Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[C:14](B(O)O)[CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>C1(C)C=CC=CC=1.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.C(O)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:19][CH3:20])=[C:12]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[NH2:8])[CH:11]=1
Reactant: Nc1ccncc1I
Reactant: COc1ccc(Cl)cc1B(O)O
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(Cl)cc1-c1cnccc1N

Procedure:
3-iodopyridin-4-amine (2.2 g, 10 mmol), (5-chloro-2-methoxyphenyl)boronic acid (1.86 g, 10 mmol) and, and K2CO3 (4.2 g, 30 mmol) were mixed in 50 mL of toluene, 5 mL of deionized water and 5 mL of ethanol. To the solution was bubbled with nitrogen for 15 min. Pd(PPh3)4 (0.23 g, 0.2 mmol) was then added. The mixture was refluxed overnight under nitrogen. After cooling, the aqueous layer was removed and the organic layer was then concentrated. The residue was then purified by column chromatography using ethyl acetate as the eluent. 2.0 g (85%) of product was collected as the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:21]([N:25]([CH3:36])[S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Cl)(=[O:28])=[O:27])[CH2:22][CH2:23][CH3:24]>C(N(C(C)C)C(C)C)C>[CH2:21]([N:25]([CH3:36])[S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)(=[O:28])=[O:27])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN(C)S(=O)(=O)CCCCCCCl
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(C)S(=O)(=O)CCCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Yield: 91.4 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and N-n-butyl-N-methyl-6-chlorohexanesulfonamide (539.7 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (50:1), to give N-n-butyl-N-methyl-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide (951.0 mg) as a pale brown oil (yield: 91.4%).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][C:2]1[C:3]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:4]=2[S:5][C:6]=1[CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:19]
Reactant: Cc1ccc2scc(C)c2c1
Reactant: O=Cc1ccccc1
Product: Cc1ccc2sc(C(O)c3ccccc3)c(C)c2c1

Procedure:
Using general procedure B, 3,5-dimethyl-benzo[b]thiophene was reacted with benzaldehyde to give (3,5-dimethyl-benzo[b]thiophen-2-yl)-phenyl-methanol as a colorless oil. MS: 251.4 ([M+H—H2O]+).
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:11]2)[CH:3]=1.[C:20](Cl)(=[O:25])[CH2:21][C:22](Cl)=[O:23].[OH2:27]>C(#N)C>[CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:11]2)[CH:3]=1.[C:20]([OH:25])(=[O:6])[CH2:21][C:22]([OH:23])=[O:27]
Reactant: O
Reactant: O=C(Cl)CC(=O)Cl
Agent: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: CC#N
Product: O=C(O)CC(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
One gram of AZT was dissolved in 30 ml of anhydrous acetonitrile and added dropwise to a solution of 632 mg of malonyl chloride in 20 ml of acetonitrile at 0° C. The reaction mixture was stirred for 2 hours at 0° C. then at 8-10° C. for 4.5 hours. Thin layer chromatography was used to indicate that the reaction was complete. Water (4 ml) was added. Solvents were removed in vacuo and the residue purified by silica gel chromatography eluting with CHCl3:MeOH. Pure product was obtained in a 68% yield.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.[CH3:23][C:24]1[C:25]([CH2:31][N:32]([CH2:39][C:40]2[C:45]([CH:46]([CH3:48])[CH3:47])=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=1>C(Cl)Cl>[S:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[NH:13][C:1]([N:36]1[CH2:37][CH2:38][CH:33]([N:32]([CH2:31][C:25]2[C:24]([CH3:23])=[CH:29][C:28]([CH3:30])=[CH:27][N:26]=2)[CH2:39][C:40]2[C:45]([CH:46]([CH3:48])[CH3:47])=[CH:44][CH:43]=[CH:42][N:41]=2)[CH2:34][CH2:35]1)=[O:2]
Reactant: Nc1nc2ccccc2s1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cnc(CN(Cc2ncccc2C(C)C)C2CCNCC2)c(C)c1
Solvent: ClCCl
Product: Cc1cnc(CN(Cc2ncccc2C(C)C)C2CCN(C(=O)Nc3nc4ccccc4s3)CC2)c(C)c1
Reaction time: 2 h
Yield: 49.6 %

Procedure:
To a solution of 1,1′-carbonyldiimidazole (125 mg, 0.77 mmol) in CH2Cl2 (5 mL) was added 2-aminobenzothiazole (95 mg, 0.64 mmol). The resulting suspension was stirred for 2 h and then concentrated under reduced pressure. The residue was dissolved in CH3CN (5 mL) and was treated with (3,5-dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-piperidine-4-yl-amine (112 mg, 0.32 mmol) and the reaction mixture was stirred at 60° C. overnight. Then the mixture was cooled and diluted with CH2Cl2/saturated NaHCO3 (1:1, 40 mL). The aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to afford a pink foam. Purification by radial chromatography on silica gel (2 mm plate; using CH2Cl2/MeOH/NH4OH; 50:1:1) afforded the product as a white solid (84 mg, 50%). 1H NMR (CDCl3) δ 0.91 (d, 6H, J=6.9 Hz), 1.60-1.72 (m, 2H), 1.91 (d, 2H, J=11.4 Hz), 2.14 (s, 3H), 2.27 (s, 3H), 2.68-2.80 (m, 4H), 3.74 (s, 2H), 3.81 (s, 2H), 4.24 (br s, 1H), 4.28 (br s, 1H), 7.13 (dd, 1H, J=7.8, 4.8 Hz), 7.148-7.24 (m, 2H), 7.35 (t, 1H, J=7.2 Hz), 7.48 (dd, 1H, J=7.8, 1.5 Hz), 7.58 (br d, 1H, J=8.1 Hz), 7.74 (br d, 1H, J=7.8 Hz), 8.18 (s, 1H), 8.31 (dd, 1H, J=4.5, 1.5 Hz). 13C NMR (CDCl3) δ 18.30, 18.47, 23.61, 27.41, 27.65, 44.94, 54.31, 57.18, 119.37, 121.81, 123.20, 123.58, 126.35319 132.04, 132.31, 133.18, 133.87, 139.07, 144.38, 146.11, 146.68, 147.39, 154.36, 156.18, 162.71. ES-MS m/z 529 [M+H]+. Anal. Calcd. for C30H36N6OS.0.1CH2Cl2: C, 67.30; H, 6.79; N, 15.64; S, 5.97. Found: C, 67.56; H, 6.86; N, 15.52; S, 5.89.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]=[CH:9][S:10][CH:11]=1.[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15].[Cl-].[NH4+]>O1CCCC1>[CH3:6][C:7]1[N:8]=[C:9]([C:14](=[O:15])[C:13]([F:20])([F:19])[F:12])[S:10][CH:11]=1
Reactant: Cc1cscn1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1csc(C(=O)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M solution in hexanes, 40.4 ml) was added dropwise to a stirred solution of 4-methylthiazole (10 g) in anhydrous tetrahydrofuran at -70° C. under an atmosphere of dry nitrogen. After 30 minutes, ethyl trifluoroacetate (12 ml) was added dropwise. After a further 2 hours the mixture was allowed to warm to room temperature and was then left stirring overnight. Saturated aqueous ammonium chloride solution was added and the organic phase was separated, dried and evaporated to dryness. The residue was purified by flash chromatography to give the hydrate corresponding to the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[CH2:20]1[N:25]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:24][CH2:23][O:22][CH2:21]1.C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([N:25]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[CH:31][CH:30]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: Fc1ccc(Br)cc1-c1nc(Nc2ccc(N3CCOCC3)cc2)c2nccnc2n1

Procedure:
The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-(4-morpholino)aniline following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[CH2:3][Mg]Cl.O1CCCC1.[F:12][C:13]1[CH:14]=[C:15]([NH:25][C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[O:27])[CH:16]=[CH:17][C:18]=1[C:19](N(OC)C)=[O:20].N1C=CC=CC=1C(O)=O>O>[F:12][C:13]1[CH:14]=[C:15]([NH:25][C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[O:27])[CH:16]=[CH:17][C:18]=1[C:19](=[O:20])[CH2:3][C:2]([CH3:6])=[CH2:1]
Reactant: CON(C)C(=O)c1ccc(NC(=O)c2ccccn2)cc1F
Reactant: C=C(C)C[Mg]Cl
Agent: O=C(O)c1ccccn1
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)CC(=O)c1ccc(NC(=O)c2ccccn2)cc1F
Reaction time: 3 h

Procedure:
9.89 ml of (2-methyl-2-propen-1-yl)magnesium chloride (0.50 M tetrahydrofuran solution) was added to a tetrahydrofuran (10 ml) solution of 500 mg of N-(3-fluoro-4-((methoxy(methyl)amino)carbonyl)phenyl)pyridine-2-carboxamide obtained in the same method as in Example 145 (step 3) or in accordance with the method or by combining it with an ordinary method but using pyridine-2-carboxylic acid, with cooling with ice. The reaction liquid was stirred for 3 hours with cooling with ice, and then water was poured into the reaction solution, extracted with ethyl acetate and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1) to obtain the entitled compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.[NH2:11][C@@H:12]1[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C>C(C#N)(C)=O.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:11][C@@H:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Reactant: N#Cc1ncc(Cl)nc1Cl
Agent: CC(=O)C#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1cnc(C#N)c(Cl)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 119 %

Procedure:
To a mixture of 3,5-dichloropyrazine-2-carbonitrile (369 mg, 2.09 mmol) and tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (500 mg, 2.3 mmol) in AcCN (7.5 mL) was added DIPEA (0.41 mL, 2.3 mmol). After stirring at room temperature for 5 h, it was diluted with EtOAc, washed with sat. NaHCO3, organic layer was separated and washed with brine, dried and concentrated to give tert-butyl (3R,4R)-4-(6-chloro-5-cyanopyrazin-2-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (880 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.C(N(CC)CC)C.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28]>ClCCl>[NH:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:27]([C:23]2[S:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(Cl)c1cccs1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCNCC1)c1cccs1
Reaction time: 0.08 h

Procedure:
Commercially available tert-butyl 4-aminopiperidine-1-carboxylate (0.50 g, 1.0 eq) was taken up in dichloromethane and treated with triethylamine (0.42 mL, 1.2 eq). After stirring for 5 minutes, thiophene-2-carbonyl chloride (0.29 ml, 1.1 eq) was slowly added. The reaction stiffed for 15 hours at room temperature. To work up, dichloromethane (5 mL) was added. The organics were washed with water (3×-5 mL) then dried over Na2SO4 and concentrated for 0.80 g tan oil (obs M+Na 323, calc M+Na 323). This product was dissolved in dioxane (5 mL) and treated with 4 N HCl in dioxane (1.88 ml). After stiffing for 15 hours at room temperature, the reaction was concentrated to oily residue (0.63 g, 100% over 2 steps, calc M+H 211, obs M+H 211).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2C(=[CH:10][CH:11]=1)N=CC=C2.[I-].C[N+]1C=CN([C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)C=1.C([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])C>C(#N)C>[CH:34]1[C:35]2[C:10](=[CH:11][C:2]([O:1][C:19](=[O:28])[N:20]([CH3:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:3][CH:4]=2)[CH:33]=[CH:32][N:31]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: Oc1ccc2ncccc2c1
Agent: [I-]
Solvent: CC#N
Product: CN(C(=O)Oc1ccc2cnccc2c1)c1ccccc1
Yield: 95.8 %

Procedure:
A solution of 6-hydroxyquinoline (0.44 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (50:50)) yielding the title compound (0.80 g, 96% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:13])[C:10]=1[CH2:11][NH2:12])[C:5](N)=[O:6].[OH-:14].[Na+].Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([OH:14])=[O:6])[CH:8]=[C:9]([Br:13])[C:10]=1[CH2:11][NH2:12]
Reactant: [OH-]
Reactant: NCc1c(Br)cc(C(N)=O)cc1Br
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NCc1c(Br)cc(C(=O)O)cc1Br
Temperature: 0 °C
Yield: 87 %

Procedure:
A mixture of 3,5-dibromo-4-aminomethyl benzamide (40 g, 0.129 mol), methanol (500 mL) and an aqueous solution of NaOH (10%, 310 mL) was refluxed for 20 h. The reaction mixture was concentrated to 150 mL and cooled to 0° C. The solid precipitate obtained was filtered, washed with diethyl ether (500 mL). The solid obtained was acidified with an aqueous solution of HCl (1.5 N, 100 mL) to pH=6 to give solid precipitate. The solid was filtered, washed with water and dried under vacuum to give 2,6-dibromo-4-carboxy benzylamine (35 g, 87%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].Br[CH2:15][CH:16]1[CH2:21][CH2:20][Si:19]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(C2C=CC=CC=2)[CH2:18][CH2:17]1>>[F:1][C:2]1[CH:3]=[C:4]([O:13][CH2:15][C@H:16]2[CH2:21][CH2:20][Si@H:19]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:18][CH2:17]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:11])([F:12])[F:10]
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(CBr)CC1
Reactant: Oc1ccc(OC(F)(F)F)c(F)c1
Product: CCCCCCC[Si@H]1CC[C@H](COc2ccc(OC(F)(F)F)c(F)c2)CC1

Procedure:
The general procedure of Example 9 was repeated using 3-fluoro-4-trifluoromethoxyphenol and 4-bromomethyl-1-n-heptyl-1-phenyl-1-silacyclohexane, thereby obtaining the intended compound.
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9]3[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][C:21]([O:24][C:25]([NH:27][C@H:28]([C:35](O)=[O:36])[CH2:29][C:30]1[S:34][CH:33]=[CH:32][CH:31]=1)=[O:26])([CH3:23])[CH3:22].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:21]([O:24][C:25]([NH:27][C@@H:28]([CH2:29][C:30]1[S:34][CH:33]=[CH:32][CH:31]=1)[C:35]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:2][CH2:3]1)=[O:36])=[O:26])([CH3:23])([CH3:20])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)O
Reactant: COC(=O)c1ccc2nc(N3CCNCC3)sc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(N3CCN(C(=O)[C@H](Cc4cccs4)NC(=O)OC(C)(C)C)CC3)sc2c1
Reaction time: 8 h

Procedure:
Methyl 2-(piperazin-1-yl)benzo[d]thiazole-6-carboxylate (0.35 g, 1.26 mmol), Boc-L-2-thienylalanine (0.34 g, 1.26 mmol), diisopropylethylamine (0.88 ml, 5.06 mmol) and HBTU (0.62 g, 1.64 mmol) were dissolved in DMF (36 ml) and the resulting mixture stirred overnight. The resulting mixture was then diluted with ethyl acetate (78 ml), washed with 1N HCl (3×39 ml), washed with brine (39 ml), dried (MgSO4) and concentrated in vacuo. The resulting residue was chromatographed eluting with dichloromethane/methanol (97:3) to yield (S)-methyl 2-(4-(2-(tert-butoxycarbonylamino)-3-(thiophen-2-yl)propanoyl)piperazin-1-yl)benzo[d]thiazole-6-carboxylate.
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:11]1[NH:16][C:15](=[O:17])[C:14]2=[CH:18][N:19]=[C:20](I)[N:13]2[N:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:36]2[CH2:37][CH2:38][O:39][CH2:40][CH:41]=2)O1>O1CCOCC1.O.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>[CH2:1]([O:8][CH:9]([C:11]1[NH:16][C:15](=[O:17])[C:14]2=[CH:18][N:19]=[C:20]([C:36]3[CH2:41][CH2:40][O:39][CH2:38][CH:37]=3)[N:13]2[N:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CC(OCc1ccccc1)c1nn2c(I)ncc2c(=O)[nH]1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(OCc1ccccc1)c1nn2c(C3=CCOCC3)ncc2c(=O)[nH]1
Temperature: 125 °C
Yield: 75.7 %

Procedure:
To a solution of compound 12 (300 mg, 0.75 mmol) in dioxane (2 mL) was added a solution of Cs2CO3 (492 mg, 1.51 mmol) in H2O (0.5 mL) dropwise, followed by addition of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (318 mg, 1.5 mmol) and Pd(PPh3)4 (86 mg, 0.075 mmol). The reaction mixture was degassed by purging with N2 for 15 min. Then the reaction was heated to 125° C. under microwave heating for 40 min. After removal of the solvent, the residue was purified by chromatography on silica gel column (eluted with PE/EtOAc=10:1 to 1:5) to afford compound 13 (200 mg, 75% yield) as white solid. LC-MS: m/z 353 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.82 (br. s, 1H), 7.91 (s, 1H), 7.37˜7.32 (m, 5H), 7.19 (br. s, 1H), 4.61 (m, 2H), 4.49 (q, J=6.8 Hz, 1H), 4.40 (m, 2H), 3.95 (t, J=5.2 Hz, 2H), 2.78 (m, 2H), 1.58 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]2[C:10]([O:12][C:13](=O)[C:3]=2[CH:2]=1)=[O:11].[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24]C(O)=O)=[CH:20][CH:19]=1)([CH3:17])[CH3:16]>>[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[C:2]2[CH:1]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=[C:4]3[CH:3]2[CH2:13][O:12][C:10]3=[O:11])=[CH:20][CH:19]=1)([CH3:17])[CH3:16]
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: CC(C)c1ccc(C=C2C=C(C(=O)O)C=C3C(=O)OCC23)cc1

Procedure:
Benzene-1,2,4-tricarboxylic anhydride and p-isopropylphenylacetic acid are reacted together as described in Example IA to give a mixture of benzylidenephthalide carboxylic acids. Fractional crystallization of this mixture from aqueous ethanol yields 2-(p-ispropylbenzylidene)phthalide-5-carboxylic acid as the less soluble isomer, and 4-(p-isopropylbenzylidene)phthalide-6-carboxylic acid as the more soluble isomer. By following the rest of the procedure set forth in part A of this example, 2-carboxy-7-isopropyl-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene was obtained with a m.p. of 178°-182° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18]3(OCC[O:27]3)[CH:17]=[CH:16]4)[C@H:13]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH:17]=[CH:16]4)[C@H:13]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC21OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC2=O
Yield: 85.1 %

Procedure:
A solution of 32.8 g of 3-benzyloxy-17,17-ethylenedioxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraene in 328 ml of acetone and 32.8 ml of water is stirred at room temperature with 1.033 g of para-toluenesulfonic acid for 2 hours. Then, it is diluted with diethyl ether, washed with sodium bicarbonate and water, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane acetone. 25.4 g of 3-benzyloxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetra-en-17-one is obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][NH:54]C(=O)OC(C)(C)C)=[CH:29][CH:28]=1)(=[O:26])=[O:25].C(Cl)Cl>FC(F)(F)C(O)=O>[NH2:54][CH2:53][CH2:52][O:51][CH2:50][CH2:49][O:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][CH2:33][C:30]1[CH:31]=[CH:32][C:27]([S:24]([CH2:23][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([NH:15][CH2:16][C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)=[O:14])=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])(=[O:25])=[O:26])=[CH:28][CH:29]=1
Reactant: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(CCCOCCOCCOCCOCCOCCOCCNC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(CCCOCCOCCOCCOCCOCCOCCN)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A solution of carbamate 60 (85 mg, 0.098 mmol) in a mixture of trifluoroacetic acid (2 mL) and anhydrous DCM (8 mL) was stirred at 20° C. for 1 h. The solvent was evaporated and the residue was purified by column chromatography, eluting with 10% MeOH/DCM containing 1% aqueous NH3, to give amine 61 (56 mg, 75%) as a white gum: 1H NMR δ 9.22 (t, J=5.8 Hz, 1H, CONH), 8.56 (d, J=1.7 Hz, 1H, H-2′), 8.46 (dd, J=4.8, 1.6 Hz, 1H, H-6′), 7.99 (br d, J=8.6 Hz, 2H, H-2, H-6), 7.89 (br d, J=8.6 Hz, 2H, H-3, H-5), 7.73 (dt, J=7.9, 1.9 Hz, 1H, H-4′), 7.68 (br d, J=8.3 Hz, 2H, H-2″, H-6″), 7.44 (br d, J=8.3 Hz, 2H, H-3″, H-5″), 7.36 (ddd, J=7.8, 4.8, 0.6 Hz, 1H, H-5′), 4.65 (s, 2H, CH2SO2), 4.51 (d, J=5.8 Hz, 2H, CH2NH), 3.49-3.50 (m, 20H, CH2O), 3.43-3.45 (m, 2H, CH2O), 3.33-3.36 (m, 2H, CH2O), 2.72 (t, J=7.3 Hz, 2H, H-r), 2.64 (t, J=5.6 Hz, 2H, H-21′″), 2.12 (s, 3H, CH3), 1.79 (br q, J=7.2 Hz, 2H, H-2′″), NH2 not observed; 13C NMR δ 165.4, 157.9, 149.8, 148.8, 148.5, 148.0, 135.7, 135.3, 135.1, 134.8, 129.1 (2), 128.7, 128.3 (2), 128.0 (2), 125.9, 125.3 (2), 123.4, 72.6, 69.7 (7), 69.6, 69.5, 69.4, 68.9, 52.8, 41.1, 40.4, 31.4, 30.4, 9.5; HRMS calcd for C39H53N4O10S (MH+): m/z 769.3477. found m/z 769.3492.