4) δ 7.89 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 5.30 (d, J=4.6 Hz, 1H), 4.80 (s, 1H), 4.69 (s, 1H), 3.70 (br. s., 1H), 3.66-3.53 (m, 3H), 3.12-3.01 (m, 1H), 2.95-2.89 (m, 1H), 2.86-2.72 (m, 2H), 2.71-2.61 (m, 3H), 2.60-2.54 (m, 1H), 2.51-2.47 (m, 1H), 2.45 (d, J=7.3 Hz, 2H), 2.27-1.90 (m, 6H), 1.89-1.79 (m, 3H), 1.76 (s, 3H), 1.73-1.18 (m, 22H), 1.23 (s, 3H), 1.11 (s, 3H), 1.06 (s, 3H), 0.97 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C:13]2([C:27]([F:30])([F:29])[F:28])[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24](Br)[CH3:25])=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.[K].O>CN(C)C=O>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C:13]2([C:27]([F:30])([F:29])[F:28])[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([N:37]4[C:36](=[O:38])[C:35]5=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]5[C:33]4=[O:43])[CH3:25])=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(Br)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
To a solution of 3.01 g of 5-[3,5-bis(trifluoromethyl)phenyl]-3-[4-(1-bromoethyl)phenyl]-5-trifluoromethyl-4,5-dihydroisoxazole in 10 mL of N,N-dimethylformamide, 1.26 g of potassium phthalimide was added and the resultant mixture was stirred at 80° C. for 3.5 hours. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature and 20 mL of water was added to the reaction mixture. The resultant mixture was extracted with ethyl acetate (70 mL×1). The organic phase was washed with water (20 mL×1) and then dehydrated and dried over saturated saline and anhydrous magnesium sulfate in this order and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with ethyl acetate-hexane (a gradient from 1:10 to 1:5) to obtain 2.80 g of the objective substance as a colorless resinoid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[C:15]([OH:17])=O.[N:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:27][CH:26]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15]([N:35]2[CH2:36][CH2:37][N:32]([CH2:31][C:28]3[CH:27]=[CH:26][N:25]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)=[O:17])[CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22]
Reactant: COc1cc(C(=O)O)cc(OCCc2ccc(Cl)cc2Cl)c1OC
Reactant: c1cc(CN2CCNCC2)ccn1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCN(Cc3ccncc3)CC2)cc(OCCc2ccc(Cl)cc2Cl)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.100 g (0.269 mmol) of 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4,5-dimethoxy-benzoic acid was dissolved in 2 ml of DMF and treated with 0.124 g (1.08 mmol) of N-NEM and 0.0477 g (0.27 mmol) of 1-Pyridin-4-ylmethyl-piperazine and 0.088 g (0.269 mmol) of TOTU. The solution was stirred for 16 h at RT. The solvent was removed under reduced pressure, the residue was taken-up in ethyl acetate and the solution was washed twice with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with a gradient of 0-17% MeOH in DCM.
Reaction SMILES: C([O:3][C:4]([CH2:6][S:7][CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=1)=[O:5])C.[ClH:26]>CO.[OH-].[Na+].CC(C)=O>[ClH:26].[C:4]([CH2:6][S:7][CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:12]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CSCCCc1cn(-c2cccnc2)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: O=C(O)CSCCCc1cn(-c2cccnc2)c2ccccc12

Procedure:
A solution of 90 mg of 3-[3-(ethoxycarbonylmethylthio)propyl]-N-(3-pyridyl)indole in 5 ml of methanol and 1 ml of 1N sodium hydroxide is refluxed for 10 hours, cooled and evaporated. The resulting oil is partitioned between ether and water. The aqueous phase is brought to pH=6 with concentrated sulfuric acid, is extracted with chloroform and the chloroform extract is dried over sodium sulfate. Filtration and evaporation gives an oil which is redissolved in 2 ml of acetone and is treated with 0.07 ml of 3N ethereal hydrogen chloride. Evaporation and crystallization from acetone-ether yields 3-[3-(carboxymethylthio)propyl]-N-(3-pyridyl)indole hydrochloride, m.p. 106°-110°.
Reaction SMILES: [K].[Cl:2][C:3]1[C:4](=[O:29])[N:5]([C:19]2[C:26]([OH:27])=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=2[F:28])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18].I[CH3:31]>CN(C)C=O>[Cl:2][C:3]1[C:4](=[O:29])[N:5]([C:19]2[C:26]([O:27][CH3:31])=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=2[F:28])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18]
Reactant: N#Cc1cc(O)c(-n2ccc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(F)c1
Reactant: CI
Agent: [K]
Solvent: CN(C)C=O
Product: COc1cc(C#N)cc(F)c1-n1ccc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reaction time: 2 h

Procedure:
The potassium salt of 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3-fluoro-5-hydroxybenzonitrile (from Step 1) (273 mg, 0.614 mmol) was stirred in 5 ml anhydrous dimethylformamide under nitrogen. Iodomethane (93 mg, 0.66 mmol) was added, and stirring continued for 2 hr. The mixture was diluted to 50 ml with ice-cold water, and the white precipitate collected by filtration. The precipitate was washed thrice with water, sucked dry under a blanket of nitrogen, and dried further in vacuo overnight (242 mg, 87%). 1H-NMR (400 MHz, DMSO-d6) δ 7.73 (m, 2H), 7.65 (m, 2H), 7.34 (dt, J=9.90, 2.39 Hz, 1H), 7.17 (dt, J=8.75, 2.47 Hz, 1H), 6.75 (d, J=7.97 Hz, 1H), 5.37 (s, 2H), 3.84 (s, 3H). 19F-NMR (400 MHz, DMSO-d6) δ −109.24 (quintet, J=7.85 Hz, 1F), −113.54 (quartet, J=9.83 Hz, 1F), −118.33 (d, J=7.77 Hz, 1F). LC/MS tr=5.40 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50° C.) ES-MS m/z 421 (M+H). ES-HRMS m/z 421.0522 (M+H calcd for C20H13ClF3N2O3 requires 421.0561).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][N:25]=1>>[F:21][C:4]1[CH:3]=[C:2]([C:27]2[CH:26]=[N:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)cn1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 2-Methoxy-5-pyridine boronic acid. MS (M+H) 384.2
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[CH2:34][CH3:35])[CH2:6][CH:7]([CH2:11][C:12](=[O:30])[N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:29])[CH2:15][CH2:14]1)[C:8](O)=[O:9])[CH3:2].[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:39][CH2:38]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[CH2:34][CH3:35])[CH2:6][CH:7]([CH2:11][C:12]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:29])[CH2:15][CH2:14]1)=[O:30])[C:8]([N:46]1[CH2:45][CH2:44][CH:43]([N:40]2[CH2:39][CH2:38][N:37]([CH3:36])[CH2:42][CH2:41]2)[CH2:48][CH2:47]1)=[O:9])[CH3:2]
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: CCc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Product: CCc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 76e) from 2-(3,4-diethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 1-methyl-4-piperidin-4-yl-piperazine
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]2[C:38]([CH3:40])([CH3:39])[CH2:37][C:36]3[C:31](=[C:32]([C:42]([OH:44])=[O:43])[CH:33]=[C:34]([Cl:41])[CH:35]=3)[NH:30]2)[CH:26]=[CH:27][CH:28]=1>CN(C)C=O>[Cl:41][C:34]1[CH:35]=[C:36]2[C:31](=[C:32]([C:42]([OH:44])=[O:43])[CH:33]=1)[NH:30][CH:29]([C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([NH:22][C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[O:9])[CH:24]=1)[C:38]([CH3:40])([CH3:39])[CH2:37]2
Reactant: O=C(O)c1cnccn1
Reactant: CC1(C)Cc2cc(Cl)cc(C(=O)O)c2NC1c1cccc(N)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(Cl)cc(C(=O)O)c2NC1c1cccc(NC(=O)c2cnccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.7 %

Procedure:
A solution of pyrazine-2-carboxylic acid (0.412 g, 3.3 mmol) and 1,1′-carbonyldiimidazole (0.7 g, 4.3 mmol) in N,N-dimethylformamide (10 mL) was stirred at 70° C. for 1 h. A solution of 2-(3-amino-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (0.75 g, 2.3 mmol) in N,N-dimethylformamide (5 mL) was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 6-chloro-3,3-dimethyl-2-{3-[(pyrazine-2-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (228 mg, 15%) as a light yellow solid: LC/MS m/e calcd for C23H21ClN4O3 (M+H)+: 437.90, observed: 437.1.
Reaction SMILES: [OH2:1].[OH2:2].O.[N+]([O-])([O-])=O.[Tl+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[C:17]([N:20]1[C:28]2[C:23](=[C:24]([O:32][CH3:33])[CH:25]=[CH:26][C:27]=2[C:29](=O)[CH3:30])[CH2:22][CH2:21]1)(=[O:19])[CH3:18].Cl(O)(=O)(=O)=O.[CH3:39]O>>[C:17]([N:20]1[C:28]2[C:23](=[C:24]([O:32][CH3:33])[CH:25]=[CH:26][C:27]=2[CH2:29][C:30]([O:2][CH3:39])=[O:1])[CH2:22][CH2:21]1)(=[O:19])[CH3:18]
Reactant: CO
Reactant: O
Reactant: COc1ccc(C(C)=O)c2c1CCN2C(C)=O
Agent: O=[N+]([O-])[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [Tl+3]
Product: COC(=O)Cc1ccc(OC)c2c1N(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 47 %

Procedure:
Thallium(III) nitrate trihydrate (3.21 g, 7.1 mmol) was added to a solution of 1,7-diacetyl-4-methoxyindoline 22 (1.65 g, 7.1 mmol) in MeOH (70 ml) containing perchloric acid (60% w/w, 1.5 ml) and the mixture was stirred at rt for 4 h. The precipitated white solid was filtered off and the filtrate was concentrated to about 10 ml, diluted with EtOAc (50 ml) and washed with water. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with saturated aq. NaHCO3 and brine, dried and evaporated to give a viscous oil. Flash chromatography [EtOAc-hexanes (4:1)] afforded 23 as white crystals (0.88 g, 47%), mp 80-81° C. (from EtOAc-hexanes) (Found: C, 63.60; H, 6.50; N, 5.28. C14H17NO4 requires C, 63.87; H, 5.51; N, 5.32%); δH (90 MHz) 7.04 (1 H, d, J 8.3, H-5), 6.63 (1 H, d, H-6), 4.06 (2 H, t, J 8.1, H-2), 3.81 (3 H, s, OMe), 3.76 (2 H, s, ArCH2), 3.71 (3 H, s, CO2Me), 2.96 (2 H, t, 3-H) and 2.24 (3 H, s, N-Ac).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[H-].[Na+].[C:22]([NH:25][CH:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])(=[O:24])[CH3:23]>O.C(O)C>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][CH2:23][C:22]([NH:25][CH:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:24])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(NC(=O)CCc1ccc(C(C)(C)C)cc1)C(=O)OCC
Temperature: 110 °C
Yield: 68.5 %

Procedure:
25 g of 4-(tert-butyl)benzyl bromide, 50 ml of anhydrous toluene and 3.1 g of sodium hydride in 80% suspension in oil are added to a three-necked flask which is surmounted by a condenser, followed by 21.8 g of diethyl acetamidomalonate. The mixture is heated at 110° C. for 17 h. After it has been cooled down, 15 ml of absolute ethanol, then 15 ml of 50% ethanol and then 50 ml of water are added slowly to it using a dropping funnel. The organic phase is decanted and the aqueous phase is washed with 3 times 50 ml of diethyl ether. The organic phases are combined, washed with water and then dried over sodium sulphate. Following filtration and concentration under reduced pressure, the product is crystallized in petroleum ether in order to yield 25 g of diethyl 4-(tert-butyl)benzylacetamidomalonate in the form of a white solid which melts at 80° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2.[Li+].CC([N-][CH:19]([CH3:21])[CH3:20])C.[CH2:22](Br)C=C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]([CH2:22][CH:19]1[CH2:20][CH2:21]1)[C:10](=[O:13])[CH2:9][CH2:8]2
Reactant: C=CCBr
Reactant: COc1cccc2c1CC(=O)CC2
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc2c1C(CC1CC1)C(=O)CC2
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a solution of 3.52 g (20 mmol) 8-methoxy-2-tetralone in 50 mL THF in a three-neck round-bottomed flask, equipped with a gas inlet and septum, was added 14.3 mL LDA (22 mmol, 1.5 M in cyclohexane) at −30° C. under a nitrogen atmosphere. The solution was allowed to warm to 0° C. over a thirty-minute period and 2.4 mL (24 mmol) allyl bromide was added. TLC analysis was used to monitor the reaction. After stirring for two hours, the TLC analysis appeared to show little progress. The reaction mixture was therefore treated with 1.1 mL (12 mmol) allylbromide and the mixture was heated to reflux for 72 hours. The reaction mixture was quenched with 10% sodium bisulfate to pH 2-3. After removal of THF under reduced pressure, the mixture was extracted with ethyl acetate (2×1 L) and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting oil was purified by liquid chromatography on 400 g of silica gel 60 (230-400 m), eluting with hexane/acetone (9:1) and collecting 40 mL fractions. Fractions homogeneous by TLC were combined and concentrated in vacuo to give 4.5 g (97.8%) of pure title compound as a near colorless oil.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:20]N1C(=O)CCC1=O>CN(C=O)C>[Br:20][C:16]1[S:17][CH:18]=[CH:19][C:15]=1[C:12]1[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCc1ccc(-c2ccsc2)cc1
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(-c2ccsc2Br)cc1
Reaction time: 2 h
Yield: 87.5 %

Procedure:
In a three necked flask under argon, 1.40 g (5.14 mmol) of YKP67 in 40 mL of DMF are cooled to 0° C. 915 mg (5.14 mmol, 1 eq.) of N-bromosuccinimide are solubilised in 20 mL of mixture [DMF/MeOH:1/1]. This solution of NBS (protected from light) is then added drop by drop (30 min) into the reaction medium. The temperature of the medium is then left to rise to ambient temperature over 2 h. The medium is hydrolysed with a 1 mol·L−1 HCL solution and extracted with ethyl ether. The combined organic phases are washed with a saturated NaCl solution then dried on anhydrous Na2SO4. After drying on Na2SO4, filtration and evaporation of the solvent, the purification is carried out on silica column with cyclohexane. 1.58 g of final compound YKP69 in the form of a translucent oil (yield of 85.7%) are obtained.
Reaction SMILES: Br[CH:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.CS(C)=[O:24]>O>[CH:12]1[C:7]2[CH:6]=[CH:5][C:4]3[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=3[C:2](=[O:24])[C:8]=2[CH:9]=[CH:10][C:11]=1[CH:13]([CH3:17])[C:14]([OH:16])=[O:15]
Reactant: CC(C(=O)O)c1ccc2c(c1)C=Cc1ccccc1C2Br
Reactant: CS(C)=O
Solvent: O
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
0.5 G. of 2-(5-bromo-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid is dissolved in 10 ml. of dimethylsulfoxide and heated at 150°-180° C. under nitrogen for 2 hours, then cooled, poured into water and worked up as in part A to afford 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid.